Microcystoid Macular Changes in Association with Idiopathic Epiretinal Membranes in Eyes with and Without Glaucoma: Clinical Insights

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Microcystoid Macular Changes in Association With Idiopathic Epiretinal Membranes in Eyes With and Without Glaucoma: Clinical Insights

ANDREA GOVETTO, DANIEL SU, MATTHEW FARAJZADEH, ALIN MEGERDICHIAN, EVA PLATNER, YVETTE DUCOURNAU, GIANNI VIRGILI, AND JEAN PIERRE HUBSCHMAN

PURPOSE: To describe the clinical and surgical signifi- CONCLUSIONS: This study reports a high frequency of cance of microcystoid macular changes in the inner nuclear microcystoid macular changes in the inner nuclear layer layer in patients with idiopathic epiretinal membranes, with in eyes with concomitant epiretinal membrane and glau- and without glaucomatous optic neuropathy. comatous optic neuropathy. In glaucomatous eyes, pars DESIGN: Retrospective case series. plana vitrectomy with epiretinal and internal limiting METHODS: Clinical charts and spectral-domain optical membrane peel was ineffective in the treatment of micro- coherence tomography images of 264 eyes of 234 consec- cystoid macular changes. (Am J Ophthalmol utive patients diagnosed with idiopathic epiretinal mem- 2017;181:156–165. Ó 2017 Elsevier Inc. All rights branes were reviewed and analyzed. Surgical data were reserved.) analyzed in a subgroup of eyes with microcystoid macular changes treated with pars plana vitrectomy and epiretinal and internal limiting membrane peel. In surgical cases, PIRETINAL MEMBRANE (ERM) IS A FIBROCELLULAR postoperative functional and anatomic results at 1 and preretinal tissue mainly composed by glial cells, fi- 6 months were compared between glaucomatous and broblasts, and hyalocytes located over the internal E 1 nonglaucomatous eyes. Associations of microcystoid limiting membrane (ILM). The presence of ERM may macular changes with visual acuity and other morpho- change the normal macular microanatomy significantly, metric parameters were assessed by means of linear or resulting in increased retinal thickness, disruption of multiple logistic regressions. retinal layers, formation of ectopic inner foveal layers, 2 RESULTS: Microcystoid macular changes in the inner and the appearance of intraretinal cystoid spaces. nuclear layer were diagnosed in 52 out of 264 eyes with Cystoid macular edema (CME) may be present in eyes epiretinal membranes (19.7%), of which 28 (55.0%) with ERMs and is frequently associated with other concom- had concomitant glaucoma. The likelihood to develop itant conditions such as diabetic retinopathy, retinal vein microcystoid macular changes increased at advanced glau- occlusions, and uveitis. Characteristic fluorescein leakage 3–5 coma and epiretinal membrane stages. The morphology of is demonstrated with fluorescein angiography. The microcystoid macular changes was similar between glau- presence of CME is infrequently seen with idiopathic comatous and nonglaucomatous eyes. Forty-four out of ERM without other concomitant conditions; when 52 eyes (84.6%) with microcystoid macular changes, of present, it is usually associated with thicker and advanced 2,6 which 20 were with glaucoma and 24 without glaucoma, membranes. In the setting of idiopathic ERMs, underwent surgery with pars plana vitrectomy and epireti- intraretinal fluid spaces often appear with optical nal and internal limiting membrane peel. At 1 and coherence tomography (OCT) imaging as multiple small 6 months after surgery the mean number of microcysts cystoid spaces located in the inner nuclear layer (INL). decreased significantly from baseline in nonglaucomatous This morphology of microcystoid macular changes in eyes (P [ .003 and P [ .002, respectively) and remained idiopathic ERMs may be similar to a specific subtype of unchanged in glaucomatous eyes (P [ .400 and P [ .700, macular edema, called retrograde maculopathy, which is respectively). observed in patients with advanced optic neuropathy of any etiology, including glaucomatous and neurologic conditions.7–20 Supplemental Material available at AJO.com. Retrograde maculopathy is defined by the presence of Accepted for publication Jun 23, 2017. multiple hyporeflective cystoid spaces, or pseudocysts, From the Retina Division, Stein Eye Institute, University of California located in the INL, characteristically in the parafoveal Los Angeles, Los Angeles, California (A.G., D.S., M.F., A.M., E.P., 11 J.P.H.); Pathological Anatomy and Cytology Department, Nantes area. There is currently no consensus on the pathophysi- University Hospital, Nantes, France (Y.D.); and Department of ology of retrograde maculopathy, and various factors may Opthalmology, Careggi University Hospital, Florence, Italy (G.V.). be responsible for its onset, including retrograde degenera- Inquiries to Jean Pierre Hubschman, Retina Division, Stein Eye Institute, University of California Los Angeles, 100 Stein Plaza, Los tion of inner retinal layers, inflammatory reactions, vitreor- 12,17,21 Angeles, CA 90095-7002; e-mail: [email protected] etinal traction, or a combination of these. Whether

156 © 2017 ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2017.06.023 microcystoid macular changes should be considered as a distinct clinical entity is controversial.21 TABLE 1. Exclusion Criteria for Study of Subjects With The morphologic similarities between microcystoid Idiopathic Unilateral or Bilateral Epiretinal Membrane macular changes seen in idiopathic ERMs and optic neuropathies may create confusion and complicate decisions Exclusion Criterion regarding surgical intervention. In fact, the presence of History of retinal detachment Intermediate or advanced age related macular degenera- intraretinal cystoid changes is often considered as a marker tion of severity in idiopathic ERMs and may lead to earlier sur- History of choroidal neovascularization of any etiology 22–24 gical intervention. Although pars plana vitrectomy Central serous chorioretinopathy (PPV) with ERM removal may result in the resolution of Proliferative diabetic retinopathy 22 microcystoid macular changes in idiopathic ERMs, its Nonproliferative diabetic retinopathy with history of clini- efficacy in eyes with concomitant optic neuropathy is cally significant diabetic macular edema uncertain. Macular telangiectasias The objectives of this study are to describe the clinical Tractional and degenerative lamellar macular holes spectrum of microcystoid macular changes in patients Full-thickness macular holes with ERM with and without concomitant glaucomatous History of central or branch retinal vein occlusion and optic neuropathy, and to report the functional and central or branch retinal artery occlusion History of inflammatory eye disorders anatomic results of PPV with ERM and ILM removal in History of Irvine-Gass syndrome eyes with ERM and microcystoid macular changes. Visually significant cataract History of endophthalmitis or any other intraocular infec- tion Retinal dystrophies Foveal hypoplasia/fovea plana History of ocular trauma METHODS Multiple sclerosis Neuromyelitis optica STUDY DESIGN: A retrospective, observational, and Intracranial tumors consecutive chart review of patients diagnosed with ERM Macular retinoschisis and seen by a single retina specialist (J.P.H.) between January 1, 2008 and June 31, 2016 at the Stein Eye Insti- tute, University of California Los Angeles, was performed. This study was approved by the Institutional Review foveal thickness was obtained with the automated ‘‘thick- Board of the University of California Los Angeles, and ness map’’ function of the Heidelberg Eye Explorer. the research project adhered to the tenets of the Declara- ERMs on OCT were defined as irregular and hyperre- tion of Helsinki. Cases were identified by a medical billing flective lines above the ILM, often accompanied by wrin- record search, using the International Statistical Classifica- kling of the underlying retina with hyporeflective spaces tion of Diseases and Related Health Problems, Ninth Revi- between the ERM and the ILM. Retinal layers were iden- sion (ICD-9) diagnosis code 362.56 for macular pucker. tified according to the lexicon proposed by the INCOCT 25 The inclusion criterion was the presence of idiopathic Consensus. ERMs were staged according to the staging 2 unilateral or bilateral ERM. Exclusion criteria are summa- system by Govetto and associates. Microcystoid macular rized in Table 1. Demographic and clinical information changes were defined as derived from the work of Burg- were reviewed and recorded. Surgical records of patients graaff and associates: presence of multiple, small hypore- with microcystoid macular changes who underwent PPV flective roundish–elliptical cystoid spaces, without the and ERM and ILM peel were reviewed. presence of cyst wall, located in the INL and not confluent with cystoid spaces in other retinal layers 16 OPHTHALMOLOGIC EVALUATION AND OPTICAL (Figure 1). COHERENCE TOMOGRAPHY IMAGING: Best-corrected Microcystoid macular changes were assessed quantita- visual acuity (BCVA) was recorded at each visit, reported tively by 2 independent and masked observers (A.G., in Snellen fraction and converted into logarithm of the D.S.) with OCT. All intraretinal cystoid spaces in each minimal angle of resolution (logMAR) values for statistical horizontal B-scan were manually counted by the 2 masked analysis. OCT images were obtained with the Spectralis observers at each visit, and separated by location (INL or OCT with eye-tracking dual-beam technology (Heidelberg elsewhere). The arithmetic mean of the values obtained Engineering GmbH, Heidelberg, Germany) and reviewed by each observer was then recorded. with the Heidelberg Eye Explorer (version 1.8.6.0) using The diagnosis of glaucomatous optic neuropathy was the HRA/Spectralis Viewing Module (version 5.8.3.0). made by a glaucoma specialist based on glaucomatous dam- All patients underwent the 20 3 15-degree macula raster age to the optic disc and abnormal visual field with or with 19 horizontal B-scans spaced 242 mm. Mean central without elevated intraocular pressure. The severity of the

VOL. 181 MICROCYSTOID MACULAR CHANGES IN EPIRETINAL MEMBRANES 157 STATISTICAL ANALYSIS: All the analyses were carried out using the STATA 14 data analysis and statistical soft- ware (StataCorp LLC, College Station, Texas, USA). Descriptive statistics were first calculated for all variables of interest. Mean and standard deviation (SD) values were calculated for continuous variables, and frequency and percentage were calculated for categorical variables. Parametric and nonparametric tests (Mann-Whitney U, Wilcoxon signed rank test) were used to compare quantitative variables, and x2 test and Fisher exact test were used to compare categorical variables. Univariate and multivariate logistic regression was used to evaluate associations of BCVA and the presence of microcystoid macular changes with the variables of interest. Differences were reported with 95% confidence intervals. A P value of <.05 was considered statistically significant.

RESULTS

BASELINE CHARACTERISTICS OF THE STUDY POPULATION: We reviewed the clinical charts of 815 patients diagnosed with ERM, of which 581 were excluded FIGURE 1. Morphology of microcystoid macular changes in owing to the presence of 1 or more exclusion criteria. At epiretinal membranes. Microcystoid macular changes were the end of the review process 264 eyes of 234 patients with defined with optical coherence tomography as multiple, small, idiopathic ERM, 122 male (52.1%) and 112 female hyporeflective, and roundish–elliptical spaces located in the (47.9%), were included in the study. Bilateral ERM was diag- inner nuclear layer of eyes with epiretinal membranes, usually nosed in 30 out of 234 patients (12.8%), and mean age of the located in the parafoveal area (white arrows). In some cases, study population was 70 6 8.6 years (range 36–90 years). especially in thicker stage 3 and 4 epiretinal membranes, Stage 1 ERM was diagnosed in 50 out of 264 eyes pseudocysts in the outer nuclear layer were also present (black (18.9%), stage 2 ERM in 126 out of 264 eyes (47.7%), stage arrow). 3 ERM in 71 out of 264 eyes (26.9%), and stage 4 ERM in 17 out of 264 eyes (6.4%). At baseline, mean central foveal thickness was 437 6 90 mm (range 240–845 mm) and glaucomatous optic neuropathy was graded according to significantly increased with ERMs of more advanced stages, the Hodapp-Parrish-Anderson scale as mild, moderate, with stage 1 ERMs being the thinnest and stage 4 ERMs the and severe glaucoma.26 thickest (P < .001). Glaucoma was present in 51 out of 264 eyes (19.3%) and SURGICAL PROCEDURES: In surgical cases, all surgeries was classified as mild in 25 out of 51 eyes (49.0%), moder- were performed by a single vitreoretinal surgeon (J.P.H.) ate in 6 out of 51 eyes (10.8%), and severe in 20 out of 51 with the Constellation vision system (Alcon, Fort Worth, eyes (39.2%). Texas, USA). All patients underwent a standard, 3-port 23 At baseline, microcystoid macular changes predominantly gauge PPV with ERM and ILM peel. Gieshaber ILM forceps located in the INL were diagnosed in 52 out of 264 eyes (Alcon, Fort Worth, Texas, USA) were used in all cases to (19.7%), of which 28 (55.0%) had concomitant glaucoma. peel both ERM and ILM. No dyes were used, but in some In eyes with microcystoid macular changes, the mean num- cases 0.1 mL of Kenalog (Bristol-Myers Squibb, Irvine, ber of pseudocysts was 61.8 6 77 at baseline. There were no California, USA) was applied over the retinal surface to significant differences in the mean number of pseudocysts enhance retinal surface visualization during ILM peel. At between eyes with and without glaucomatous optic neurop- the end of the surgery, partial air–fluid exchange was athy (50 6 62 and 82 6 92, respectively, P ¼ .100). performed in all cases, and subconjunctival vancomycin At baseline, the morphology of microcystoid macular and dexamethasone were injected over the sclerotomy changes in the INL was similar between eyes with and sites. without glaucomatous optic neuropathy, as shown in All patients were evaluated at 1 month and 6 months Figure 2 (Top, Bottom). However, among the eyes with after surgery, and potential postoperative complications microcystoid macular changes in the INL the presence of were recorded during the follow-up period. isolated, not confluent cystoid spaces in the outer nuclear

158 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2017 FIGURE 2. Morphology of microcystoid macular changes in eyes with and without glaucomatous optic neuropathy. (Top) The retinal nerve fiber layer thickness measured with optical coherence tomography is within normal limits. In this stage 3 epiretinal membrane, microcystoid macular changes can be seen in the inner nuclear layer (white arrows). Additionally, 2 roundish isolated pseudocysts in the outer nuclear layer are also present (black arrows). The pseudocysts in the outer nuclear layer are not confluent with those in the inner nuclear layer. (Bottom) The retinal nerve fiber layer thickness measured with optical coherence tomography is outside normal limits. The patient was diagnosed with advanced glaucoma. In this stage 2 epiretinal membrane, microcystoid macular changes are present exclusively in the parafoveal inner nuclear layer (white arrows).

layer (ONL) was seen in 12 out of 24 eyes (50.0%) without glaucomatous optic neuropathy and only in 5 out of 28 eyes TABLE 2. Multivariate Logistic Regression Model: (18.0%) with glaucomatous optic neuropathy, with a sig- Association of Microcystic Macular Changes and Predictors nificant difference (P ¼ .010). P Only 4 out of 28 eyes (14.9%) with INL microcystoid Predictors OR (95% CI) Value macular changes and glaucoma had history of topical hypo- Mild glaucoma 7.78 (2.6–23.7) <.001 tensive treatment with prostaglandin analogues. Twelve Moderate glaucoma 12.2 (1.9–79.5) .009 out of 52 eyes with microcystoid macular changes had his- Severe glaucoma 218 (37.2–1273) <.001 tory of topical treatment with ketorolac tromethamine Stage 2 ERM 2.06 (0.5–8.7) .324 (Acular, Parsippany-Troy Hills, New Jersey, USA) during Stage 3 ERM 11.9 (2.5–54.9) .002 Stage 4 ERM 37.5 (6.2–227) <.001 a mean of 10.4 6 7.4 months (range 2–24 months). Despite topical anti-inflammatory therapy, microcystoid macular CI ¼ confidence interval; ERM ¼ epiretinal membrane; changes persisted in all cases. OR ¼ odds ratio; SE ¼ standard error.

BASELINE ASSOCIATIONS OF MICROCYSTOID MACULAR CHANGES WITH BEST-CORRECTED VISUAL ACUITY, GLAU- sion model the likelihood to develop microcystoid macular COMA, AND OTHER SPECTRAL-DOMAIN OPTICAL COHER- changes increased significantly in eyes with advanced glau- ENCE TOMOGRAPHY/MORPHOMETRIC PARAMETERS: At coma, when compared with earlier stages of glaucoma baseline, mean BCVA among the study population was (P < .001). 0.2 6 0.23 logMAR (range 0–1.8 logMAR). In a multivar- In addition to their association with glaucoma, microcys- iate logistic regression model, lower baseline BCVA was toid macular changes were also significantly associated with associated with advanced glaucoma (P ¼ .002), stage 3 more advanced stages of ERM. At baseline, microcystoid and 4 ERMs (P < .001 and P ¼ 0.003, respectively), the macular changes were present in 7 out of 50 eyes (14.0%) presence of microcystoid macular changes (P ¼ .003), and with stage 1 ERM, in 18 out of 126 eyes (14.2%) with stage thicker central foveal thickness (P < .001). 2 ERM, in 19 out of 71 eyes (26.7%) with stage 3 ERM, and The association of microcystoid macular changes in the in 8 out of 17 eyes (47%) with stage 4 ERM. The difference INL and glaucoma was significant. Microcystoid macular in microcystoid macular changes between stages of ERM changes were present in 28 out of 51 patients (55.0%) was found to be statistically significant (P ¼ .002). Further- with glaucoma and only in 24 out of 213 patients more, in a logistic regression model the likelihood of devel- (11.3%) without glaucoma (P < .001). In a logistic regres- oping microcystoid macular changes increased significantly

VOL. 181 MICROCYSTOID MACULAR CHANGES IN EPIRETINAL MEMBRANES 159 TABLE 3. Baseline Characteristics of Surgical Eyes

Group (Number of Eyes) ERM (Stage) Glaucoma (Stage) CFT (mm) BCVA (logMAR)

Glaucoma (n ¼ 20) Stage 1: 3/20 (15.0%) Mild: 9/20 (45.0%) 461 6 89 0.35 6 0.19 Stage 2: 10/20 (50.0%) Moderate: 1/20 (5.0%) Stage 3: 4/20 (20.0%) Severe: 10/20 (50.0%) Stage 4: 3/20 (15.0%) No glaucoma (n ¼ 24) Stage 1: 0 (0%) N/A 522 6 84 0.38 6 0.16 Stage 2: 5/24 (20.8%) Stage 3: 15/24 (62.5%) Stage 4: 4/24 (16.7%) P value .010a .030b .700b

BCVA ¼ best-corrected visual acuity; CFT ¼ central foveal thickness; ERM ¼ epiretinal membrane; logMAR ¼ logarithm of minimal angle of resolution; N/A ¼ not applicable. aFisher exact test. bMann-Whitney U test.

with worsening ERM stage, being higher in stage 4 ERMs after surgery the mean number of microcysts did not change (P ¼ .003). significantly in glaucomatous eyes (P ¼ .400 and P ¼ .700, At baseline, earlier stage 1 and 2 membranes were diag- respectively), as illustrated in Figure 3, Left. On the other nosed in the majority of eyes with glaucoma and microcys- hand, in nonglaucomatous eyes the mean number of micro- toid macular changes (20 out of 28 eyes, 71.4%). On the cysts decreased significantly from baseline at 1 and other hand, more advanced stage 3 and 4 ERMs were pre- 6 months after surgery (P ¼ .003 and P ¼ .002, respec- dominant among eyes without glaucoma and microcystoid tively), as shown in Figure 3, Right. Furthermore, at macular changes (16 out of 24 eyes, 66.7%). The differ- 6 months after surgery the microcysts completely resolved ences among the 2 groups were significant (P ¼ .001). in 13 out of 24 nonglaucomatous eyes (54.0%), but only The significant association of microcystoid macular in 4 out of 20 eyes (20.0%) with glaucoma (Figure 4). changes with glaucoma and ERM stage was confirmed in a Central foveal thickness decreased significantly at both 1 multivariate logistic regression model, as shown in Table 2. and 6 months after surgery in both glaucomatous and nonglaucomatous surgical groups (P ¼ .009 and P ¼ .002, PREOPERATIVE CHARACTERISTICS OF THE SURGICAL P < .001 and P < .001, respectively). SUBGROUP: The majority of eyes with microcystoid macu- Postoperatively, changes in mean IOP at 1 and 6 months lar changes (44 out of 52 eyes, 84.6%), of which 20 were were not significant in both glaucomatous (P ¼ .630 with glaucoma and 24 without glaucoma, underwent surgery and P ¼ .090, respectively) and nonglaucomatous eyes with PPV and ERM and ILM peel. Preoperative BCVA was (P ¼ .080 and P ¼ .378, respectively). There were no cases similar between glaucomatous (0.35 6 0.19 logMAR) and of glaucoma progression to more advanced stages during nonglaucomatous surgical eyes (0.38 6 0.16 logMAR), the postoperative period. Postoperative functional and without significant differences (P ¼ .700). In this surgical anatomic results are summarized in Table 4. subgroup, the mean preoperative number of pseudocysts No severe intraoperative or postoperative complications was also similar between glaucomatous eyes (52.2 6 70) were reported. However, in the glaucomatous subgroup and nonglaucomatous eyes (91 6 98; P ¼ .100). In addition, there was a case of IOP spike at 1 month after surgery, the mean central foveal thickness associated with ERMs in possibly related to topical treatment with corticosteroids, the nonglaucomatous surgical group was significantly which was controlled with topical hypotensive therapy. thicker compared with the glaucomatous surgical group (522 6 84 mm and 461 6 89 mm, respectively; P ¼ .030). Mean preoperative IOP was 14.8 6 4 mm Hg in eyes with glaucoma and 14.6 6 3 mm Hg in eyes without glaucoma, DISCUSSION without significant differences (P ¼ .900). Preoperative characteristics of the surgical eyes are presented in Table 3. THIS STUDY EXPLORED THE CLINICAL AND SURGICAL SIG- nificance of microcystoid macular changes in idiopathic POSTOPERATIVE FUNCTIONAL AND ANATOMIC ERMs, and found a high frequency of this peculiar subtype RESULTS: Postoperative BCVA at 1 and 6 months were of macular change in eyes with ERMs and concomitant similar between eyes with and without glaucoma glaucomatous optic neuropathy (Figure 5). In glaucoma- (P ¼ .370 and P ¼ .700, respectively). At 1 and 6 months tous eyes, the prevalence of microcystoid macular changes

160 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2017 FIGURE 3. Box-plot chart. Surgical results: variations of the number of pseudocysts over the follow-up period in eyes with and without glaucoma. (Left) The number of pseudocysts did not change signiﬁcantly in the postoperative period in eyes with glaucoma. (Right) The number of pseudocysts signiﬁcantly reduced at both 1 and 6 months after surgery in eyes without glaucoma.

FIGURE 4. Surgical results: Morphologic changes over the follow-up period in eyes with and without glaucoma. (Top left) At baseline, microcystoid macular changes in the inner nuclear layer can be seen in this stage 3 epiretinal membrane without glaucoma (white arrows). (Center left) At 1 month from surgery, microcystoid macular changes in the inner nuclear layer resolved. (Bottom left) At 6 months from surgery, no microcystoid macular changes are present. (Top right) At baseline, numerous microcystoid macular changes are seen in the inner nuclear layer both temporally and nasally to the macula in this stage 3 epiretinal membrane associated with glaucoma (white arrows). (Center right) At 1 month from surgery, microcystoid macular changes persisted (white arrows), although their number is reduced temporally to the fovea. (Bottom right) At 6 months from surgery, despite significant retinal thin- ning, microcystoid macular changes are still present (white arrows). in the INL was approximately 55%, a value remarkably and without glaucoma. However, in glaucomatous eyes higher if compared with other published reports. For microcystoid macular changes were located exclusively in instance, Abegg20 and Pott and associates8 reported the INL, whereas in eyes without glaucoma nonconfluent microcystoid macular changes in roughly 9% and 20% pseudocysts in the ONL were occasionally present. This of eyes with optic neuropathy without ERM. Similar to finding may be explained by the fact that nonglaucomatous other reports, the prevalence of microcystoid macular eyes with microcystoid macular changes were often diag- changes increased significantly at later stages of glaucom- nosed with advanced and thicker stage 3 and 4 ERMs, atous optic neuropathy.17 Such data suggest that the pres- which may produce stronger traction, causing both inner ence of ERM may lower the threshold for the and outer retinal disruption with subsequent interstitial development of microcystoid macular changes, especially fluid accumulation. in eyes with optic neuropathy. Morphologic similarities may complicate the surgical de- In the present study, morphology and location of micro- cision. Although in idiopathic ERMs there is still lack of cystoid macular changes were similar between eyes with consensus on the timing of surgery, the presence of CME

VOL. 181 MICROCYSTOID MACULAR CHANGES IN EPIRETINAL MEMBRANES 161 TABLE 4. Functional and Anatomic Results in Surgical Eyes

BCVA (logMAR) CFT (mm) Pseudocysts (Mean 6 SD)

Group (Number of Eyes) Baseline 1 Month 6 Months Baseline 1 Month 6 Months Baseline 1 Month 6 Months

Glaucoma (n ¼ 20) 0.35 6 0.19 0.34 6 0.16 0.32 6 0.25 461 6 89 409 6 43 392 6 46 52 6 70 50 6 67 51 6 66 No glaucoma (n ¼ 24) 0.38 6 0.16 0.3 6 0.21 0.3 6 0.2 522 6 84 424 6 65 398 6 64 91 6 98 33 6 81 17 6 32 P value .700 .370 .700 .030 .400 .800 .100 .040 .010

BCVA ¼ best-corrected visual acuity; CFT ¼ central foveal thickness; logMAR ¼ logarithm of minimal angle of resolution. P value by Mann-Whitney U test.

FIGURE 5. Multimodal imaging of retrograde maculopathy. This eye with a stage 1 epiretinal membrane was diagnosed with advanced glaucoma. The en face segmentation of the inner nuclear layer reveals multiple hyporeflective cystoid spaces surrounding the foveal area (white arrows). RNFLT [ retinal nerve fiber layer thickness. may tip the scale toward earlier surgical intervention, as been referred to as retrograde maculopathy.17 The patho- CME may be considered a marker of ERM severity.22–24 genesis of retrograde maculopathy is uncertain, but transsy- In the present study, microcystoid macular changes naptic degeneration of inner retinal layers was proposed as improved significantly after surgery in eyes without one of its main determinants.17 Retrograde transsynaptic glaucoma (Figure 6, Top) but persisted in eyes with glau- degeneration is a phenomenon previously described in his- coma (Figure 6, Bottom). The significant differences in topathologic ex vivo studies, which can cause significant postoperative anatomic outcomes may suggest that micro- cellular loss in the INL, compromising fluid absorption cystoid macular changes have different pathophysiology in from the retina.17,27 Distinct from retrograde eyes with and without glaucoma. maculopathy, traction may play an integral role in the In eyes with glaucomatous optic neuropathy, the pres- pathophysiology of microcystoid macular changes in ence of microcystoid macular changes in the INL has idiopathic ERMs. As proposed by Johnson, anterior

162 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2017 FIGURE 6. Anatomic results at 6 months from surgery in eyes with and without glaucomatous optic neuropathy. (Top) At baseline, microcystoid macular changes are visible temporally and nasally to the fovea in this stage 3 epiretinal membrane without glaucoma (white arrows). At 6 months from surgery, microcystoid macular changes completely resolved. (Bottom) Microcystoid macular changes (white arrows) appeared unchanged 6 months after surgery in this stage 3 epiretinal membrane associated with glaucoma. RNFLT [ retinal nerve ﬁber layer thickness.

traction on the macular area may result in multicystoid certain similarities, they may represent different pathologic foveal thickening without capillary leakage.28 Although conditions with equally different clinical implications. the concept of ‘‘tractional CME’’ originally referred to After ERM removal, the postoperative persistence of vitreomacular traction disorders, it may be extended to CME may be considered a bad prognostic factor for func- include idiopathic ERMs.2 tional and anatomic recovery, and it is often treated with Tractional microcystoid macular changes and retrograde topical nonsteroidal anti-inflammatory drugs and cortico- maculopathy are both primarily located in the INL, which steroids.30 In refractory cases, treatment of persistent is the preferred location of CME of any etiology.29 This is CME may rely on more aggressive therapies such as intra- because the INL contains structures that are seminal in vitreal injections of anti–endothelial growth factor drugs maintaining retinal homeostasis, like the body of the and intraocular dexamethasone implants.31,32 In eyes Mu¨ller cells and the capillary bed of the deep retinal plexus. with glaucoma, in which persistent microcystoid macular As proposed by Spaide, there may be a gradient of intersti- changes in the INL are likely related to retrograde tial fluid moving from the superficial to the deep capillary maculopathy, the postoperative presence of pseudocysts plexus, which in physiologic conditions is reabsorbed by may be mistakenly considered a sign of inflammation and the Mu¨ller cells via aquaporin-4 (AQP4) channels.29 cause unnecessary treatments. Both mechanical stresses exerted by ERMs and trassynaptic The present study also raises questions on the effect of degeneration of Mu¨ller cells in optic neuropathies may ILM peel in glaucomatous eyes. To reduce the risk of disrupt this delicate equilibrium of forces and cause the ERM recurrence, systematic ILM peeling has been intro- accumulation of fluid in the inner retina. duced in ERM surgery, with promising results.33 However, Both tractional microcystoid macular changes and retro- the ILM is the basal lamina connected to the end feet of the grade maculopathy are part of the diverse clinical spectrum Mu¨ller cells, and its removal may cause changes in retinal observed within the broad term ‘‘CME.’’ However, despite physiology.34 ILM peeling may also damage the Mu¨ller cells

VOL. 181 MICROCYSTOID MACULAR CHANGES IN EPIRETINAL MEMBRANES 163 themselves, which may be already compromised in the macular changes. Finally, this was a single-surgeon series, setting of glaucomatous optic neuropathy.17,34 These which may have limited data heterogeneity. factors, together with the increasing evidence that PPV In conclusion, this study reports a high prevalence of itself may be a risk factor for developing or worsening microcystoid macular changes in ERMs and concomitant glaucoma, require careful consideration in the surgical glaucomatous optic neuropathy. These changes increased decision in these patients.35,36 significantly with more advanced ERM and glaucoma Finally, we feel that a revision of the current terminology stages. In glaucomatous eyes, PPV with ERM and ILM and classification of CME may be needed, as this term is too peel was ineffective in the treatment of microcystoid mac- broad and inclusive. In the literature, the presence of INL ular changes. The long-term clinical significance of microcystoid spaces has been referred to as ‘‘microcystic microcystoid macular changes in eyes with glaucomatous macular edema’’ or ‘‘microcystic macular changes.’’ Howev- optic neuropathy is still unknown, and the surgical deci- er, in the present study the term ‘‘microcystoid macular sion in these patients should be taken with caution. changes’’ was preferred, as it better reflects the nature and Persistent postoperative INL microcystoid macular morphology of these lesions. changes in eyes with glaucoma are likely related to retro- Limitations of this study include its retrospective design, grade maculopathy and most likely do not require addi- which may have increased the risk of bias; limited follow- tional treatment. up period; and the lack of fluorescein angiography imaging. Additional larger, prospective, and controlled studies are Strengths of our work include an appropriate study popula- necessary to confirm our results and to investigate the effects tion size and detailed quantitative analysis of microcystoid of ILM peeling in eyes with advanced optic neuropathy.

FUNDING/SUPPORT: THIS WORK WAS SUPPORTED BY AN UNRESTRICTED INSTITUTIONAL GRANT FROM RESEARCH TO PRE- vent Blindness (RPB), New York, New York, USA, and by a donation from the Hess Foundation, New York, New York, USA. Financial Disclosures: Jean Pierre Hubschman: consultant for Alcon (Fort Worth, Texas, USA), Pixium-Visium (Paris, France), Allergan (Parsippany-Troy Hills, New Jersey, USA), and Avalanche Biotechnologies (Menlo Park, California, USA). The following authors have no ﬁnancial disclosures: Andrea Govetto, Daniel Su, Matthew Farajzadeh, Alin Megerdichian, Eva Platner, Yvette Ducournau, and Gianni Virgili. All authors attest that they meet the current ICMJE criteria for authorship.

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