Macular degeneration (AMD) is one of the main causes of central vision loss in the developed world and affects approximately 25% of people above age 75. This debilitating ocular disease appears clinically in one of two presentations, either dry or wet forms. Wet AMD, also known as “exudative” or “neovascular” AMD, is significantly more sight-threatening than the dry, non-exudative form.
Advanced AMD affects approximately 2 million Americans. Advanced AMD occurs when dry AMD progresses to geographic atrophy (GA) or when wet AMD leaves a disciform scar after the presence of prolonged choroidal neovascular membrane (CNVM).
The easiest way for patients to understand the disease process of macular degeneration is by explaining the compromised exchange of nutrients and waste products within the eye. Numerous mechanisms are proposed in the clinical manifestation of AMD. In general, AMD occurs when the retina/retinal pigment epithelium’s (RPE) ability to metabolize waste products is compromised. It can also occur when the choriocapillaris is unable to adequately deliver nutrients to (or adequately remove waste products from) the retina.
The progression of AMD can be variable, depending on the patient’s age, systemic/lifestyle risk factors, and family ocular history. Age is the greatest risk factor for developing AMD, followed by Caucasian race and history of past/present smoking. A positive family history also increases patients’ risk for developing AMD.
Several emerging therapies are making headway in addressing the unmet need of more durable suppression of this sight-threatening disease. Over the past decade, anti-vasoendothelial growth factor agents (anti-VEGF) have dramatically transformed the treatment approach to macular degeneration, particularly wet AMD.
I thought it would be interesting to write an update on what we have to look forward to in the management of Wet AMD. I love to tell my patients about these upcoming advancements on the horizon, keeping them excited for the future and letting them know they are not destined to see me every four-to-six weeks for the rest of their lives!
Pathogenesis of macular degeneration
The etiology and pathogenesis of macular degeneration is multifaceted and thought to occur via several mechanisms. Regardless of AMD presentation, the retinal pigment epithelium (RPE) and choriocapillaris are greatly compromised. Through various age-related retinal changes, the RPE’s ability to maintain photoreceptor cells is slowly diminished.
The “sick RPE” theory proposes that the RPE layer is unable to fully metabolize photoreceptor waste products. This occurs by the altered permeability and degeneration of RPE/Bruch’s complex, leading to the formation of subretinal drusen deposits, pigment epithelial detachments, CNVM, and eventual geographic/outer retinal atrophy.
Figure 1: Fundus photo showing small/medium sized drusen deposits in intermediate dry AMD. Large drusen are defined as > 125 micrometers in size (diameter of central retinal vein) Photo courtesy of Kevin Cornwell, OD
Figure 2: OCT scan showing subretinal soft drusen deposits in dry AMD. Photo courtesy of Kevin Cornwell, OD
The “vascular ischemic” theory proposes insufficient nutrient delivery and poor RPE waste removal via an atrophic/atherosclerotic choriocapillaris. It has been shown that patients with AMD have a thinner, more atrophied choriocapillaris layer.
Inflammation and oxidative stress have also been shown to be involved in the pathogenesis of AMD. Various components of the complement cascade have been found within drusen deposits. This may partly explain why smokers, who are prone to more inflammation, develop AMD at higher rates. Some genetically susceptible patients have also been shown to have increased choroidal C-reactive protein levels, which may link genetics and inflammatory etiology in AMD.
The compromised RPE can eventually lead to the upregulation of VEGF. This pro-angiogenic state occurs within the retina and new blood vessels break through an already compromised RPE/Bruch’s complex to form a CNVM. Similar to weeds growing up through cracks in a driveway, the formation of CNVM is the hallmark of wet AMD. The end result of uncontrolled CNVM is usually a disciform scar that results in irreversible loss of central acuity for the patient.
Figure 3: Fundus photo showing early CNVM in wet AMD. Formation of CNVM will initially appear grayish/green, and progresses to appear more red in color during later stages. Photo courtesy of Kevin Cornwell, OD
Dry vs. wet macular degeneration
Regardless of what form of AMD a patient has, they are at a significantly higher risk for irreversible vision loss, and require close monitoring. Patients presenting with dry AMD will initially have mild RPE disruption within their macula, often classified as “pigment mottling” or “pigment granulation.” The RPE will typically have areas of coalesced hyper and/or hypopigmentary changes. Dry AMD typically progresses to form small “hard” drusen deposits, or larger “soft” drusen deposits, all of which consist of photoreceptor waste material.
Numerous AMD grading scales exist to help clinicians determine disease severity and necessary treatment protocols. The American Academy of Ophthalmology has adopted the AREDS grading scale in the clinical classification of AMD severity.
The presence of numerous small/medium hard drusen (<125 micrometers in size) typically indicates early AMD classification (AREDS category 2). Multiple soft drusen, typically greater in size (>125 micrometers), are generally indicative of intermediate dry AMD stages (AREDS category 3). The presence of CNVM and/or any fovea-involving geographic atrophy places the patient at advanced/late stage disease (AREDS category 4).
Of the patients with dry AMD, up to 20% will convert to the wet form. Dry AMD is typically treated with patient education (eg. smoking cessation counseling and use of home amsler grid) and nutritional supplementation (e.g., AREDS/Preservision vitamins, increased dietary intake of lutein/zeaxanthin and omega 3 fatty acids).
The wet form of AMD is more sight-threatening. Approximately 10% of all AMD cases occur in the wet form and require aggressive management with anti-VEGF therapy. Unfortunately, patients with wet AMD can still progress and lose central vision, despite standard-of-care treatment and close monitoring. This occurs when the CNVM partially “resolves”, leaving a disciform macular scar in its place.