In this study, we demonstrated the clinical characteristics of FTMH formed secondary to RVO. These atypical macular holes achieved favorable anatomical and functional success after operation.
Previous studies have suggested several possible pathogeneses of FTMHs after RVO. Inflammation caused by RVO can lead to retinal ischemia and hemorrhage, which increased the expression of vascular endothelial growth factor (VEGF), transforming growth factor-β, and other inflammatory factors, disrupted the blood-retinal barrier, causing the onset and progression of macular edema [11]. The cystoid degeneration and the circulatory disturbances could furthermore induce the thinning of the inner wall at the foveal cystoid spaces. When the central foveal cysts deroofed, the FTMH formed [12, 13].
In addition, some researchers thought that the secondary ERM caused by persistent ischemia after RVO could contract and exert extra tangential traction on the damaged macular retina, which might be a possible cause of FTMH formation [3, 14–15]. In this study, we found 38.5% of the eyes combined with ERM, which is slightly lower than the incidence as 50.0% reported in the study by Mishra et al. [4].
Moreover, another possible cause of FTMH is the dramatic and rapid shrinkage of macular thickness combined with possible peripheral vitreous traction could exerted by vitreous incarceration at the site of the injection, leading to the posterior vitreous detachment [16–18]. The perturbation of the blood-retinal barrier possibly induced by a transient increase in intraocular pressure, might induce tangential tractional forces at the surface of the retina and could predispose in the formation of FTMH [19, 20]. After the laser therapy, CME could briskly resolve due to the barrier effect of the laser scar, inducing posterior vitreous detachment and contributing to the formation of FTMH [21]. Some studies considered the vitreous adherence to the fovea also represent an etiopathogenetic factor in the development of FTMH after RVO [22, 23].
Some secondary macular holes might be difficult to close and have worse structural and functional outcomes, because of the primary disease [24]. Several studies have reported that most FTMHs secondary to RVO could achieve anatomical closure after surgery, and had visual acuity improved [3–6]. All of the eyes in our study provided satisfactory anatomic outcomes, with a similar visual prognosis to previous studies. Previous studies had observed that the atypical macular holes with edematous edges usually had more satisfactory surgical outcomes than the ones with atrophic edges [25]. The included eyes with both edematous edges and flattened edges showed anatomical success after vitrectomy. In our research, 76.9% of the macular holes showed edematous edges, in contrast to Mishra’s study, 75.0% of their study eyes with rounded and raised edges [4].
Furthermore, we found that for the large FTMHs after RVO (MLD > 400µm), both ILM peeling and ILM flap insertion were effective, the eyes could all achieve anatomic closure and have similar visual acuity improvement. According to other studies, the intraocular tamponade for FTMH after RVO was usually long-acting gas, such as C3F8 and SF6 [3–6]. Some studies have suggested that using of long-acting gas in FTMHs after RVO, because of the lower surgical success rates inferior to idiopathic macular holes [24]. Though we used sterile air for most of the eyes (61.5%), the FTMHs were all closed with vision improved. This might inform that using sterile air as intraocular tamponade could also lead to desirable surgical outcomes in the FTMH secondary to RVO, as Zhang K et al. have reported in the research of highly myopic macular holes [26].
All the eyes of our study showed improvement in visual function after vitrectomy, 46.2% of the eyes achieved a final BCVA of 20/40 or above. We found the final BCVA was associated with the initial BCVA, RVO duration, and postoperative EZ recovery. The size of the holes depicted by MLD and BD exhibited no correlations to the final BCVA, as well as the postoperative CFT, similar to the conclusion in the previous study on traumatic macular holes [27]. The eyes secondary to recent onset RVO had better final BCVA than the ones after long-standing RVO. We hypothesized that this might be due to retinal dysfunction resulting from prolonged retinal ischemia and hypoxia because of the continuous development of nonperfusion and ischemia proximal to the occlusion [2]. The vascular cells would lose progressively. The persistent ischemia could conduce to epithelium degeneration and irreversible damage to macular ganglion cells. The visual acuity might tend to worsen over time [28]. These facts suggested that complete assessments at the early stage and regular follow-ups of RVO patients are crucial.
Mishra et al. [4] reported that the FTMHs with a RVO history of 6 months or more had a better visual prognosis after surgery than the ones after recent onset RVO. They explained this paradoxical result as the ones with recent onset RVO combined persistent intra- or sub-retinal edema, which led to lesser visual acuity gains than the cases with RVO longer than 6 months. Because there is little research on FTMH secondary to RVO at present, the exact reason for this difference is not clear. We speculated that the major reason for this discrepancy might be attributed to their shorter follow-up period of 6 months. The central photoreceptor regeneration might proceed longer than 6 months. The restoration of the outer retina by photoreceptor migration and realignment was the basis for higher postoperative visual acuity [28, 29]. Therefore, the visual acuity of the eyes in Mishra’s study would likely improve after the edema regressed and outer retinal layers recovered in further follow-ups.
EZ band integrity has been reported as an independent prognostic factor for visual acuity outcomes after treatment for both FTMH and RVO [29–31]. After the recovery of the ELM defect mediated by Müller cells, the photoreceptor cells underwent centripetal displacement approximately. The disrupted EZ band would be restored over a longer period than that of ELM [29, 32]. In our research, 46.2% of the eyes showed complete restoration of ELM integrity at 1 month postoperatively, but only 15.4% of the eyes achieved EZ band recovery. 61.5% of the eyes had intact ELM and 38.5% of the eyes restored both ELM and EZ band at the last visit. In previous studies focused on the idiopathic and traumatic FTMHs, the postoperative visual acuity was more highly correlated with the EZ defect rather than the ELM defect [27, 33]. Hence, the integrity of the EZ band might be a dominant predictor of the visual acuity prognosis after the surgical repairment of FTMH after RVO. And it might take a longer time to get a complete recovery than our follow-up period. Probably, more intact EZ bands would be observed if we could take further consultation.
There was one patient who emerged CNV 1 month after vitrectomy and subsided after being treated with intravitreal injection of Ranibizumab. We postulated the growth of CNV might be related to the progressive damage of the RPE and the Bruch’s membrane disruption caused by chronic macular edema. Moreover, the decrease in perfusion to the retina and choroid because of RVO, led to structural and functional derangement of the retinal microcirculation, resulting in ischemia and chronic hypoxia of the retina, increasing the expression of VEGF, which might develop foveal neovascularization. The foveal neovascularization did not receive blood supplements from the retinal circulation and relied on the choroidal vascular system for nutrient and oxygen supply, which could extend to the choroid. RVO could increase hydrostatic pressure in venous collaterals, initiate or potentiate the development of such anastomoses between the fibrovascular lesion and the retina, that these spontaneously occurring anastomoses decompressed the occluded retinal venous vasculature into the fibrovascular lesion and into the choroid when combined Bruch’s membrane rupture [34–36]. In addition, vitrectomy conduced perturbations in the retinal microenvironment, triggered activated microglia, and then results in the secretion of inflammatory cytokines, which contribute to the development of CNV. Activated microglia could also induce the release of proangiogenic factors, providing a favorable environment for CNV [37].
This study has some limitations as its retrospective nature, with a relatively small sample size. Not all enrolled eyes underwent cataract surgery at the same time. There were 3 phakic eyes combined cataract progression after the operation and might cause little vision loss, one with finial BCVA as 20/40, one with 20/67 and the other reached 20/20 at the final follow-up examination. There was no significant difference in the final BCVA between the eyes underwent cataract surgery or not (0.5 ± 0.4 vs. 0.3 ± 0.3 logMAR, P = 0.339). Therefore, the patients who did not undergo cataract surgery might have no significant impact on the results of this present study. Moreover, some patients had a relatively short follow-up time. For patients who participated in follow-up for 4 months (n = 5) and 10 months at least (n = 8) after operation, there were significant differences in only the preoperative BCVA (0.7 ± 0.2 vs. 1.0 ± 0.3 logMAR, P = 0.026), whereas the other preoperative and postoperative anatomical parameters and visual acuity did not significantly differ. Therefore, it seems the patients whose initial BCVA was worse had better compliance. Some patients who participated in a short follow-up had little impact on the whole cohort. Further prospective studies with multiple institutions is required to confirm these outcomes of this present study.
In conclusion, the PPV combined ILM peeling, or ILM flap insertion could achieve favorable anatomical and functional improvement in FTMHs after RVO. Eyes with FTMHs secondary to a recent RVO might have better prognosis after surgery. The ones with better initial BCVA and postoperative EZ recovery usually achieved better final BCVA. In addition, early assessments and regularly follow-ups of RVO patients are needed to avoid the formation of the secondary FTMHs.