PATIENTS AND METHODS

The patients included in this report were attendees at a specialist macular clinic between 1997 and 1999. Subjects attending this clinic routinely undergo visual function assessments, biomicroscopic examination of the fundus, and bilateral stereo pair colour photography. Fluorescein angiography is also performed if clinically indicated. General examination findings and clinical history are also recorded for each patient. The latter includes information on cardiovascular status (history of treated or untreated hypertension, angina, myocardial infarction, or peripheral vascular insufficiency), diabetes, any other serious disorder, medications, and smoking habit including pack years of cigarettes smoked. A standard photographic protocol for fundus photography has been in use and consists of 35° colour stereo pair photography of each macula recorded on 35 mm transparencies using the Topcon TRC 50 IX fundus camera. Digital fluorescein angiography is undertaken if clinically indicated with early frames obtained on the eye presenting with CNV and late frames from both eyes.

The photographic database was searched for cases of unilateral neovascular AMD. Inclusion criteria were a full complement of stereo angiographic frames on the eye with CNV, late angiographic frames of the fellow eye and gradable stereo pair colour fundus photographs of the fellow eye. Mounted 35 mm stereo pair colour slides of the fellow eye were sent to the grading centre of the Rotterdam Eye Study Centre.

Each pair of slides from fellow eyes was graded by two graders independently and any discrepancies were resolved by the adjudicator, an experienced ophthalmologist. The graders were unaware of the aims of the study and did not have access to colour slides or angiographic frames of the eye with the CNV. Following grading, the eye was then assigned a severity stage based on the features (Table 1) that were present within the central 6000 μm zone (radius 3000 μm) only, as described in a previous report.³

Grading of the digital fluorescein angiograms was undertaken by two independent graders in the Belfast Angiogram Reading Centre. CNV was classified by the type of fluorescein leakage based on guidelines from the MPS and other studies.^11,12 MPS guidelines define classic CNV as early distinct hyperfluorescence with well demarcated boundaries, which is seen during the early transit phase of the angiogram with leakage in the late phase that obscures the boundaries. Occult CNV is defined as hyperfluorescence which is not well delineated on angiography and the two types of occult CNV which are recognised as distinct entities are fibrovascular RPE detachments and late phase leakage of undetermined source.

The total area of the lesion was defined as the area covered by the CNV (classic or occult) plus blocked fluorescence. This blocked fluorescence usually corresponded to blood or when blood was not detected on the colour photographs presumably to some other component such as fibrous tissue and pigment. As fibrous tissue can be hyperfluorescent, when this feature was present and contiguous to the margins of the CNV, this was included in the measurements of the total area of the lesion. The total area of the lesion was measured on one of a suitable stereo pair of angiographic frames using standard templates to overlay the area of interest displayed on the computer screen. The independent contributions from each parameter—that is, classic or occult CNV, blocked fluorescence, haemorrhage and fibrosis were also ascertained by sequentially overlaying specific lesion features with templates of circles of increasing area (these circles were 1.0, 2.0, 3.0, 3.5, 4.0, 6.0, 9.0, 12.0, and 16.0 optic disc areas). Classic leakage was measured using angiographic frames taken before 30 seconds had elapsed after injection of the dye and occult leakage was measured on frames taken between 2 and 10 minutes after injection. Where fluorescein leakage accounted for all of the lesion these eyes were classified as 100% classic or occult depending upon the characteristics of the leakage.

Statistical analysis

Data were analysed using the statistical package for social sciences (spss version 11). A Kruskall-Wallis one way ANOVA was used to explore the relation between severity of ARM stage in the fellow eye and the subtypes of CNV in the first eye. For the purposes of analysis we assumed that each increasing stage of ARM represented a one point rise in severity and we assigned severity scores on a scale of 0 to 5 which were equivalent to ARM stages 0, 1A, 1B, 2A, 2B, and 3 respectively.

Also, for the purposes of analysis we subdivided the CNV into four ordered categories—occult (100% of the lesion was comprised of occult only leakage), minimally classic (1–49% of lesion is classic), predominantly classic (50–99% of the lesion is classic), and classic with no occult (100% of lesion is classic). Several studies have suggested that classic (wholly or predominantly) behave differently from occult (minimally classic or occult only) CNV.^11–13 We therefore subdivided the cohort into group 1, consisting of patients with classic or predominantly classic CNV, and group 2, consisting of those with minimally classic or occult. A further analysis was then carried out using a logistic regression model to identify the relation between ARM severity in the fellow eye and the dichotomised variable (classic or occult). Other independent variables that were entered were total area of lesion, age of subject, sex, cardiovascular status, and number of pack years smoked.

RESULTS

Of the 237 cases scrutinised in the database, 67 fulfilled the inclusion criteria. The mean age of the 24 men and 43 women who comprised the group was 74 years (minimum 56 and maximum 91). Analysis of the angiograms from the 67 eyes with neovascular AMD showed that 43 were classic or predominantly classic and 24 were minimally classic or occult only lesions. Severity of ARM changes in fellow eyes ranged from 0 (having no drusen or small hard drusen only) to stage 3 ARM (Table 1).

In 41 subjects with wholly or predominantly classic CNV in the first affected eye, 33 fellow eyes were classified as stage 0, 1A, or 1B ARM (80.5%), an example of which is shown in Figure 1. By contrast, 61.5% of the 26 subjects with minimally classic or occult CNV in the first eye (Table 2), had ARM features at a level of severity that was stage 2A or worse (Fig 2) . For each CNV category ranging from “classic only” to “occult only” the stage of ARM worsened progressively in severity (Table 3). Fellow eyes of patients with classic CNV in the first eye had a mean ARM severity score of 2.3 when compared with a mean score of 4.8 in fellow eyes of subjects with “occult” CNV in their first eye.

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Figure 1

Upper panels show fundus photographs of the macular retina of the right (stage 1A ) and left (stage 4) eye. Early and late phase fluorescein angiographic frames of the left eye confirm presence of a classic CNV with no occult.

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Figure 2

Upper panels show fundus photographs of the macular retina of the right (stage 4) and left eye (stage 3). Early and late phase fluorescein angiographic frames of the right eye are shown in the lower panels. Fluorescein leakage typical of occult CNV is seen.

The Kruskall-Wallis one way ANOVA by ranks demonstrated a monotonic relation between severity/extent of ARM in the fellow eye and CNV subtype in the first eye (Table 4) with a χ² value of 14.39 on 3 degrees of freedom (p = 0.002). When the status of CNV subtype in the first eye was dichotomised into classic (classic leakage occupies 50% or more of the lesion) or occult (classic leakage occupies 49% or less of the lesion), logistic regression (Table 5) showed that subjects in this category were significantly more likely to have been assigned to a higher ARM severity stage in the second eye (p = 0.019). The total area of the lesion in the first eye also contributed to the model but just failed to reach significance (p = 0.057). Age, sex, cardiovascular disorder, and smoking status were not significant predictors for ARM severity in this model.

DISCUSSION

A previous study of 150 patients by Pauliekhoff et al showed that fellow eyes of subjects with serous pigment epithelial detachments had larger, more densely packed, and less fluorescent drusen suggesting that the characteristics of the drusen were important predictors for wet AMD.¹⁰ At the time of publication of that report, the subclassification of CNV types into the currently accepted categories had not yet been developed. More recently, the nomenclature has evolved for the classification of CNV subtypes,^11,12 and methods have been developed to assess severity and extent of ARM features.^2,3

In the Rotterdam Study, incidence and progression rates of ARM in the more severely affected eye were determined by stratification of ARM features to one of four exclusive stages at baseline and at follow up.³ This staging system was based on previous findings^14–17 and assumed that more extensive macular changes would be associated with a higher risk of development of AMD with each successive stage of early ARM. The Rotterdam Study found that progression of early ARM stages to a more advanced stage occurred in a distinct pattern at a stable rate providing support for their model. We therefore used this method to stage the severity of ARM in the fellow eyes of our cohort. We also classified CNV in the first eye using the definitions developed in multiple clinical trials.^11,12 Using the Rotterdam severity stages and MPS definitions we have shown that a clear relation exists between increasing severity of ARM characteristics in the fellow eye with increasing proportion of occult disease in the first eye. Conversely, the fellow eyes of subjects with predominantly or wholly classic CNV in the first eye tended exhibited less severe stages of ARM.

Pauleikhoff et al¹⁰ subdivided their study cohort into five groups—namely, (1) serous pigment epithelial detachments, (2) neovascular RPE detachments, (3) well defined subretinal vascular complexes, (4) early ill defined hyperfluorescence, and (5) late ill defined hyperfluorescence. Group 3 of Pauleikhoff’s study corresponds to the classic CNV subgroup in the present study. It was therefore noteworthy that Pauleikhoff et al found significantly larger and more densely packed drusen in their group 2 eyes in comparison with their group 3 eyes. Thus, the findings of the present study not only support those of Pauleikhoff et al but also suggest that occult CNV is associated with widespread RPE dysfunction whereas classic CNV may be the consequence of a more focal breakdown of the barrier between the retina and the choroid. As many pathogenetic studies implicate drusen, pigmentation, and RPE atrophy in RPE dysfunction^16–23 our findings are consistent with the body of evidence that supports the view that drusen develop as a consequence of overloading and failure of the RPE over a long period of time.

Our findings also imply that classic and occult CNV occur as a result of distinct pathological processes, albeit sometimes in the same eye at adjacent locations and concur with the observations of several investigators^10,24 that changes in Bruch’s membrane that induce exudative lesions should not be regarded as a single process.

Our hypothesis is also consistent with clinical findings that have been observed in many studies for which sound scientific explanations have not been forthcoming. For example classic and occult CNV respond differently to treatment by argon laser, with the former being easily ablated in its entirety, whereas treatment of the latter by argon laser simply results in the expansion of the lesion.^13,22,23 More recently, clinical trials have shown a strong beneficial effect of verteporfin PDT in eyes with wholly classic or predominantly classic CNV with no effect on eyes with minimally classic CNV (TAP and VIP trials).^12,25 Finally, the largest cohort study of eyes without CNV at baseline (study of fellow eyes enrolled into the MPS juxtafoveal and subfoveal trials) has shown that even those free of large drusen and hyperpigmentation have a 10% chance of developing CNV over a 5 year period indicating that the risk is not negligible.^15,26

The present study which was cross sectional was not designed to answer the question whether the morphological composition of the CNV in the first eye influenced the rate of development of CNV in fellow eyes. The MPS study on the 5 year follow up of fellow eyes without neovascular AMD at baseline did not find a difference in risk of neovascularisation when subjects were characterised by the type of CNV in the first eye.²² None the less, as the present study has demonstrated a dose relation between the proportion of occult CNV in the first eye and the severity of ARM in the fellow eye there would appear to be a strong scientific rationale for examining the relation between the extent of occult CNV and risk of neovascularisation in the fellow eye.

Although we found no association between the severity of ARM in the fellow eye with smoking status, sex, or history of cardiovascular problems, the present study had limited numbers and hence limited power to identify contributions from systemic factors.

It is also limited by its cross sectional approach and its retrospective nature. None the less, our findings suggest that the health of the RPE is compromised in the fellow eyes of patients with occult CNV in the first eye and may be an important pathogenetic factor. Our data suggest that multiple pathogenetic mechanisms operating in tandem determine whether an eye will develop classic or occult CNV and which subtype will predominate. This hypothesis could be tested by longitudinal studies of fellow eyes of subjects with unilateral CNV utilising the newer technologies that can image the RPE choroidal interface with precision. The results of the present study provide clues for improved prognostic indicators and may help in designing protocols to evaluate the risk of developing CNV in the fellow eye.