Our results suggest that in patients with non-exudative AMD, eyes with a larger extent of drusen, as measured by total drusen area and average druse area, tend to have decreased ChBVol
. The development of drusen is a characteristic sign in the clinical presentation of AMD. Drusen are extracellular deposits located in the outer retina between Bruch’s membrane and the retinal pigment epithelium (RPE). Conventionally, drusen are categorized as small (<63 μm in diameter), medium (63 to 124 μm), or large (>124 μm) on the basis of studies that classified the grade of age-related macular degeneration.11
Large drusen are associated with increased severity of the disease. This suggests that area covered by drusen may be an important determinant of disease risk. The gold standard used for measuring drusen size in many of the largest studies to date relies on trained graders using pre-formed plastic cards containing open circles of set diameter.12,13,14
Drusen are then grouped into one of the three size categories. However, such a technique requires that drusen extent be estimated by human graders in terms of percent of total area covered by drusen rather than calculated quantitatively.
The advantages of manual grading include better discernment of drusen versus non-drusen, decreased false positives and false negatives, and a known standardization scale. As the technology of computer programs and retinal imaging has improved, many labs have investigated automated or semi-automated means of quantifying drusen.15,16,17
The advantages of computer-assisted measurements include reduced grading time, improved quantitative data, and utilization of technical advances in digital image manipulation. These technologies, however, have not become the standard means of quantification for large-scale studies. Some labs have recognized the disadvantages of fully automatic quantification, such as over- or underestimation of drusen, and have included means of selective observer intervention in the computer program.14,15
For the current study, we used a computer program designed to provide specific, quantitative data on drusen characteristics while maintaining the accuracy and reproducibility of manual identification techniques. Such a combination utilizes the computer’s superior ability to quantify information and a human grader’s superior ability to distinguish and accurately outline drusen. As our results reveal, the computer program used had high inter- and intra-grader reliability with intraclass correlations ≥ 0.85 for both inter-grader and intra-grader agreement, thereby confirming the reproducibility of these measurements. By using the computer program, we were able to quantitate the actual size of individual drusen, rather than estimate their diameter. As a result, we were able to determine area measurements of drusen extent. This allowed us to investigate circulatory measurements as they relate to drusen extent in individual eyes. The disadvantage of the current technique was the time- and labor-intensive qualities inherent in manual drusen identification.
Our results revealed an inverse relationship between choroidal blood flow and extent of drusen. This association remained significant for average druse area even after adjustment for age, a known independent risk factor associated with drusen development and decreased choroidal blood flow.18
The fact that the average druse area, independent of age-related factors, was associated with circulatory abnormalities further supports the use of advanced computer-assisted quantitative measurement techniques that allow for precise rather than estimated measurements of drusen size.
While the association between average druse size and choroidal blood flow and volume was strong (p-values of 0.001 and 0.003, respectively) and remained strong after age-adjustment (p=0.004 and 0.017), the association between total drusen area and choroidal blood flow and volume was less strong (p-values of 0.03 and 0.049) and became weaker after age-adjustment (p=0.13 and 0.09). As stated above, large drusen have long been recognized as a risk factor for AMD progression. Possibly, a reason for a stronger association with average druse size than total drusen area may be that in cases of advanced AMD some drusen start coalescing into a few very large drusen and that may skew the association with blood flow. Because a few drusen of large size may have a larger effect on the total drusen area than on average druse size, total drusen area may not be as strongly associated with decreased choroidal blood flow as average druse size.
A decrease in choroidal blood flow may lead to a decrease in the removal of waste material from the RPE-Bruch’s membrane complex, which in turn, may lead to the accumulation of drusen in this disease. However, our cross-sectional study cannot answer with certainty the question of cause-effect relationship. In other words, we cannot conclude whether the decrease of choroidal blood flow causes the development of drusen or whether the presence of drusen leads to decreased blood flow by perhaps causing a barrier to the free distribution of trophic substances that may be needed to maintain a normal, viable choriocapillaris network. Further studies are needed to clarify this question.
Interestingly, our results showing that the number of drusen was not significantly correlated with circulatory parameters suggest that the total area of drusen is more correlated with decreased flow than the actual number of drusen. The possibility that outliers in the data affected the statistical significance of the associations between blood flow parameters and drusen extent was analyzed and found to have a very marginal influence.
Potential confounding factors in this study include the possibility that choroidal blood flow measurements are affected by the presence of drusen. A previous study, however, suggested that drusen may not interfere with LDF blood flow measurements.1
In that study, comparison of blood flow between eyes with foveal drusen and extrafoveal drusen showed no significant differences in any of the circulatory parameters. In addition, there was increased flow pulsatility in eyes with AMD as compared to normal eyes. One would expect pulsatility to be decreased if blood flow measurements were influenced by AMD-related change. These findings suggest that AMD-related change in the outer retina may not have a very large effect on choroidal circulatory measurements in eyes with AMD.
In summary, our study demonstrates an association between decreased choroidal circulation and increased drusen extent. Further longitudinal studies are required to determine whether decreases in choroidal blood flow over time precede the increase in the extent of drusen. Such findings would support the hypothesis that decreases in choroidal blood flow may have an etiologic role in the accumulation of drusen.