The Relationship of Ocular Factors to the Incidence and Progression of Age-Related Maculopathy

Objective  To examine the association between ocular factors and the incidence and progression of age-related maculopathy.

Participants  A population of 3684 adults (43-86 years of age at baseline) living in Beaver Dam, Wis, studied at baseline and 5 years later.

Methods  Standardized protocols for refraction and determination of iris color, administration of a questionnaire, and slitlamp and retroillumination photographs of the lenses to determine cataract type and stereoscopic color fundus photographs to determine presence and severity of age-related maculopathy. Standard univariate and multivariate analyses were performed.

Main Outcome Measures  Incidence and progression of age-related maculopathy.

Results  After controlling for age, eyes that had undergone cataract surgery before baseline were more likely to have progression of age-related maculopathy (odds ratio, 2.71; 95% confidence interval [CI], 1.69-4.35) and to develop signs of late age-related maculopathy (odds ratio, 2.80; 95% CI, 1.03-7.63) than were eyes that were phakic at baseline. These relationships remained after controlling for other risk factors in multivariate analyses. There was no relationship of nuclear cataract, cortical cataract, or iris color to the incidence and progression of age-related maculopathy.

Conclusion  These findings indicate a relationship between cataract surgery and increased risk of progression of age-related maculopathy.

AGE-RELATED maculopathy (ARM) is an important cause of loss of vision in older Americans.^1-6 Its pathogenesis is poorly understood.^6,7 Many ocular factors have been reported to be related to higher risk of developing end-stage ARM. These include the presence of various types of cataract,^8-11 cataract surgery,^10,12 lighter iris pigmentation,^13-15 and hyperopia.^16-21 However, the findings from epidemiological studies that have examined these relationships have not been uniform.^8-11,22-25 The purpose of this report is to examine the relationship of these and other ocular factors to the 5-year incidence and progression of ARM in a large population-based study in Beaver Dam, Wis.

Methods used to identify the population and descriptions of the population have appeared in previous reports.^5,26-29 Briefly, a private census of the population of Beaver Dam (99% white) was performed from September 15, 1987, to May 4, 1988, to identify all residents in the city or township of Beaver Dam who were 43 to 84 years of age. Of the 5924 eligible individuals, 4926 participated in the baseline examination between March 1, 1988, and September 14, 1990. Nonparticipants consisted of 226 persons (3.8%) who had died before the examination, 18 (0.3%) who could not be located, 337 (5.7%) who permitted an interview only (of these, 61 had moved), and 417 (7.0%) who refused to participate (of these, 39 had moved). Comparisons between participants and nonparticipants at the time of the baseline examination have appeared elsewhere.²⁷ Participants in the study had a lower prevalence of cataract surgery than did nonparticipants at baseline (right eye, 3.5% vs 5.3%, P=.03; left eye, 3.1% vs 4.8%, P=.02). There were no differences in rates of early ARM and cataract surgery occurring together in the same eye at baseline between participants and nonparticipants (right eye, 0.9% vs 0.7%, P=.68; left eye, 0.9% vs 0.8%, P=.85).

Before the start of the 5-year follow-up examination on March 1, 1993, 385 (7.8%) participants had died. Of the 4541 surviving participants in the baseline examination, 3684 (81.1%) participated in the follow-up examination between March 1, 1993, and June 14, 1995.⁵ Four participants (0.1%) could not be located, 259 (5.7%) permitted an interview only (of these, 48 had moved out of the area), 423 (9.3%) refused to participate (of these, 44 had moved out of the area), and 171 (3.8%) died during the examination period. Both the mean and median times between the baseline and 5-year follow-up examinations were 4.8 years and the SD was 0.4 years.

Comparisons between participants and nonparticipants at follow-up have been presented elsewhere.⁵ Persons who were alive and did not participate in the follow-up eye examination (n=686) were older at baseline than those who did (62.7 vs 60.4 years; P<.001). After adjusting for age, those who were alive during the study period and did not participate were more likely to have fewer years of education, lower income, poorer visual acuity, a history of cardiovascular disease, a history of never drinking alcohol, more pack-years of smoking, higher serum cholesterol level, and higher systolic and diastolic blood pressure, and to have been retired at baseline, than persons who participated. After adjusting for age and sex, participants with early ARM at baseline were more likely to participate than those in whom ARM was absent (Cochran-Mantel-Haenszel test for general association, P=.003).

Similar procedures were used at both baseline and follow-up examinations and have been described in detail elsewhere.^5,27-33 Informed consent was obtained from each participant at the beginning of the examination. The examination at baseline and follow-up included measuring the blood pressure by means of the Hypertension Detection and Follow-up Program protocol³⁴; measuring refractive error and best-corrected visual acuity for distance; measuring intraocular pressure by applanation tonometry; determining iris color by viewing the iris with penlight illumination before dilation of the pupil and comparing it with color photographic standards; dilating the pupils; administering a medical history questionnaire; taking slitlamp photographs of the lens of each eye with a slitlamp camera (model SL5, Topcon America Corp, Paramus, NJ) and anterior and posterior retroillumination photographs of the lens of each eye with a camera (Neitz CT-T, Tokyo Optical Corp Ltd, Tokyo, Japan)^35,36; and taking stereoscopic 30° color fundus photographs centered on the disc (Diabetic Retinopathy Study standard field 1), macula (Diabetic Retinopathy Study standard field 2), and a nonstereoscopic color fundus photograph temporal to but including the center of the fovea of each eye. For purposes of this report, the 3583 people with at least 1 eye free of confounding lesions (eg, retinal detachment or non–age-related scars affecting the macular area) at both examinations (right eye, n=3497; left eye, n=3519; both eyes, n=3435) are included in the analyses.

Slitlamp and retroillumination photographs of the lenses were graded by means of standardized systems reported previously.^35-37 For this study, nuclear cataract was defined as present if the photograph of the lens was graded as more opaque than standard photograph 3. For grading the severity of cortical and posterior subcapsular opacities, a grid dividing the lens into 8 sectors and a central circle was used. Cortical opacity was considered present if, on grading the retroillumination photograph, 5% or more of the lens surface area was affected; posterior subcapsular opacity was considered present if 5% or more of any of the 8 sectors or of the central circle of the surface area of the lens was involved.

The color of the iris was defined as gray or blue, yellow or green, or tan or brown as compared with photographic standards. Any iris with equal to or less than the amount of pigment in iris standard 1 was defined as gray or blue; similarly, any iris with equal to or less than the amount of pigment in iris standard 2 but greater than that in iris standard 1 was defined as yellow or green, and pigment darker than standard 2 was defined as tan or brown. When irises were found to have more than 1 color present, the color assigned was based on which color was present in more than 50% of the iris surface. "Can't grade" was the grade assigned when corneal scarring obscured the view of the iris or when there was aniridia, surgery, or trauma extensive enough to render the color indeterminable.

Ocular perfusion pressure (OPP) in each eye was defined by the following formula: OPP=[D+(S−D)/3]−IOP, where S indicates systolic blood pressure; D, diastolic blood pressure; and IOP, intraocular pressure.³⁸ Myopia was defined as a refractive error, in spherical equivalent, of −0.50 diopter or less and hyperopia was defined as a refractive error, in spherical equivalent, of +0.50 diopter or more based on a refraction according to the Early Treatment Diabetic Retinopathy Study. Refractive error was set to "missing" when visual acuity was 20/40 or worse or when an eye was aphakic or had an intraocular lens present. On the basis of replicating the measurement of refractive error on a sample of eyes, it has been determined that the measurement error of this variable is less than 0.50 diopter (data not shown).

Fundus photographs were graded for ARM in a masked fashion by means of a standardized protocol, the Wisconsin Age-Related Maculopathy Grading System.^30-33 Grading procedures, lesion descriptions, and detailed definitions for the presence and severity of specific lesions have appeared elsewhere.^31-33 The incidence of early ARM was defined by either the presence of soft indistinct drusen or the presence of any type of drusen associated with retinal pigment epithelial (RPE) depigmentation or increased retinal pigment at follow-up when none of these lesions was present at baseline. The incidence of late ARM was defined by the appearance of either exudative macular degeneration or "pure" geographic atrophy (ie, geographic atrophy not accompanied by exudative macular degeneration) at follow-up when neither was present at baseline.

For each eye, a 6-level severity scale for ARM was defined as follows: level 10, no drusen, or hard drusen or small soft drusen (<125 µm in diameter) only, regardless of area of involvement, and no pigmentary abnormality (increased retinal pigment or RPE depigmentation) present; level 20, hard drusen or small soft drusen (<125 µm in diameter), regardless of area of involvement, with increased retinal pigment present but no RPE depigmentation present or soft drusen (≥125 µm in diameter) with drusen area less than 196350 µm² (equivalent to a circle with a diameter of 500 µm) and no pigmentary abnormalities present; level 30, soft drusen (≥125 µm in diameter) with drusen area less than 196350 µm² and RPE depigmentation present or soft drusen (≥125 µm in diameter) with drusen area greater than or equal to 196350 µm² with or without increased retinal pigment but no RPE depigmentation present; level 40, soft drusen (≥125 µm in diameter) with drusen area greater than or equal to 196350 µm² involvement and RPE depigmentation present with or without increased retinal pigment; level 50, pure geographic atrophy; and level 60, exudative macular degeneration with or without geographic atrophy present.

Progression for an eye was defined as an increase in the maculopathy severity by 2 steps or more from level 10 through 30 and 1 step or more from level 40 or level 50 at the 5-year follow-up examination.

The SAS³⁹ was used for all statistical analyses. The relationships between baseline measures of cataract by type, cataract surgery, iris color, refractive error, and ocular perfusion pressure to the incidence or progression of specific maculopathy lesions in each eye were examined by χ² statistics. Tests for trends in proportions were performed with the Mantel-Haenszel procedure.⁴⁰ The direct method was used to obtain age-adjusted frequencies, and the Cochran-Mantel-Haenszel procedure produced age-adjusted P values. Logistic regression was used to determine whether cataract type, cataract surgery, iris color, perfusion pressure, intraocular pressure, or refractive error was associated with the incidence of signs of ARM. All logistic models controlled for age by means of a continuous variable by year, after determining that there was no gross departure from linearity by the Box-Tidwell transformation.⁴¹ Other risk factors for these lesions, including smoking status (never, past, or current), history of beer consumption at baseline (no or yes), history of heavy alcohol drinking status at baseline (never, past, or current), pulse pressure, hypertension, and history of vitamin use were separately run in each model to check for possible confounding. Liang-Zeger models were used to assess multivariate relationships with data from both eyes.⁴² This method adjusts for the correlation between the 2 eyes.

The frequencies of nuclear cataract, cortical cataract, posterior subcapsular cataract, aphakia, pseudophakia, and hyperopia increased with age at baseline (Table 1). Higher prevalences of blue or gray iris color were found with increased age. After controlling for age, women compared with men had higher frequencies of nuclear cataract (16.7% vs 9.3%, right eye, P<.001; 17.4% vs 8.2%, left eye, P<.001), cortical cataract (14.2% vs 8.5%, right eye, P=.001; 15.8% vs 9.1%, left eye, P=.001), myopia (30.1% vs 27.7%, right eye, P=.005; 29.9% vs 25.6%, left eye, P<.001), and green iris color (23.1% vs 19.4%, right eye, P=.005; 23.2% vs 19.4%, left eye, P=.004). Mean perfusion pressures and intraocular pressures did not change with age (data not shown). The 5-year incidence and rates of progression of ARM increased with age (Table 2). Late ARM developed in 18 right eyes and 25 left eyes during the 5 years of the study and was infrequent (2 right eyes and 1 left eye) in persons younger than 65 years. In addition, it developed in only 1 person without signs of early ARM. For these reasons, we limited analyses of late ARM to those who were 65 years of age or older and who had signs of early ARM at baseline (259 right eyes and 280 left eyes).

The incidence, age-adjusted relative risks (RRs), and 95% confidence intervals (CIs) for early and late ARM, exudative macular degeneration, pure geographic atrophy, and progression of ARM by exposures of interest at baseline are presented in Table 3, Part A, and Table 3, Part B. The data for both eyes are included to provide a sense of consistency of the findings (magnitude and direction of the relationships) between ocular specific variables. After controlling for age, eyes with nuclear cataract present at baseline had higher relative risks of developing early ARM; however, this relationship was significant only for left eyes. The presence of nuclear cataract at baseline was associated with higher incidence of RPE depigmentation and increased retinal pigment (data not shown); however, these associations were significant only in left eyes (for incidence of RPE depigmentation: RR, 2.40; 95% CI, 1.33-4.31; for incidence of increased retinal pigment: RR, 1.70; 95% CI, 1.03-2.82). Neither nuclear nor cortical cataract was related to the incidence of late ARM in either eye. After controlling for age, eyes with cortical cataract at baseline had higher RR of progression of ARM; however, this relationship was significant only for left eyes. There were too few eyes with posterior subcapsular cataract present at baseline to examine the relationship of this type of cataract to incidence and progression of ARM.

Previous cataract surgery at baseline was associated with a statistically significant (P<.05) increased risk of incidence of late ARM, but this was significant only in left eyes. There was increased risk of progression of ARM in both right and left eyes (Table 3, Part A, and Table 3, Part B). Previous cataract surgery was associated with an increased incidence of RPE depigmentation; this relationship was significant only in left eyes (RR, 2.27; 95% CI, 1.11-4.65) but not right eyes (data not shown). Persons who had cataract surgery between baseline and follow-up had higher age-adjusted incidence of early ARM (right eye: RR, 1.69; 95% CI, 1.12-2.54; P=.01; left eye: RR, 2.07; 95% CI, 1.42-3.05; P<.01); incidence of late ARM (right eye: RR, 1.67; 95% CI, 0.58-4.78; P=.34; left eye: RR, 2.61; 95% CI, 1.20-5.65; P=.02); and progression of ARM (right eye: RR, 2.16; 95% CI, 1.36-3.42; P=.001; left eye: RR, 2.93; 95% CI, 1.94-4.44; P<.001). There was no relationship between refractive status (Table 3, Part A, and Table 3, Part B), iris pigmentation (Table 3, Part A, and Table 3, Part B), intraocular pressure (data not shown), or perfusion pressure (data not shown), and the incidence and progression of ARM.

In multivariate analyses using the Liang-Zeger method⁴² and controlling for age, the presence of nuclear or cortical cataract at baseline was not related to the incidence of early or late ARM or to the progression of ARM (Table 4). Inclusion of other possibly confounding factors related to cataract or ARM, such as history of beer consumption, vitamin consumption, perfusion pressure, or hypertension, did not change these relationships (data not shown). These relationships remained unchanged after excluding eyes that had a nuclear or cortical cataract at baseline and cataract surgery before follow-up (data not shown). Previous cataract surgery was associated with an increased odds of developing early and late ARM; however, only the relationships between cataract surgery at baseline and the incidence of late ARM and the progression of ARM were statistically significant (P<.05). The presence of hyperopia at baseline was associated with a lower odds of developing early ARM. There was no relationship between iris pigmentation (Table 4) and intraocular pressure or perfusion pressure (data not shown) to the incidence or progression of ARM.

In Beaver Dam, eyes that had undergone cataract surgery were more likely to have progression of ARM and develop signs of late ARM than were phakic eyes. This finding is consistent with the 60% higher frequency of signs of early ARM in eyes that had undergone cataract surgery compared with phakic eyes in people 75 years of age or older found at the baseline Beaver Dam Eye Study examination.¹¹ In the National Health and Nutrition Examination Survey, a significant association was found between aphakia and age-related macular degeneration (odds ratio, 2.00; 95% CI, 1.44-2.78).¹⁰ Our finding is also consistent with a higher frequency of exudative macular degeneration found by histopathological study of eyes after implantation of an intraocular lens compared with phakic eyes.¹² However, no association was found between cataract surgery and ARM prevalence in the Rotterdam Study.⁴³

It is possible that some of the signs of ARM in eyes that had undergone cataract surgery may be related to photic retinal injuries (increased retinal pigmentation and RPE depigmentation). This association may also be a result of easier visualization and detection of ARM lesions after cataract surgery. It has also been hypothesized that inflammatory changes that may occur in eyes after cataract surgery may be related to the development of late ARM.¹² In our study, the relationship between cataract surgery, progression of ARM, and the incidence of late ARM remained significant after controlling for cigarette smoking, history of beer consumption, history of vitamin consumption, presence of hypertension, and perfusion pressure. It is possible that other common environmental exposures, not measured in the study, may explain the association. The relationship may also be the result of chance.

In Beaver Dam, there was no association between the nuclear or cortical cataract type and the incidence of early or late ARM or progression of ARM. Results from previous cross-sectional population-based studies that have evaluated this relationship have been inconsistent.^8,10,11 In Beaver Dam we previously reported a positive association between nuclear cataract and early (odds ratio, 1.96; 95% CI, 1.28-3.01) but not late ARM. This has been postulated to be caused by environmental factors, such as diet^44,45; light exposure^24,46,47; or genetic factors,^48,49 which may be related to both these conditions. On the other hand, it has been postulated that the presence of cataract may protect against the development of ARM and that cataract removal may result in increased risk.^50,51

In Beaver Dam, there was a protective effect (of borderline significance) of hyperopia at baseline on the incidence of early ARM, but no relationship to the incidence of late ARM or to the progression of ARM. In a large case-control study, eyes with exudative macular degeneration were more likely than eyes of control subjects to be hyperopic. This finding may be a result of study design, where the control subjects seen in ophthalmological practices without ARM or other conditions may be more likely to be seen because of a refractive error, myopia, than persons with exudative ARM who are referred because of decreased vision.²¹

No relationship was found in our study between iris color and the incidence or progression of ARM. The frequency of ARM has been reported to be higher in eyes with light iris color than in those with darker iris color in some^13-16 but not all^22-25 studies. One reason for our inability to find a relationship of iris color with late stages of the disease may be the low incidence of ARM. Ocular melanin, which is correlated to iris pigmentation, has been hypothesized to protect the retina from ARM both by light absorption and by protecting the retina from free radicals associated with photo-oxidation. Moreover, we did not assess changes in iris color in our study. Holz et al¹⁴ showed an increased risk of ARM in persons who reported having had light irises in youth (RR, 2.38; 95% CI, 1.2-4.7) and in those who reported having had dark irises in youth that changed to a light color by adulthood (RR, 9.37; 95% CI, 2.9-32.0) compared with persons with dark irises that did not change. They postulated that there may be a decrease in RPE melanin as well as a loss of the protective effect against factors associated with ARM. Sandberg et al¹⁵ showed that among eyes with exudative ARM, those with lighter irises had larger scars than eyes with dark irides. They hypothesized that inconsistencies in findings regarding the relationship of iris pigmentation and age-related macular degeneration may be explained, in part, by persons with lighter irises, because they were more symptomatic and were more likely to be referred and included as cases in case-control studies of iris pigmentation and ARM.

Many statistical tests were performed in evaluating the potential risk factors and end points. Although we cannot exclude the possibility of chance associations, there is biological rationale and consistency in our findings. The relationships need further study where longer follow-up and larger populations of older subjects are possible.

In summary, 5-year incidence data from this study show an increased risk of progression of ARM and incidence of late ARM in eyes that underwent cataract surgery. The relationship of cataract surgery to ARM needs further confirmation in other studies.

Accepted for publication December 5, 1997.

This research was supported by grant EYO6594 from the National Institutes of Health, Bethesda, Md (Drs R. Klein and B. E. K. Klein) and, in part, by a Senior Scientific Investigator Award from Research to Prevent Blindness, New York, NY (Dr R. Klein).

We thank the Beaver Dam Eye Study Scientific Advisory Board: Mary Frances Cotch, PhD, Mae Gordon, PhD, Lee Jampol, MD, Daniel Seigel, PhD, and Robert Wallace, MD, and our collaborators: George Davis, MD, Alan Ehrhardt, MD, Mari Palta, PhD, and Julie Mares-Perlman, for their contributions.

Reprints: Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, 610 N Walnut St, 460 WARF, Madison, WI 53705-2397.