In the present study, we found there was greater decrease in the peripapillary vessel density in the NAION group than the OAG group, while there was even greater decrease in the macular vessel density in the OAG group than the NAION group. To the best of our knowledge, this is the first study to demonstrate the difference in the retinal vessel density between NAION and OAG.
The retinal blood vessels serve for nutrition of the retinal ganglion cells (RGCs) and their axons. Several studies have shown changes in these vessels after glaucomatous and nonglaucomatous optic neuropathy. By using laser Doppler flowmetry and laser speckle flowgraphy, emerging studies
16–19 have demonstrated reduced blood flow dynamics in the optic nerve head and peripapillary area in glaucoma. With the recently developed OCT-A, decreased peripapillary retinal perfusion has been shown in glaucoma and correlates with VF damage.
10,20 Decrease in peripapillary retinal perfusion has also been reported in NAION eyes by using Doppler OCT.
21 Our previous study
8 also has found there is decrease in peripapillary retinal vasculature, by using OCT-A, in patients with optic atrophy after NAION.
The reasons for decrease in peripapillary retinal vasculature in glaucoma are thought to be either an effect of an ischemic basis for glaucoma damage, or an effect of autoregulation whereby neural loss reduces metabolic load and leads to decrease in blood flow. Since the presence of inner retinal hypoperfusion reportedly coincides with the RNFL defect, Lee et al.
22 suggest the decreased retinal microvasculature indicates the closure or degeneration of capillaries due to RNFL loss rather than primary reduction of retinal perfusion, in which the area of vascular insufficiency should follow the territory of the retinal arterial branches as in cases of branched retinal arterial occlusion. In eyes with NAION, since the primary location of ischemia is in the retrolaminar portion of the optic nerve head, which is supplied by the short posterior ciliary arteries,
1 the decreased peripapillary retinal vasculature in chronic phase is thought to be the result of secondary changes of tissue loss and diminished metabolic demands.
8,23 This hypothesis is supported by the close correlation between thinning of RNFL and changes of peripapillary retinal vasculature.
Though attenuation of peripapillary retinal vasculature was found in both NAION and glaucoma, the distribution and severity was different to some extent as revealed by the present study. The decrease in peripapillary VD was more prominent in eyes with NAION than eyes with OAG even with similar change in peripapillary RNFL thickness and MD in VF. This finding may reflect the different pathogenesis and impact of vascular ischemia on these two diseases. RGC death is the final common pathway in glaucoma and most optic neuropathies. Porciatti and Ventura
24 have suggested that, under exposure to a stressful environment, RGCs undergo a stage of reversible dysfunction and will finally die when autoregulatory mechanisms fail to sustain normal RGC function. The period of RGC reversible dysfunction may be relatively longer in glaucoma than in NAION. Since our study recruited patients with moderate-stage instead of end-stage glaucoma, the RGCs may still be in the stage of reversible dysfunction, and therefore, the attenuation of peripapillary retinal vasculature in most sectors was less severe in glaucomatous eyes than in NAION eyes. For the inferior sector, the cpVD was similarly involved in both glaucomatous and NAION eyes because this region was affected earlier in glaucoma.
25,26
In addition, we found marked attenuation of macular retinal vasculature in the OAG group. There is growing evidence that macular damage is very common in early glaucoma.
26,27 The macula contains more than 30% of the RGC, of which the axons, bodies, and dendrites make up the RNFL, ganglion cell layer, and inner plexiform layer, respectively. A mouse model of chronic ocular hypertension shows that the ganglion cells die initially from their synapses and cell bodies, while the eventual axonal death detected as RNFL thinning on OCT measurement may occur many months later.
28 However, there is also a study that argues against these sequential changes of nerve damage, suggesting instead that the initial site of damage in glaucoma begins at the axons and progresses toward the cell body.
29 No matter which theory is right, clinical application of OCT has shown that glaucomatous damage of the macula in early stage is common. The detectable change of macular RGC on OCT measurement precedes the change of its corresponding RNFL loss, and the outside macular RGC loss even precedes macular RGC loss in glaucoma.
25 The macular wiVD composed of superficial retinal vascular plexus
7 was found to be highly associated with macular GCC thickness in the present study. Yarmohammadi et al.
30 have also reported that the involvement of macular vessel density in glaucoma could be a relatively early event, even in the perimetrically intact hemiretina. Therefore, marked decrease in macular retinal vasculature was found in the OAG group in the present study, and the macular wiVD demonstrated stronger discriminating power than pfVD because the former covers wider peripheral changes.
By contrast, the attenuation of macular retinal vasculatures in NAION eyes was relatively insignificant. This result was unexpected because the macular GCC thinning in NAION eyes was as prominent as in OAG eyes. One possible explanation for this result is that chronic NAION only affects the inner retinal layer in the macular area, while the middle and outer retinal layers are still unchanged,
31 which could maintain autoregulation of macular blood flow in its normal status. But this still does not explain why the macular blood flow was more decreased in OAG eyes than NAION eyes, since both diseases affect the inner retina only. Moreover, given that the visual loss after NAION correlates with severity of the damage to the papillomacular bundle,
32 the less severe visual loss of NAION eyes in our study may be associated with less damage to the papillomacular bundles, and relative preservation of the macular retinal vasculatures. Taken together, the attenuation of macular retinal vasculature was more severe in OAG than NAION eyes as revealed in the current study.
There were several limitations in our study. The sample size was relatively small. However, a prospective power calculation suggested the total sample size of more than 21 eyes was sufficient to test the hypothesis at a significance level of 0.05 and power of 0.8. Besides, the severity of disease stage was restricted to a specific range, so the OAG and NAION groups could be comparable. Patients with advanced diseases or poor acuity were also excluded in the present study to obtain images with adequate quality. However, it might limit the external validity of the current study. In addition, both high-tension and normal-tension glaucomatous eyes were recruited in the OAG group in the present study. Vascular dysfunction has been proposed as a contributing factor in the development of glaucoma, especially in normal-tension glaucoma,
33 and other confounding factors including ocular hypotensive eye drops, medications, and other systemic vascular conditions might also affect retinal vasculature and its relationship between structural and functional measurements. Further research is required to determine the effects of these variables. In addition, the present study only measured the retinal vasculature because the current OCT-A modality has limitations in analysis of deeper layers. Further investigations using swept-source OCT or enhanced-depth imaging SD-OCT may help to evaluate the deeper vessels of the optic nerve head and choroid.
In summary, this study demonstrated the difference in peripapillary and macular retinal vessel densities between OAG and NAION eyes. OCT-A may help to elucidate the structure–perfusion relationships and offer a better understanding of the pathophysiology of these two diseases.