SRP is mainly known as a complication of RRD and is part of the spectrum of PVR. It has been reported in 3–15.5% of eyes with uncomplicated RRD and in 47% of eyes with RRD associated with PVR[4, 5, 13]. SRP may also occur in several uveitis syndromes[14, 15], choroidal melanoma[16], and Coats disease[17]. However, to the best of our knowledge, our study is the first to report SRP in PDR.
Although subretinal fibrosis in diabetic macular edema (DME) has been reported in the literature before[18], that fibrosis is completely different from the SRP we reported in the present study. Subretinal fibrosis is an elevated mound or a flat sheet of gray or white tissue located deep to the retina at or near the center of the macula. Subretinal fibrosis always develops after very severe, hard exudate and has no association with RD[18]. Clinicopathologic studies have shown that the accumulation of hard exudate in the outer retina in juxtaposition to the retinal pigment epithelium (RPE) is associated with focal metaplasia of the RPE, leading to fibrotic scar formation. The optical coherence tomography (OCT) findings revealed that the fibrosis appears to have replaced at least a portion of the outer retina, suggesting that the fibrosis may be “intraretinal” rather than “subretinal”[19].
In our study, all PDR patients with SRP had epiretinal FVMs and TRD. We did not find any retinal breaks preoperatively or intraoperatively. Our observation suggested that RRD was not likely the main mechanism in PDR patients with SRP. In RRD, liquefied vitreous flows through the retinal breaks into the subretinal space and forms SRF. SRF may result in breakdown of the blood-retina barrier, and some serum components that stimulate the proliferation of RPE cells and retinal glial cells may penetrate the blood-ocular barrier, such as fibronectin, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), glial maturation factor, glial growth factor, IL-1, glial growth-promoting peptides, and thrombin[20]. In addition, once the neural retina has separated from the RPE, increased distance to the choroidal blood supply and reduced oxygen flux from the choroid to the inner segments lead to a loss of photoreceptor outer segments and, furthermore, to a proliferation of glial cells[21]. Ultimately, SRP develops. In our study, though all PDR patients with SRP had non-RRD, they may have had a similar pathogenesis. Our observation suggested that the FBG level was higher in the study group, which indicates that the blood-retina barrier may be poorer in the study group. The analysis of various indications for vitrectomy revealed that TRD was more likely and VH was less likely to be seen in the study group than in the control group, implying rapid progression of vitreoretinopathy in the study group once retinal neovascularization with VH occurred. Following the advance of TRD, long-standing accumulation of the SRF, which also contains some growth factors, could continuously stimulate RPE cells and glial cells, leading to SRP.
In a previous study, RRD of long duration, atrophic retinal breaks, young age, and greater number of detached quadrants were identified as factors significantly associated with SRP[5]. Wallyn and Hilton reported that the incidence of SRP was associated with the duration of RRD, ranging from 0.8% in cases with a duration < 1 month to 22% in cases with more than 2 years[13]. In our investigation, we found that the study group had a significantly higher rate of TRD and a lower rate of VH. Furthermore, the severity of VH in the study group was much lower compared with the control group. These results may be explained by the longer course of PDR and more advanced PDR in the study group. This severity was also reflected by the higher percentage of eyes requiring silicone oil tamponade in the study group. On the other hand, the BCVA was significantly poorer in the study group at 1 week after operation, which can also reflect the severity of the study group. The systemic risk factors of developing SRP in PDR have also been studied. The prevalence of hypertension, cardiovascular disease and nephropathy showed no significant difference between the two groups except for a longer duration of hypertension in the control group. The average creatinine was also higher in the control group. These results may suggest rapid progression of vitreoretinopathy in the study group, even earlier than the onset of nephropathy and hypertension. Both the preoperative IV-anti-VEGF and PRP rates were similar in the two groups, which suggests that the SRP in PDR had no association with anti-VEGF injection or PRP.
We observed that 77.8% of the eyes had only linear-shaped subretinal bands. Previous laboratory works have demonstrated that most cells exhibit polarity. Cells need a surface to grow on, and they usually settle onto a surface with a specific polarity[22]. The subretinal space is a hostile environment for cells to proliferate under normal conditions. After detachment, the subretinal space converts into a tissue culture system, where the RPE cell-derived macrophages originally settle onto the back surface of the retina and then multiply[23]. Some cells transform into fibroblasts, which in turn produce collagen. This process creates a surface that can be populated by additional cells[24, 25]. As the cells proliferate around this material, they form a circular pattern and a linear band. The glial cells undergo a similar process. They can transform into myofibrocytes after long-standing RD. Once stabilized, the attached cells also begin to synthesize collagen and create the proliferation surface[26, 27]. Finally, the linear-shaped band forms. In our study, the linear-shaped subretinal bands were mainly located in the midperiphery, and the direction of the subretinal bands was parallel to the borderline between the detached and unaffected retina. This finding may indicate that the RPE-derived cells and glial cells that compose the subretinal bands tend to accumulate along the borderline and proliferate. We also found that 22.8% of the eyes had branching subretinal bands, both of which were located at the posterior pole. This condition may be explained by the TRD at the posterior pole having relatively irregular borderlines; therefore, the cells could proliferate in multiple directions. The case with the band near the optic disc had posterior TRD. However, in another case with both a branching SRP beneath the macula and a long linear SRP at the nasal area, we found RD extending from the para-inferotemporal arcade to the nasal area without involving the macula. We presumed that in this case, the TRD involved the macula at the beginning, and the submacular fluid absorbed gradually over time for some reason, leaving only the branching SRP beneath the macula. The mechanism underlying the development of spontaneous macular reattachment in this case presumably involved the occurrence of posterior vitreous detachment[28].
Previous studies have evaluated different surgical management strategies for SRP in PVR, including PPV and scleral buckling surgery[6, 8, 9, 29, 30]. PPV is needed for eyes with posterior and extensive anterior epiretinal proliferation in order to remove the contractile membranes and release the retinal traction. Lewis et al. reported that only 28% of subretinal strands require removal or transection therapy during vitrectomy and the patients who do not require removal or transection surgery have a relatively better visual prognosis[4]. Many PVR patients with only SRP and no preretinal membrane can be treated successfully by scleral buckling surgery. Wallyn and Hilton reported a retinal reattachment rate of 95% with scleral buckling surgery in 20 eyes with pure SRP[13]. Yao et al. reported that single scleral buckling surgery anatomical success was 90% in 40 eyes with RRD and SRP[29]. Ghasemi Falavarjani K et al. reported that the single surgery anatomical success rate was 88.7% in 44 eyes with RRD associated with SRP[9]. Some earlier studies classified SRP following RRD into two main types[31]. The first type tends to form diffuse cell sheets that do not interfere with RD, and the retina may be reattached with scleral buckling procedures alone in the absence of contractile epiretinal proliferation[32]. The second type embodies taut membranes or bands, which raise the neuroretina and impede RD surgery[4]. Laboratory investigations found that the first type is usually composed of glial cells and contains little or no extracellular material. Glial membranes are thin, and therefore, they rarely cause structural changes requiring surgical intervention. In contrast, the second type is composed of up to 95% RPE-derived cells, while the extracellular component includes fibrin and collagen types I to IV[31]. In our study, eight eyes (88.9%) in the study group underwent PPV without a subretinal band removal or transection procedure. We only performed retinotomy and SRP removal in one eye (11.1%), since the subretinal band prevented retinal flattening after drainage of the SRF. The SRP removed from this eye contained a lot of pigment, which indicates that this SRP is more likely to be the second type. The retina was attached in all eyes after the silicon-oil-removal surgery, even in the eyes with submacular bands. This result may indicate that most SRPs in PDR do not interfere with conventional RD maneuvers. Therefore, we speculate that glial cells are the main component of most subretinal bands in PDR, which may also contain some RPE-derived cells.
Our study has several limitations. The sample size was relatively small and imbalanced across groups. Statistically nonsignificant findings may be attributable to the sample size. Additionally, the study was retrospective and uncontrolled. The data of systemic conditions such as HbA1c, long-term blood sugar, blood pressure and renal function data were incomplete. The follow-up time was also not uniform and varied broadly among the patients. Since only one eye had undergone SRP removal and no pathological examination was performed, we cannot determine the exact pathological composition of SRP in PDR. Further evaluation and observation over a longer period as well as pathological study are required. Despite these limitations, this is the first report analyzing the clinical manifestations and surgical results of PDR patients with SRPs.