Five-year incidence of age-related maculopathy

Five-Year Incidence of Age-Related Maculopathy The Visual Impairment Project Bickol N. Mukesh, PhD,1,2 Peter N. Dimitrov, BOrth,2 Sophia Leikin, MBBS, PhD,2 Jie J. Wang, MMed, PhD,3 Paul Mitchell, MD, PhD,3 Catherine A. McCarty, PhD, MPH,2,4 Hugh R. Taylor, AC, MD2 Purpose: To describe the 5-year incidence of age-related maculopathy (ARM) and the progression of the early stages of ARM lesions in Melbourne, Australia. Design: Population-based cohort study. Participants: A total of 3271 participants aged 40 years and older from Melbourne, Victoria, Australia. Main Outcome Measures: The 5-year incidence and progression of ARM lesions. Methods: Participants were recruited through a cluster random sampling from 9 urban clusters. Baseline examinations were conducted from 1992 through 1994, and the follow-up data were collected from 1997 through 1999. Presence of ARM lesions was graded from color stereo fundus photographs according to the International Classification and Grading System. Results: The overall cumulative 5-year incidence of age-related macular degeneration (AMD) was 0.49% (95% confidence interval [CI], 0.2– 0.8) and that of early ARM was 17.3% (95% CI, 8.7–26.0). The incidence of all ARM lesions increased with age (all P⬍0.001). The 5-year incidence of AMD was 0%, 0.69%, 1.7%, and 6.3% and that of early ARM was 13%, 22.7%, 29.8%, and 20% for participants aged 60 years and younger, aged 60 to 69 years, aged 70 to 79 years, and aged 80 years and older at baseline, respectively. People with soft indistinct drusen with pigmentary abnormalities had a 9.5 times (95% CI, 1.9 – 45.6) higher risk of developing AMD compared with people with soft drusen or pigmentary abnormalities. After adjusting for age, people with unilateral early ARM at baseline were 3 times (95% CI, 0.98 – 8.0) as likely to have early ARM in their second eye when compared with people with no ARM in both eyes. Conclusions: These data suggest that 1 in 3 persons aged 70 years or older will have ARM lesions over a 5-year period and that the disease will progress to a more severe form after the age of 80 years. The presence of soft indistinct drusen with pigmentary abnormalities significantly increased the risk for development of AMD. Ophthalmology 2004;111:1176 –1182 © 2004 by the American Academy of Ophthalmology.

Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in the elderly population

Originally received: January 6, 2003. Accepted: August 19, 2003. Manuscript no. 230032. 1 Peter MacCallum Cancer Centre, East Melbourne, Australia. 2 Centre for Eye Research Australia, The University of Melbourne, Melbourne, Australia. 3 Centre for Vision Research, Department of Ophthalmology, the University of Sydney, Westmead Hospital, Sydney, Australia. 4 Marshfield Clinic Research Foundation, Marshfield, Wisconsin. The Visual Impairment Project was funded in part by grants from the National Health and Medical Research Council, the Victorian Health Promotion Foundation, the estate of the late Dorothy Edols, the Ansell Ophthalmology Foundation, the Jack Brockhoff Foundation, the Eye Ear Nose and Throat Research Institute, and the Ian Potter Foundation, Australia. Dr McCarty was the recipient of the Wagstaff Research Fellowship in Ophthalmology from the Royal Victorian Eye and Ear Hospital, East Melbourne, Australia. Correspondence to Bickol Mukesh, PhD, Biostatistics and Bioinformatics Core, Marshfield Clinic Research Foundation, Marshfield, WI 54449. E-mail: [email protected].

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© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.

in economically developed countries.1–5 Age-related macular degeneration is a progressive disease, commencing with the less severe signs (early age-related maculopathy [ARM]) that ultimately can lead to the loss of central vision. Age-related macular degeneration is the most common cause of irreversible vision loss for people more than 60 years of age. Most population-based epidemiologic studies of AMD provide information on disease prevalence,6 –10 and only a few have reported the incidence of the disease.11–15 A few other prospective, randomized, controlled trials16,17 also have reported the incidence of the disease in a selected population. The purpose of this study was to describe the 5-year incidence and progression rates of ARM lesions in the Melbourne Visual Impairment Project (VIP), a population-based study of age-related eye diseases in Melbourne, Australia.

Materials and Methods The Melbourne VIP is a population-based study of eye disease in Melbourne residents aged 40 years and older. The study population ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.08.042

Mukesh et al 䡠 Age-Related Maculopathy Incidence is representative of the Victorian population and of Australia as a whole.18 A detailed methodology for the Melbourne VIP has been published previously.19 In brief, 9 pairs of census collector districts in Melbourne were selected randomly. A door-to-door household census was conducted to identify all eligible persons, defined as those aged 40 years or older in the calendar year of the examination who had lived at that address for at least 6 months. Baseline examination was conducted from 1992 to 1994. All eligible residents were invited to complete an interview and eye examination at locally established test sites. At the time of a household census, basic demographic details, including age, gender, education level, country of birth, language spoken at home, and use of eye care services, were collected. Interpreters were used for non–English-speaking participants, and home visits were conducted when participants were unable to attend the local examination center. The study protocol was approved by the Human Research and Ethics Committee of the Royal Victorian Eye and Ear Hospital. A 5-year follow-up examination was conducted from 1997 through 1999. All participants again were invited to attend the locally established test sites for the follow-up examinations.20 Similar procedures were used both at baseline and at the follow-up examinations, including a standardized eye examination and photography of the lens and fundus. Informed consent was obtained from each participant at the beginning of each examination. Reported deaths were confirmed through the Nation Death Index at the Australian Institute of Health and Welfare in Canberra. The fundus was examined on a slit lamp using a 90-diopter convex lens. The presence, nature, and size of the drusen; retinal pigmentary abnormalities; geographic atrophy; and exudative macular degeneration were recorded. Color stereo-photographs centered on both the optic disc and fovea of each eye (Diabetic Retinopathy Study fields 1 and 2) were taken using a Topcon EFT camera (Topcon Corporation, Tokyo, Japan) with Kodachrome 64 slide film (Kodak, Melbourne, Australia). The 35-mm slides were mounted in clear plastic sheets (Bardes Products, Milwaukee, WI) that permitted close apposition of stereo pairs for grading. Age-related maculopathy was graded according to the International Classification.21 A detailed grading system has been published previously.10 In brief, a clear plastic grid, supplied courtesy of Dr Ronald Klein, University of Wisconsin-Madison, was placed over 1 of the stereo pair of field 2 for each eye and was centered on the fovea. The grid included 3 concentric circles with radii of 500, 1500, and 3000 ␮m and had 4 radial lines dividing the photograph into subfields. Sets of 3 circles designated C0, C1, C2, I1, I2, O1, O2, corresponding to sizes 63, 125, and 250 ␮m in diameter, were used to estimate drusen size and the area involved with drusen or retinal pigmentary abnormalities. Photographs were considered gradable if field 2 was present and two thirds of the macular area (ⱖ5 subfields, including the area of the central circle) was visible. Age-related macular degeneration or late ARM was graded as either neovascular AMD or atrophic AMD. Neovascular AMD included serous or hemorrhagic detachment of the retinal pigment epithelium (RPE) or sensory retina; intraretinal, subretinal, subRPE hemorrhages, or a combination thereof; or subretinal fibrous scars. The size of neovascular lesions was assessed in area by projecting the number of optic disc areas occupied by the lesion. Even minimal fibrous lesions, including photocoagulation scars, were classified as neovascular AMD, regardless of the degree of surrounding atrophic RPE changes. Atrophic AMD was defined as a central areolar zone of RPE atrophy with visible choroidal vessels, at least 175 ␮m in diameter, in the absence of signs of neovascular AMD in the same eye. Early ARM was defined as the presence of soft distinct, soft indistinct, or reticular drusen or presence of any retinal pigmentary

abnormalities in the absence of signs of AMD lesions. Small hard drusen were not considered as early ARM. Maximum drusen size and area of involvement in the central, inner, and outer circles of the grid were also assessed. Retinal pigmentary abnormalities were defined to include hypopigmentation, a discrete area of retinal depigmentation without visible choroidal vessels, or hyperpigmentation, the presence of clumps of gray or black pigment within the retina. Comparison of early ARM incidence in the VIP with that in other population-based studies12,14 is difficult because of the different definitions used for early ARM. To make comparison with the Blue Mountain Eye Study (BMES)14 and the Beaver Dam Eye Study (BDES),12 we also defined early ARM in the absence of AMD lesions as (1) the presence of soft indistinct or reticular drusen in a field-2 fundus photograph or (2) the presence of any soft drusen and retinal pigmentary abnormalities in the same field. The incidence of an ARM lesion was defined as absence of this particular lesion within the grid area of either eye at baseline and presence of this lesion in at least 1 eye at follow-up. To assess the progression of early ARM features, ARM at baseline was stratified into 5 exclusive stages: (1) no drusen or only drusen ⱕ63 ␮m, (2) soft distinct drusen or pigmentary abnormalities, (3) soft indistinct drusen or reticular drusen or soft distinct drusen with pigmentary abnormalities, (4) soft indistinct drusen with pigmentary abnormalities or reticular drusen with pigmentary abnormalities, and (5) atrophic or neovascular AMD. Progression of early ARM was defined as an increase in 1 or more stages of ARM based on the worse eye. A total of 3271 participants were examined at baseline. Of these, 231(7%) had died before the 5-year follow-up examinations commenced, 446 (14%) had moved overseas or interstate or had declined to participate in the follow-up examination. The remaining 2594 (85% of eligible) participants attended the incidence study. Of this group, gradable fundus photographs of either at baseline or at follow-up were not available on 969 participants, because the fundus camera malfunctioned at the start of the examination in one of the largest test sites, causing us to miss most of the photographs in that test site. It was not possible to reexamine many of these participants. Two participants who had bilateral AMD and 5 participants who had unilateral AMD at baseline also were excluded from the incidence analysis. Hence, the remaining 1618 of the 2594 eligible participants (62%) with gradable fundus photographs were included in the study. Data collected at each interview were entered directly into a computer using a questionnaire programmed in Paradox (Borland International, Scotts Valley, CA). Clinical data were entered twice and checked for consistency. SAS software (SAS Institute, Cary, NC) was used for all statistical analysis. Ninety-five percent confidence intervals (CIs) around the incidence estimates were calculated according to Cochran22 to account for the cluster sampling design. Ninety-five percent CIs for the age-standardized incidence estimates were calculated according to Breslow and Day.23

Results The mean age of the participants at the baseline examination was 58.7 years (range, 40 –98 years; standard deviation, 11.4), and the mean age of the participants with gradable fundus photographs at follow-up was 61.2 years (range, 44 –91 years; standard deviation, 10). The mean duration between the baseline and follow-up examination was 4.5 years (range, 4 –7 years; standard deviation, 0.64). After adjusting for age, there was no statistically significant difference in the baseline prevalence of ARM lesions between participants with gradable and ungradable photos at the follow-up examination.

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Ophthalmology Volume 111, Number 6, June 2004 Table 1. Five-Year Incidence of Drusen >63 ␮m Age at Baseline (yrs) 40–49 50–59 60–69 70–79 80⫹ Age standardized rate

Gender

>250 ␮m

No. at Risk

% (95% Confidence Interval)

No. at Risk

% (95% Confidence Interval)

No. at Risk

176 214 217 278 169 181 65 63 6 12 633

23.3 (15.6–31.0) 29.9 (19.5–40.4) 28.1 (21.5–34.8) 35.3 (25.6–44.9) 43.2 (33.9–52.5) 41.4 (30.1–52.7) 41.5 (30.6–52.4) 44.4 (26.9–62.0) 0 41.7 (20.3–63.1) 31.9 (29.0–34.9)

186 230 244 306 200 211 86 73 10 16 726

2.7 (0.66–4.7) 3.0 (0.75–5.3) 5.3 (1.6–9.0) 6.9 (3.7–10.1) 14.0 (9.4–18.6) 12.8 (7.5–18.1) 17.4 (7.3–27.6) 8.2 (1.0–15.4) 40.0 (11.1–68.9) 18.7 (6.1–31.4) 9.0 (7.5–10.4)

188 232 248 311 208 223 93 79 12 18 749

1.1 (0–2.5) 0.43 (0–1.2) 0 0.32 (0–0.93) 1.9 (0.18–3.7) 3.6 (0.50–6.7) 8.6 (1.7–15.5) 5.1 (0.41–9.7) 8.3 (0–20.9) 5.6 (0–14.9) 2.0 (1.6–2.4)

748 1381

36.1 (32.8–39.4) 34.2 (26.8–41.6)

836 1562

7.7 (6.4–8.9) 8.3 (5.1–11.4)

863 1612

1.7 (1.4–2.1) 1.9 (1.2–2.5)

Male Female Male Female Male Female Male Female Male Female Male Female Combined

>125 ␮m

The 5-year incidence of drusen size ⱖ63 ␮m in diameter in either eye was 34.2% (95% CI, 26.8 – 41.6), drusen size ⱖ125 ␮m was 8.3% (95% CI, 5.1–11.4), and drusen size ⱖ250 ␮m was 1.9% (95% CI, 1.2–2.5), as shown in Table 1. During the 5-year period, persons aged 80 years or older at baseline were 14.9 times (95% CI, 5.1– 43.2) as likely to have drusen size ⱖ125 ␮m in diameter and 11 times (95% CI, 1.8 – 68.9) as likely to have drusen size ⱖ250 ␮m when compared with people aged 40 to 49 years at baseline. The 5-year incidence of soft distinct drusen was 6.1% (95% CI, 4.0 – 8.1) and soft indistinct drusen was 4.3% (95% CI, 2.3– 6.3) (Table 2). Persons aged 80 years and older at baseline were 5.8 times (95% CI, 1.5–22.6) as likely to have soft distinct drusen and 25.7 times (95% CI, 6.4 –98.0) as likely to have soft indistinct drusen when compared with people aged 40 to 49 years at baseline. The 5-year incidence of hypopigmentation was 12.9% (95% CI, 5.0 –20.8) and hyperpigmentation was 10.8% (95% CI, 4.2–17.5) (Table 3). The 5-year incidence of early ARM was 17.3% (95% CI, 8.7–26.0) (Table 4). Persons aged 80 years or older at baseline were 2.4 times (95% CI, 0.83– 6.9) as likely to have early ARM when compared with people aged 40 to 49 years at baseline. The 5-year incidence of AMD was 0.49% (95% CI, 0.2– 0.8) (Table 4). The 5-year incidence of AMD was 0%, 0.69%, 1.7%,

% (95% Confidence Interval)

and 6.3% for participants aged 60 years and younger, 60 through 69 years, 70 through 79 years, and 80 years and older at baseline, respectively. People aged 80 years and older at baseline were 31.3 times (95% CI, 5.1–194) as likely to have either atrophic or neovascular AMD when compared with people aged less than 70 years at baseline. No participants aged less than 60 years at baseline had AMD over a 5-year period (Fig 1). After adjusting for age, there was no gender difference in the incidence of any of the ARM lesions. Women aged 70 years and older had higher incidence of AMD when compared with men. However, this difference was small and was not statistically significant (3.6% vs. 1.1%). Incident AMD was strongly associated with the presence of baseline ARM stages (Fig 2). Of the 155 participants with early stage ARM at baseline, 26 (16.8%) participants progressed 1 or more ARM stages and 13 (8.4%) participants regressed 1 or more stages over a 5-year period. Presence of soft indistinct or reticular drusen with pigmentary abnormalities at baseline had a significantly increased risk of having AMD over the 5-year period compared with participants with soft drusen or pigmentary abnormalities at baseline (age-adjusted relative risk, 9.5; 95% CI, 1.9 – 45.6). The overall rate of progression of drusen size, an increase of 1 or more stages of drusen size, was 36.6% (95% CI, 30.6 – 42.7).

Table 2. Five-Year Incidence of Soft Distinct and Indistinct Drusen Distinct Drusen Age at Baseline (yrs) 40–49 50–59 60–69 70–79 80⫹ Age standardized rate

Gender Male Female Male Female Male Female Male Female Male Female Male Female Combined

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Indistinct Drusen

No. at risk

% (95% Confidence Interval)

No. at risk

% (95% Confidence Interval)

173 220 232 295 193 194 76 60 8 13 682

2.3 (0.65–4.0) 3.2 (0.63–5.7) 3.4 (0–6.9) 3.7 (1.3–6.1) 10.9 (7.5–14.3) 9.3 (4.7–13.9) 14.5 (4.8–24.1) 10.0 (3.1–16.9) 12.5 (0–30.5) 15.4 (1.6–29.1) 6.6 (5.6–7.6)

176 219 235 300 197 202 81 60 9 15 698

1.1 (0–2.5) 0.91 (0–2.2) 3.4 (1.5–5.3) 4.3 (1.6–7.1) 5.1 (1.5–8.7) 7.9 (3.9–11.9) 6.2 (1.0–11.3) 5.0 (0–10.5) 33.3 (18.2–48.4) 13.3 (0–28.9) 4.0 (3.3–4.7)

782 1464

5.6 (4.7–6.6) 6.1 (4.0–8.1)

796 1494

4.5 (3.6–5.5) 4.3 (2.3–6.3)

Mukesh et al 䡠 Age-Related Maculopathy Incidence Table 3. Five-Year Incidence of Pigmentary Abnormalities Hypopigmentation Age at Baseline (yrs)

Gender

40–49

Male Female Male Female Male Female Male Female Male Female Male

50–59 60–69 70–79 80⫹ Age standardized rate

Female Combined

Hyperpigmentation

No. at risk

% (95% Confidence Interval)

No. at risk

% (95% Confidence Interval)

184 229 245 307 202 220 92 76 12 18 735

8.2 (1.5–14.8) 8.7 (0–17.9) 9.4 (2.8–16.0) 10.7 (2.3–19.2) 18.3 (8.2–28.4) 19.5 (7.6–31.5) 21.7 (13.0–30.5) 13.2 (5.0–21.3) 8.3 (0–24.2) 22.2 (3.0–41.4) 13.1 (11.0–15.1)

183 226 239 298 230 218 88 76 12 17 725

7.7 (3.2–12.1) 8.0 (0–16.1) 8.4 (2.7–14.0) 7.0 (0.86–13.2) 14.8 (5.5–24.0) 15.6 (3.6–27.6) 17.0 (11.6–22.5) 17.1 (9.0–25.2) 8.3 (0–24.2) 23.5 (4.9–42.2) 11.0 (9.7–12.4)

850 1585

12.9 (10.0–15.8) 13.0 (5.1–20.9)

835 1560

10.8 (8.3–13.3) 10.9 (4.2–17.6)

After adjusting for age, persons with drusen size 125 to 249 ␮m were 12 times (95% CI, 2.9 – 48) as likely to progress to drusen size more than 250 ␮m when compared with participants with drusen size 63 to 124 ␮m (Fig 3). The overall rate of regression or disappearance of drusen in this study was 22.5% (95% CI, 15.2– 29.7). No participants with drusen size ⱖ125 ␮m disappeared, and no participants with drusen size ⱖ250 ␮m regressed over the 5-year period. Based on the BMES14 definition, the 5-year incidence of early ARM was 5.4% (95% CI, 2.8 – 8.0) (Table 4). Persons aged 80 years or older at baseline were 17.1 times (95% CI, 4.6 – 63.2) as likely to have early ARM when compared with people aged 40 to 49 years at baseline. After adjusting for age, people with unilateral early ARM at baseline were 3 times (95% CI, 0.92– 8.0) as likely to have early ARM in the second eye when compared with people with no ARM in either eye. People with bilateral early ARM at baseline were 5.3 times (95% CI, 1.0 –27.9) as likely to have AMD when compared with people with unilateral early ARM at baseline.

Discussion This study reports the 5-year incidence and progression of ARM lesions from the VIP, a population-based study conducted in Melbourne, Australia. The study population is representative of the Victorian population and of the population of Australia as a whole.18 Most studies have reported the incidence of AMD lesions, and only a few studies have reported the incidence of individual lesions. The 5-year incidence of AMD in this population was 0.49%, which was lower than that of the BDES12 (0.9%) and that of the BMES14 (1.1%), the latter another Australian study of an older population. The difference in the incidence of AMD from the 2 Australian populations could be the result of the age differences of the 2 study populations, because only 2% (32/1618) of the VIP participants with gradable fundus photographs were aged 80 years and older compared with 4.8% (111/2312) of BMES14 participants.

Table 4. Five-Year Incidence of Age-Related Macular Degeneration

Age at baseline 40–49 50–59 60–69 70–79 80⫹ Age standardized rate

Early Age-Related Maculopathy

Early Age-Related Maculopathy Using Blue Mountains Eye Study Definition

Gender

No. at risk

% (95% Confidence Interval)

No. at risk

Male Female Male Female Male Female Male Female Male Female Male

181 220 228 286 191 196 77 67 8 12 685

9.4 (3.7–15.1) 12.3 (1.4–23.1) 13.6 (6.1–21.1) 15.4 (6.5–24.3) 24.1 (12.7–35.5) 21.4 (8.7–34.2) 29.9 (16.7–43.0) 29.9 (13.0–46.7) 12.5 (0–33.6) 25.0 (0–57.9) 17.2 (14.9–19.6)

187 229 247 310 207 218 89 73 11 18 741

1.6 (0.36–2.8) 0.87 (0–2.1) 4.0 (1.5–6.6) 5.5 (2.0–9.0) 8.2 (3.4–13.0) 9.2 (4.5–13.8) 7.9 (0–15.8) 6.8 (2.2–11.5) 27.3 (9.8–44.8) 11.1 (0–32.6) 5.4 (4.6–6.2)

188 232 248 311 209 225 94 79 12 20 751

0 0 0 0 1.0 (0–2.4) 0.4 (0–1.3) 2.1 (0–4.6) 1.3 (0–3.8) 0 10.0 (0–25.1) 0.53 (0.43–0.64)

781 1466

17.4 (13.8–21.0) 17.3 (8.7–26.0)

848 1589

5.4 (4.3–6.5) 5.4 (2.8–8.0)

867 1618

0.46 (0.36–0.56) 0.49 (0.2–0.8)

Female Combined

% (95% Confidence Interval)

Age-Related Macular Degeneration No. at risk

% (95% Confidence Interval)

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Figure 1. Incidence of age-related maculopathy (ARM). AMD ⫽ agerelated macular degeneration.

The Melbourne VIP incidence of AMD, however, was similar to that reported from the Rotterdam Study.13 Klaver et al13 reported a 2-year cumulative incidence of 0.2% from a group of 2953 participants aged 55 years and older living in Rotterdam. Bressler et al11 reported a single occurrence of neovascular AMD (0.2%) over a 5-year period in the Waterman Study, a cohort study of 483 Maryland watermen. Sparrow et al15 reported an incidence of AMD per eye of 1.3% over 7 years from 82 survivors aged 84 to 97 years from Melton Mowbray Study. Because of the age differences, comparison between the VIP and Melton Mowbray Study15 is not possible, because our study population included participants aged 40 to 86 years. Our study may present an underestimate of the true incidence of AMD in the elderly population, so caution should be exercised when interpreting results. The incidence of AMD was strongly associated with age, which is consistent with other studies.12–14 Our 5-year incidence of early ARM was higher than that reported from the Waterman Study.11 The AMD-3 stage in the Waterman study was very similar to our early ARM definition. To allow more comparison with other studies,12,14 we also defined early ARM as the presence of soft

Figure 2. Progression of age-related maculopathy (ARM) stages: stage 1, soft distinct drusen or pigmentary abnormalities; stage 2, soft indistinct drusen or reticular drusen, or soft distinct drusen with pigmentary abnormalities; stage 3, soft indistinct drusen with pigmentary abnormalities or reticular drusen with pigmentary abnormalities; stage 4, neovascular or atrophic age-related macular degeneration.

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Figure 3. Progression of drusen size.

indistinct or reticular drusen or soft distinct drusen with pigmentary abnormalities. Using this definition, our 5-year incidence of early ARM was lower than those reported in the BMES14 and BDES.12 As explained in the other studies, the differences in the incidence of early ARM could be the result of the age differences between the study populations and of the differences in lesion classification. Comparison of early ARM features in the Rotterdam Study13 is not possible from the published report. The incidence of early ARM increases significantly with age. Similar trends have also been reported from other studies.12,14 The 5-year incidence of large drusen (ⱖ125 ␮m) was similar to that of the BDES.12 The incidence of soft indistinct drusen was similar to that of the BMES14 and was slightly lower than that of the BDES.12 A higher incidence of soft distinct drusen was found in our study compared with that of the BMES,14 whereas the BDES12 reported a similar incidence of soft distinct drusen. The incidence of hyperpigmentation and hypopigmentation in our study was higher than those of the BMES and BDES, but was consistent with our prevalence report.10 People aged 80 years and older had a higher risk of having soft distinct drusen, indistinct drusen, and pigmentary abnormalities. These results were consistent with those of other studies.12,14 A nonsignificant higher incidence of AMD was observed among women aged 70 years and older when compared with that of men. A similar finding also was reported in the BMES.14 Unlike other studies,12,14 we did not find any gender differences in the incidence of any of the early ARM lesions. People with signs of early ARM in 1 eye had higher risk for development of early ARM in their second eye. Previous studies12,14 have reported increased risk for development of AMD in the second eye of patients with AMD in their first eye. There were 5 participants in our study with AMD in 1 eye at baseline, among whom AMD developed in 1 patient (20%) in the fellow eye over 5 years. Our study also suggests that people with early ARM in both eyes had a 5-fold increased risk for the development of AMD. Our 5-year incidence of AMD among people with bilateral early ARM at baseline (23.8%) was higher than that of the BDES.12 Klein et al12 reported that 11.7% of persons in the

Mukesh et al 䡠 Age-Related Maculopathy Incidence BDES with signs of early ARM in both eyes at baseline went on to have AMD. We have not described the progression, regression, or disappearance of individual ARM lesions. However, we defined the early ARM lesions into 3 exclusive stages based on the severity of the disease. The Rotterdam Study13 used a similar method. Our overall 5-year progression rate of 1 or more stages of early ARM (16.8%) was lower than that of the Rotterdam Study. Klaver et al13 reported a 2-year cumulative progression rate of 21.5%. The incidence of AMD increased with the severity of baseline early ARM stages, increased from no risk for stages 0 and 1 to a 5-year risk of 12.5% and 24% for stages 2 and 3, respectively.13 This is comparable with the 2-year incidence of 0%, 2.4%, and 7.5% in Rotterdam for stages 0 and 1, 2, and 3, respectively. Like other studies, we also found that persons with soft indistinct or reticular drusen with pigmentary abnormalities had a higher risk of developing AMD lesions over a 5-year period. Age-related macular degeneration did not develop in eyes with only small hard drusen or soft distinct drusen or pigmentary abnormalities over this period. Incidence and progression of soft indistinct drusen was more frequent than that for regression or disappearance. The overall regression of 1 or more stages of early ARM or disappearance was 8.4% in our population. Other studies11,15 also have reported that soft drusen and pigmentary abnormalities may regress and disappear. In the Chesapeake Bay Waterman Study,11 larger drusen, ⬎63 ␮m in diameter, disappeared in 34% of participants, and in the Melton Mowbray study,15 20% of soft drusen regressed over a 7-year period. The high proportion of regression or disappearance of ARM lesions is unknown. Klein et al12 reported that 12.2% of soft indistinct drusen disappeared, with 26% a result of the appearance of more severe lesions. Strengths of this study include its sampling strategy, relatively high response rate, and standardized examination procedure at both baseline and follow-up examinations. This study also is representative of the Melbourne population aged 40 years and older. A limitation of the study, however, is that the baseline and follow-up photographs were assessed by different graders. Although there was a high degree of agreement between the baseline and follow-up graders (74%– 83% for various lesions), it is still possible that there could have been some grading inconsistencies in lesion classification. A significant number of missing and ungradable photographs (37.6%) also could have affected the true incidence rate of ARM in our population. Based on our data, we estimate that over the course of 5 years, some 39 864 people aged 40 years and older in Australia will have signs of AMD, and 439 322 people will have signs of early ARM, that is, development of soft indistinct or reticular drusen or soft distinct with pigmentary abnormalities. In conclusion, findings from this study indicate that 1 in 3 people aged 70 years or older will have ARM lesions over a 5-year period and that the disease will progress to a more severe form after 80 years of age. The presence of soft indistinct drusen with pigmentary abnormalities significantly increases the risk for development of AMD. Because AMD is the leading cause of severe visual impairment in a growing number of elderly people, preventive strategies are

required to reduce the visual disability resulting from this condition. Acknowledgments. The authors thank Dr Robyn Guymer, head of the macular degeneration unit at the Center for Eye Research Australia, for adjudication of fundus photographs.

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