Coexistence of ERMs was reported to be 15%-38% of ARMD eyes [3,4, 21,22]. The higher prevalence of ERMs with eyes with ARMD than normal eyes adjusted for age was considered to be caused by inflammation or preretinal glial cells found more frequently in ARMD than control [23]. In our results, 61% of ARMD eyes at baseline and 79% of those after three years of treatment had presented any ERMs and these were much higher than the existing reports. Previous studies had no strict definition of length of ERMs. The higher prevalence was considered to be caused by criteria used in the form of the minimum region of ERMs in this study. The agreement rate for evaluation between observers was 82%. The remaining 18% were evaluated simultaneously and a consensus was reached.
The reported incidence of VMA in ARMD eyes in literature ranged from 12%-41% [18,19,22,24], and the higher prevalence than that in controls with adjusted age was considered to be a pathogenesis of ARMD, as traction would lead to pigment epithelial detachment and spread of VEGF [25] . In our results, 61% of eyes with ARMD had complete PVD, 24% of eyes presented with VMA, 5% had no PVD, and 11% had progressed to PVD during three years, and were in keeping with the reports discussed.
Cho et al. stated no spontaneous resolution of ERMs in ARMD patients in their study [3] and there were no other reports, to the best of our knowledge, about progression or resolution of ERMs in ARMD. The present study is the first report to investigate the progression of ERMs in ARMD patients and evaluate the influences of injection. Regarding other reports among eyes without ARMD, Byon et al. reported that progression from GA to PA was observed in 33% of eyes of idiopathic ERM during 24 months [15]. In our study, GA to PA progression was observed in 26% (9/34) during 36 months.
Regarding the reports [13,26,27], which had stated that PVD was significantly associated with the formation of ERMs, Ota et al. reported that idiopathic ERMs with partial PVD had worse visual prognosis than with no PVD or with complete PVD. They suggested that the chronic vitreous traction caused the migration of glial cells, macrophages, or pigment epithelial cells [13]. It led that ARMD itself would have nature in that ERM likely progress throughout higher prevalence of VMA. Moreover, there was a possibility that injection would evoke PVD, though Veloso et al. reported only 7/125 (5.6%) eyes with VMA newly developed PVD after 5 years of treatment with injections [24]. In this study, the proportion of developed PVD during 36 months was 8/76 (11%) and was slightly higher. Therefore, several factors would work together as progressive factors for ERMs in ARMD patients.
The results of the logistic regression analysis, among considerable determining factors, revealed that presence of VMA or progression of PVD during 36 months against no PVD or complete PVD was significantly associated with ERM appearance or progression[OR, 5.76; 95% CL, 1.72-19.3; p=0.005]. Moreover, the presence of peripheral retinal degeneration was significantly associated [OR, 3.85; 95% CL, 1.15-13.0; p=0.029]. The other factors examined were not significantly associated.
As referred previously, incomplete PVD had been considered to progress ERMs with chronic traction [13]. We considered that progression of PVD could also cause rapid migration of glial cells, macrophages, or pigment epithelial cells.
We carefully excluded eyes with a retinal break to prevent contamination of ERMs secondary to the break, and most of the peripheral degeneration prevalence was not due to lattice degeneration (1 eye), but due to cobblestone, naevus, or CHRPE, etc. We could search only one article that reported the prevalence of peripheral degenerations of idiopathic ERMs was similar to that of normal eyes [28]. Though other article reported higher prevalence in ARMD than in controls [29]. We hypothesized that these peripheral degenerations co-exist with or are evoked by vitreoretinal adhesion in the pathogenesis of ARMD, and both are related to the development of ERMs.
Exposure to cigarette smoke extracts had been reported to provoke activation of the TGF-β pathway and up-regulate genes related to fibrosis, that was known to play a critical role in the pathogenesis of ERMs [10,11]. However, the reported results of epidemiologic studies of the relationship between smoking and risk of ERMs were unexpectedly protective and our results had also weak tendency of decreasing odds ratio [30].
Moreover, there was a limited relationship between the history of subretinal hemorrhage and the development of ERMs. We had started this study with the impression that there might be a relationship between developing ERMs in ARMD patients and subretinal hemorrhage treated with aflibercept. However, this hypothesis seemed to be contradicted by the observations. Subretinal hemorrhage inside the retina itself would be unable to cause the development of ERMs, whereas ERMs following vitreous hemorrhage had been distinguished as secondary ERMs [16].
The BMES Ⅱ study revealed the rate of new appearance of ERMs to be 9.1% in eyes with history of cataract surgery during 5 years from BMES Ⅰ, whereas it was 4.9% in non-surgical group [12]. In the present study, only one of the 30 eyes that had no ERMs at baseline had undergone cataract surgery during 36 months; therefore, there was no significant influence on the results. The only eye had the new appearance of ERMs.
In the BMESⅡstudy, moreover, 13.5% of another eye of the first eye with ERMs at baseline had reported developing new membranes, while 5.3% of another eye of the first eye without ERMs [12]. In our study, these proportions were 60% and 40%, not significantly different. Our high prevalence of ERMs would influence this difference of results.
The observation that the number of injections did not have an impact on the appearance or progression of ERMs could suggest the absence of side effect of anti- VEGF injection in the development of ERMs, but we had no controls of ARMD eyes that had not received any injections. The fact that the proportion of GA to PA was 26% during 36 months and had no priority to 33% during 24 months of idiopathic ERMs [15] also supports this possibility. Moreover, further comparison of each injection times of aflibercept and ranibizumab independently had no impact on the development of ERMS.
We hypothesize that NO would decrease due to anti-VEGF injection and PDGF-A, TNF-α, TGF-β and some other cytokines would be up-regulated [7-9], however, the changes would be weak due to the dose or present time or these cytokines were unable to develop ERMs by themselves without migration of glial cells, macrophages, or pigment epithelial cells [13], caused by vitreous change. Though there were no further investigations about developing ERMs by injections at BRVO from Marticorena et al. report [6], further prospective studies would be necessary to explain the pathogenesis of secondary ERMs in both BRVO and ARMD.
This study had a few limitations. First, there was no control of eyes with ARMD and without any injection, previously referred. Second, this was a retrospective study and invitation spans had variety. A further prospective study is necessary.