Newborns have their vascular trunk in the central area of the ONH in most cases10. In the Boramae Myopia Cohort Study, we demonstrated actual shifting of vascular trunk in contrast to the preserved BMO during myopic axial elongation5–7. Because the central retinal vascular trunk is embedded in the dense connective tissue of the LC11, shift and deviation of the vascular trunk from the BMO center would be related to shift of the underlying LC. Moreover, vascular trunk deviation from the BMO center is closely related to the location of optic nerve damage in myopic OAG patients8,9. This could be an explanation for the close association between vascular trunk location and the location of glaucomatous damage, which were reported in many other reports12–15. Taken together, LC shift on the en-face plane, possibly as the reason of vascular trunk deviation from the BMO center, could reflect stress exerted on the LC. In the present study, we found that the vascular trunk position was deviated farther from the BMO center in glaucoma eyes than in fellow control eyes in unilateral OAG patients. This implies that a more shifted LC might be more susceptible to glaucomatous damage than a less shifted LC within the same subject.
To evaluate the effect of LC shift on glaucoma development, we included exclusively unilateral OAG patients having one glaucoma eye and one non-glaucoma eye. In this manner, we could exclude the effects of systemic factors such as aging and other general health-related conditions16. Subsequently, we focused on the local factors that make eyes more susceptible to glaucomatous damage. Although, the fellow eyes of unilateral OAG patients might differ from the healthy eyes, and unilaterality might exist only within a limited period of time17, our study, at the time of its conduct, informed us which eye was more susceptible to damage: the eye with larger LC shift was affected by glaucomatous damage earlier than the fellow eye with smaller LC shift. This might explain why glaucoma occurs in the eye that it does, only under the same systemic risk factors and similar IOP.
Shift of the LC can increase the susceptibility of the ONH to glaucomatous damage, because it reflects the tangential stress that had been applied to the ONH during eyeball growth5–9. Interestingly, in the present study, LC shift did not show a linear correlation with axial length (Fig. 1A). Rather, the correlation between LC shift and axial length was a J-shaped curve, and the GEE regression model showed that the shift index was the smallest for the axial length of 23.7 mm (Table 3), from which point, it increases in either direction. This could be understood by the various shapes of ocular expansion during growth18. The average axial length of newborns is around 17 mm, which is about 7 mm shorter than that of adults19. This means that every eyeball has to grow after birth, regardless of how short it will be in adulthood. Therefore, the process of outer-wall shift would not be limited to myopic eyes only, but would manifest in eyes of larger-than-17 mm axial length as well. In contrast to the prolate (= axial overgrowth) growth of myopic eyes18,20, some eyes, especially hyperopic ones, have been reported to have oblate growth18,21. We speculated that oblate growth in hyperopic eyes would lead to the temporal shift of the outer-wall, which could be the cause of shift index increase in the reverse direction in eyes of axial length less than 23.7 mm (Fig. 1A).
Our study showed that such a shift, across the entire range of axial length, was larger in the OAG group than in the control group (Table 3). The GEE regression model revealed that the shift index of the OAG eye was larger than that of the control eye for a given axial length (Fig. 1A). This suggested that the OAG eyes had to endure more shifting than the control eyes with similar axial lengths. Therefore, LC shift could be an indicator of cumulative tensile stress exerted on the LC during growth, and not in myopic eyes only but in any eyes.
It should be noted that the direction of LC shift was associated with the location of glaucomatous damage in cases either of nasal or temporal shift. The large pores of the LC in the superior and inferior regions are considered to be more susceptible to glaucomatous damage4,11,22. Moreover, the LC is reported to have a horizontal ridge11,23, which might protect the LC from tensile stress acting parallel to it. Therefore, we speculated that tensile stress would converge to the susceptible pores in the superior and inferior regions 8,9, even if the direction of LC shift was nearly parallel to the horizontal meridian.
Park et al. showed by means of a subgroup analysis that β-zone-PPA-associated variables could be risk factors for unilateral normal-tension glaucoma24. Also in our study, the β-zone PPA area was larger in the OAG group, though it was not significant in the multivariable analysis. In our previous study, we showed that a part of β-zone PPA, which is to say, not only γ-zone PPA but also some of β-zone PPA with Bruch’s membrane, appeared as the manifestation of LC and scleral shifting beneath the preserved BMO7. In this type of β-zone PPA, the extent of LC shift, as measured by vascular trunk dragging, was larger than the extent of β-zone PPA change7. Therefore, in this study, the effect of β-zone PPA might have been smeared out by the larger amount of vascular trunk deviation, which is more representative of LC shift (Fig. 1B)7. The following implication of β-zone PPA, however, should be noted: at least in some eyes, larger β-zone PPA would represent a larger LC shift below the BMO, which makes the ONH more susceptible to a second insult such as increased IOP or other tissue-toxic factors1,3.
In the present study’s multivariable analysis, baseline IOP was not the factor associated with OAG presence. This can be explained in two ways. First, most of the OAG patients in this study had baseline IOP within the normal range: normal-tension glaucoma. Second, even in the presence of unilateral OAG, the baseline IOPs of the subjects were highly correlated with each other (r = 0.883, P < 0.001). Therefore, the intra-individual difference of IOP was too small to make any substantial effect. This, however, should not be interpreted to mean that IOP is not an important factor. LC shift might make the ONH more susceptible to fundamental IOP-mediated insult. Furthermore, the concept of LC shift could explain why IOP reduction is the most effective treatment for OAG, even in cases of normal IOP. IOP lowering can reduce not only the direct IOP-related axial force but also the tensile stress exerted on the outer load-bearing structures, which could act as a tangential force exacerbating, by the shearing effect, damage to the ONH. Since growth-acquired shift cannot be reversed, additional stress in susceptible eyes with large LC deviation should be reduced instead, especially in cases of evident glaucoma progression.
This study has several limitations. First, the study design was cross-sectional. As such, we could not demonstrate actual LC shifting during earlier growth periods. The premise of this study was based on our previous prospective cohort study results5–7. Thus, we cannot exclude the possibility of confounding effect of LC remodeling on the CRVT position in the OAG eyes. However, glaucomatous ONH change has been reported not to affect the position of the CRVT in the LC portion9,25. Second, the location of the vascular trunk within the BMO, which was used as the indicator of LC shift, has a limitation. Since the vascular trunk outside the BMO could not be visualized with angiography, the extent of LC shift could be underestimated in such cases. Moreover, some eyes showed bifurcation of the vascular trunk on its emergence. Since we excluded such cases, we did not have any means of measuring the LC shift in those eyes. Additionally, the initial location of the vascular trunk was presumed to be the BMO center, which would not be certain for all eyes. However, most newborns had the central retinal vascular trunk in the center of the optic disc10, and the hyaloid artery is reported to be in the middle of the orbital part of the nerve when the back of the globe is formed in the embryo state26. Finally, we exclusively included subjects with unilateral OAG. Unilateral and bilateral OAG patients might have different characteristics16. Patients with systemic risk factors might have bilateral glaucomatous damage16, though they were selectively excluded from this study. Therefore, our relevant study results should be interpreted with caution.
In conclusion, the LC had been shifted farther from the BMO center in the glaucoma eye than in the fellow control eye of unilateral OAG patients. Larger LC shift might represent the larger cumulative stress exerted on the ONH during growth, which makes the ONH more susceptible to additional insults induced by increased IOP or other factors.