Age-Related Macular Degeneration

An update on the condition and its relation to cataract surgery.
By Raja Narayanan, MD, and Baruch D. Kuppermann, MD, PhD
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over 50 years of age in developed countries.1-3 The condition was first reported as a clinical entity in 1885 by Otto Haab.4 Early manifestations of AMD include focal drusen associated with minor visual complaints, but the later stages of the disease result in severe vision loss. The nonexudative or dry form of AMD is approximately 10 times more prevalent than the exudative form, but the latter is the leading cause of blindness from AMD.

PREVALENCE

Various population-based studies have sought to estimate the prevalence of AMD in the general population, including the Framingham Eye Study,5 the National Health and Nutrition Examination Survey,6 the Beaver Dam Eye Study,7 the Rotterdam Study,8 and the Blue Mountains Eye Study.9 The prevalence of exudative AMD in the Framingham Eye Study was 1.5%, whereas the dry type of AMD accounted for 90% of all cases. The Beaver Dam Eye Study defined early age-related maculopathy (ARM) as the presence of any drusen (except for hard, distinct drusen) with degeneration of the retinal pigment epithelium (RPE) or increased pigment in the macular area. It defined late ARM or AMD as the presence of geographic atrophy or exudative disease or both. The prevalence of late ARM was 1.6% in this study, and exudative maculopathy in at least one eye was present in 1.2% of the population. The prevalence of late ARM was 7.1% in subjects older than 75 years.

RISK FACTORS
Demographic Factors

All studies indicate that both the prevalence and the incidence of all forms of AMD increase with age. The Framingham Study found a 17-fold increased risk of AMD when comparing the oldest to the youngest age group.5 Although there was no overall difference in the frequency of AMD between men and women in the Beaver Dam Eye Study, exudative AMD was more common in women 75 years or older compared with men. This subset of women also had approximately twice the incidence of early ARM compared with men in the study.10 Several studies indicate a genetic factor in the pathogenesis of the disease.11-14 Those examining the concordance of AMD in monozygotic and dizygotic twins strongly support the role of genetics in the pathogenesis of AMD.15

Lifestyle Factors
Most of the epidemiological evidence indicates a strong positive association between dry and wet AMD with smoking.16-18 Risk grows as pack-years of smoking increase, indicating a dose-dependent relationship. Supplementation with zinc and vitamins A, C, and E helped prevent wet AMD in the Age-Related Eye Diseases Study (AREDS).19

Excessive exposure to light can damage the retina. In the Beaver Dam Eye Study, participants exposed to the summer sun for more than 5 hours a day during their teens, in their 30s, and at the baseline examination were at a higher risk of developing increased retinal pigmentation and early ARM by 10 years than those exposed less than 2 hours per day during the same periods.20 The shorter wavelengths of light pose the greatest hazard to the retinal photoreceptors, because they contain more energy. Exposure to these wavelengths has been called the blue-light hazard, because they appear blue to the human eye. It has also been suggested that the removal of the natural lens, as in cataract surgery, should be followed by replacement with a tinted IOL to restore the eye’s natural barrier to light radiation.21

Cardiovascular Factors
High cholesterol, especially HDL cholesterol17,22 and oxidized LDL,23 as well as hypertension16,18 have been associated with a higher incidence of AMD. In the Macular Photocoagulation Study, there was an increased risk of exudative AMD associated with hypertension in the second eye of individuals with exudative AMD in one eye at baseline.

Ocular Risk Factors
The Macular Photocoagulation Study group described the risk factors for a patient’s developing choroidal neovascularization (CNV) in his fellow eye when his opposite eye already has CNV. They include five or more drusen, focal hyperpigmentation, one or more large drusen (> 63µm), and systemic hypertension.24 Based on the follow-up of patients with juxtafoveal CNV, the 5-year incidence rate for the development of CNV was 87% if all four risk factors were present. Lanchoney et al25 reported that the 10-year risk of developing CNV in patients with bilateral soft drusen ranged from 8.6% to 15.9%. Hyperopia has a higher association with AMD, whereas darker irides may be protective against AMD.26,27

PROTECTIVE MECHANISMS IN THE RETINA AND CRYSTALLINE LENS

Carotenoids, including the xanthophyllic yellow pigments lutein and zeaxanthin, protect the macula from damaging blue light because of their maximum absorption spectrum at the lower wavelengths. By absorbing shorter wavelengths, the xanthophyllic pigments defend the photoreceptors against thermal damage. When molecules within the RPE absorb blue light, however, the formation of free radicals ensues, leading to cellular injury.28 The crystalline lens is the major protective barrier to near-UV radiation (between 300 and 400nm). Yellowing of the natural crystalline lens results in a greater absorbance of light of lower wavelengths such as blue light.29

Data from the Framingham Eye Study showed that nuclear cataracts were associated with a slightly reduced incidence of mild-to-severe macular changes compared with cortical cataracts.30 Mild changes were defined as pigmentary changes or fewer than 10 small drusen, whereas moderate-to-severe changes were defined as more than 10 small drusen, large drusen, or hemorrhagic or exudative disease. Cortical cataracts were associated with a slightly increased risk for the development of the macular changes.31

Recent analysis of data from the AREDS showed no correlation between cataract surgery and advanced neovascular AMD, although there was a possible risk of advancing geographic atrophy.31 In a subset analysis of patients in the AREDS who underwent cataract surgery, the risk for developing exudative (neovascular) AMD after cataract surgery was only 1% greater when compared with subjects who did not undergo cataract surgery. Cataract surgery did appear to affect patients’ risk for developing geographic atrophy, the form of dry AMD associated with severe vision loss, however. AREDS subjects who underwent cataract surgery had a 47% greater risk of developing poor vision secondary to geographic atrophy compared with those who did not undergo cataract surgery; the P value of .05 barely met statistical significance, however, and thus leaves some doubt as to whether the finding was valid.

In a retrospective study of patients with early AMD and extracapsular cataract extraction, progression to wet AMD occurred more often in the pseudophakic than in unoperated eyes.32 Ophthalmologists’ interest in the use of IOLs that have light radiation-blocking mechanisms has increased. Insoluble lens proteins accumulate in the brunescent nuclear cataract, perhaps due to photo-oxidation by UV light. One theory is that this yellow filter protects the retina against blue light in the visible spectrum. If so, replacing this natural filter to high-energy wavelengths with a lens implant could allow damaging near-UV radiation and blue light to reach the retina, depending on the spectral transmittance of the IOL.33

Recently, Alcon Laboratories, Inc. (Fort Worth, TX), began marketing the Acrysof Natural lens, an IOL that blocks both UV radiation and blue light.34 Researchers have demonstrated that yellow-tinted IOLs reduce the death of RPE laden with the lipofuscin fluorophore A2E.35 Moreover, the incidence of CNV in patients with bilateral drusen and pigmentary changes was much higher in eyes that received untinted IOLs than in phakic fellow eyes.32

The use of blue-blocking IOLs has been controversial, however. They may affect color and scotopic vision, especially in the elderly,36 but no studies to date have been conducted to prove this hypothesis. The decrease in scotopic vision with age has been attributed by some researchers to an age-related reduction in rod phoropter cells37 and a dysfunction of central visual pathways.38 Braunstein and Sparrow39 therefore consider it prudent to use a blue-blocking IOL, because it reduces the transmission of blue light similarly to an adult, cataractous, crystalline lens. Prospective, controlled studies need to be conducted to determine the benefits and effects on color and scotopic vision of these IOLs.

CONCLUSION

Removing the natural crystalline lens after cataract surgery increases the retina’s exposure to light of low wavelength and may increase the incidence of macular changes. The relationship between cataract surgery and AMD is not clear, however. A large, multicenter, prospective clinical trial would help to determine the significance. 

Baruch D. Kuppermann, MD, PhD, is Chief of the Retina Service for the Department of Ophthalmology at University of California, Irvine. He states that he holds no financial interest in the product or company mentioned herein.
Dr. Kuppermann may be reached at (949) 824-6256; bdkupper@uci.edu.
Raja Narayanan, MD, is Clinical Instructor for the Department of Ophthalmology at University of California, Irvine. He states that he holds no financial interest in the product or company mentioned herein. Dr. Narayanan may be reached at (714) 456-7360; rnarayan@uci.edu.

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