In this series, no significant linear relationship was identified between drusen volume and LLD, with central 3 mm drusen volume accounting for only 4% of the variability in LLD (R2). A bootstrap simulation, in which the sample data are resampled over a large number of iterations to generate a distribution for a statistic of interest, was used to generate a 95% CI for R2. This simulation, assuming that subjects in the present sample are representative members of the population of interest (i.e., intermediate AMD patients), revealed a 95% CI of 0 to 0.222 for R2. Thus although both drusen volume and LLD are thought to be markers of AMD severity, the current data suggests that the underlying processes reflected by these measures are not fully congruous.
Low-luminance, or mesopic, conditions represent a transition between rod-dominated scotopic vision and cone-dominated photopic vision during which both rods and cones contribute to visual function. However, their respective contributions are not simply additive, and the precise determinants of mesopic VA are incompletely understood. Modeling of mesopic vision is complicated by a number of factors, including differences in rod and cone sensitivities, interactions between rod and cone signaling, the existence of multiple postreceptoral pathways for signal processing, and different spatial distributions of rods and cones on the retina.
24 Rod-cone interactions are particularly complex, involving direct cell–cell coupling through gap junctions, shared neural pathways, and temporal and phase interactions. Furthermore, rods appear to play a role in mediating cone survival.
25 Therefore although LLVA is generally considered a measure of cone function owing to the scarcity of rods in the fovea,
20,21 the potential contribution of rods to low-luminance dysfunction should not be overlooked, considering that rods are preferentially damaged before cones in AMD.
26
Beyond the basic idea that drusen are indicators of an underlying disease process that may also manifest functional impairments such as LLD, there are several plausible links between drusen and retinal function. The presence of drusen has been associated with focal degenerative changes in the overlying photoreceptors, such as loss of photoreceptor density, outer segment thinning, and disruption of the ellipsoid zone as seen on both histological studies and on SD-OCT.
5–9,27,28 These changes may explain associations identified between drusen and retinal sensitivity deficits in early and intermediate AMD.
7,29–31 It follows that these same morphologic changes may impact LLD,
14 although the current study does not provide evidence to support this conclusion. Indeed, even when the analysis was restricted to the central 1 mm (i.e., fovea), in which one might anticipate the greatest degree of correlation with acuity, no significant relationship was identified between drusen volume and LLD. One potential contributor to the absence of an observed correlation in this study is the fact that drusen volume is not strictly unidirectional; that is, although drusen volume tends to increase over time, it is also known that drusen can shrink or disappear altogether, with the latter occurrence sometimes preceding progression to GA or neovascularization.
32 The inclusion of some patients who may have been in the midst of drusen regression despite being more advanced in their disease progression might explain the large range of LLD observed at low drusen volumes in this study.
Furthermore, it is likely that more than one mechanism contributes to LLD. Given the importance of rod-cone integration in mesopic vision, one hypothesis is that there may be pathologic postreceptoral changes in the inner retina, secondary to ischemia or photoreceptor damage, that affect visual function.
33,34 Another possibility is that thickening of Bruch's membrane in AMD may impair transport of vitamin A and impair photoreceptor kinetics.
26,35 It remains possible that other anatomic parameters, such as hyperreflective foci or assessment of ellipsoid zone integrity,
31,36 or other known markers of AMD severity, such as pigmentary abnormalities, may correlate more directly with LLD. Further investigation of these potential associations may be revealing.
The authors have observed anecdotally that lens status may impact measurements of LLD, and cataract has previously been associated with poorer subjective low-luminance function.
37 In this study, no significant differences in LLD were identified between phakic and pseudophakic eyes, and inclusion of lens status in the linear model did not impact results. However, the amount of lens change in phakic eyes was not specifically assessed in this study.
Similarly, it has been suggested that the presence of SDD may impair low-luminance vision.
38 For this reason, patients with fovea-involving SDD or SDD >9 DA were excluded from the present study. However, six patients with SDD not meeting either of these exclusion criteria were included in analysis. Notably, censoring of these patients did not substantially impact the results of the regression analysis, and the risk of bias as a result of the inclusion of this small group of patients is likely low.
It is important to acknowledge that data regarding LLD in early and intermediate AMD have been mixed. In some series, LLD was found to be significantly worse in early and intermediate AMD patients compared with normal patients.
16,20 In contrast, Wu et al.
14 found that LLD in nonexudative AMD patients was significantly different from normal controls only in patients with nonfoveal GA. The same group later reported that baseline LLD was not correlated with 12-month changes in VA measures or microperimetric sensitivity, although changes in VA were minimal over this period.
15 Cocce et al.
3 found that LLD was significantly different between early and intermediate AMD patients, but only on computerized assessment. Although the utility of LLD in the classification of AMD remains unclear, it is likely still useful as a practical measure of patient functionality.
23
A key consideration in assessing markers for intermediate AMD severity is risk of progression. A number of studies have demonstrated that increased central drusen volume is associated with progression to GA or neovascular AMD, and that above certain thresholds for drusen volume, the risk of progression greatly increases.
11–13 Although self-reported night vision symptoms have been associated with progression to GA or neovascularization,
19 it is currently unknown whether LLD specifically carries an increased risk of progression from intermediate to advanced AMD. The results of the current study suggest that if LLD does predict disease progression, it may do so independently of drusen volume.
This study has several limitations. First, the sample size is relatively small, and there are a limited number of observations available at higher drusen volumes. These points may therefore have had a disproportionate impact on regression analyses relative to other data points. Second, differences in methodology used to measure drusen volume in the present study may hinder comparison to previous studies on drusen volume. Specifically, the present study utilized Heidelberg SD-OCT images with drusen volume measurements made using the in-built functionality of the Heidelberg module. In contrast, many previous studies utilized Cirrus OCT (Carl Zeiss Meditec, Dublin, CA) with drusen volume measured using Cirrus software or custom software.
11–13,39 In the Cirrus module, drusen volume is based on the space between the segmented RPE and an interpolated “virtual” RPE containing no deformations,
40 whereas the Heidelberg module measures the space between the inner border of the RPE and Bruch's membrane. Although unlikely to have a substantial impact of the present results, these subtle differences in methodologies may hinder generalizability of the current findings.