There has been renewed interest in neurodegenerative changes in early diabetes. Optical coherence tomography of the retina and around the ONH can quantify neurodegenerative changes in subjects with diabetes.
14 Many studies have demonstrated that, even in the absence of vascular changes, several layers in the retina and RNFL thickness around the optic disc become significantly thinner in eyes with type II diabetes compared with those without diabetes.
8,9 Our study demonstrated that average RNFL thickness and sector RNFL thickness in superior and inferior quadrants in diabetes were significantly thinner than those of nondiabetic, nonglaucomatous controls (
Table 1).
Several studies regarding preferential RNFL losses in diabetes showed that the most frequent location was the superior hemisphere,
6–8 whereas others reported that both superior and inferior RNFL thickness were decreased with progression of DR.
29–31 In this study, 34 (85%) diabetic subjects had photographic RNFL defects on the superior hemisphere (
Table 2). On the contrary, the highest AUROC value was found in the inferior quadrant followed by superior quadrant RNFL (
Table 3). It may be associated with the relative differences of crowding of axonal density between superior and inferior hemisphere.
32 Hood et al.
32 reported that the relative inferior location of fovea to ONH results in the crowding of the retinal ganglion cell axons in the inferior temporal side of the ONH. Thus, inferior RNFL is normally thicker than superior RNFL and the distribution of RNFL in superior hemisphere is relatively wider compared with that in inferior hemisphere.
33 Therefore, the ability of inferior RNFL thickness discriminating normal from abnormal condition seems to be better than that of superior RNFL thickness.
It is interesting that in subjects with type II diabetes and photographic RNFL defect, 52.5% of subjects revealed no DR or mild NPDR, although the average duration of the disease was relatively long (12.5 ± 7.3 years). There is increasing recognition that diabetes is associated with early neurodegeneration and the impairment in neurovascular coupling mechanism occurs as an early event in the pathogenesis of DR. The response of retinal vessel dilatation to visual stimulation, one of the methods for the assessment of neurovascular coupling in the ONH and retina, was impaired in subjects with clinically detectable DR, and it was progressively decreased with more severe stage of DR.
34 Even in diabetes without clinically visible retinopathy, neural and neurovascular dysfunction were detected.
35 Lasta et al.
36 reported that neurovascular coupling was reduced in type I diabetes before the alteration of neural activity. Injuries in neurovascular coupling mechanism, which is important in the brain homeostasis, are also present in pathologic conditions such as stroke, subarachnoid hemorrhage, and dementias.
37 Recent surveys have found that localized RNFL defects are also associated with neurodegenerative diseases such as stroke
38 or small vessel disease
39; they are also associated with arterial hypertension.
40 In this regard, RNFL defect in diabetes seems to be one manifestation other than DR, which could be used as one of the surrogate markers of impaired neurovascular coupling in neurodegenerative disease.
Intriguingly, we found that RNFL defects detected by red-free photographs in DM subjects were narrower than those of glaucoma subjects as shown in representative cases (
Table 2;
Fig. 4). The width of RNFL defect was the best parameter discriminating RNFL defects in type II diabetes from those in open angle glaucoma and very early stage glaucoma subgroup (
Figs. 3A,
3B). It suggests that width of RNFL defects (Youden's index; 6.6°) can be useful in identifying diabetes-associated RNFL defects in clinical practice.
Suh et al.
14 showed that nonprogressive RNFL defects in diabetic subjects could be well differentiated from those in glaucoma by preservation of neuroretinal rim. Lim et al.
29 also reported that the ONH cupping did not increase with severity of disease classification in diabetes. In agreement with their studies, rim area measured with OCT was the second-best parameters discriminating RNFL defects in diabetes from those in open angle glaucoma (
Fig. 3). Optic neuropathy has different pathophysiology when it is caused by diabetes versus glaucoma. In glaucoma, the ganglion cells in the lamina cribrosa are damaged in the process of compression with large pores,
41,42 which results in characteristic cupping of the ONH. In this regard, the size and depth of ONH and RNFL damage in glaucoma can be more severe than diabetic RNFL loss.
The possibility of identification of RNFL defects by all OCT maps were significantly lower in the diabetes group (all
P < 0.05;
Fig. 2A). However, the detection rate of RNFL defects on the thickness map was not significantly different between subjects with diabetes and those with glaucoma in very early glaucoma subgroup (
P = 0.074;
Fig. 2B). This seems to be related with the fact that the thickness map is not based on normative data, whereas other OCT maps are based on the internal normative database. This indicates that the depth of RNFL defects in diabetes is relatively shallow, and they can be detected using red-free fundus photographs and the OCT thickness map, which detects RNFL defects based on relative difference in thickness from adjacent structures. However, RNFL defects in diabetes are not deep enough to be assessed as outside the normal range in OCT. The thickness map showed a sensitivity (70%) and specificity (69.1%) superior to those of all other maps in eyes with diabetes (
Table 4). The significantly lower values for the area under receiver operating curves in subjects with diabetes compared with glaucoma subjects also support this finding (
Table 3).
The strength of this study is that we characterized RNFL defects in diabetes by comparison with those in age-matched nondiabetic, nonglaucomatous controls and primary open angle glaucoma. However, potential limitations of our study should be mentioned. First, this study was clinically based and did not use population-based screening. The participants were all Korean, and participants with PDR or neovascular glaucoma were excluded. Secondly, to avoid possible overlap between DM and glaucoma groups, we included type II diabetic subjects with nonglaucomatous optic discs showing a normal VF. In addition, subjects with diabetes were excluded from the glaucoma group. However, since diabetes is a probable risk factor of glaucoma, there is a possibility that nonglaucomatous eyes with diabetes may develop glaucomatous changes of the optic disc. A normal RNFL thickness profile is affected by various factors such as age, ethnicity, axial length, and optic disc area, resulting in considerable variation in RNFL thickness in the normal population. Conditions such as lens opacities and dry eye could affect RNFL thickness profile. In this study, we utilized Cirrus OCT scans with signal strength greater or equal to 6. However, there are still possibilities that low signal strength associated with in mild cataracts could affect the RNFL thickness. Also, using the entire region of the deviation map and the thickness map as parameters may be influenced by artifacts such as vitreous opacities, magnification errors due to high myopia. Further prospective studies are warranted to investigate changes in nonglaucomatous RNFL defects in diabetes over time. Finally, subjects with type II diabetes and RNFL defects were included in the study. Thus, many diabetic patients were excluded, which may cause a possible statistical bias.
In conclusion, subjects with type II diabetes and photographic RNFL defect, 52.5% of subjects revealed no DR or mild NPDR. The RNFL defects of DM subjects were differentiated from early glaucomatous RNFL defects. The RNFL defects in diabetes were located predominantly in the superior hemisphere and tended to be narrower, shallower, and farther from the fovea compared to those in glaucoma. The thickness map in Cirrus OCT seems to be an effective tool for detecting RNFL defects in diabetes.