The Impending Vision-Loss Cascade: A Review of Macular Degeneration

AUTHORS:
Casey Bateman, OD, and Leonid Skorin Jr, DO, OD, MS

CITATION:
Bateman C, Skorin L. The impending vision-loss cascade: a review of macular degeneration. Consultant. 2016;56(11):987-992.

ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of vision loss in the elderly population in developed nations. In the United States, it is the leading cause of blindness in persons aged 65 years and older. Timely diagnosis and treatment of this disease can help slow its progression, potentially preventing irreversible vision loss. This article reviews the pathophysiology, diagnosis, and management of AMD. Several commonly prescribed systemic medications and supplements are discussed in the context of their potential interaction with the course and treatment of the disease.

KEYWORDS: Macular degeneration; retina; vision loss; lutein, zeaxanthin, and zinc supplementation; vascular endothelial growth factor inhibitors

Age-related macular degeneration (AMD or ARMD) is a multifactorial disease affecting the macula, which is the portion of the retina responsible for central, detailed vision. According to the World Health Organization, AMD is the leading cause of blindness in developed countries and is the third leading cause of blindness worldwide.¹ AMD affects more than 1.75 million people in the United States, causing 16,000 new blindness diagnoses annually.² It is also the leading cause of blindness in people aged 65 and older in the United States.^3-5 The US Census Bureau has projected that the number of Americans over age 65 will more than double between the years 2010 and 2050.⁶ Accordingly, proper diagnosis and care of AMD will continue to be critical in the prevention of blindness in this population.

Classification

The Age-Related Eye Disease Study (AREDS)⁷ developed a classification system for describing the severity of AMD. The disease is classified as absent, early, intermediate, or late, depending on the extent of signs present compared with a standardized set of retinal photographs. Late AMD is then classified into 1 of 2 types based on how far the disease has advanced. “Dry” AMD is typified by geographic atrophy of sensory retinal tissues without evidence of neovascularization (Figure 1).⁷ “Wet” AMD denotes the presence of a pathologic subretinal neovascular membrane (Figure 2).⁷ Wet AMD accounts for only 20% of all AMD cases but causes nearly 90% of cases of blindness from AMD of any form.^8,9

Figure 1. Geographic atrophy of the sensory retinal tissues (green arrow), the hallmark sign of dry AMD.

Figure 2. Retinal (green arrow) and subretinal (blue arrow) hemorrhages of the retina seen in wet AMD, with adjacent geographic atrophy (pink arrow).

Symptoms, Differentials, and Diagnosis

Early and intermediate AMD are typically asymptomatic.⁸ The earliest detectable symptoms of macular degeneration are mild central blur and/or distortion.⁹ Late AMD presents with a range of symptoms, including visual distortion and/or blur, reduced contrast sensitivity, reduced color vision, decreased vision in low-light conditions, slower adaptation to low-light conditions, and reduced central vision. The reduction in central vision can range from mild blur to an area or areas of complete blindness. AMD only affects central vision, with peripheral vision remaining unaffected. Dry and wet AMD share very similar symptomatology, with the main difference being that wet AMD symptoms tend to be more severe and have a more rapid onset.

Differential diagnoses of AMD include any ocular disease that might cause reduction or distortion of central vision. Examples include central serous chorioretinopathy, diabetic macular edema, cystoid macular edema, epiretinal membrane, choroidal melanoma, Stargardt disease, Best disease, toxic retinopathy, multifocal choroidopathy syndromes, presumed ocular histoplasmosis syndrome, and retinal detachment.

Visualization of the ocular fundus is key in ruling out differentials, since the pattern of retinal changes seen in AMD is highly unique to the disease. Direct ophthalmoscopy is the method of visualizing the fundus that is most readily available, but the low magnification and often poor image quality makes diagnosis using this method difficult. A dilated fundus examination by an ophthalmologist or optometrist is usually necessary for definitive diagnosis of AMD.

Perhaps the simplest method of detecting AMD is the use of a printed pattern known as an Amsler grid. An Amsler grid is simply a square orthogonal grid with a black dot in the center (Figure 3). The patient is instructed to hold the grid at a distance of 14 to 16 inches, cover one eye, stare directly at the black central dot, and report any distortion or missing areas of the grid. This is repeated for either eye individually. The presence of distortion or missing areas in the grid is indicative of retinal abnormality, which may be the result of AMD. The grid is usually given to the patient for home monitoring of their AMD, as well.

Figure 3. Amsler grid. The perception of distortion or missing areas in the grid is indicative of retinal abnormality.

Pathophysiology and Progression

AMD is a degenerative disease of the retina involving several retinal layers. The exact pathogenesis of the disease has not been definitively identified, but it has been suggested that the disease process is precipitated by inflammation, oxidative stress, thickening of the retinal basal lamina, and the cumulative deposition of metabolic end products of normal retinal processes.¹⁰ These factors result in the accumulation of aggregates known as drusen (Figures 4-6).¹⁰

Figure 4. Soft drusen (green arrow), seen here in early AMD.
 

Figure 5. Soft drusen, both discrete (blue arrow) and confluent (green arrow), seen here in intermediate AMD.

Figure 6. Soft drusen (pink arrow) and pigment clumping (green arrow) in early AMD.
 

Drusen deposits occur between 2 deep layers of the retina: a layer of collagenous cells within the retina known as the Bruch membrane (involved in structural and metabolic support of the retina), and a layer of pigmented cells known as the retinal pigment epithelium, or RPE (involved primarily in metabolic support of photoreceptor cells).^10,11 These deposits act as a physical barrier to metabolites and normal blood perfusion within the RPE, starving the retinal tissue as well as mechanically disrupting it. It has also been thought that the presence of drusen precipitates an immune attack, which leads to atrophy of the RPE cells.¹²

The accumulation of drusen over an individual’s lifetime is inevitable, and the presence of drusen is quite ubiquitous. A recent study found that in a population of 444 white persons aged 18 to 54, macular drusen was present in 91.48% of eyes.¹³

Wet AMD occurs as a consequence of focal ischemia of the macula, caused by the drusen sandwiched between the RPE and the Bruch membrane. This ischemia causes retinal cells in the macula to release vascular endothelial growth factor (VEGF), a factor that induces the formation of a neovascular membrane in an underlying retinal vascular layer known as the choroid. This neovascular membrane causes distortion and damage to the overlying retinal tissue, resulting in the reduction in vision seen in wet AMD.

AMD is a progressive disease, and the progression always occurs sequentially from early, to intermediate, to dry, and finally to wet. This disease progression is variable in speed but is usually gradual. Wet AMD is always preceded by dry AMD, but not all cases of dry AMD will progress to wet AMD. Similarly, dry AMD is always preceded by drusen, but not all cases of drusen will progress to dry AMD.

Risk Factors

The primary nonmodifiable risk factors for developing late AMD (both dry and wet) are advanced age, white ethnicity, and genetic factors.¹⁴ Genetic factors include variation in genes involved in the alternative complement pathway, extracellular matrix function, and lipid metabolism.^12,15-17 AMD risk has been strongly positively correlated with white ethnicity and negatively correlated with black ethnicity.¹⁸ Additionally, a correlation between lighter iris color and increased AMD risk has been found.¹⁸ Genetic variation between individuals with different iris colors and among different racial groups is a confounding factor, such that darker pigmentation (both of the skin and of the iris) cannot definitively be identified as the main risk factor in the context of race or iris color.¹⁸ Some studies have suggested that women are at a higher risk for certain forms of AMD than are men, but the correlation is minor compared with the correlation seen with advanced age, white ethnicity, and genetic factors.

Cigarette smoking has been found to be the primary modifiable risk factor that is most consistently reported across studies.¹⁴ Additionally, studies suggest a correlation between increased tobacco exposure (ie, a longer period of tobacco use and more frequent tobacco use) and increased AMD risk.^19,20 Smoking cessation has been associated with both decreased risk of developing AMD and decreased risk of AMD progression.¹⁹ Therefore, counseling on smoking cessation is key for reduction of this critical modifiable risk factor.

Systemic hypertension and cardiovascular disease have long been suggested as risk factors for AMD. Studies regarding the impact of these diseases on AMD risk have produced conflicting results.¹⁴ However, AMD does share several common risk factors associated with both systemic hypertension and cardiovascular disease, such as increased dietary intake of saturated fats and cholesterol and increased body mass index (BMI).²¹

Treatment and Management

Early AMD. There is no treatment for early AMD.¹⁴ Lifestyle modifications such as BMI reduction, cholesterol intake reduction, increased ω-3 fatty acid intake, and smoking cessation may decrease risk of advancement and are recommended for all forms of AMD.^22,23

Intermediate AMD. The current standard of care for intermediate AMD is high-dose antioxidant vitamin and mineral supplementation.¹⁴ This supplementation has not been shown to have any affect for early AMD. The original AREDS study employed a supplement consisting of high doses of vitamins C and E, β-carotene, zinc, and copper.²⁴ The study showed a 25% relative risk reduction for the development of advanced AMD in patients with certain forms of AMD including intermediate AMD or advanced AMD in one eye.²⁴ However, β-carotene was found to be associated with increased mortality in smokers in several studies.^25,26

A follow-up study, AREDS2,²⁷ explored the efficacy of a modified version of the original AREDS supplement formulation on a patient population that was identified as having a high risk of AMD progression. This new formulation replaced β-carotene with 2 other carotenoids (lutein and zeaxanthin) and reduced the amount of zinc. The AREDS2 study showed similar efficacy of the AREDS2 formulation compared with the original AREDS formulation. Today, the AREDS2 formulation is the recommended supplement for intermediate AMD. It is sold under numerous brand names, but patients should be instructed to look for the words “AREDS2 formulation” on the container. Daily AREDS2 supplementation must be continued indefinitely in order to remain effective in the prevention of progression to advanced AMD.

A recent study²⁸ has suggested high-dose (80 mg) atorvastatin as a potential treatment for certain cases of intermediate AMD classified as having a high risk of conversion to advanced AMD. The study, a phase 1-2 clinical trial, appeared to show a protective effect with atorvastatin against the development of wet AMD. Remarkably, regression of drusen was seen in a significant percentage of the atorvastatin-treated population studied. More research into the use of atorvastatin in AMD treatment is needed, but this may represent a novel and effective treatment option for reducing the risk of progression into advanced AMD.

Advanced AMD: Dry AMD. No specific treatment currently exists for dry AMD. However, many potential treatments are in clinical trials. Perhaps the most promising of these is the use of monthly intravitreal injections of lampalizumab, a humanized monoclonal antibody that is an inhibitor of complement factor D. Complement factor D is a protein component involved in the regulation of the alternative complement pathway.^29,30 The alternative complement pathway has been previously implicated in the pathogenesis of AMD.¹⁷

Advanced AMD: Wet AMD. The earliest treatment for wet AMD involved the use of focal laser photocoagulation of the neovascular membrane within the eye. The goal was to arrest the bleeding and proliferation of the neovascular membrane by direct application of a thermal laser, cauterizing the capillaries comprising the membrane. For years, this was the only available treatment option for wet AMD. While this treatment is still in use today, the advent of safer, more effective therapies has diminished the use of lasers in the treatment of wet AMD.

Concern for the amount of collateral damage in the retina being induced by laser photocoagulation led to the second major advancement in wet AMD treatment: retinal application of photodynamic therapy (PDT). 

PDT utilizes a medication called verteporfin. Verteporfin selectively accumulates in neovascular blood vessels and is activated by a specific wavelength of light. The patient is slowly injected intravenously with a dose of verteporfin over the course of 10 minutes. After the medication has had a chance to absorb into the neovascular membrane beneath the retina (5 minutes after the injection is completed), laser light of a specific wavelength is applied to the retina. The laser-activated verteporfin causes clotting within the neovascular membrane, reducing blood and plasma leakage from the membrane. This treatment was shown to have a similar effect to focal laser photocoagulation, with less damage to noninvolved treatment-adjacent areas of the retina.³¹ PDT usually must be administered several times for optimal treatment effect.

The introduction of intravitreal injection of inhibitors of VEGF represented a paradigm shift in the treatment of wet AMD and is the current standard of care.¹⁴ This treatment was the first one shown to not only slow the progression of wet AMD, but also to actually improve vision. There are 3 anti-VEGF medications currently in use: bevacizumab, ranibizumab, and aflibercept. 

Ranibizumab and aflibercept were developed specifically for the treatment of wet AMD and are approved by the US Food and Drug Administration (FDA) for this use. Bevacizumab was originally FDA-approved for use in combination with chemotherapy drugs for the treatment of metastatic colon cancer. It has since been FDA-approved for use in the treatment of several other cancers but is used off-label for wet AMD. 

The anti-VEGF medications are injected directly through the sclera and into the vitreous humor of the eye. The medication diffuses toward the back of the eye, where it binds to VEGF molecules, inhibiting their action and subsequently reducing choroidal neovascularization. These medications have the strongest effect of any FDA-approved therapy for wet AMD. However, these injections must be repeated frequently (usually every 4-6 weeks initially) and often must be continued for the life of the patient.

Iatrogenic Impact and Management

Research suggests intravitreal administration of anti-VEGF medications is quite safe, with very few contraindications and no known drug interactions. Contraindications include ocular or periocular infection, hypersensitivity to the drug, and active ocular inflammation.^32-34 Intravitreal anti-VEGF medications are in pregnancy category C, and their use in women who are nursing, pregnant, or may become pregnant is strongly cautioned.

Systemic anti-VEGF medication use has been associated with reports of adverse effects such as hypertension, an increased risk of bleeding, and an increased risk of thrombotic events such as stroke and myocardial infarction. Research on intravitreal anti-VEGF use has shown conflicting results regarding their risk of these adverse effects.³⁵ The general consensus, however, seems to be that intravitreal administration of anti-VEGF agents carries much lower risk than systemic administration—a difference attributed to the lower dosage and decreased systemic perfusion of intravitreal injection compared with systemic uses.³⁵

The use of systemic antiplatelet and anticoagulant medications has been associated with an increase in the risk for and size of intraocular bleeds in wet AMD.^36,37 This risk may be compounded by a positive history of systemic hypertension in patients who use blood-thinning medication.³⁶ Given that these types of medications are often critical in the prophylaxis of serious systemic thromboembolic events, they are usually not discontinued prior to starting intravitreal anti-VEGF therapy.

Conclusion

Age-related macular degeneration is an extremely common and sight-threatening condition. Early detection and swift intervention are key for preserving vision in patients with AMD. Annual dilated eye examination is the most effective tool in the diagnosis and monitoring of AMD. New therapies such as the anti-VEGF medications have brought about a sea change in the treatment of wet AMD.

Casey Bateman, OD, is an optometric ocular disease resident at Associated Eye Care in Stillwater, Minnesota.

Leonid Skorin Jr, DO, OD, MS, is an ophthalmologist at Mayo Clinic Health System in Albert Lea, Minnesota.

References:

1. World Health Organization. Prevention of blindness and visual impairment: priority eye diseases. http://www.who.int/blindness/causes/priority. Accessed October 4, 2016.
2. Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;​122(4):​​564-572.
3. National Advisory Eye Council. Report of the Retinal and Choroidal Diseases Panel. Bethesda, MD: US Dept of Health and Human Services; 1983. Vision Research: A National Plan 1983-1987; vol 2 pt 1. NIH publication 83-2471.
4. Klein R, Klein BEK, Linton KLP. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1992;99(6):933-943.
5. Bressler NM, Bressler SB. Preventative ophthalmology: age-related macular degeneration. Ophthalmology. 1995;102(8):1206-1211.
6. Vincent GK, Velkoff VA. The Next Four Decades: The Older Population in the United States: 2010 to 2050. Washington, DC: US Census Bureau; May 2010. Publication P25-1138. https://www.census.gov/prod/2010pubs/p25-1138.pdf. Accessed October 4, 2016.
7. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS report No. 17. Arch Ophthalmol. 2005;​123(11):1484-1498.
8. Kahn HA, Leibowitz HM, Ganley JP, et al. The Framingham Eye Study: I. Outline and major prevalence findings. Am J Epidemiol. 1977;​106(1):17-32.
9. Ferris FL III, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102(11):1640-1642.
10. Facts about age-related macular degeneration. National Eye Institute website. https://nei.nih.gov/health/maculardegen/armd_facts. Reviewed September 2015. Accessed October 4, 2016.
11. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;​358(24):2606-2617.
12. Montezuma SR, Sobrin L, Seddon JM. Review of genetics in age related macular degeneration. Semin Ophthalmol. 2007;22(4):229-240.
13. Silvestri G, Williams MA, McAuley C, et al. Drusen prevalence and pigmentary changes in Caucasians aged 18-54 years. Eye (Lond). 2012;​26(10):1357-1362.
14. Remington LA. Clinical Anatomy and Physiology of the Visual System. 3rd ed. St Louis, MO: Elsevier Butterworth Heinemann; 2012:57-59.
15. Chen W, Stambolian D, Edwards AO, et al. Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A. 2010;107(16):7401-7406.
16. Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A. 2010;107(16):7395-7400.
17. Swaroop A, Branham KEH, Chen W, Abecasis G. Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet. 2007;16(R2):​R174-R182.
18. Frank RN, Puklin JE, Stock C, Canter LA. Race, iris color, and age-related macular degeneration. Trans Am Ophthalmol Soc. 2000;98:109-117.
19. Silvestri G, Williams MA, McAuley C, et al. Drusen prevalence and pigmentary changes in Caucasians aged 18–54 years. Eye (Lond). 2012;​​26(10):1357-1362.
20. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern: Age-Related Macular Degeneration. San Francisco, CA: American Academy of Ophthalmology; 2015. http://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-2015. Accessed October 4, 2016.
21. Khan JC, Thurlby DA, Shahid H, et al; Genetic Factors in AMD Study. Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol. 2006;​90(1):​75-80.
22. Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE. A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA. 1996;276(14):1147-1151.
23. Age-Related Eye Disease Study Research Group. Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report No. 19. Ophthalmology. 2005;112(4):533-539.
24. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report No. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
25. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029-1035.
26. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155.
27. Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-2015.
28. Vavvas DG, Daniels AB, Kapsala ZG, et al. Regression of some high-risk features of age-related macular degeneration (AMD) in patients receiving intensive statin treatment. EBioMedicine. 2016;5:198-203.
29. Volanakis JE, Narayana SVL. Complement factor D, a novel serine protease. Protein Sci. 1996;​5(4):553-564.
30. Xu Y, Narayana SVL, Volanakis JE. Structural biology of the alternative pathway convertase. Immunol Rev. 2001;180(1):123-135.
31. Kallitsis A, Moschos MM, Ladas ID. Photodynamic therapy versus thermal laser photocoagulation for the treatment of recurrent choroidal neovascularization due to AMD. In Vivo. 2007;​21(6):1049-1052.
32. Eylea [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals Inc; 2016.
33. Lucentis [package insert]. South San Francisco, CA: Genentech; 2016.
34. Avastin [package insert]. South San Francisco, CA: Genentech; 2015.
35. Dedania VS, Bakri SJ. Systemic safety of intravitral anti-vascular endothelial growth factor agents in age-related macular degeneration. Curr Opin Ophthalmol. 2016;27(3):224-243.
36. Kuhli-Hattenbach C, Fischer IB, Schalnus R, Hattenbach L-O. Subretinal hemorrhages associated with age-related macular degeneration in patients receiving anticoagulation or antiplatelet therapy. Am J Ophthalmol. 2010;149(2):316-321.
37. Kiernan DF, Hariprasad SM, Rusu IM, Mehta SV, Mieler WF, Jager RD. Epidemiology of the association between anticoagulants and intraocular hemorrhage in patients with neovascular age-related macular degeneration. Retina. 2010;​30(10):​1573-1578.