**5. Discussion**

Soliman et al*.* [21], using AO fundus camera to acquired images of parafoveal cones, from patients with type II diabetes mellitus with or without retinopathy, captured the cone mosaic at 0 and 2 degrees eccentricities along the horizontal and vertical meridians. The density of the parafoveal cones was calculated within 100 100-μm squares located at 500-μm from the foveal center along the orthogonal meridians. They found that the cone density was significantly lower in the moderate non-proliferative diabetic retinopathy (NPDR) and severe PDR/proliferative DR groups compared to the Control, No DR, and mild NPDR groups. Also, they found that the mean percentage of cones with hexagonal Voronoi tiles in the Control and No DR groups was 44.8% and 45.6%, respectively. In the DR groups, the percentage of cones with hexagonal Voronoi tiles ranged between 43.4% and 40.0%. They therefore *Analysis and Modeling of Polygonality in Retinal Tissue Based on Voronoi Diagram… DOI: http://dx.doi.org/10.5772/intechopen.106178*


### **Table 5.**

*Value-*P *for maximum angles in 5, 6 and 7 Voronoi ties.*

conclude that decreased cone density may be linked to the prior use of anti-VEGF therapy in these patients. Since VEGF is known to have a neuroprotective effect on photoreceptors, anti-VEGF agents may potentially have a deleterious effect on photoreceptors. Other progress against the wet form of the disease has come through the use of drugs that target vascular endothelial growth factor, or VEGF, a substance in the body that promotes the growth of new blood vessels. It has also been found that, cone photoreceptor counts in the control group reported in this study fall within the range reported in previous studies, high inter subject variability of cone density may also play a significant role [22].

Likewise, Li and Roorda showed that the percentage of hexagonal Voronois tended to decrease between 0.25 and 5 degrees from the fovea; a study on a post-mortem human retina showed that the cones were more hexagonally arranged near the edge of the fovea (between 0.20 and 0.25 degrees eccentricity) than in the foveal center [7, 23, 24]. According to the current study and previous work from others [25, 26] a model of the parafoveal mosaic by a lattice with continuous hexagonal regularity cannot be considered completely adequate to describe the cone mosaic arrangement in a healthy eye. In addition, in an AO retinal image of the photoreceptor mosaic, deviations from hexagonal order can be attributed to some phenomena, such as point defects and linear cracks. 'Point defects' of the cone lattice occur within otherwise intact mosaic areas and may be represented by smaller cones (S cones), cones with no wave guiding properties or isolated rods (it is plausible that rods cannot be always distinguished by point defects). Other phenomena that can contribute to change the hexagonal order

are represented by local variance of the cone shape and the compression along the vertical meridian as a consequence of the expansion along the horizontal meridian of the photoreceptor mosaic [7, 24, 27–29].

Lombardo [30] identified several possible limitations based on the preferred packing arrangement of the cone mosaic: resolution of AO system, study size, and the presence of several sources of confounding orbias. Firstly, the resolution of the rtx1 camera is insufficient to assess the density of extremely tightly packed cones at the center of the fovea. Whether or not this loss of parafoveal cones reflects similar changes at the foveal center remains unclear. To date, the association of photoreceptor loss and vision loss in patients with DR remains obscure. Secondly, small sample size is another limitation of this prospective observational cohort study. This variability could be attributed to several factors, including the lack of a standardized approach to cone counting and differences in image processing software, AO systems, sampling window size, and foveal reference point location.

Methodology based on the optical coherence tomography (OCT) allows it to quantify retinal thickness in diabetic retinopathy. A total of 136 patients in different stages of diabetic retinopathy were examined with OCT [31]. In the controls, retinal thickness was 153 15 μm in the fovea, 249 19 μm in the temporal parafoveal region, and 268 20 μm in the nasal parafoveal region. In diabetic patients, retinal thickness was increased to 307 136 μm in the fovea, 337 88 μm in the temporal retina, and 353 95 μm in the nasal retina, respectively. The differences between diabetics and controls were highly significant (*P* < 0.001). There was an intermediate correlation between retinal thickness and visual acuity, particularly in patients without macular ischemia. Sensitivity of detecting clinically significant macular edema by measuring foveal retinal thickness was 89% and specificity was 96%. Apparent correlation between the increase and decreased visual acuity in the retina thickness, can be explained by the results of an increase in the thickness will be related to the increase in time axonal loss. In diabetic retinopathy, retinal spaces can take place between the inner and outer plexiform layer, outer limiting membrane or the outer plexiform layer. These results demonstrate the retinal tissue integrity, as a measure of the retention axon connection, and as an index of visual function. The strength of the correlation between the retention structure and visual function as expected decreases in the eccentricity increases from the center of the fovea.

There is disagreement in the literature concerning the effects of age on PR packing density. Curcio et al. [32] found a nonsignificant change in the number of cone photoreceptors with age. However, they reported that the range of peak density variation at older ages was narrower, overlapping the lower end of the cone density from younger subjects.

As mentioned above, there are mixed results of histology on age-related changes in PR packing. It is clear that nonhuman primates undergo changes in the central retina with age [33, 34]. Ordy et al. [35] studied the visual acuity and foveal PR density in the retina of aged rhesus monkeys, finding that the foveal photoreceptor density decreased significantly in the oldest age group of macaque monkeys compared with the middle age group. Other properties of the photoreceptors have been found to change with age, in addition to the cone packing density. Gartner and Henkind [36] reported loss of photoreceptor nuclei. Keunen et al. [37] and Kilbride et al. [38] found that the cone pigment density decreased as a function of age. Elsner et al. [39] showed that young healthy people typically have steep foveal peaks in photopigment density, but older people have shallower distributions.

## *Analysis and Modeling of Polygonality in Retinal Tissue Based on Voronoi Diagram… DOI: http://dx.doi.org/10.5772/intechopen.106178*

Our approach emphasizes the local density of the PR rather than the total area. Thus, we found that a significant decrease in photoreceptor packing density occurred primarily, at distances less than 1890 μm from the center of the fovea.

Changes in the central fovea are also evident from the analysis of foveal shape by Gorrand and Delori [40], who found that the curvature of the foveola increases with increasing age. Elsner et al. [39], Bone et al. [41], and Chang et al. [42] found changes in the distribution of macular pigment with age, but Delori [43] did not. Since macular pigment is deposited preferentially in the photoreceptor axons and inner plexiform layers of the retina. Similarly a loss of PR could cause an increased curvature. An alternative possibility is that central cones spread outward, and the foveal curvature increases due to this spread, but again, the mechanism would be more complex and not easily tested by PR packing measurements alone.

However, despite the seeming transparency of DR pathogenesis and the progress in its treatment observed in recent years, a number of issues remain that warrant further study [44–46]. One of them is the temporal sequence of pathological changes in DR development [47, 48]. Studies in rodents have highlighted that biomarkers of inflammation, such as leukostasis, overexpression of adhesion molecules in retinal vascular endothelial cells and leukocytes, vascular permeability alteration, and aggravated production of nitric oxide, prostaglandins, cytokines, and other inflammatory mediators appears in the retina during 1–6 months of diabetes crisis [49].

Most developed therapies for DR, have primarily focused on the terminal stage of this disease, and as thus, failed to address the early potentially reversible stage of this disease. In addition, most of these therapies have been associated with severe sight threatening side effects [44]. With that, understanding of the temporal sequence and stages of pathological disturbances of DR development is of great prognostic and scientific value, as it might contribute to improvements to current methods or even the development of new methods of diagnosis and treatment of such a serious complication of diabetes.
