Prevalence of Age-related Maculopathy in Australia

Prevalence of Age--related Maculopathy in Australia The Blue Mountains Eye Study Paul Mitchell, MD, 1 Wayne Smith, BMed, MPH, 2 Karin Attebo, MBBS, 1 ]ie ]in Wang, MBBS 1 Purpose: To examine the prevalence of age-related maculopathy (drusen and retinal pigmentary abnormalities) and end-stage age-related macular degeneration lesions (neovascular maculopathy or geographic atrophy) in a defined older Australian urban population. Subjects: All non institutionalized residents 49 years of age or older who were iden­ tified in a door-to-door census of two postcode areas west of Sydney, Australia. Methods: All participants received a detailed eye examination, including stereoscopic photographs of each macula. Two trained graders used the Wisconsin Age-related Maculopathy Grading System to assess the presence and severity of typical lesions. Results: A marked age-related increase in all typical lesions of age-related macu­ lopathy and macular degeneration was observed. End-stage age-related macular de­ generation was present in 1.9% of the population, rising from 0% among people younger than 55 years of age to 18.5% among those 85 years of age or older. Soft drusen were found in 13.3% of people, with distinct drusen more frequent than indistinct soft drusen. Retinal pigmentary abnormalities were found in 12.6% of people. For end-stage lesions and soft drusen, females had higher age-specific prevalence rates than males, whereas retinal pigmentary abnormalities were more frequent in males, although most of these differences were not significant. Prevalence rates for all lesions were lower (statistically significant for retinal pigmentary abnormalities and soft drusen) than for the United States Beaver Dam Eye Study which examined a similar population. Conclusions: These data provide detailed prevalence rates for most components of ARM in an Australian population and reinforce the Beaver Dam Eye Study findings for the relative age-specific frequency of age-related macular degeneration components. Ophthalmology 1995; 102: 1450-1460

Originally received: February 13, 1995. Revision accepted: May 19, 1995. 1 Department of Ophthalmology, University of Sydney, Westmead, Australia.

2 Department ofCommunity Medicine, University of Sydney, Westmead, Australia.

Supported by the Australian Department of Health, Housing and Com­ munity Services (RADGAC grant), the Save Sight Institute, University of Sydney, the Ophthalmic Research Institute of Australia and the West­ ern Sector Public Health Unit, NSW Australia. Reprint requests to Paul Mitchell, MD, FRACO, FRACS, Department of Ophthalmology, University of Sydney, Hawkesbury Rd, Westmead, NSW, Australia, 2145.

1450

Age-related maculopathy (ARM) is the leading cause of blindness in Australia 1 and in most western countries, including the United States. 2 Despite this, few population­ based studies have examined the prevalence ofthis disease. As our population ages, accurate prevalence data will be of use in planning future eyecare services, and will provide important baseline information to help plan intervention trials for treating and preventing ARM. Table 1 summarizes prevalence data from studies of ARM. The relatively wide variation in published preva­ lence rates can be attributed to several major factors. These include variation in the definition of ARM, differing age profile of study populations and differences in sampling

Mitchell et al · AMD in Australia Table 1. Age-related Maculopathy Prevalence Studies No. of Subjects

Reference

Site of Study

Vingerling, 11 1995

Rotterdam, The Netherlands

6251

Klein et al, 10 1992

Beaver Dam, CO

4771

Bressler et al, IZ

Chesapeake Bay

755 men only

1989

Kahn et al/ 1977

Framingham, MA (FES)

2631 Method

Klein and Klein, 6

USA(HANES)

3056 whites

Sydney, Australia

3283

Melton Mowbray, England Gisborn, New Zealand

484

Copenhagen, Denmark Guangzhou, China

946

1982 Mitchell, 9 1993

Gibson et aV

1985 Martinez et a!. 4 1982 Vinding, 13 1989 Wu, 5 1987 Jonasson and Thordarson, 8

Iceland

III

481

1019 925

1987

Age Groups (yrs)

55-64 65-74 75-84 85+ 43-54 55-64 65-74 75+ <50 50-59 60-69 70-79 80+ 52-64 65-74 74-85 45-64 65-74 50-64 65-74 75-84 85+ 76-84 85+ 65-74 75-84 85+ 60-69 70-80 50-59 60-69 70+ 43-52 53-62 63-72 73-82

ARM Prevalence(%) ARM Diagnostic Criteria WARMGS 14

WARMGS 14

Early refers to soft drusen

Drusen, pigment, exudative lesions, atrophy, vision Criteria similar to FES Self report only, ophthalmologist record check

Late

0.2 0.8 3.7 11.0 0.1 0.6 1.4 7.1

4.3 13.6

Early

Late or Early

8.4 13.8 18.0 29.7 4.0 6.0 13.0 26.0

FES criteria Criteria similar to FES Criteria similar to FES FES criteria Criteria similar to FES

~83

1.6 11.0 27.9 2.3 9.0 9.6 14.8 18.8 25.7 38.8 53.3 2.1 11.4 22.8 4.1 20.0 7.7 11.3 22.5 0.0 1.1

5.1 22.2 48.8

ARM = age-related maculopathy; WARMGS = Wisconsin age-related maculopathy grading system; FES = Framingham Eye Study.

and response rates for study populations. Among preva­ lence studies presented in Table I, Melton Mowbray, 3 New Zealand, 4 and Chinese5 studies defined ARM in terms offunduscopic findings (not photographic grading) with or without visual acuity loss, the HANES, 6 Fra­ mingham, 7 and Icelandic8 studies from funduscopic find­ ings only in the presence of visual acuity loss. The Australian 9 study used subject self-report retrospectively checked against ophthalmologists' records, using no par­ ticular diagnostic criteria. Until recently, no population­ based studies had determined prevalence rates for the in­ dividual lesions of ARM using a reproducible photo­

graphic grading system. Three of the reported studies in Beaver Dam, 10 Rotterdam, 11 and Chesapeake Bay 12 used a detailed grading system and similar definitions for the macular area to be graded from 35-mm slides, using a transparent grid. The Copenhagen report 13 also defined ARM from graded funduscopic photographs. In 1991, details of the Wisconsin Age-related Macu­ lopathy Grading System (WARMGS) 14 were published. Since then, a number of versions of the system have evolved, which have reduced grading time while preserv­ ing the essential characteristics. This simplified form has been used in a number of population-based studies of

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Volume 102, Number 10, October 1995

ARM, including the Rotterdam Study and three sites in Australia (Blue Mountains west of Sydney, Melbourne, and Nambour). The International ARM Study Group re­ cently proposed a grading approach, based on the Wis­ consin system. 15 The purpose of this report is to describe the prevalence ofa number ofthe typical lesions of ARM in an Australian population. The Blue Mountains Eye Study was set up to assess the prevalence and causes of visual impairment in a representative urban population and is the first Aus­ tralian study to assess ARM prevalence using standardized grading of fundus photographs.

Methods Study Population

the period after its completion. An additional 625 resi­ dents born before January 1, 1943, were identified living in eight nursing homes in the two postcode areas studied. However, the survey was limited to free-living residents; therefore, these people are not included in the current study. The population was examined over 2 years, from January 1992, to December 1993. Of the 4433 eligible people, 3654 (82.4%) participated in the eye study. The age-sex profile of the participating population is presented in Figure 1. A total of 501 people (11.3%) refused to par­ ticipate, of whom 353 (8.0%) permitted a brief interview about their vision and any history of eye disease, and 148 people (3.3%) refused both the examination and interview. When the study coordinator contacted eligible house­ holds to arrange clinic appointments, 68 people (1.5%) had died and 210 (4.8%) had moved from the area. Thus, a total of278 people (6.3%) identified in the census could not be examined. After excluding this group, a response rate of 87.9% was achieved. This compares favorably with other major eye surveys. 7 •10­ 12

Two adjoining urban postcode areas in the Blue Moun­ tains area, west of Sydney, Australia, were selected as the target population. This area has a relatively stable and homogeneous population which is representative of the Data Handling and Statistical Methods state ofNSW for income and socioeconomic status. 16 The population was chosen because it has an older structure Data were entered into computer'databases using auto­ compared with the age distribution of the state and is matic skips and range checks. The Statistical Analysis geographically well defined, enhancing the potential for System (SAS) 17 was used for tabulations and statistical publicity, community support, and a high response. analyses, including the chi-square statistic and logistic A door-to-door census was conducted by trained in­ regression analyses. In all logistic regression analyses, age terviewers from November to December 1991 for the first was entered as a 5-year categorical variable. All confidence postcode area and from March to April 1993 for the sec­ intervals (CI) presented are 95%. Inter-grader and intra­ ond postcode area. Each census was preceded by local grader reliability was assessed using the quadratic weighted publicity in newspapers and community radio and noti­ kappa statistic. 18 This statistic was used because many fication by mail to all dwellings in the postcode area. All comparisons had multiple possible grades and the qua­ noninstitutional, permanent residents born before January dratic weighted kappa statistic is equivalent to the intra­ 1, 1943, at the time of the census were eligible. This in­ class correlation coefficient. 19 Comparisons with the cluded persons 49 years of age or older, with no upper Beaver Dam Eye Study results were assessed using age age limit. Permanent residents were defined as people liv­ ing in the dwelling for more than 6 months of the year.. ranges 49 to 54, 55 to 64, 65 to 74, and 75 to 86 years in the Blue Mountains Eye Study to compare with age ranges Call-back visits to each house were made until contact 43 to 54, 55 to 64, 65 to 74, and 75 to 86 years, respec­ with a resident occurred, usually by door knock but also tively, in the Beaver Dam Eye Study. 10 Statistical signif­ by telephone, using an electronic directory sorted by street. icance was tested using the Mantel-Haenszel chi-square A final classification as "no contact" was made if at least statistic using Epi Info version 5.0 1a. five separate calls to the house at different times of the day and on different days of the week, and after three letters to the household, identified no eligible residents. 400 Nursing home residents were counted for comparison with the Australian National Census but were excluded from this analysis. A sample of 134 nursing home residents was 300 examined and will be the subject of a separate report. Interviewers administered a short doorstep question­ ~E 2oo naire to each eligible resident. This questionnaire included ::I c:: self-reported vision and hearing problems and any past diagnosis of cataract, glaucoma, macular degeneration, 100 diabetes, or hypertension. Last attendance to an ophthal­ mologist or optometrist also was recorded. A detailed in­ Q. formation sheet about the eye study was given or sent to 6 "' each eligible resident. ~ "' "'
I c.

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Mitchell et al · AMD in Australia

Procedures Eligible residents identified in the census were contacted by telephone after a letter from the principal investigator described the eye study and invited participation. The study coordinator answered any questions or concerns and made appointments for the eye examination. These were held at the local public hospital. This clinic was no further than 6 km from any dwelling in the study area, and transportation was arranged, if necessary. Residents who did not wish to have an eye examination were asked brief questions about their eye health. At the clinic visit, informed consent was obtained. A detailed questionnaire was administered covering demography, medications, family history, and medical history of systemic disorders. Problems with vision, history of eye diseases or eye treat­ ment, and ocular symptoms were included. A detailed eye examination was conducted, including subjective re­ fraction, using the Beaver Dam Eye Study modification of the Early Treatment Diabetic Retinopathy Study pro­ tocol with logMAR chart.2° After pupil dilatation with 1.0% tropicamide and I0% phenylephrine, stereoscopic 30° photographs were taken by a single photographer us­ ing the Zeiss FF3 fundus camera and Kodachrome 25 slide film (Kodak). Photographs were centered on the macula (Diabetic Retinopathy Study field 221 ), the optic disc (field I), and temporal to but including the fovea of each eye. The 35-mm slide transparencies were mounted in clear plastic sheets, allowing close apposition of stereo pairs. Of the 3654 participants, 3568 (97.6%) had retinal photographs of both eyes, 14 (0.4%) had photographs of one eye only, and 72 (2.0%) had no retinal photographs taken. For 39 frail, elderly people, the eye examination took place during a home visit, and photographs were not possible. For the other 33 people, photographs were not taken because of refusal (n = 12), frailty or confinement to a wheelchair (n = 9), camera malfunction (n = 5), dementia (n = 4), or poor pupil dilatation (n = 3). Thus, 3582 people (98%) had retinal photographs ofat least one eye. The W ARMGS, developed by Klein et al, 14 was used to grade individual lesions of ARM. Definitions of areas graded and individual lesions closely followed the WARMGS descriptions. Clear plastic grids, supplied by Dr. Ronald Klein and photographically duplicated in Sydney, were used to define subfields of the macular area. Dimensions of the duplicate grids were measured carefully and found to be accurate. A grid was placed over one of the stereo pair offield 2 for each eye and carefully centered on the fovea. The grid then was fixed in place on one 35­ mm transparency slide for each eye of all participants, allowing for accurate adjudication or regrading ofthe same area. The grid included three concentric circles, with radii of 500, 1500, and 3000 Jim, respectively, and had four radial lines dividing the outer and inner areas each into superior, nasal, inferior, and temporal subfields. Together with the zone bounded by the central circle, nine subfields thus were defined by the grid. This report includes only

lesions ofARM present within the grid, which corresponds to the retinal area in which the ganglion cell layer is more than one cell in thickness and is considered the limits of the anatomic macula. 22 Sets of three circles printed on clear plastic, designated C0 , C 1 , C2 , 11 , 12 , 0 1 , and 0 2 , corresponding to sizes 63, 125, 250, 175, 350, 325, 650 Jim, also were supplied by Dr. Ronald Klein. These were used by the grader to es­ timate drusen size and the area involved by drusen or retinal pigmentary abnormalities. In estimating lesion size or area, the grading circles were passed beneath one side of the slide sheet and viewed through the stereoviewer. The relation ofgrading circles to grid subfields is described and illustrated in W ARMGS. 14 All photographs were graded by one or both of two graders, who were trained for this purpose. One grader spent 3 weeks at the Fundus Photograph Reading Center, University of Wisconsin-Madison, under the supervision of Dr. Ronald Klein. Adjudication of queries and dis­ crepancies was provided by the chief investigator (PM). Intergrader and intragrader reliability was assessed on a random subsample of gradeable eyes. Eyes were consid­ ered gradeable if field 2 was present and two thirds of the macular area (~5 subfields, including the area of the cen­ tral circle) was visible (for grading of drusen) or if definite endstage AMD was evident, even with a poor view from media or other confounding lesions. Confounding ocular lesions, such as media opacity also prevented grading of retinal pigment abnormalities in 4 people and of drusen characteristics in 86.

Grading Definitions The protocol description of the W ARMGS was followed with minor modifications. Grades for each lesion were determined for three zones: the area of the central circle, the central and inner circles combined, and for the whole grid. Lesion characteristics were not determined for the eight subfields produced by diagonal lines crossing the grid. This is an area of departure from the W ARMGS protocol. 14 The grading form first assessed the presence ofa field 2 photograph and its photographic quality, judg­ ing the focus, field definition, and stereo effect. Grading for signs of ARM within the grid used a hierarchy, with end-stage lesions graded first, then retinal pigmentary ab­ normalities, and finally drusen. The form used was a modification of the shortened form of macular grading that evolved from W ARMGS.

Grading of Age-related Macular Degeneration The late stages of ARM were defined to include the end­ stage lesions of "neovascular" AMD ("wet AMD") or geographic atrophy ("dry AMD"). These late stages are now termed age-related macular degeneration using no­ menclature adopted by the International ARM Study Group. 15 Neovascular AMD lesions graded included se­ rous or hemorrhagic detachment of the retinal pigment epithelium (RPE) or sensory retina, the presence of sub­ retinal or sub-RPE hemorrhages, or subretinal fibrous scar

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Volume 102, Number 10, October 1995

tissue. The size of neovascular lesions in disc areas was assessed. Lesions with minimal signs ofsubretinal fibrosis and widespread surrounding atrophy arbitrarily were classified as neovascular, because this appearance indi­ cated the likelihood of a previous neovascular lesion. Photocoagulation scars in patients previously documented as having neovascular lesions also were classified as neo­ vascular. Geographic atrophy was defined as a discrete area of retinal depigmentation characterized by a sharp border and the presence of visible choroidal vessels and needed to be at least equal to circle I 1 in area.

Grading of Early Age-related Maculopathy Early ARM was defined as either ( 1) the presence of soft indistinct or reticular drusen within the grid, or (2) the presence of both soft distinct drusen within the grid and RPE abnormalities.

Grading of Early Age-related Maculopathy Components Retinal Pigmentary Abnormalities. "Hypopigmenta­ tion" was defined as a discrete area of retinal depigmen­ tation without visible choroidal vessels and having a gray­ ish-white color, often with adjacent pigment clumping. "Hyperpigmentation" was defined as the presence ofdef­ inite clumps of gray or black pigment beneath the retina. These terms currently are recommended by the Interna­ tional ARM Study Group. 15 Grades used to estimate geo­ graphic atrophy, hypopigmentation, and hyperpigmen­ tation followed the W ARMGS protocol. For the grading ofhyperpigmentation, five participants had this sign in both eyes, assessed as being caused by other processes than ARM, including retinal dystrophy (n = 2), myopic retinopathy (n = 2), and chorioretinitis (n = 1). In an additional 15 participants, other well-defined causes for hyperpigmentation were present in one eye only. For these participants, the fellow eye was used to estimate the presence of hyperpigmentation. Included were lesions of presumed toxoplasmic retinochoroiditis (3 eyes), previous retinal detachment (5 eyes), retinal vein occlusion (3 eyes), choroidal rupture (2 eyes), and laser scars from treated diabetic retinopathy (2 eyes). In an ad­ ditional 46 subjects, one or both eyes had small areas of isolated pigment clumping outside the central circle and within the grid, but without typical ARM lesions or any other obvious underlying cause. These lesions were in­ cluded in assessing hyperpigmentation because it was not possible to judge with any certainty whether the pigment had resulted from processes other than ARM. Grading of retinal pigmentary abnormalities was pos­ sible for 3505 participants (95.9%). This included 3582 participants with photographs of at least one eye but ex­ cluded the 68 people photographed with AMD in either eye, 4 with confounding ocular lesions, and 5 with other causes for hyperpigmentation in both eyes. Drusen. The grading of maximal drusen size was es­ timated for the largest drusen seen within the grid using

1454

the grading circles, which also were used to grade drusen area. The presence of soft drusen within the grid was graded as soft distinct drusen only, both soft distinct and soft indistinct drusen, or indistinct soft drusen only. Re­ ticular drusen, which formed ill-defined networks of broad, interlacing ribbons, also were graded if present within the grid and were included as soft indistinct drusen. For the grading of soft drusen, 86 people had confounding ocular lesions which were assessed as preventing an ac­ curate assessment of macular drusen in both eyes. In­ cluded were cataract and other media opacities (n = 47), diabetic retinopathy (n = 14), and myopic and other ret­ inopathies (n = 25). Soft drusen presence was not further assessed in people with signs of AMD (neovascular AMD or geographic atrophy) in either eye. Soft drusen status thus could be graded confidently in 3428 persons (93.8%) of those examined, including 3582 with photographs of at least one eye, and excluding 68 with AMD and 86 with confounding lesions.

Results Inter-grader and Intra-grader Agreement The photographs were assessed by two graders, who graded approximately half of the sample each. The quadratic weighted kappa statistic was calculated for inter-grader and intra-grader agreement on a random subset oversam­ pled for advanced lesions. Good agreement was found for presence of soft indistinct drusen and distinct drusen, area of hyperpigmentation and hypopigmentation and maxi­ mum drusen size (Table 2).

Age-related Macular Degeneration Age-related macular degeneration was seen in 71 partic­ ipants ( 1.94%; CI, 1.49%-2.39%), including 68 for whom gradeable photographs were available. In the other three people, clinical signs were used to make the diagnosis be­ cause they were not able to be photographed: two were seen in the home and a third had dementia. Among these, AMD was unilateral in 31 people (9 with geographic atro­ phy only and 22 with neovascular AMD). Bilateral in­ volvement by AMD was found in 40 people (56%). Among bilateral cases, geographic atrophy only in both eyes was found in 14 people (35%) and neovascular AMD was found in both eyes of 24 people (60%). Only two mixed cases were found (5%) in which geographic atrophy was present in one eye and neovascular AMD in the other. In the remaining 69 participants (95%) in whom only one lesion was present in one or both eyes, neovascular AMD was seen twice as commonly (67%) as pure geographic atrophy (33%). The prevalence of AMD was strongly age related. Rates were less than 1% for the population youn­ ger than 7 5 years of age, with a steep rise in prevalence from this age (chi-square for trend = 140; P < 0.001; Table 3). Consistently higher rates were found in women in each 10-year age group. However, this difference was not significant using logistic regression with an age-ad­

Mitchell et al · AMD in Australia Table 2. Inter-grader and Intra-grader Reliability for Various Components of Age-related Maculopathy

Variable Graded

Inter-grader Agreement Quadratic­ Weighted Kappa (n = 317 eyes) (95% Cl)

Intra-grader Agreeement Grader 1 Quadratic-weighted Kappa (n = 208 eyes) (95% Cl)

lntragrader Agreement Grader 2 Quadratic-weighted Kappa (n = 134 eyes) (95% Cl)

Soft drusen type Increased pigment area within grid Drusen within grid RPE depigmentation Drusen number Maximum drusen size

0.88 (0.84-0.93) 0.82 (0.72-0.93) 0.93 (0.92-0.95) 0.69 (0.51-0.87) 0.64 (0.53-0.74) 0.85 (0.81-0.90)

0.83 (0.76-0.90) 0.66 (0.50-0.83) 0.91 (0.86-0.96) 0.67 (0.49-0.84) 0.85 (0.77-0.92) 0.81 (0.73-0.88)

0.94 (0.88-0.99) 0.86 (0.68-1.00) 0.89 (0.81-0.97) 0.90 (0.78-1 .00) 0.54 (0.38-0.71) 0.89 (0.83-0.94)

CI

=

confidence interval; RPE

=

retinal pigment epithelium.

justed odds ratio of 1.58 (CI, 0.80%-2.36%). A sex differ­ ence also was found in the Beaver Dam Eye Study, but this difference was not significant with an age-adjusted relative risk of 1.27 (CI, 0.76%-2.12%) using the Mantel­ Haenszel chi-square statistic. Comparison with the rates for AMD found in the Beaver Dam Eye Study from 1988 to 1990 10 also are shown in Table 3. The Blue Mountains Eye Study found a lower prevalence of AMD in all age strata, but the age-adjusted relative risk ofO. 72 (CI, 0.51%1.03%; Mantel-Haenszel summary chi-square = 0.08) was not significant.

Early Age-related Maculopathy A total of 246 subjects (7.2% CI, 7.0%-7.4%) had signs of early ARM. The age- and sex-specific prevalence of early ARM rises steeply with age from 1.3% among those younger than 55 years to 28.0% among those 85 years of

age or older (chi-square for trend= 159; P < 0.001; Ta­ ble 4).

Components of Early Age-related Maculopathy Retinal Pigmentary Abnormalities. H ypopigmentation. Hypopigmentation was identified in 5.8% (CI, 5.0%-6.6%) of subjects (Table 5). As with all other components of ARM, the prevalence increased with age, but there was no significant differences between the sexes. Hyperpigmentation. Hyperpigmentation was found in 12.1% (CI, 11.0%-13.2%) of subjects, with the prevalence increasing dramatically with age (chi-square for trend = 87; P < 0.001; Table 5). The prevalence among men was consistently higher than that among women in each age group, with the age-adjusted relative risk for hyperpig­ mentation among men significantly higher than for women (odds ratio, 1.24; CI, 1.04%-1.48%). Overall, ret-

Table 3. Prevalence of Age-related Macular Degeneration (neovascular age-related maculopathy or geographic atrophy) by Age and Sex in the Blue Mountains Eye Study, Australia 1992-1993, versus the Beaver Dam Eye Study, 1988-1990 Females Blue Mountains Eye Study

Males Beaver Dam

Blue Mountains Eye Study

Total Beaver Dam

Blue Mountains Eye Study

Beaver Dam

Age (yrs)

%

No. at Risk

%

%

No. at Risk

%

%

No. at Risk

%

49-54 55-64 65-74 75-84 75-86

0.0 0.3 0.9 6.1 6.6

270 659 682 374 407

0.1* 0.5 1.5

0.0 0.0 0.6 4.3 4.3

215 513 527 279 299

0.0* 0.8 1.1

0.0 0.2 0.7 5.4 5.7

485 1172 1209 653 53

0.1* 0.6 1.4

Subtotal

85+

1.7

21.8

1985 87

1.0 12.5

1534 48

1.4 18.5

3519 135

1.6

Total

2.4

2072

1.3

1582

1.9

3654

7.8 1.9

5.6 1.2

7.1

*Age range, 43-54 years.

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Volume 102, Number 10, October 1995

Table 4. Prevalence of Early Age-related Maculopathy* by Age and Sex in the Blue Mountains Eye Study, after Excluding Patients with Late Age-related Maculopathy in Either Eye Females

Males

100

Total

90

D
80

D
70

•
60

•>==C2

Age (yrs)

No.

(%)

No.

(%)

No.

(%)

49-54 55-64 65-74 75-84 85+

264 639 654 323 47

(0.4) (2.2) (9.3) (16.1) (29.8)

211 503 506 246 35

(2.4) (3.2) (7.5) (14.6) (25.7)

475 1142 1160 569 82

(1.3)

40

(2.6) (8.5) (15.5) (28.0)

30

Total

1927

(7.4)

1501

(6.9)

3428

(7.2)

o/o50

20 10 0 49-54

55-64

65-74

75-84

85 +

age group

* Defined as either soft indistinct drusen within the area of the grid or soft distinct drusen within the area of the grid in the presence of any retinal pigment abnormality.

Figure 2. Distribution of maximum drusen size by age.

Mantei-Haenszel summary chi-square< 0.001) compared with those from the Beaver Dam Eye Study. Higher rates for retinal pigmentary abnormalities among men younger than 75 years of age also were found in the Beaver Dam Eye Study. Drusen. One or more drusen were found in 98.8% (CI, 98.4%-99.2%) of the population with gradeable pho­ tographs (3428 persons) 'and there were no significant age or sex differences in the overall frequency of drusen. Drusen Size. Within the grid, small "hard" or distinct drusen less than 631-Lm in diameter were the most frequent type found in all age groups. The largest drusen size in-

inal pigmentary abnormalities were found in 12.6% of participants (CI, 11.5%-13.7% ), after exclusions. As noted, the frequency of both components increased with age, whereas the prevalence of hypopigmentation was consis­ tently approximately half that of hyperpigmentation for each age group. The presence of any retinal pigmentary abnormality (either hyperpigmentation or hypopigmen­ tation) was less prevalent in subjects in the Blue Moun­ tains Eye Study than in those in the Beaver Dam Eye Study. Subjects from the Blue Mountains Eye Study had an age-adjusted relative risk of 0.82 (CI, 0.73%-0.92;

Table 5. Prevalence of Retinal Pigmentary Abnormalities by Age and Sex in the Blue Mountains Eye Study, after Excluding Patients with End-stage Age-related Maculopathy in Either Eye Pigmentary Abnormality Depigmentation

Increased pigment

Any pigmentary abnormality

1456

Age (yrs)

49-54 55-64 65-74 75-84 85+

Females

Males

Total

No.

(%)

No.

(%)

No.

(%)

264

(1.9) (3.0) (6.9) (8.6) (21.1)

214 508 519 257 38

(6.1) (2.8) (7.5) (7.8) (15.8)

478 1152 1186 594 95

(3.8) (2.8) (7.2) (8.2) (18.9)

(5.6) (5.3) (6.5) (12.6) (16.0) (38.6)

1536 214 508 519 257 38

(6.0) (8.4) (9.6) (15.0) (18.7) (36.8)

3505 478 1152 1186 594 95

(5.8) (6.7) (7.9) (13.7) (17.5) (37.9)

1536 214 508 519 257 38

(13.5) (10.3) (9.6) (15.8) (19.5) (39.5)

3505 478 1152 1186 594 95

(12.1) (7.5) (8.2) (14.2) (17.7) (38.9)

1536

(14.2)

3505

(12.6)

644 667 337 57

Total 49-54 55-64 65-74 75-84 85+

1969 264

Total 49-54 55-64 65-74 75-84 85+

1969 264 667 337 57

(11.0) (5.3) (7.1) (13.0) (16.3) (38.6)

Total

1969

(11.4)

644

667 337 57

644

Mitchell et al · AMD in Australia creased with age as shown in Figure 2. For " large" drusen, those greater than C 1 in diameter, the prevalence was less than 5% in participants younger than 65 years ofage, I 0% for participants 65 to 74 years of age, and almost 20% for those 75 years of age or older. Drusen larger than 250 J.Lm in diameter more frequently were found in women among participants 65 years of age or older, although this trend was not significant. The macular area involved by drusen was estimated by the graders using the grading circles, passed under one ofthe 35-mm slide stereo pair. Drusen covered more than 4.7% of the area within the grid in 6.2% of subjects and 0.2% of the area within the grid in 15.3% of subjects. The grid area occupied by drusen increased with age (chi­ square for trend = 229; P < 0.00 I). A proportionately larger area was involved in women at each age group from 55 years of age, with a significant age-adjusted relative risk of 1.34 (CI, 1.04%-1.88%) for women with lesions over 6.3% (;:::C2) of the grid, compared with men. Soft Drusen. Soft drusen were found within the area of the grid in 13.3% (CI, 12.2%-14.4%) of the population, after excluding participants with AMD in either eye. Dis­ tinct soft drusen were present in 10.4% (CI, 9.4%-11.4%), whereas indistinct soft drusen were present in 5.0% (CI, 4.3%-5.7%) ofthe population. The frequency ofboth types increased progressively with age. Soft indistinct as a pro­ portion of any soft drusen also increased with age (chi­ square for trend = 13.5; P < 0.00 I; Table 6). Overall, women had a higher prevalence of soft drusen than men, but this difference was greater for indistinct than for dis­ tinct soft drusen. The age-adjusted sex differences were not significant. Significantly fewer soft drusen were found

in this study than in the Beaver Dam Eye Study. Subjects in the Blue Mountains Eye Study had an age-adjusted relative risk of 0.57 (CI, 0.51 %-0.63%; Mantei-Haenszel summary chi-square < 0.00 I) for soft drusen in the grid compared with subjects from the Beaver Dam Eye Study.

Discussion Previous studies examining the prevalence of ARM un­ fortunately have used a variety of definitions, and have not consistently used standardized stereoscopic photo­ graphs of the macula. In many cases, a clinical definition only has been used. In addition, development of an in­ ternationally agreed grading system for ARM has not oc­ curred until recently. 15 In particular, careful definition of the macular area for grading has been used only in three recent studies. 10- 12 This makes comparison with earlier published prevalence rates difficult. The current study used a grader who received training from graders in the Beaver Dam Eye Study using W ARMGS. This enables a direct comparison with findings from the Beaver Dam Eye Study. The recently published Rotterdam Study 11 de­ parted from the W ARMGS protocol, using nonstereos­ copic Topcon 35° rather than stereoscopic Zeiss 30° pho­ tographs. This difference in protocol may contribute to the lower rates found for early ARM lesions in the Rot­ terdam Study. It is less likely to contribute to differences in AMD prevalence. Age-related macular degeneration was found in 1.9% of the Blue Mountains Eye Study population. Neovascular

Table 6. Prevalence of Soft Drusen by Age and Sex in the Worst Eye from Blue Mountains Eye Study, after Excluding Patients with End-stage Age-related Maculopathy in Either Eye Drusen Type Soft distinct

Soft indistinct

Males

Total

No.

(%)

No.

(%)

No.

(%)

49-54 55-64 65- 74 75­ 84 85+

264 639 654 323 47

(2.7) (5.3) (12.4) (19.5) (34.0)

211 503 506 246 35

(2.8) (6.2) (11.9) (19.1) (28.6)

475 1142 1160 569 82

(2.7) (5.7) (12 .2) (19.3) (31.7)

Total

1927 264 639 654 323 47

(10.4) (0) (1.3) (7.0) (13.0) (21.3)

1501 211 503 506 246 35

(10.3) (1.9) (1.6) (4.2) (10.2) (17.1)

3428 475 1142 1160 569 82

(10.4) (0.8) (1.4) (5.8) (11.8) (19.5)

49-54 55-64 65-74 75­ 84 85+

1927 264 639 654 323 47

(5.5) (2.7) (6.1) (17.0) (27.2) (46.8)

1501 211 503 506 246 35

(4.3) (4.7) (7 .0) (14.4) (24.4) (31.4)

3428 475 1142 1160 569 82

(5 .0) (3.6) (6.5) (15 .9) (26.0) (40.2)

23.5 21.6 36.4 45.3 48.5

Total

1927

(13.9)

1501

(12.6)

3428

(13 .3)

34.6

49-54 55-64 65-74 75-84 85+ Total

Any soft drusen

Females

Age (yrs)

% Soft Indistinct

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Volume 102, Number 10, October 1995

AMD was the most frequently found lesion (in either eye of 1.3% of people in this community), whereas geographic atrophy occurred in at least one eye in 0.7% of the pop­ ulation. This 2: 1 ratio for neovascular:atrophic AMD also was found in the Beaver Dam Eye Study and in the Rot­ terdam Study. Potential underestimation of the true fre­ quency is possible because a higher frequency of AMD (7. 7%) was found among the 39 frail elderly people who were not photographed but permitted a home visit. The slightly higher proportion of people 85 years of age or older who did not participate also may contribute to a small underestimate. A nonsignificant lower prevalence rate was found for AMD in the Blue Mountains Eye Study compared with the Beaver Dam Eye Study (Table 3) among per­ sons 86 years of age or younger ( 1.4% compared with 1.6%). This rate also is comparable to rates found in the Rotterdam Study 11 ( 1.2%), the Framingham Eye Study 7 (1.5%), and in the Chesapeake Bay Watermen Study 12 ( 1.8%) for this age group. There is a steep rise in prevalence from 7 5 years of age, which also was found in the Beaver Dam Eye Study and in other stud­ ies. The Rotterdam Study is the only other study to have included persons older than 86 years of age. The current study had no upper age limit and examined 133 people, a response of 75% among persons 85 to 97 years of age, and found an AMD prevalence of 18.5%. The Rotterdam Study had only a 32% response in 326 persons 85 to 98 years of age, and found AMD in 11.0%. These differences in response rates, together with differences in protocol, may have contributed to the lower rates for AMD found in the Rotterdam Study. In the current study, we found consistently lower age­ and sex-specific prevalence rates for both soft drusen and retinal pigmentary abnormalities in the Blue Mountains population compared with the Beaver Dam Eye Study population. The age-adjusted differences were significant for both soft drusen and retinal pigmentary abnormalities, and lower but not reaching statistical significance for AMD. Despite the different prevalence rates, a similar proportion of soft indistinct to total soft drusen was found in the two studies. In the Rotterdam Study, however, lower rates were found for both types of retinal pigmentary ab­ normalities. No comparisons with the Rotterdam Study are possible for the prevalence of soft drusen from the published data. A direct comparison with rates for early ARM found in the Beaver Dam Eye Study is not possible. In the Beaver Dam Eye Study, early ARM included patients with hard distinct drusen with any retinal pigment abnormalities. In grading photographs for the current study, a differen­ tiation between hard distinct and hard indistinct drusen was not made. Because hard drusen are an almost constant finding in people 50 years of age or older, we considered that the Beaver Dam definition might not adequately dis­ criminate the risk of progression to AMD. A number of diverse disease processes may cause retinal pigmentary abnormalities, and it is frequently not possible to distin­ guish these from ARM. In the absence of any large pop-

1458

ulation-based natural history study of early ARM using graded photographs, we considered that the inclusion of soft drusen in its definition more specifically may identify people at risk of progression. Obligatory retinal pigmen­ tary changes were included in the definition for people with only the milder and more frequent soft distinct drusen. The differences between results of the Beaver Dam Eye Study and those of the Blue Mountains Eye Study could be caused by systematic grading differences for the individual lesions or by a true difference between the two populations in the prevalence of ARM. In sup­ port of this latter hypothesis are (I) consistently lower rates in the Blue Mountains Eye Study for both early and late lesions, (2) similar ratios of indistinct to dis­ tinct soft drusen for both studies, (3) similar ratios of hypopigmentation to hyperpigmentation for both studies, and (4) Blue Mountains Eye Study graders and chief investigator (PM) were trained by Beaver Dam Eye Study personnel. An inter-center grading reliabil­ ity study of a representative sample of the macular photographs from Blue Mountains Eye Study and Beaver Dam Eye Study is planned to test the former hypothesis. Considering that both areas have a largely northern-European-derived white population, the lower prevalence rate for ARM lesions in the Austra­ lian study also lends little support to the hypothesis linking sunlight to ARMY The difference in latitude (37° in the Blue Mountains Eye Study compared with 45 o in the Beaver Dam Eye Study) would be expected to result in higher sunlight and ultraviolet light ex­ posure to the Australian population. If sunlight were etiologically associated with ARM, the prevalence of ARM would be expected to be higher in the Blue Mountains Eye Study, not in the Beaver Dam Eye Study as found, assuming other confounding variables are equally distributed. There were consistent though not significant sex dif­ ferences in prevalence for most lesions of ARM, with women having higher rates for AMD and soft indistinct drusen, but not retinal pigmentary abnormalities which were slightly more frequent in men. Women had a sig­ nificantly larger area of the macula involved by drusen than men, after adjusting for age, with an odds ratio of 1.34. A nonsignificant increased risk for late ARM and drusen area among women also was found in the Beaver Dam Eye Study, but not in the Rotterdam Study. Blind­ ness caused by ARM (defined as visual acuity less than 20/200 in both eyes, after refraction) occurred in 13 women and in only 2 men in the Blue Mountains Eye Study population. This is related to increased longevity of women, but also could reflect an increased risk for the disease among women. Many elderly women are living alone, compounding the disability from bilateral visual loss. Extrapolating the prevalence estimates from the Blue Mountains Eye Study to 1991 census data, 16 we cal­ culate that 72,220 Australians may have signs of late ARM in one or both eyes. With the major expected increase in the population living past 75 years of age,

Mitchell et al · AMD in Australia a substantial increase in the number of people with this disease is likely. Age-related maculopathy will remain the leading cause of severe visual loss in Australia. Al­ though some new medical therapies are being explored, laser treatment to well-defined choroidal new vessels is currently the only modality with proven benefit in ran­ domized controlled clinical trials. However, only a small proportion of patients with AMD are eligible for extra­ foveal laser treatment because the disease is treatable only for a relatively short time after the onset of symp­ toms?4 Recurrences occur in more than 50% of patients after treatment. Although treatment for subfoveal new vessels has been shown to have a small benefit over no treatment, treated patients mostly have poor vision. 25 Strategies are needed both to increase the proportion of treatable patients with neovascular AMD and to de­ crease the incidence of AMD. Increasing treatability will need to include improved public and professional education regarding the early symptoms and fast-track access to ophthalmic units for at-risk patients. Prom­ ising evidence that this may have some effect was re­ ported by the Macular Photocoagulation Study, 26 which found that presence of large drusen and focal hyper­ pigmentation increased the risk of clinical choroidal neovascularization developing in the fellow eye of pa­ tients with exudative maculopathy. The Beaver Dam Eye Study, the Rotterdam Study, and the current study have determined the prevalence ofthese lesions in de­ fined population samples. The results of follow-up studies are not yet available; therefore, the risk of pro­ gression of these lesions in a population is not known. Decreasing the incidence of AMD requires the identi­ fication of protective measures and risk factors for AMD through epidemiologic research and confirmed through intervention trials.

Conclusions The Blue Mountains Eye Study used a recently described and standardized grading system to provide detailed age­ and sex-specific prevalence estimates for the individual lesions of ARM in a representative, largely white Austra­ lian population. The methods used to assess ARM are comparable to the methods of the Beaver Dam Eye Study, which was conducted from 1987 to 1990. In the current Australian study, slightly lower rates were found for all early lesions of ARM. Acknowledgments. The authors thank Ronald Klein,

Barbara Klein, Matthew Davis, Yvonne Magli, and other staff of the Fundus Photograph Reading Center, Madison, Wisconsin, as well as Paula Kennedy and Mireille Moffitt for their valuable contributions.

References 1. Cooper RL. Blind registrations in Western Australia: a five­ year study. Aust N Z J Ophthalmol 1990;18:421-6.

2. Hyman L. Epidemiology ofAMD. In: Hampton GR, Nelsen PT, eds. Age-Related Macular Degeneration: Principles and Practices. New York: Raven Press, 1992;9-12. 3. Gibson JM, Rosenthal AR, Lavery J. A study of the prev­ alence of eye disease in the elderly in an English community. Trans Ophthalmol Soc UK 1985; 104:196-203. 4. Martinez GS, Campbell AJ, Reinken J, Allan BC. Prevalence of ocular disease in a population study of subjects 65 years old and older. Am J Ophthalmol 1982;94:181-9. 5. Wu LH. Study of aging macular degeneration in China. Jpn J Ophthalmol 1987;31:349-67. 6. Klein BE, Klein R. Cataracts and macular degeneration in older Americans. Arch Ophthalmol 1982;100:571­ 3. 7. Kahn HA, Leibowitz HM, Ganley JP, et a!. The Fra­ mingham Eye Study. I. Outline and major prevalence find­ ings. Am J Epidemioll977;106:17-32. 8. Jonasson F, Thordarson K. Prevalence of ocular disease and blindness in a rural area in the eastern region oflceland during 1980 through 1984. Acta Ophthalmol Suppl 1987;182:40~3.

9. Mitchell RA. Prevalence of age related macular degeneration in persons aged 50 years and over resident in Australia. J Epidemiol Community Health 1993;47:42-5. 10. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1992;99:933-43. 11. Vingerling JR, Dielemans I, Hofman A, eta!. The prevalence of age-related maculopathy in the Rotterdam Study. Oph­ thalmology 1995;102:205-10. 12. Bressler NM, Bressler SB, West SK, eta!. The grading and prevalence of macular degeneration in Chesapeake Bay wa­ termen. Arch Ophthalmol 1989;107:847-52. 13. Vinding T. Age-related macular degeneration. Macular changes, prevalence and sex ratio. An epidemiological study of 1000 aged individuals. Acta Ophthalmol (Copenh) 1989;67:609-16. 14. Klein R, Davis MD, Magli YL, eta!. The Wisconsin age­ related maculopathy grading system. Ophthalmology 1991;98:1128-34. 15. The International ARM Epidemiological Study Group. An international classification and grading system for age-re­ lated maculopathy and age-related macular degeneration. Surv Ophthalmol 1995;39:367-74. 16. Australian Bureau of Statistics. 1991 census of population and housing. Canberra: Australian Government Publishing Service, 1992. 17. SAS Institute, SAS/STAT Users Guide, Version 6, 4th ed. Cary, NC: SAS Institute Inc., 1989. 18. Fleiss JL. Statistical Methods for Rates and Proportions, 2nd ed. New York: Wiley, 1981. 19. Streiner DL, Norman GR. Reliability. In: Health Mea­ surement Scales: A Pactical Guide to Their Development and Use. New York: Oxford University Press, 1989;Chapter 8. 20. The Beaver Dam Eye Study: Manual of Operations. Mad­ ison, Department of Ophthalmology, University of Wis­ consin School of Medicine, 1991. Available from: National Technical Information Service (Accession No. PB91­ 149823/AS). 1991. 21. ETDRS Coordinating Center University of Maryland, De­ partment of Epidemiology and Preventive Medicine. Early Treatment Diabetic Retinopathy Study (ETDRS). Manual of Operation. In: Springfield, VA 22161: National Technical Information Service. (Accession Number #PB85223006). 1980.

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22. Hogan MJ , Alvarado JA, Weddell JE. Histology of the Hu­ man Eye; An Atlas and Textbook. Philadelphia: WB Saun­ ders, 1971. 23 . Cruickshanks KJ, Klein R, Klein BE. Sunlight and age­ related macular degeneration. The Beaver Dam Eye Study. Arch Ophthalmol 1993;111 :514-8. 24. Macular Photocoagulation Study Group. Argon laser photo­ coagulation for senile macular degeneration. Results of a ran­ domized clinical trial. Arch Ophthalmol 1982; I 00:912-8.

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25. Macular Photocoagulation Study Group. Laser photoco­ agulation of subfoveal neovascular lesions in age-related macular degeneration. Results ofa randomized clinical trial [see comments]. Arch Ophthalmol 1991; 109:1220-31. 26. Bressler SB, Maguire MG, Bressler NM, Fine SL. Relation­ ship of drusen and abnormalities of the retinal pigment ep­ ithelium to the prognosis of neovascular macular degener­ ation. The Macular Photocoagulation Study Group. Arch Ophthalmol 1990; 108: 1442-7.