NON-EXUDATIVE (DRY) MACULAR DEGENERATION

Signs and Symptoms

Age-related macular degeneration (AMD) is the leading cause of acquired legal blindness in the United States for persons over the age of 65.1-11 By 2020, AMD is expected to affect 2.95 million individuals in the US alone.5 AMD is present in approximately 10% to 18% of the population over the age of 52 and in up to 33% of individuals over the age of 75.8

The disease involves complex interplay between genetic, environmental and metabolic factors.6,7,12,13 Smoking, hypertension, obesity, suboptimal nutrition (e.g., increased cholesterol, low dietary intake of carotenoids, alcohol consumption), older age, sunlight exposure and family history are all risk factors.6,7,12-14

New evidence supports hypotheses implicating systemic inflammation and immune system involvement.6 All AMD variants begin in the subretinal tissues under the retinal pigment epithelium (RPE). The non-exudative (dry) form develops from pathology that takes root in the RPE/Bruch’s membrane complex and matures to involve the photoreceptors.1-5,12,15

The earliest clinical manifestations of AMD are hard and soft drusen (focal thickenings of Bruch’s membrane) and macular pigmentary atrophy.15,16 The presence of drusen does not alone indicate AMD, but may serve as a precursor.

AMD is bilateral in 55% of cases.17 Visual symptoms associated with AMD depend on the severity and type of disease. The more common dry, atrophic form (with no choroidal neovascularization) tends to be less severe, producing a gradual, painless distortion and loss of central vision, although many patients maintain excellent visual acuity.12,15 Some patients complain of color distortion. The clinical signs of non-exudative AMD include drusen of the posterior pole, granular clumping and disorganization of the RPE in the macular area, macular RPE hyperplasia and degeneration of the outer retinal layers with circumscribed areas of geographic atrophy of the RPE as the disease progresses.15,16

In individuals with advanced, late-stage dry AMD, approximately one third will develop geographic atrophy.9-11 This advanced dry stage is characterized by single or multiple well-demarcated areas of partial or complete depigmentation of the RPE, with loss of adjacent choriocapillaris and photoreceptors.9-11 Clinically, it appears as hypopigmented, circular patches where the choroidal vasculature is visible.9-11 When these changes involve the macula, the effects on acuity are significant.

Pigment epithelial detachment (PED) is another non-exudative complication of the advancing process.18 PEDs are defined by their discrete, subretinal, yellow, nodular appearance. They are seen adjacent to drusen and result from the movement of protein-laden fluid between Bruch’s membrane and the RPE.15-18 Patients who develop a PED in the vicinity of the macula will often experience significant reduction of acuity.18 Their appearance often marks disease progression, and may precede the formation of choroidal neovascularization and conversion to the “wet” form of the disease.18

Pathophysiology

All forms of AMD begin with alterations in the macular RPE.15-21 While the mechanisms and processes are poorly understood, it is postulated that these changes are initiated by isolated regions of choriocapillaris vascular dysfunction.19-21 This occurs in conjunction with genetic, vascular and lifestyle risks as the choroid naturally thins with age (after 50 to 60 years of age, choroidal thickness has been shown to progressively decrease by 4µm to 5µm each year).19,23,24 The process is hastened in the setting of missing natural protectants (macular pigment density and carotenoids such as zeaxanthin, mesozeaxanthin and lutein).1-4,8,19,24,27

Natural age-related thinning of the choroid is mirrored by reduction in oxygen and metabolite supply to the RPE and outer retina.20,25 Exposure to ultraviolet light in the absence of natural RPE construction and in the setting of inadequate quenching by antioxidants creates reactive oxygen species (ROS), which alter biomolecules, including proteins, nucleic acids and lipids.27

New pathophysiologic hypotheses categorize the damage into three distinct stages:

(1) Initial RPE oxidative injury, caused by any number of endogenous or exogenous oxidants resulting in extrusion of cell membranes (blebs). This occurs in concert with decreased activity of matrix metalloproteinases (MMPs) and the incomplete digestion of constantly shed photoreceptor outer segments, promoting elemental accumulation under the RPE as basal laminar deposits.15,28

(2) RPE cells under the influence of various plasma-derived molecules and hormones subsequently stimulate increased synthesis of MMPs and other molecules responsible for extracellular matrix turnover, decreasing collagen production. This affects both RPE basement membrane and Bruch’s membrane, leading to linear basal laminar deposits and the formation of drusen via the admixture of the formed blebs into Bruch’s membrane.15,28 This contributes to the formation of drusen and the propagation of oxidative stress.28 In this stage, a new basement membrane forms under the RPE, trapping these deposits within the Bruch’s membrane.

(3) Macrophages are recruited via inflammatory mediators, growth factors or other substances to the sites of RPE injury and deposit formation.15

The recruitment of non-activated or scavenging macrophages may remove the deposits without further injury. In this instance, no loss of function is realized. In the disease state, however, the pathology reaches clinical threshold, creating visual loss.15,28 As the RPE fails under stress, photoreceptor loss becomes progressive with the inner nuclear layer collapsing and contacting Bruch’s membrane, initializing the degeneration of the outer retinal layers.1-4,8

Investigators have determined that increased choroidal thickness may be protective, as individuals with thicker choroids have been reported to retain better visual function.24,26

Management

Patients at risk for AMD should be educated on its associated risk factors and preventative measures.1-31 While the genetic susceptibilities that accompany having a family history of AMD or a pedigree for cardiovascular disease or dyslipidemia cannot be altered, lifestyle changes—such as practicing good dietary choices, wearing UV light protection, not smoking and taking evidence-based supplements—can.1-4,6,7,29 Semiannual eye examination with dilated funduscopy is critical to uncovering the early changes associated with the disease’s development and progression.

Home therapy aimed at early detection of AMD using an Amsler grid permits at-risk patients to home monitor for stability. New early detection instrumentation includes dark adaptometry as cone and rod dark adaptation may be biomarkers for early AMD (AdaptDx, MacuLogix), macular pigmentary density evaluation as missing protective macular pigment may increase the vulnerability to short wavelength light (MPS II detector, Elektron Technology) and fundus autofluorescence, a technology that takes advantage of the fluorescent properties of drusen (early subretinal lesion detection, grading, progression, monitoring).30-32

Researchers have indicated that oral antioxidant supplements containing vitamins C, E, beta-carotene, copper and zinc appear to play a role in reducing retinal damage by limiting the chemical reactions initiated by the free radicals created by retinal metabolism.34-37 Ordinary multivitamins, zinc, beta-carotene or products specifically designed for AMD are aimed at distributing the correct combinations of these ingredients and have been shown to be a useful tool for slowing the progression of non-exudative AMD and preventing the conversion to the exudative form.34-37 Consider these supplements for patients with intermediate size drusen (64µm to 124µm), one or more large druse (>125µm), non-central geographic atrophy in one or both eyes, or AMD with vision loss in one or both eyes without the contraindication of smoking.34-37

The original Age-Related Eye Disease Study (AREDS1) formulation multivitamin (vitamins C, E, beta-carotene, zinc and copper), taken as directed, has been reported to reduce the risk of progression of non-exudative AMD by 25% over a five-year period.36 People with dry AMD taking these supplements during the same time period were less likely to lose 15 or more letters of visual acuity.34 No evidence for an effect of supplementation was seen in smaller trials of shorter duration.37 Since beta-carotene is associated with increased lung cancer in former smokers, lutein/zeaxanthin may serve as a replacement to provide additional beneficial effects beyond the effects of the original AREDS1 formulation.35,36 In addition, a randomized clinical trial of B vitamins demonstrated a beneficial effect with the vitamin B complex.36

The objective of the lutein antioxidant supplementation trial (LAST) was to determine whether nutritional supplementation with lutein or lutein together with antioxidants, vitamins and minerals, improved visual function and symptoms in atrophic AMD.38,39 While the LAST trial suggested improved function may be plausible, results released by the AREDS2 study group supported the change of beta carotene to lutein and zeaxanthin because of their safer profile with smokers, but stopped short of endorsing any effectiveness over the AREDS1 formula.35,39 The Central Retinal Enrichment Supplementation Trial (CREST) aims to follow up on the results of AREDS2 by investigating the potential impact of macular pigment enrichment following supplementation with a formulation containing 10mg lutein, 2mg zeaxanthin and 10mg mesozeaxanthin on visual function in normal subjects and in subjects with early age-related macular degeneration.37

Dietary omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake and increased fish consumption (broiled or baked) have both been associated with protecting against the conversion of dry AMD to wet AMD.40 Both oral docosahexaenoic acid (DHA) and oral eicosapentaenoic acid (EPA) in supplementation form have demonstrated protective effects against nonexudative AMD conversion to exudative AMD.41 Rare reported spontaneous remissions from AMD suggest the retina has a regenerative capacity.42 Researchers are currently investigating the potential for over-the-counter oral resveratrol (Longevinex, Resveratrol Partners).42

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

Clinical Pearls

The risk of patients with dry AMD progressing to wet AMD, for any given five-year period, is approximately 14% to 20%.

While geographic atrophy is commonly associated with AMD, other causes include adult-onset foveomacular vitelliform dystrophy, pattern dystrophy, choroideremia, central areolar choroidal sclerosis and degenerative myopia.

While vitamins offer hope for stability and improvement, excessive use can be harmful. Zinc can produce yellow skin color and has been associated with pathological mechanisms related to metal dyshomeostasis in Alzheimer’s disease. Beta carotene has been associated with increased risk of lung cancer in smokers. Prescribing supplementation should be treated carefully, gathering a full history and consulting with the patient’s internist.

1. Bowes Rickman C, Farsiu S, Toth CA, Klingeborn M. Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging. Invest Ophthalmol Vis Sci. 2013;54(14):68-80.

2. van Lookeren Campagne M, LeCouter J, Yaspan BL, Ye W. Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol. 2014;232(2):151-64.

3. Machalińska A. Age-related macular degeneration as a local manifestation of atherosclerosis — a novel insight into pathogenesis. Klin Oczna. 2013;115(1):74-8.

4. Turlea C. New aspects in age related macular degeneration. Oftalmologia. 2012;56(1):36-44.

5. Akpek EK, Smith RA. Overview of age-related ocular conditions. Am J Manag Care. 2013;19(5 Suppl):S67-75.

6. Cheung LK, Eaton A. Age-related macular degeneration. Pharmacotherapy. 2013;33(8):838-55.

7. Sin HP, Liu DT, Lam DS. Lifestyle modification, nutritional and vitamins supplements for age-related macular degeneration. Acta Ophthalmol. 2013;91(1):6-11.

8. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004; 122(4):598-614.

9. Biarnés M, Monés J, Alonso J, et al. Update on geographic atrophy in age-related macular degeneration. Optom Vis Sci. 2011;88(7):881-9.

10. Lindblad AS, Lloyd PC, Clemons TE, et al. Age-Related Eye Disease Study Research Group. Change in area of geographic atrophy in the age-related eye disease study: AREDS report number 26. Arch Ophthalmol. 127(9):1168–1174.

11. Lujan BJ, Rosenfeld PJ, Gregori G, et al. Spectral domain optical coherence tomographic imaging of geographic atrophy. Ophthalmic Surg Lasers Imaging. 2009;40(2):96-101.

12. Nano ME, Lansingh VC, Pighin MS, et al. Risk factors of age-related macular degeneration in Argentina. Arq Bras Oftalmol. 2013;76(2):80-4.

13. Shahid H, Khan JC, Cipriani V, et al. Age-related macular degeneration: the importance of family history as a risk factor. Br J Ophthalmol. 2012;96(3):427-31.

14. Cougnard-Grégoire A, Delyfer MN, Korobelnik JF, et al. Elevated high-density lipoprotein cholesterol and age-related macular degeneration: the alienor study. PLoS One. 2014;9(3):e90973.

15. Mettu PS, Wielgus AR, Ong SS, Cousins SW. Retinal pigment epithelium response to oxidant injury in the pathogenesis of early age-related macular degeneration. Mol Aspects Med. 2012;33(4):376-98.

16. Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med. 2012;33(4):295-317.

17. Alexander LJ. Exudative and Nonexudative Macular Disorders. In: Alexander, L.J. Primary Care of The Posterior Segment. East Norwalk, CT, Appleton and Lange 1994:277-344.

18. Cukras C, Agrón E, Klein ML, Ferris FL 3rd, et al. Natural history of drusenoid pigment epithelial detachment in age-related macular degeneration: Age-Related Eye Disease Study Report No. 28. Ophthalmology. 2010;117(3):489-99.

19. Ding X, Li J, Zeng J, et al. Choroidal thickness in healthy Chinese subjects. Invest Ophthalmol Vis Sci. 2011;52(13):9555-60.

20. Manjunath V, Taha M, Fujimoto JG, et al. Choroidal thickness in normal eyes measured using Cirrus HD optical coherence tomography. Am J Ophthalmol. 2010;150(3):325-329.

21. Ikuno Y, Kawaguchi K, Nouchi T, et al. Choroidal thickness in healthy Japanese subjects. Invest Ophthalmol Vis Sci. 2010;51(4):2173-6.

22. Wu L, Alpizar-Alvarez N. Choroidal imaging by spectral domain-optical coherence tomography. Taiwan Journal of Ophthalmology. 2013;3(1):3-13.

23. Zhang L, Lee K, Niemeijer M, et al. Automated Segmentation of the Choroid from Clinical SD-OCT. Invest Ophthalmol Vis Sci.2012;53(12):7510-9.

24. Wei WB, Xu L, Jonas JB, et al. Subfoveal choroidal thickness: the Beijing Eye Study. Ophthalmology. 2013;120(1):175-80.

25. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol. 2009;47(5):811-5.

26. Lee JY, Lee DH, Lee JY, et al. Correlation between subfoveal choroidal thickness and the severity or progression of nonexudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(12):7812-8.

27. Tokarz P, Kaarniranta K, Blasiak J. Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD). Biogerontology. 2013;14(5):461-82.

28. Wiktorowska-Owczarek A, Nowak JZ.Pathogenesis and prophylaxis of AMD: focus on oxidative stress and antioxidants. Postepy Hig Med Dosw (Online). 2010l 28(7);64:333-43.

29. Sin HP, Liu DT, Lam DS. Lifestyle modification, nutritional and vitamins supplements for age-related macular degeneration. Acta Ophthalmol. 2013;91(1):6-11.

30. Gaffney AJ, Binns AM, Margrain TH. The effect of pre-adapting light intensity on dark adaptation in early age-related macular degeneration. Doc Ophthalmol. 2013;127(3):191-9.

31. Schachar IH, Zahid S, Comer GM, et al. Quantification of fundus autofluorescence to detect disease severity in nonexudative age-related macular degeneration. JAMA Ophthalmol. 2013;131(8):1009-15.

32. Kaya S, Weigert G, Pemp B, et al. Comparison of macular pigment in patients with age-related macular degeneration and healthy control subjects – a study using spectral fundus reflectance.Acta Ophthalmol. 2012;90(5):e399-403.

33. García-Layana A, Recalde S, Alamán AS, Robredo PF. Effects of lutein and docosahexaenoic Acid supplementation on macular pigment optical density in a randomized controlled trial. Nutrients. 2013;5(2):543-51.

34. 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):1417-36.

35. Age-Related Eye Disease Study 2 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):2005-15.

36. Chew EY. Nutrition effects on ocular diseases in the aging eye. Invest Ophthalmol Vis Sci. 2013;54(14):42-7.

37. Akuffo KO, Beatty S, Stack J, et al. Central Retinal Enrichment Supplementation Trials (CREST): Design and Methodology of the CREST Randomized Controlled Trials. Ophthalmic Epidemiol. 2014;21(2):111-23.

38. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2012;11:CD000254.

39. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004;75(4):216-30.

40. SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007;125(5):671-9.

41. Souied EH, Delcourt C, Querques G, et al. Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the Nutritional AMD Treatment 2 study. Ophthalmology. 2013;120(8):1619-31.

42. Richer S, Stiles W, Ulanski L, et al. Observation of human retinal remodeling in octogenarians with a resveratrol based nutritional supplement. Nutrients. 2013;5(6):1989-2005.