Posterior vitreous detachment (PVD) is typically an agerelated

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1 Retina Epiretinal Membranes and Incomplete Posterior Vitreous Detachment in Diabetic Macular Edema, Detected by Spectral-Domain Optical Coherence Tomography Avinoam Ophir 1,2 and Michael R. Martinez 1 PURPOSE. To present the vitreoretinal interface in diabetic macular edema (DME) associated with both epiretinal membrane (ERM) and incomplete posterior vitreous detachment (PVD), as detected by spectral-domain optical coherence tomography (SD-OCT). METHODS. In a retrospective study, findings were analyzed in one eye in consecutive patients. Excluded were eyes that had undergone vitreoretinal intervention or that had complete PVD or complete vitreous attachment. RESULTS. Of 44 eyes with DME and ERM, incomplete PVD was apparent in 23 (52.2%) eyes. A hyperreflective unified ERM/ posterior vitreous cortex (PViC) membrane, or EVi membrane, was apparent in various sizes in 20 (87.0%) of the 23 eyes. This unified membrane (n 20) was associated with vitreopapillary adherence in 19 (82.6%) of 23 eyes. Two major OCT presentations (n 23) were encountered: incomplete vitreopapillary detachment (n 11; 25% of 44), with attachment to the macular ERM, and posterior vitreous detachment from the macula, associated with vitreopapillary adhesion (n 10; 22.7%), in four different manifestations. In the remaining two eyes, there was no association between the ERM and the PViC. CONCLUSIONS. In eyes with DME, ERM, and incomplete PVD, the posterior cortical vitreous and ERM appeared as one united EVi membrane in various lengths in most eyes, typically associated with vitreopapillary adhesion. These findings may have clinical importance in the context of epimacular membrane characteristics and its removal in DME. (Invest Ophthalmol Vis Sci. 2011;52: ) DOI: /iovs Posterior vitreous detachment (PVD) is typically an agerelated process that originates at the perifoveal site, gradually progresses to vitreopapillary separation, and terminates in its late stage at the vitreous base. 1,2 Two major steps precede the detachment of the posterior vitreous cortex (PViC): vitreous liquefaction and the weakening of the vitreoretinal adhesion. 1,2 Accelerated vitreous liquefaction may occur before adequate weakening of the vitreoretinal adhesion in various entities and may result in anomalous PVD. 3 5 The anomalous PVD may result in either splitting in the multilamellar PViC From the 1 Division of Ophthalmology, Hillel-Yaffe Medical Centre, Hadera, Israel; and the 2 Ruth and Bruce Rappaport Faculty of Medicine, the Technion, Haifa, Israel. Submitted for publication October 25, 2010; revised March 8 and April 3, 2011; accepted June 25, Disclosure: A. Ophir, None; M.R. Martinez, None Corresponding author: Avinoam Ophir, The Division of Ophthalmology, Hillel-Yaffe Medical Centre, Hadera, Israel; ophthalmology@hy.health.gov.il. (vitreoschisis) 3 5 or in its full-thickness adherence to the retina, typically detected in areas of firm vitreoretinal adhesion. 4 7 Epiretinal membranes (ERMs) are recognized by optical coherence tomography (OCT) as thin, hyperreflective bands anterior to the retina or bright red bands in a pseudocolored OCT presentation. 8 The ERM may originate as idiopathic or secondary to various ocular conditions and may result in chronic traction vitreomaculopathy that manifest as macular striae, vessel distortion, and/or macular edema. Recent OCT studies have indicated that the pathogenesis of idiopathic ERM is commonly related to an earlier PVD process, either partial or complete. 6,9 11 After spontaneous PVD, remnants of PViC were found in the foveal area in 44% of cadaveric normal eyes by scanning electron microscopy, including eyes considered to have complete PVD. 6 In a recent study of eyes with idiopathic macular pucker using OCT/scanning laser ophthalmoscopy (SLO), vitreoschisis was detected in 42% (19/44) of the eyes. 3 Researchers have proposed that, if the split occurs anterior to the monolayer of the hyalocytes at the cortical vitreous, the remaining hyalocytes can stimulate cell migration from both the circulation and retina, stimulate cell proliferation on the retinal surface, release connective tissue growth factors, and induce collagen gel contraction These processes could result in hypercellular, thick, and contractile ERMs, causing macular pucker. The premacular vitreous cortex harbors the posterior wall of the posterior precortical vitreous pocket (PPVP), and the ERM is thought to develop on the posterior wall of the PPVP Several studies have noted that a fibrocellular ERM may increase the strength of the adhesion between the vitreous and the macula by anchoring the PViC to the underlying retinal surface. 3,4,10,20,21 A second proposed mechanism for the formation of ERM relates to dehiscences in the inner limiting membrane (ILM) that occur by transient vitreoretinal traction during the PVD process, which enables the migration and proliferation of cells of glial origin on the inner retinal surface. 6,7,20 However, such breaks have not been routinely detected on histopathologic analysis. 22 The association of PVD and ERM in eyes with diabetic macular edema (DME) is more complex. As for PVD in eyes with DME, a time-domain (TD) OCT study on 49 eyes with DME and 49 diabetic eyes without DME in patients aged 60 years or older, found prevalences of completely attached posterior vitreous in 38.8% and 69.4% of eyes, respectively, incomplete PVD in 55.0% and 22.4%, respectively, and total PVD was detected in 6.2% in each group. 23 The prevalence of ERM in diabetic retinopathy eyes of 661 U.S. patients (mean age, 63 years) detected in fundus photographs was studied. Cellophane macular reflex (the early stage of ERM) was detected in 28.4%, and ERM with preretinal macular fibrosis in 4.8% of the eyes. 24 Regarding ERM in DME, studies using either TD-OCT or Investigative Ophthalmology & Visual Science, August 2011, Vol. 52, No Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc.

2 IOVS, August 2011, Vol. 52, No. 9 Diabetic ERM and Incomplete PVD 6415 spectral-domain (SD)-OCT have found a prevalence of ERM ranging between 27% and 34.5% Gandorfer et al. 7 examined 61 eyes with DME and tangential vitreomacular traction: 23 (37.7%) of the eyes showed ERMs, which consisted of multilayered membranes situated on a layer of native vitreous collagen, predominantly coupled with fibroblasts and fibrous astrocytes. 7 In their study, only 15% (3/20) of the ERM eyes that had not undergone earlier pars plana vitrectomy, had total PVD. 7 However, an electron microscopic examination of the 61 DME specimens found native vitreous collagen covering the ILM in 98.3% (60/61) of them, including eyes diagnosed as having total PVD. 7 The activation of the hyalocytes, which may induce proliferation, migration, and gel contraction, may be induced by tumor necrosis factor (TNF)-, an inflammatory cytokine, as was found in a study of bovine eyes. 28 Recent studies suggest that vitreopapillary adhesion (VPA) may also significantly influence the vectors of force at the vitreoretinal interface by inducing centrifugal tangential contraction. This effect may result in secondary macular edema, cysts, and holes in both DME 29 and in the so-called idiopathic ERM. 4,30 The clinical diagnosis of either total PVD or complete attachment of the vitreous cortex, including the interpretation of the findings of ultrasonography and SD-OCT is subjective and can be challenging. In addition, the current resolution of SD- OCT does not often allow for differentiation between the completely attached PViC and the adjacent ILM. On the other hand, SD-OCT may accurately identify the PViC when it is partially detached. Using SD-OCT, we sought to determine the association between ERM and partial PVD in eyes with diffuse DME. METHODS In a retrospective study we reviewed the files and OCT scans of 49 eyes of 44 consecutive patients with DME associated with ERM that were recruited from our SD-OCT 1000 (Topcon Corp., Tokyo, Japan) data. Clinical ophthalmic examination included Snellen BCVA and slit lamp and fundus examinations. On biomicroscopy, all eyes had signs of proliferative or nonproliferative diabetic retinopathy, macular edema, and ERM. OCT scans of all eyes were performed through a dilated pupil by one of two trained examiners. 3-D data sets centered on the fovea (6 6 mm) were obtained for each patient. As a rule, 3-D data sets were also centered on the ONH in association with the central macula and were obtained using a raster scan program of 8.2 (horizontal) 3 (vertical) 1.7 mm (axial). Volumetric rendering of the data set was performed using image-processing software within the SD-OCT for 3-D image reconstruction. The SD-OCT characteristics are described elsewhere. 31 Data, including the B- and 3-D modes, could be evaluated by re-examining the recorded videos. ERM was defined as a membrane adherent to the inner retina, which presented as being either globally adherent and/or focally adherent. 8 The diagnosis of globally adherent ERM by the SD-OCT is based on a difference in the brightness (or bright red color by the pseudocolored OCT representation) of the surface tissue, which is more accurately and plainly noticeable by SD-OCT than by TD-OCT. 10 In comparison with TD-OCT, we could depict approximate measurements of the ERM area from the running movie of the SD-OCT B-mode. In this study, when the two membranes, the ERM and the PViC, appeared as one unified ERM/ PViC hyperreflective membranous tissue, it was termed an EVi membrane. The definition of cystoid spaces at the fovea and diffuse DME as detected by OCT has been given elsewhere. 32,33 The fovea could be designated as edematous when cystoid spaces were located at its site, even if the tissue was not abnormally thickened, because it could thin secondary to atrophy or lamellar hole formation. The 6-mm macular maps and the pseudocolored maps provided quantitative and qualitative information on the thickness of the retinal tissue at the site in question and were quantitatively compared with those of the normal controls. Based on our normative database (n 43 eyes of 43 patients; mean age, years, range, 29 89), the mean central subfield thickness (CST) on the 6-mm macular map was m. The study was limited to eyes with DME that was associated in each with ERM, as verified by SD-OCT. Exclusion criteria were eyes that had undergone (1) complete PVD or had completely attached PViC, (2) vitreoretinal surgery, (3) intravitreal administration of medication(s), (4) another retinopathy that could affect the data analysis, or (5) OCT scans of poor quality for a proper analysis. If both eyes of an individual had DME, ERM, and incompletely detached PViC, we used only one eye for analysis the one that had a better SD-OCT scan quality otherwise it was randomly chosen. Calculations of best corrected visual acuity (BCVA) were converted to the logarithm of the minimum angle of resolution (log-mar). Research complied with the Declaration of Helsinki, and the approval of the institutional ethics committee was obtained. RESULTS Of 49 eyes of 44 consecutive patients (mean age, [SD] years) with diffuse DME associated with ERM and qualified SD-OCT scans, only one eye per patient was analyzed. The PViC was incompletely detached in 23 (52.2%) of the 44 eyes (Table 1). Excluded from the analysis were eyes that were diagnosed to have either completely attached vitreous or complete PVD (n 19), that had been treated with intravitreal bevacizumab (n 1) or that had undergone pars plana vitrectomy (n 1). Patient characteristics and SD-OCT findings in each eye are presented in Table 1. In this study, an EVi membrane composed of the two membranous tissues, the ERM and the PViC, appeared as one unified ERM/PViC membrane in various sizes (Table 1) or split in different levels (Table 1; Figs. 1 5, 7; Supplementary Videos S1 S5B; iovs /-/dcsupplemental). The EVi membrane was detected in 20 (87.0%) eyes. Of these 20 eyes, the EVi membrane was associated with vitreopapillary adhesion in 19 (82.6% of all 23) eyes. In comparison with the hyperreflective adherent ERM, the PViC was commonly minimally reflective or hyperreflective to a certain extent. That hyperreflectivity was detected at the immediate site of its continuity with the ERM and was sized from 283 m in length (patient 17) and up to hyperreflectivity of most of the detached membrane (patient 18; Supplementary Video S3; iovs /-/dcsupplemental). Three hyperreflective PViC membranes were vascularized to a certain extent (patients 6, 12, and 13). The OCT presentations are divided into three groups (presented as a scheme in Fig. 7): Group A: incomplete PVD from the ONH (n 11 eyes; 25% of all 44 eyes), but attached to the macular ERM (Fig. 1, Supplementary Video S1, doi: /iovs /-/dcsupplemental), thus presenting as EVi membrane. Horizontally, continuation between the vitreopapillary vitreous cortex and the EVi membrane as one united membrane was seen in 10 of the 11 eyes. Group B: PVD from the macula, associated with vitreopapillary adhesion (10 eyes; 22.7%). The SD-OCT findings presented four variants (Table 1): B-I: incomplete vitreomacular detachment (n 4). The hyperreflective EVi membrane was split at the macular site but was reunited at an extrafoveal site (n 3; Supplementary Video S2, DCSupplemental) or centrally (n 1), associated with vitreopapillary adhesion.

3 6416 Ophir and Martinez IOVS, August 2011, Vol. 52, No. 9 TABLE 1. Data on Patients with DME, ERM, and Partial PVD Patient A/S/E BCVA Central Subfield Thickness ( m) Hyperreflective Epimacular Membrane Size (mm) Retinopathy/Laser Treatment Group A: Partial Vitreopapillary Detachment 1 62/F/L 20/ PDR/No 2 47/F/R 20/ PDR/PRP 3 79/F/R 20/ PDR/No 4 63/F/R 20/ PDR/PRP 5 77/M/R 20/ NPDR/No 6 66/M/R 20/ PDR/PRP 7 66/M/L 20/ PDR/PRP 8 70/F/L 20/ PDR/Grid 9 63/F/L 20/ PDR/No 10 66/F/L 20/ PDR/No 11 75/F/R 20/ NPDR/No Mean 67 20/ SD Group B-I: Partial Vitreomacular Detachment 12 65/M/R 20/ NPDR/Grid 13 51/M/R 20/ PDR/No 14 62/M/R 20/ PDR/PRP 15 71/F/L 20/ NPDR/No Mean 62 20/ SD Group B-II: Vitreomacular Traction 16 81/M/R NPDR/No 17 72/F/R NPDR/No 18 70/F/L PDR/No Mean 74 20/ SD 6 43 Group B-III: Full-Thickness Split of the Unified ERM/PViC Membrane 19 77/F/R 20/ NPDR/No 20 84/F/R 20/ NPDR/No Mean 81 20/ SD 5 18 Group B-IV: Total Detachment of the Unified ERM/PViC Membrane from Macula 21 81/M/L 20/ No epiretinal membrane NPDR/No Group C: Total Separation between the ERM and the Posterior Vitreous Cortex 22 65/F/L 20/ PDR/PRP 23 82/M/R 20/ NPDR/No Mean 74 20/ SD A/S/E, age/sex/eye; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; PRP, panretinal photocoagulation. B-II: vitreomacular traction (n 3). The EVi membrane was adherent to the foveal site and associated with CME in each (Fig. 3A; Supplementary Video S3, doi: /iovs /-/dcsupplemental). The EVi membrane was detached perifoveally and separated, and a small part of it remained adherent as an ERM at the adjacent extrafoveal site. More peripherally, the two separated ERM/ PViC membranes were reunified as one EVi membrane that was detached from the retina (Fig. 3B, Supplementary Video S3, lookup/suppl/doi: /iovs /-/dcsupplemental), associated with vitreopapillary adhesion. B-III: incomplete PVD from the macula, coupled with fullthickness localized split of the EVi membrane (n 2; 4.5%). The full-thickness split in the relatively thin membrane was coupled with its retraction and rolling (Fig. 4, Supplementary Video S4, DCSupplemental). B-IV: complete separation of the hyperreflective united EVi membrane from the macula (n 1; 2.3%). The detached membrane was continuous with an adherent hyperreflective membrane at a site adjacent and nasal to the ONH (Fig. 5; Supplementary Videos S5A, S5B, suppl/doi: /iovs /-/dcsupplemental). Group C: complete separation of the minimally reflective PViC from the adherent ERM (n 2; 4.5%). In each, the PViC was attached to the ONH and was not in continuity with the ERM (Fig. 6; Supplementary Video S6, lookup/suppl/doi: /iovs /-/dcsupplemental). A schematic presentation of the OCT findings is summarized in Figure 7. DISCUSSION In 44 eyes (44 patients) with diffuse DME associated with ERM, we detected, by using SD-OCT, 52.3% (23/ 44) of eyes with incomplete PVD. In most (n 20; 87%) of these 23 eyes, the partially detached, commonly minimally reflective PViC and the hyperreflective adherent membrane, which is generally designated as ERM, appeared as one continuous

4 IOVS, August 2011, Vol. 52, No. 9 Diabetic ERM and Incomplete PVD 6417 FIGURE 1. A 63-year-old patient (group A) with DME in his right eye (patient 4, Table 1). The B-mode SD-OCT reveals a unified adherent ERM/posterior vitreous cortex (PViC) membrane, or EVi membrane, at the macula and incompletely detached vitreopapillary adhesion. Continuation between these two membranes is evident. See also Supplementary Video S1, iovs /-/dcsupplemental. membrane (Figs. 1 5; Supplementary Videos S1 S5B, DCSupplemental). Based on these observations, which can be supported by histologic findings, 7 it can be assumed that the hyperreflective adherent epimacular membrane is commonly composed of a united fibrocellular membrane (ERM)/ PViC complex, or the EVi membrane. This membrane appeared unified as one membrane, but commonly also separated for various lengths. The EVi membrane was typically in continuum with the posterior vitreous cortex associated with vitreopapillary adherence, which could be verified in 19 of the 20 eyes with EVi membrane. Naturally, the EVi membrane would present only in eyes with partial PVD or completely attached vitreous. It may be assumed that the EVi membrane would be continuously involved in the dynamic PVD process. The various associations between the ERM, the EVi membrane, and the PVD are also presented in a scheme, which provides a proposed scenario of the evolution of ERM and its relation with the incomplete PVD in DME (Fig. 7). If the above findings are verified, the hyperreflective EVi membrane engaging the PViC, adhering to the retina and stretched to some extent between the macular area and the FIGURE 3. A 70-year-old patient (subgroup B-II) with DME and vitreomacular traction in his left eye (patient 18; see also Supplementary Video S3, (A) The B-mode SD-OCT reveals a unified ERM/PViC (EVi) membrane that is adherent to the central macular site. The relatively thick EVi membrane (arrow), which is overlying cystoid macular edema and tiny amount of subretinal fluid, splits and continuous with both a detached hyperreflective membrane at the posterior vitreous cortex and a broken and thinner hyperreflective adherent ERM. (B) The B-mode SD-OCT discloses reunion between these separated membranes at an extrafoveal site. ONH may suggest explanations for some of the complications associated with incomplete PVD in DME, including diffuse macular edema, tangential vitreoretinal traction, and vitreomacular, vitreoretinal, and vitreopapillary traction. The exception was the eyes of group C, which presented complete separation of the PViC from the adherent ERM. The PViC was attached to the ONH and was not in continuity with the ERM. Although it might present another variant that followed ERM generation in diabetic retinopathy, the possibility that detachment of the PViC from the macula took place before the ERM was generated, as often occurs in idiopathic ERM, cannot be ruled out. The frequent separation or split within the EVi membrane in some eyes, such as in subgroups B-I and -II, looked FIGURE 2. A 51-year-old patient (subgroup B-I) with DME and incomplete vitreomacular detachment (patient 13). The unified EVi membrane, composed of the posterior vitreous cortex (arrowhead) and an ERM (arrow) is split into two hyperreflective membranes. The membrane is vascularized for a certain extent (star), and associated with vitreopapillary adhesion (not presented). See also Supplementary Video S2, DCSupplemental. FIGURE 4. An 84-year-old patient (subgroup B-III) with DME in his right eye (patient 20). The B-mode SD-OCT discloses a full-thickness split in the relatively thin unified ERM/PViC membrane coupled with its retraction and rolling. See also Supplementary Video S4, iovs.org/lookup/suppl/doi: /iovs /-/dcsupplemental.

5 6418 Ophir and Martinez IOVS, August 2011, Vol. 52, No. 9 FIGURE 5. An 81-year-old patient (subgroup B-IV) with DME in his left eye (patient 21). A detached unified ERM/PViC (EVi) membrane is continuous with an adherent hyperreflective membrane (arrow) adjacent and nasal to the ONH (as seen in the videos). The findings indicate a spontaneously detached EVi membrane. The inner retina under the detached membrane looks distorted (arrowhead). See also Supplementary Videos S5A, S5B, /iovs /-/DCSupplemental. somewhat similar to that described in vitreoschisis. 3 5 However, we used the term vitreoschisis when the split was apparent only at the native PViC during the anomalous PVD process (i.e., before ERM emerged, as previously described for the nondiabetic, idiopathic ERM). Yet, the splitting of the EVi membrane may be a variant of vitreoschisis. On the other hand, it is difficult to tell whether the split outer membrane is an ERM, an outer layer of vitreous cortex, an ILM, or an ILM with overlying proliferated cells. The split of the hyperreflective EVi membrane having been recognized in subgroup B-I, for example, leaving an epimacular membrane intact, is different from the full-thickness separation of the EVi membrane in subgroup B-IV, which may be of more benefit than the former. According to Sebag, 4 it is possible that at least part of the multilamellar structure present at the vitreoretinal interface in pathologic eyes is the internal limiting membrane of the retina rather than the PViC alone. In light of such understanding, it would be important to determine (1) the origin of the initial ERM in diabetic retinopathy; (2) the trigger for its generation in human eyes (e.g., TNF- or other cytokines); and (3) whether the hyperreflective EVi membrane, totally detached from the macula (subgroup B-IV), adheres to the underlying ILM in a different mode than in the one that enabled the EVi membrane itself to split in B-I, for example. The spontaneously detached EVi membrane seems to mimic spontaneous FIGURE 6. A 65-year-old patient (group C) with DME and minimally reflective posterior vitreous cortex completely separated from the ERM in his left eye (patient 22). No continuation was detected between these two membranes. See also Supplementary Video S6, iovs.org/lookup/suppl/doi: /iovs /-/dcsupplemental. FIGURE 7. Top: A proposed scenario of the evolution of ERM, the unified ERM/ PViC (EVi) membrane and incomplete PVD in DME, and the various associations between them and the posterior vitreous cortex as detected by SD-OCT. Typically, an early ERM is initially generated in an eye with diabetic retinopathy with completely attached vitreous. The ERM, which gradually thickens, and the posterior vitreous cortex, which is also associated with a vitreopapillary adhesion and the internal limiting membrane gradually become adherent to each other. *Posterior premacular vitreous cortex; **liquefied vitreous. Group A: incomplete vitreopapillary detachment with attachment to the macular hyperreflective EVi membrane. Group B: incomplete vitreomacular detachment with vitreopapillary adherence. The four variants are: (B-I) The hyperreflective EVi membrane is split at the macular site but reunites at an extrafoveal site. (B-II) Vitreomacular traction. The EVi membrane is adherent to the foveal site and detaches perifoveally, whereas part of it remains as ERM at the adjacent extrafoveal site. (B-III) Incomplete detachment of EVi membrane from the macula, associated with localized full-thickness break of this membrane. (B-IV) Complete separation of the hyperreflective EVi membrane from the macula. The detached membrane was continuous with an adherent hyperreflective membrane at a site adjacent and nasal to the ONH. Group C: The posterior cortical vitreous is completely separated from the ERM and is attached to the optic nerve head. ERM detachment, as previously described before the OCT era. 34 We found an anomalous initial emergence of incomplete vitreopapillary PVD in 11 eyes (25% of 44, group A; Fig. 1, Supplementary Video S1, /iovs /-/DCSupplemental). This emergence occurred before the presentation of perifoveal PVD, which would typically occur as the first site of a normal PVD process. This atypical initial location may be related in part to the probable existence of the adherent fibrocellular ERM during the period of completely attached vitreous, which could anchor the PViC to the underlying retinal surface as suggested in the idiopathic ERM, 10,20,21 and interfere with the natural PVD process at the perifovea (Figure 7, top). That notion is based on the belief that diabetic retinopathy is a risk factor for ERM, which may initially present as a cellophane macular reflex. 24 Furthermore, the prevalence of total PVD in DME was found in only 6% of patients 60 years old. 23 These data may suggest a higher prevalence of ERM in the general

6 IOVS, August 2011, Vol. 52, No. 9 Diabetic ERM and Incomplete PVD 6419 population, before total PVD takes place, which contradicts the relatively common finding of PVD before the emergence of the so-called idiopathic ERM. 3 The occurrence of a fullthickness split in the EVi membrane in two eyes in the present study (subgroup B-III) may serve as a gross perception of the force generated during the anomalous PVD process and the strong resistance imposed from the retinal site for that process to occur. During complete attachment of the PViC, the meticulous relation between the attached PViC and the underlying ERM was often not recognized using the current SD-OCT (6- m resolution). Therefore, a higher OCT resolution and/or an adequate follow-up of eyes with diabetic retinopathy associated with ERM in the stage of complete posterior vitreous attachment may help determine when PVD is initiated and whether the adherent hyperreflective tissue was already composed of both the attached PViC and the ERM. This finding may have a clinical significance in the context of the prevention and treatment of this complication, at this early stage or even earlier. In an earlier study, using TD-OCT we demonstrated that vitreopapillary traction was associated with diffuse DME. 29 Recently, Wang et al. 30 presented data on 28 eyes that had nondiabetic, idiopathic macular pucker. 30 Most of these eyes with ERM and macular pucker, presumably associated with centripetal contraction, have already had PVD, whereas the minority also had vitreopapillary adhesion associated with macular cysts. 30 In contrast, most of the eyes (19/23) in our present study had vitreopapillary adhesion, which was in continuum with vitreomacular adhesion at some site(s) as well. The relatively wide EVi membrane being stretched between the ONH site and the macula might be indirectly affected by anterior forces that are generated during the PVD process. These vectors would probably be more potent on the less tightly vitreoretinal adherent sites (i.e., on the extramacular and extra-papillary ones). Such vectors may support the notion of a centrifugal force impacted on the EVi membrane that is stretched between the macula and the ONH. Limitations of the present study relate to the relatively small series and the lack of follow-up in eyes with ERM and completely attached vitreous when partial PVD is initiated, as described. However, the study results indicate that in eyes with DME, the posterior vitreous cortex and the adherent ERM are commonly united into one membrane, the unified ERM/ PViC (EVi) membrane, which is typically associated with vitreopapillary adherence. Additional studies with a larger cohort and adequate follow-up may add to our understanding the initiation and characteristics of the hyperreflective ERM and the unified ERM/ PViC membrane in DME as well as their prevention and removal, either therapeutically 35 or surgically. References 1. Wilkinson CP, Rice TA. Michels R. Retinal Detachment. 2nd ed. St. Louis: Mosby; 1990: Gass JDM. 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