Patients and methods

The second eyes of unilaterally affected patients with exudative (neovascular) AMD were followed up in our clinic for the last 10 years (from 1988 to 1997), and were carefully examined by one of the two authors who are experienced specialists (MU or KT). Routine ophthalmological examination, direct and indirect binocular ophthalmoscopy, slit lamp biomicroscopy with a contact lens, fluorescein fundus angiography, and indocyanine green (ICG) angiography were performed in all patients. Macular manifestations were retrospectively reviewed from patient records. The patients were regularly followed up at 1–3 month intervals, and whenever a patient presented with any new symptom.

Using procedures described above, it was confirmed that the second eye did not show any evidence of CNV at the first examination. During the follow up period development of CNV in the second eye was confirmed by fluorescein angiography and/or ICG angiography, when findings in the macula showed any sign of CNV (haemorrhage, exudation, or elevation).

INCLUSION CRITERIA FOR EXUDATIVE AMD IN THIS SERIES

Patients were more than 50 years of age. The macula showed serous and/or haemorrhagic retinal detachment, with or without serous and/or haemorrhagic retinal pigment epithelial detachments (PEDs), subretinal fibrinous exudations with subretinal fibrovascular membrane, or subretinal fibrous scarring in the macula. Fluorescein and/or ICG angiography clearly demonstrated evidence of CNV, both classic and occult types, in the macula. CNV was confirmed as the following standard with fluorescein angiography:

Classic CNV—

In the early phase, lacy hyperfluorescence with a well demarcated margin, and in the late phase progressive leakage from them.

Occult CNV—

Ill defined early hyperfluorescence and late leakage. On ICG angiography, early network of hyperfluorescence and late subretinal staining were demonstrated.

 Exclusion criteria were patients with other causes of exudative maculopathy such as angioid streaks, high myopia, presumed ocular histoplasmosis syndrome, idiopathic polypoidal choroidal vasculopathy, and central serous chorioretinopathy, follow up period less than 1 year, lack of regular follow up, and incomplete patient records.

Macular manifestations, such as hard drusen, soft drusen, serous and haemorrhagic PED, and retinal pigment epithelium (RPE) abnormality (pigmentary degeneration, RPE atrophy and degeneration) were defined according to the international classification and grading22 as follows. Hard drusen are small, round, sharply margined, and yellowish white deposits at the level of RPE. Soft drusen are large, fuzzy bordered, solid, thick in appearance, and yellowish grey deposits at the deep retina. Some are confluent and dome-shaped.

Pigment epithelial detachment (PED)—Serous PED is round or oval, yellow or yellow brown, sharply demarcated mound of elevated RPE, without evidence of CNV on angiography. Haemorrhagic PED contains bleeding from CNV, showing a hyphaema-like horizontal line and a dark elevated mound under the retina.

RPE abnormalities—RPE at the macula shows brownish degeneration, or an atrophic appearance, or a small area of mottled pigmentation, hyperpigmentation, or hypopigmentation.

Results

During the last 10 years, 170 patients with unilateral exudative AMD met the criteria described above. The average follow up period was 42 months, ranging from 12 to 108 months. There were 110 men (65%) and 60 women (35%). The average age of these patients was 67 years of age, ranging from 44 to 87, at the first examination. All patients were Japanese.

Macular lesions of the affected eyes of 170 patients at the first examination were as follows. The most frequently seen finding in the involved eyes was serous neurosensory retinal detachment with a small nodular yellowish-white lesion (fibrovascular membrane) at the macula associated with tiny subretinal haemorrhage (Fig 1). These findings were seen in 81 eyes (48%).

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Figure 1

Fundus photograph of serous retinal detachment associated with a small nodular yellowish-white lesion (fibrovascular membrane), tiny haemorrhage, and lipid deposits. A typical macular manifestation in the early stage of exudative age related macular degeneration.

Secondly, large dense subretinal and/or subpigment epithelial haemorrhages were seen at the macula in 36 eyes (21%) (Fig 2). Massive subretinal fibrinous exudation with subretinal fibrovascular membrane, subretinal haemorrhage and serous retinal detachment, which is a typical manifestation of exudative AMD and described as a disciform lesion, were seen in 30 eyes (18%) (Fig 3). Subretinal fibrous scarring was seen in two eyes (1%) (Fig 4). Large serous and/or haemorrhagic PEDs associated with serous retinal detachment were seen in 22 eyes (13%) (Fig 5A–D).

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Figure 2

Fundus photograph of subretinal and subpigment epithelial haemorrhage (haemorrhagic pigment epithelial detachment, PED). A typical manifestation of exudative AMD.

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Figure 3

Fundus photograph of subretinal fibrinous exudation and fibrovascular membrane with serous retinal detachment, subretinal haemorrhage, and lipid deposits. This lesion is a so called disciform lesion, and one of the typical manifestations of exudative AMD.

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Figure 4

Fundus photograph of subretinal fibrous scar. This lesion is the end stage of exudative AMD.

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Figure 5

Exudative AMD derived from predisposing a serous PED. (A) Fundus photograph of a large serous PED accompanied by a small fibrovascular membrane (arrow) and lipid deposits. (B) Fundus photograph of haemorrhagic PED. A large serous PED contained bleeding at the bottom of the PED. (C) Fundus photograph of a large serous PED associated with serous retinal detachment and lipid deposits. (D) Fundus photograph of serous PED (large arrow) associated with subretinal exudation, serous retinal detachment, and subretinal fibrovascular membrane (small arrow).

Macular lesions of the second eye at the first examination (baseline) are shown in Table 1. The most frequently seen finding was RPE abnormalities in 52 eyes (30%) (Fig 6). Soft drusens were seen in only 11 eyes (6%) (Figs 7, 8, 9). Serous PEDs were seen in eight (5%) (Fig10). Half of the eyes (49%) showed no abnormality in the macula.

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Figure 6

Fundus photograph of degeneration of the retinal pigment epithelium (RPE) at the macula. This is one of the predisposing findings for developing choroidal neovascularisation (CNV).

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Figure 7

Fundus photograph of hard drusen, seen in elderly patients.

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Figure 8

Fundus photograph of soft drusen.

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Figure 9

Fundus photograph of large confluent soft drusen. This is a typical predisposing finding of developing CNV. In the elderly, particularly in white people with AMD, they are very prevalent, but in Japanese they are not so prevalent.

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Figure 10

Fundus photograph of a serous PED. This lesion is the commonest predisposing finding for developing CNV in Japanese. CNV develops inside or beside serous PED.

During the follow up period, CNV, newly developed in the second eye, was seen in 12 (7%) of 170 eyes, at an average of 30.3 months (12–59 months), after the first examination (Table 2). The patient age in these 12 cases was 70.8 years on average, ranging from 58 to 82. There were eight men and four women. The cumulative incidence of the development of CNVs was estimated using the Kaplan–Meier life table analysis. Cumulative incidence of developing CNV in the second eye was 0.6% at 1 year, 5.6% at 3 years, and 12.3% at 5 years (Fig 11).

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Figure 11

Kaplan–Meier survival curve for development of CNV in the second eye in unilateral exudative AMD (170 eyes).

Macular lesions from which CNV developed in the second eye of these 12 patients are shown in Table 3. In these 12 eyes, the most frequently seen predisposing manifestation was serous PED, which was seen in seven eyes (58%) (Fig 10). The size of PED in which CNV developed varied from 0.3 disc diameter (DD) to 1.5 DD, and was 0.6 DD on average. Of these seven eyes with serous PED it was pre-existing at the first examination in one eye. Among the other six eyes, serous PED developed from soft drusen in one eye, from hard drusen in two eyes, from RPE abnormalities in two eyes, and there was no macular abnormality at the first examination in one eye. These serous PEDs in which CNV developed spontaneously and suddenly appeared from various manifestations at the macula. Thereafter, CNV usually developed in a short period within or adjacent to the serous PEDs.

CNV developed from soft drusen in two eyes (18%) (Fig 8). In these two eyes, many large soft drusen were present at the first examination (Fig9); thereafter CNV developed within these lesions. CNV developed from RPE abnormalities in three eyes (25%) (Fig 6), (Table3).

After developing CNV, most eyes showed serous detachment of the neurosensory retina in the macula with a small fibrovascular membrane (Fig 1), and the remaining eyes had subretinal haemorrhage (Fig 2), or serous PED associated with serous retinal detachment and fibrovascular membrane (Fig 5A–D).

Discussion

The incidence of CNV in the second eye of white patients with unilateral exudative AMD was reported to be high. Many studies reported the incidence of developing CNV in the second eye were 12–15% per year,10 5–10% per year,7 3–15% per year13; the cumulative incidence of developing CNV was estimated as 13% at 1 year, 22% at 2 years, and 29% at 3 years11; 3% at 1 year, 10% at 2 years, and 20% at 3 years13; 4% at 1 year, 10% at 2 years, and 17% at 3 years.12 These were retrospective studies.

Prospective studies estimated the incidence was 6% per year,15 and 8.8% each year.16 Moreover, the MPS report23 mentioned four independent risk factors for developing CNV—focal hyperpigmentation, large drusen, multiple drusen, and systemic hypertension. CNV developed in 35% within 5 years with the cumulative incidence of 10%, 28%, and 42% at 1, 3, and 5 years, respectively. A recent population based study (Beaver Dam Eye Study17) reported 0.6% in intact eyes for a 5 year period, a marked increase in patients more than 75 years in age, and a high risk in soft drusen and pigmentary abnormalities at the macula.

Yuzawa et al 18 reported that CNV developed in the second eye in 19 (10.4%) of 183 Japanese patients with unilateral exudative AMD during a 52 months follow up period, and estimated the cumulative incidence of CNV was 3% at 1 year, 8% at 3 years, and 12% at 5 years. Our results showed the incidence of CNV in the second eye was almost consistent with that reported by Yuzawaet al, and demonstrated a relatively low incidence of CNV developing in Japanese patients compared with white people.

The present study was performed retrospectively using patient records. Patients did not return for regular check ups and incomplete records were excluded. Incidence of developing CNV in the fellow eye of unilaterally involved AMD was estimated on the basis of referral to an ophthalmic clinic. Thus, there was some bias and limitations of evidence, but the low incidence of developing CNV in the fellow eye of unilateral exudative AMD in Japanese patients was distinct. These results suggested the low prevalence of exudative AMD in Japanese people.

Regarding predisposing findings in the macula for the development of CNV in AMD patients, many reports1-4 7-17 described the marked prevalence of soft drusen in elderly white people, indicated that soft drusen showed the highest risk for developing CNV, and that large and confluent soft drusen showed a particularly high risk. In Japanese patients, soft drusen were not as prevalent (6%) as in white people, and not a high risk (18%) for developing CNV compared with white people. These results were consistent with reports18 19 on pigmented and Asian people. Formation of soft drusen derives from age related alternations in the RPE and Bruch's membrane. However, the reasons why soft drusen were not as prevalent in these populations as that in white people are not clear.

In white people, reports on risk factors for developing CNV also indicated that focal hyperpigmentation of the RPE was a high risk.2-4 Our result indicated that incidence of CNV from RPE abnormalities was 25% and at the second rank of predisposing findings in Japanese patients.

Serous PED was the highest risk (58%) for developing CNV in Japanese patients, and CNV developed from any size of serous PED. Gass1 and Teeters and Bird8 described serous PED in the elderly as a predisposing finding for developing CNV. Meredith et al 24 reported that in 50 eyes with serous PED, 14 eyes (28%) developed CNV at an average of 22 months of follow up, and there was greater risk in eyes with serous PED larger than 1.0 disc diameters and in patients older than 55 years. Braunstein and Gass,25 Casswellet al,26 Elmanet al,13 and Polineret al 27 confirmed a similar risk in serous PED. Maguire28 described the incidence of CNV in patients presenting with only serous PED was estimated to be approximately 40%–50% at 3 years.

Yuzawa et al 18 reported that serous PED showed a great risk for developing CNV (30%) and a much higher risk than that of soft drusen (4.8%) in Japanese. Limet al 19 recently reported on symptomatic patients with AMD and found a high percentage of serous PED in Asian patients.

In Japanese and Asian patients with unilateral exudative AMD the incidence of developing CNV in the second eye was relatively low. The predisposing finding indicating the greatest risk for developing CNV was serous PED, while soft drusen were not as prevalent and not as high risk compared with that in white people. Serous PED is caused by accumulation of fluid under the RPE, and is derived from damage to fluid movement from the subretinal space through Bruch's membrane. There may be a reduction in adhesive force between the basement membrane and plasma membrane of the RPE and also impairment of electrical conductivity as a result of hydrophobic lipid metabolism in Bruch's membrane.29 However, the reason why serous PED is prevalent and soft drusen is not prevalent in elderly Japanese and other Asian patients with AMD is not clear.

In AMD, it was pointed that there were many differences in epidemiology between white people and Asians, as well as in black people.1-6 17 19 In Asian people, AMD is not as prevalent as in white people, AMD in Asian patients was more prevalent in men than in women. In relation to serous PED, central serous chorioretinopathy is prevalent in Asian people compared with in white people. To confirm these differences, further population based prospective studies are essential.

Development of choroidal neovascularisation in exudative AMD may be associated with many factors such as food, smoking, life style, environment, and genetic background.1-4 Although the reason for differences in the incidence of new CNV and predisposing findings in AMD between white people and Japanese is unclear, it seems that the difference between these two populations above may be mostly genetic.

In conclusion, the incidence of developing CNV in the second eye of unilateral exudative AMD was lower in Japanese patients than in white people, showing 12% at 5 years on a cumulative life table analysis. Regarding predisposing findings for exudative AMD, there were some differences between the two populations. Serous PED was the highest risk factor in Japanese patients among findings predisposing towards the development of CNV. Soft drusen were not as prevalent in Japanese AMD patients and were not a high risk for development of CNV.