Discussion

Wound healing and RPE proliferation of RPE tears have been studied by several authors.6 ,10 In time domain OCT, the reattachment of the RPE layer and RPE repopulation have been documented.7 We also found a considerable tissue remodelling over several years using FAF and SD-OCT. We saw RPE repopulation in one case, that is, a small RPE tear which is in line with other reports.8 ,10 These new RPE cells lacked lipofuscin, as shown in hypofluorescent FAF.

Histological studies of RPE tears also reported RPE cell migration and proliferation. In a case reported by Green et al, the RPE proliferated to the underside of the ripped basement membrane of the flap tear (cf, figure 15 in Green et al).11 Although RPE proliferation might theoretically lead to a functional RPE layer, this proliferation is not directed.11 In our study, we found misdirected RPE migration into the retina, which possibly did not lead to a functional RPE layer supporting the photoreceptors.

Intraretinal RPE cell migration has been described in various retinal diseases, for example, retinitis pigmentosa, congenital RPE hypertrophy12 or early to late dry age-related macular degeneration.13–16 In OCT images, migrating intraretinal RPE cells are hyper-reflective lesions with high backscattering and appear as hyperfluorescent areas in FAF. Other structures, such as hard exudates, may also appear as HRDs in SD-OCT,17 but appear as hypofluorescent lesions in FAF (figure 3). The origin of migrated RPE cells seen in this study is unclear; there is a possibility also that these cells are remnants of RPE cells attached to the photoreceptors left from the traumatic event of the RPE tear. In course of time due to lack of suitable scaffolding structures, they migrate into the retina. Individual cells might also proliferate into clumps, which are then big enough to be detected using FAF. This mechanism is however speculative.

RPE cells migrate towards various chemokines and cytokines, such as tumour necrosis factor α or interleukin 1.18–21 After the acute event of an RPE tear, it is likely that such chemo attractants are secreted. Nevertheless, it is unclear why certain RPE cells remain in the level of Bruch's membrane and why others migrate into the retina. One possible explanation might be the absence of scaffolding structures, which are important for RPE cells for proliferation.

Some authors described small RPE tears where the RPE denuded area became covered by a layer of relatively normal-looking, hypopigmented RPE derived from cells from the margin of the defect.22 ,23 We also documented a case with a small RPE tear, where RPE cells migrated and covered the defect. This healing property might not be enough for large RPE tears. In 41.7% (15 eyes) of all cases, we identified a homogenous subretinal mass in the RPE denuded area. This substance may represent fibrin or proliferated RPE cells. Nevertheless, this subretinal mass failed to build a single layer, which is a prerequisite for RPE cell function in terms of ion and fluid transport.24 In our study, only in 2.8% of cases RPE cells could fully cover the defect.

Animal studies of retinal pigment epithelial wound healing in rabbits25 and monkeys26 suggested that newly proliferated RPE cells are hypopigmented. In our study, we also saw a hypofluorescent RPE layer in FAF. We hypothesise that these new RPE cells originate from old RPE cells from tear border. But since by means of mitosis cells also give about half of their cytoplasm to the new cells, they have only about half as many lipofuscin as their original cells. Therefore, they emit less FAF signal. Although not shown in this study, it is logical to assume these new RPE cells will also accumulate lipofuscin over time as well.

There are some limitations in this study, such as the retrospective nature of the study prone to bias of uncertain kind and a relatively small number of patients. However, giving the fact that RPE tears are rare, we presented a relatively large number of patients observed. Also by combining FAF and SD-OCT we are able to observe RPE tears more efficiently.

We observed in this study 12 patients with RPE tear grade 1 or 2; however, only one patient showed self-healing mechanism. Although the exact reason is speculative, there are in vitro studies suggesting that RPE cells proliferation is dependant of age27 and health of the scaffolding structure (Bruch's membrane).28 We hypothesise that the patient with a self-healing RPE tear might have a relatively undamaged Bruch's membrane after the traumatic event, allowing the RPE cells to repopulate the area. Using current in vivo technologies, however, the health of Bruch's membrane cannot be easily assessed.

In conclusion, there is a chance that small RPE tears are populated by RPE cells, and so waiting might be appropriate. As shown previously, photoreceptors in the RPE denuded area are able to survive up to 325 days after the acute event;2 we propose therefore to continue anti-vascular endothelial growth factor therapy to slow down scar progression, to protect the photoreceptors from further damage (unpublished data) and giving the chance of self-healing. In large RPE tears, however, RPE proliferation and migration might not happen in the right plain, which is under the photoreceptors. In these cases, therapies aiming at RPE layer replacement, such as in macular translocation or autologous RPE and choroid transplantation can offer help. Although we are not able to predict which patient has the greatest chance of self-healing, because only one patient in this study showed self-healing, knowing the facts that photoreceptors will survive up to 325 days2 and there is a chance of self-healing of small RPE tears, we propose that therapies aiming at RPE layer replacement do not have to be performed as an emergency procedure. In fact, such risky procedures can be planned and offered, if after waiting the self-healing properties have been proven to be insufficient.