Age-related Maculopathy: A Multifocal Approach

Field: Medicine (Health Sciences)

Age-related maculopathy (ARM) is a central retinal disease with unclear pathogenesis. It is the major cause of permanent vision loss in adults over 50 years and is increasing in prevalence and incidence, faster than the aging population would suggest. Early in the disease process (early ARM) there is little or no vision loss and there are only slight retinal changes with abnormal deposits within Bruch's membrane. As the disease progresses (late ARM or age-related macular degeneration, AMD) vision loss may be quite severe due to atrophy (dry AMD) or the development of chorioretinal neovascularisation (CNV, wet AMD). It is hard to predict from conventional eye examinations and clinical vision tests which cases will progress to the severe, dry or wet forms of the disease. Moreover, most of the conventional clinical tests are based upon subjective vision measures. Objective tests which detect ARM earlier would be a useful aid to diagnosis and to monitoring progression.

The multifocal electroretinogram (mfERG) is a relatively new clinical tool which enables the recording of electrical potentials from multiple, small areas of the central retina and thus assesses function from specific retinal locations. It is therefore useful in detecting focal retinal diseases such as hereditary or acquired maculopathies or in monitoring retinal laser or surgical treatment effects.

There is cone and rod impairment in ARM and histopathological and psychophysical evidence for a preferential vulnerability of rods compared to cones. This research project investigated if an objective tool such as the mfERG could detect early ARM,its progression and the treatment effects of multiple photodynamic therapies (PDT) on retinal function in late ARM, prior to a battery of subjective vision measures.

For comparison purposes a subjective assessment of central retinal function was performed using high and low contrast distance visual acuities (VA), near VA, low luminance VA (SKILL cards), contrast sensitivity (Pelli-Robson, P-R), saturated and desaturated Panel D-15 (sat Panel D-15, desat Panel D-15) and central visual fields (Humphrey 10-2, mean sensitivity, MS and mean defects, MD). As an objective assessment of central retinal function the cone- and rod-mediated multifocal electroretinograms were recorded.

Subjective and objective tests of retinal function were compared in early ARM and an age-matched control group (chapter 3). Seventeen eyes of seventeen subjects with early ARM and twenty control subjects with normal vision were measured. For the cone-mediated mfERG responses conventional averaging methods were used and results were correlated with subjective vision tests. The conventional cone-mediated mfERG failed to distinguish between the early ARM and control subjects whereas subjective vision measures such as HC- and LC-VA, desat Panel D-15, MS, P-R were significantly reduced in the ARM group. However, there were significant correlations between the cone-mediated mfERG and the desat Panel D-15 results in the ARM group. This suggests that the mfERG measures similar retinal processes that detect colour vision deficiency under desaturated conditions. There was no significant correlation between cone-mediated mfERG measures and funduscopic changes. The conclusion from this study was that the subjective vision tests detected early ARM better than the objective cone-mediated mfERG. Thus the aim of detecting early ARM objectively was not met by the cone-mediated mfERG suggesting the need to develop other objective tests such as a rod-mediated mfERG.

Whether the preferential rod vulnerability others have reported in early ARM could be detected by the rod-mediated mfERG was determined in the next study (chapter 4). A protocol for recording rod-mediated mfERG responses was developed by determining the optimal testing luminance to reduce the effect of stray light and elicit maximal rod-mediated responses. Sixteen of the seventeen ARM subjects and seventeen control subjects from the previous study were tested. For analysis, a customized computer template fitting method was developed in MATLAB (Mathworks, Natick, MA, USA). This method has been shown to be useful for low signal-to-noise ratio responses that characterize the rod-mediated mfERG. Significantly delayed rod-mediated mfERG responses were found whereas cone-mediated mfERG responses were within the normal range. This suggested that the effect of ARM on the rod system could be detected objectively with the rod-mediated mfERG before changes in the cone-mediated mfERG.

Which of the tests best detected progression of vision loss was investigated in chapter 5. Visual function of 26 (13 ARM and 13 control subjects) of the original 37 subjects (17 ARM and 20 control subjects) had cone- and rod-mediated mfERG and the subjective vision measures repeated after one year. The main purpose was to determine which of the tests best detected progression of vision loss. The mfERG results were analysed by using both averaged and local responses and by using the computer template fitting procedure. On average no significant worsening of either objective or subjective function measures was evident after one year. These results reinforce the slow progression of the disease. With a longer follow-up period progression of ARM may translate into measurable changes in the mfERG and the other visual function tests.

The effect of multiple photodynamic therapies (PDT) on cone- and rod-mediated function was assessed with the mfERG in the last study (chapter 6). The cumulative treatment effects of PDT in five subjects with late ARM were determined. Having demonstrated that the rod-mediated mfERG was applicable in early ARM, this study also aimed to investigate how useful it was in late ARM where there is substantially greater rod loss. Cone- and rod-mediated mfERGs, visual acuities, contrast sensitivities and central visual fields were investigated a week before treatment began and then one month after each PDT treatment. The subjects received three treatments each over an average period of five and a half months. In some subjects there were significant transient reductions in cone- and rod-mediated amplitudes possibly reflecting alterations in choroidal hypoperfusion dynamics one month after treatment. Further, b-wave component of the mfERG became increasingly misshapen after each PDT treatment suggesting an ischemic insult mainly targeting post-receptoral sites. However, objective and subjective function was stabilized after multiple PDT treatments in most of the subjects. This pilot study of five cases showed that there was no additional damage to cone- and rod-mediated outer retinal function after three PDT treatments.

One of the novel findings of this research was that the rod-mediated function measured with the mfERG was impaired in early ARM. This finding supports histopathological and psychophysical evidence of rod vulnerability in early ARM.

The results of these studies also suggest that early ARM affects different aspects of visual function which is reflected by different outcomes from objective and subjective vision tests. A model (chapter 7) based upon the results was developed proposing a hypoxic insult with a preferential alteration of post-receptoral sites in early ARM.

The cone-mediated mfERG documented the retinal damage and possible treatment effects on outer retinal function of the multiple PDTs which did not further deteriorate. Thus, this technique might assist in the development of optimal treatment modalities for ARM, especially in retreatment regimes. Greater variability was found for the rod-mediated mfERG and its clinical use in PDT treatment regimes still needs to be investigated.

In conclusion, this research has provided a better understanding of the disease process and treatment effects in ARM and might contribute to improvements in diagnosis and treatment of ARM.