This study was designed with the major objective of evaluating the association between macular thickness and glaucoma; we found this association to be significant. We also wished to determine whether macular thickness compared favorably with NFL thickness in its association with disease and found that NFL thickness was more closely tied to glaucoma status. Finally, we compared measurements made with our prototype OCT device with those made with the commercially available device. We found a significant correlation between measurements made with the two devices.
According to Zeimer et al’s hypothesis,4,6
quantitative detection of glaucomatous damage at the posterior pole by retinal thickness mapping may provide a unique method for the detection and monitoring of early glaucomatous tissue loss. The macula is defined anatomically as that region of the retina where the ganglion cell layer is more than one cell thick. Because the photoreceptor layer is not believed to decrease in thickness in glaucoma, this loss of retinal thickness is attributed mainly to the ganglion cell and NFL. The ganglion cells and NFL contribute 30% to 35% of the retina thickness in the macula, where the ganglion cells are known to be most concentrated.4,5
According to Zeimer et al’s hypothesis, it would be logical to expect that glaucoma detection would be most readily accomplished through macular thickness assessment, because the RGC soma is 15 μ
m or more in size, and its axon is only 1 to 2 μ
m in size.
When first proposed, the concept that macular thickness decreased in glaucoma was viewed as heretical. It is most unusual to see macular visual field defects early in the disease, but this is because of the redundancy of the macular visual system. Many studies have shown generalized loss of RGCs in glaucoma.26–28
Ganglion cells are lost in the macular region, as well as in the retinal periphery; however, detection by perimetry requires the loss of twice as many RGCs in the central visual field compared with the more peripheral retina. Each macular cone is subserved by two to three ganglion cells. The consequently greater number of ganglion cells in the macular region allows substantial redundancy in the detection of simple stimuli.7,27,29
We looked at our data in a number of ways, most specifically comparing means between groups, performing regression analysis, and analyzing AROCs. With regard to AROCs, we chose this statistical method to facilitate future comparison between studies and because it is a summary statistic for sensitivity and specificity. The disadvantage of the AROC is that it does not describe the shape of the curve, only the area underneath it, so the number alone does not define the relationship between the sensitivity and specificity for the given comparison; actual visual analysis of the curve provides some of this information ().
Figure 11 Receiver operator characteristic (ROC) curve: Overall mean macular thickness comparing normal and advanced glaucoma (prototype optical coherence tomography); area under the curve (AROC) is 0.87. This curve is shown as an example of the ROC curves summarized (more ...)
Despite the hypothetical advantages to macular thickness assessment in glaucoma in this study, whereas macular thickness was significantly associated with glaucoma, NFL thickness showed a still stronger relationship with the disease. This finding may be due to undersampling of the tissue at risk, because only approximately 50% of the RGC are present in the macula, yet nearly 100% of the RGC are assessed in a peripapillary OCT NFL scan. Because glaucoma is a diffuse disease, the ability to measure the damage done by glaucoma in the entire eye may give peripapillary NFL assessment a distinct advantage over macular thickness evaluation in detecting glaucoma. Furthermore, the absolute thickness changes are greater when measuring nearly all of the RGCs, even if just their axons, than when measuring just the subpopulation in the macula, despite the greater size of the RGC soma than that of its axon. In addition, the nature of the OCT macular map leaves large areas of the macula unsampled; another configuration of macular sampling might produce results more related to glaucoma. The problem in increasing sampling density is balancing the number of scan points and the length of scan time. As the technology continues to improve, it is possible that reductions in scan time will allow a higher macular transverse scan density.
Another major advantage of NFL over macular thickness assessment is the confounding of macular thickness measures by nonglaucomatous macular disease. Entities such as diabetes and macular degeneration, for example, directly affect macular thickness and could obscure or exaggerate the abnormalities seen with glaucoma. These are not significant issues in peripapillary NFL assessment.
This is not to say that macular thickness measurement may not be a useful parameter in the evaluation of glaucoma. It is significantly associated with the disease, and there may be fewer technical challenges in its measurement than in the quantitation of peripapillary NFL thickness. Interestingly, we found that the outer ring macular thickness with our prototype OCT device provided better correlation than did the inner ring thickness in comparing normal with glaucomatous. This more peripheral area of the macula showed a stronger association with the disease than did the more central macula, and yet this area was not presented by the commercial OCT software (revision A6). This finding points to the importance of the inclusion of our prototype dataset in this study. Both OCT devices use six 6-mm radial scans in constructing a macular map; however, whereas the prototype device presents the entire 6-mm diameter macular map, only the central 3.45 mm is presented using the commercial OCT software revision A6. Had we not had the prototype data, we would have missed the strength of the macular thickness–glaucoma association. On the basis of these findings, we recommend that future software revisions should include at least the central 6 mm of the macula, data that are already acquired in a macular OCT scan.
Outer ring and mean macular thickness using the prototype OCT device distinguished normal subjects from both early and advanced glaucoma patients in this study. With the commercial device, inner ring, outer ring, and mean macula each discriminated between the groups.
Zeimer and coauthors,4
using the Retinal Thickness Analyzer (RTA, Talia Technologies, Neve-Ilan, Israel), studied 19 eyes of 18 subjects and found losses up to 34% of normal macular thickness in the posterior poles of patients with glaucoma, presumably because of the loss of ganglion cells and NFL. Their data were a stimulus for this investigation, because OCT theoretically offers a significant advantage in macular thickness assessment over the RTA. Specifically, OCT allows 10 μ
m resolution (versus approximately 50 μ
m resolution for RTA), providing more precise tissue measurement. OCT also uses near-infrared light, as opposed to visible light used by the RTA; this gives OCT an advantage in patient comfort during scanning. RTA has the advantage of a tighter scan pattern, producing more scan lines per unit area than OCT.
This study showed once again that the inferior NFL was the parameter most strongly associated with glaucoma status. In the prototype OCT data, the inferior NFL was the only parameter that could show a statistically significant difference between normal subjects and the glaucoma suspect group. It is well known that optic nerve defects associated with glaucoma often occur initially at the inferior pole and that visual field defects associated with glaucoma frequently manifest first in the superior visual field, corresponding to the inferior pole defects.22
There were other interesting findings in this study. We separated our glaucoma suspects into three groups: ocular hypertensives, suspicious cupping, and miscellaneous (which included family history of glaucoma or asymmetric cupping), in reverse hierarchical order. We were surprised to find that those subjects who were glaucoma suspects by suspicious cupping had a trend toward the thinnest macular and NFL measurements, although this finding achieved statistical significance only for the inferior quadrant NFL with the prototype device (P = 0.01; and ). On more thoughtful reflection, however, it is possible that those individuals who were glaucoma suspects by suspicious cupping might be those most likely to have glaucoma compared with suspects by OHT, family history, or asymmetric cupping. Our data bear out the importance and value of careful clinical examination and suggest that those people with glaucomatous-appearing optic nerves should be the suspects we follow most closely. Furthermore, these findings confirm the relevance of OCT macular and NFL measurements in correlating with clinical findings and their potential role in helping to guide clinical care.
OHTs had a trend toward the thickest macular measurements of any of the suspect groups, more pronounced with the prototype device where all sectors were found to be significantly thicker, except the center ring when comparing the OHT and cupping subgroups and only the mean macula when comparing the OHT and the miscellaneous subgroups (). In the commercial device, the OHT was significantly thicker compared with the cupping subgroup for the inner + outer sector only (). The reason for these findings is unclear, as is the reason for the age-related thickness increase of approximately 0.25 μm/year in this parameter.
It is encouraging to find that measurements made with the prototype and commercial OCT devices were highly correlated and similar. These findings support the ability to extrapolate from the datasets that have been accumulated using the prototype device to clinical patient care with the commercial device. The fact that the findings in the larger dataset with the prototype device were close to the same as those from the smaller commercial OCT dataset suggest that the two devices function in a similar way, despite different delivery systems (slit-lamp based for the prototype, fundus camera based for the commercial unit).
Macular thickness measurement may provide a new tool for the detection of glaucoma. Our study results support Zeimer et al’s hypothesis that macular thickness is reduced in glaucoma. Conversely, we found that peripapillary NFL thickness was a more sensitive indicator of the presence or absence of glaucoma than was macular thickness. Nevertheless, macular thickness assessment clearly may have a role in the assessment and care of glaucoma patients. Future goals in this direction include the creation of new algorithms to specifically measure the macular NFL/ganglion cell layer, or ganglion cell layer alone, and the development of ultrahigh-resolution OCT devices (2–3 μm) to actually image and count ganglion cells. Further investigation is necessary to improve the early detection of glaucoma damage. The recognition of the importance and benefits of macular thickness measurements in glaucoma represents a new approach to the evaluation and management of the disease.