Understanding the arrangement of RNFL bundle trajectories is of great importance for generating a topographically accurate map of structural and functional damage and, therefore, inevitably for glaucoma diagnosis and management. Several attempts have been made to describe the pattern of RNFL bundle trajectories, ranging from histologic examinations
22–24 to mathematical models.
15,25 In 2000, Garway-Heath and colleagues developed a map by relating visual field test locations to the ONH entry position of retinal nerve fiber bundles.
10 As noted and discussed in the latter publication, photoreceptors and retinal ganglion cells that are stimulated at a specific point during visual field testing are not necessarily correspondent with the RNFL bundles crossing that area; these fibers can contain axons of ganglion cells from different and even remote areas of the retina.
In accordance to the previous study, we superimposed a 24-2 visual field grid pattern on the fundus photographs. Due to the displacement of retinal ganglion cells (RGCs) subserving the cones within the human fovea, the effect of RGC displacement should be corrected when test locations in the fovea region (1.8–2.9° eccentricity)
26 are densely sampled. This is the case for the 10-2 test grid pattern and should be considered for future investigations. The 24-2 test pattern starts from 3° eccentricity and is less affected by RGC displacement. Therefore, the effect was not compensated in this study.
Comparing the map by Garway-Heath et al. and the current map, the mean difference of entry position was less than 5° (in 32 out of 33 locations, the difference was ≤10° and in 20 locations, the difference was ≤5°). Interestingly, these 20 positions were mainly located in the central visual field, corresponding to the central fundus area between the two main vessel arcades. Weaker agreement was found in locations close to the main vessel arcades where accurate tracing is more difficult.
There was greater between-individual variability in ONH entry position in this study (mean standard deviation 12.4°) compared with the previous report (mean standard deviation 7.2°). A possible explanation is that in this study, we aimed to recruit patients with a wide range of refractive error and axial length and this will have increased the range of values of parameters associated with axial length (such as disc area and tilt).
This study investigated the influence of variation in ocular parameters on the mapping of retinal locations to the ONH in human eyes. For some locations, only a couple of ocular parameters were found to influence this relationship (e.g., locations 7, 25, 32, 34, 40, 46, 48), while other locations were found to be highly influenced by several different ocular parameters (up to seven parameters, principally for locations 24, 12, 16, 21, 23, 30 and 37). In general, two to four parameters were important for each model. The most prominent parameters were the position of the ONH in relation to the fovea and optic disc area. Axial length, spherical equivalent, and ellipticity ratio were the next most strongly associated, followed by the orientation of the ONH and tilt. It must be emphasized that all statements of “magnitude” regarding relative importance in this paper are based on frequency of each factor's appearance in the models and that certain biometric factors could have a large influence on just a few test points.
The influence of ONH position as a parameter explaining between-subject variability had been previously identified by Garway-Heath et al.
10 Normalization/rotation methods for reducing this variation by bringing the centers of the ONH and fovea into line have been recently described by Jansonius et al.
25 and Hood et al.
27
Our findings are of special interest in view of recently published data by Denniss et al.
14 and Jansonius et al.
15 Denniss et al. developed a simulation model to relate the visual field to a range of clinically plausible anatomical ocular parameters. They found ONH position in relation to the fovea, axial length, and horizontal and vertical ONH diameters heavily influencing the structure-function relationship. The agreement regarding the parameters with the strongest effect on the structure-function relationship between their computational model and our study based on human RNFL bundle trajectories and measured anatomic ONH parameters is remarkable. Jansonius et al. recently developed a mathematical model for describing RNFL bundle trajectories, and evaluated the influence of refraction (spherical equivalent), optic disc size, and disc position on the course of these trajectories in the superior-temporal and superior-nasal fundus regions. They found considerable location-specific, intersubject variability for trajectories and an asymmetry between superior and inferior locations for the effect of ocular parameters; refraction was the only significant predictor in the superior-temporal fundus region (corresponding to the inferior-nasal field) with apparently some influence of disc position. None of the parameters appeared to influence the trajectories in the temporal-inferior region (corresponding to the superior-nasal field). Our studies might not be entirely comparable since ocular parameters (except for spherical equivalent) were measured somewhat differently: Jansonius et al. calculated disc size from the macula-disc center distance in the fundus image and defined the position of the ONH by the papillomacular position, compared with magnification-corrected measurements of disc size and displacement from the fovea (in the horizontal and vertical directions, separately) in this study. Furthermore, they used a different model that is not entirely comparable with the model used in this study (parametric model compared with cubic splines).
In recent years, many different ways of measuring ocular parameters have been described. The current study measured optic disc tilt on the basis of SD-OCT cross-sectional scans. We used HRA reflectance images (Spectralis-OCT) for measurement of disc diameters and scanning laser ophthalmoscopy for the assessment of optic disc size. A recent study by Reis et al. introduces an alternative way of measuring the optic disc margin by SD-OCT. They found Bruch's membrane opening a more consistent anatomical structure than the clinically identified disc margin.
28,29 It cannot be excluded that variation of measurement techniques will somehow influence the results of this study, which would be an interesting topic for future work.
30 A potential influence on the results may arise from cyclotorsion during imaging.
10,30 It remains uncertain whether this variability in cyclorotational alignment is due to differences in head tilt or to accommodative stimulus/response or a combination of both.
Difficulty in the tracing of retinal nerve fiber bundles is another potential source of error in the resultant map. The identification of bundle trajectories is mainly limited by lower image quality in the periphery of the fundus or relative ocular media opacity. High resolution, sharpness, and contrast are inevitable quality parameters for accurately tracing RNFL bundles. The current study was started after a pilot study in which the authors tested several imaging and image processing techniques. The technique adopted facilitated the tracing of visible trajectories. In order to evaluate inter- and intrasubject variability, eight RNFL bundle photographs were retraced. The mean difference in entry angle position differed by −1.6° between the principal investigator (JL) and an independent, nonmedical coinvestigator (HZ). The mean absolute difference between the two investigators was 8.9°. This is comparable to the mean difference between the current study and the previously presented study by Garway-Heath et al. In comparison, the mean difference in entry angle position for the principal investigator was reduced to 1.4°, with a mean absolute difference of 5.1°.
It is known that the position of the main blood vessels around the ONH is associated with the location of the maxima (thickest) RNFL regions around the disc.
31 It is likely that the same ocular parameters influence both of these, and so blood vessel position was not considered as an independent factor in the model. Whether blood vessel position and RNFL distribution are associated with the same ocular parameters may be considered in future investigations.
The current study found a strong influence of ocular parameters on the structure-function relationship, which can be explained by a large intersubject variability of RNFL bundle courses and the association between the bundle course and various ocular parameters. Several studies have investigated the influence of ocular parameters on RNFL thickness. RNFL thickness and the RNFL bundle trajectories are likely to be related. Hwang et al. showed that eyes with a myopic temporal optic disc tilt and counterclockwise rotation had a thicker temporal RNFL and more temporally positioned superior peak location.
32 Tong et al. showed that ONH parameters and RNFL thickness obtained with scanning laser ophthalmoscopy are strongly influenced by the tilting of the ONH but not by refractive error or axial length.
33 ONH tilt, however, is associated with higher axial length and myopia.
12,34 The influence of axial length on peripapillary RNFL thickness has been controversial. Choi et al. reported a decreasing peripapillary RNFL thickness as the level of myopia increases and Yoo et al. reported that peripapillary RNFL thickness varies differently in different peripapillary locations as the eye gets longer.
11,35 This is in contrast with results by Hoh et al. and Wakitani et al.
36,37 who did not find any influence of axial length on the peripapillary or macular RNFL thickness. Axial length influences the lateral “magnification” in an image such that in a longer eye, a fixed angular distance of an OCT scan relates to a longer linear distance on the retina.
18 The RNFL is thinner farther from the ONH than it is closer to the ONH margin. For a scan circle centered on the ONH, the distance of the circle from the ONH center is greater in a long eye than a short eye, resulting in a thinner RNFL measurement. This effect may be offset to some extent if larger eyes have more RGCs and RGC axons.
It was shown that RNFL profiles from the two eyes of an individual are very similar.
38 However, there is considerable intersubject variation in the RNFL profiles, especially in amplitude and profile across individuals.
39 Intersubject variability in ocular parameters may have a strong genetic influence. It was demonstrated that approximately 80% of the variability of the ONH appearance, especially its diameter (disc size) as well as its general shape forms, is heritable and that 20% of the variability is caused by nonshared environmental effects.
13,38,40
In conclusion, this study has demonstrated a strong influence of ocular parameters on the structure-function relationship of the eye and emphasizes the need for individualized approaches when assessing agreement, or association, of structure-function measurements. Patient-tailored structure-function maps can be built by taking into account ocular parameters. These maps are important for more accurately correlating structural measurements with functional measurements and should be useful to assist clinicians detecting glaucoma as well as monitoring glaucomatous progression.