Purpose
To evaluate the effects of epiretinal membranes on the response of uveitic macular edema to therapy and on visual acuity outcomes.
Design
Retrospective case series.
Methods
One hundred four eyes of 77 patients with uveitic macular edema were identified at a tertiary care center. Epiretinal membranes were diagnosed when identified by 2 investigators’ grading of spectral-domain optical coherence tomography and scored for the presence or absence of surface wrinkling. Outcomes included best-corrected visual acuity, central subfield thickness, and rates of macular edema improvement (>20% reduction in central subfield thickness) and resolution (reduction of central subfield thickness to <315 μm) at 3 and 6 months follow-up.
Results
Seventy-two eyes of 59 patients had an epiretinal membrane on presentation. Eyes without epiretinal membranes and with epiretinal membranes without surface wrinkling were not significantly different at presentation or at 3 and 6 months follow-up. Conversely, eyes with an epiretinal membrane with retinal surface wrinkling had a greater proportion of eyes with 20/200 or worse visual acuity at presentation, and had worse mean acuities at 3 months (20/94 vs 20/35 for eyes without an epiretinal membrane, P = .002) and at 6 months follow-up (20/110 vs 20/36 for eyes without an epiretinal membrane, P = .02). At 6 months of follow-up the mean central subfield thicknesses were: eyes without an epiretinal membrane, 338 ± 23 μm; and eyes with an epiretinal membrane and surface wrinkling, 405 ± 22 μm ( P = .05).
Conclusions
In eyes with epiretinal membranes and retinal surface wrinkling, uveitic macular edema had a poorer visual acuity response to medical therapy and thicker maculae at 6 months.
Uveitic macular edema is the most common cause of visual impairment in patients with uveitis and the most frequent structural complication of uveitis. Epiretinal membrane formation in association with uveitis and uveitic macular edema is a relatively common structural complication of the uveitis. The advent of optical coherence tomography (OCT), and, in particular, spectral-domain optical coherence tomography, has improved our ability to detect epiretinal membranes and describe their morphologic effects on the retina. Detrimental clinical effects of epiretinal membrane formation on uveitic macular edema have been described. Epiretinal membranes have been associated with worse visual acuity in uveitic macular edema patients 3 months after treatment with intravitreal triamcinolone acetonide, as well as a higher risk of failing medical therapy for uveitic macular edema. In one study, foveal involvement of the epiretinal membrane and focal attachment of the epiretinal membrane to the inner retinal surface were predictors of poor vision. The goal of our study was to characterize the effects of epiretinal membranes in uveitic macular edema on visual acuity, and on improvement and resolution of the edema.
Methods
A retrospective review of patients with uveitic macular edema seen at the Department of Ophthalmology at the Icahn School of Medicine at Mount Sinai from 2008 through 2011 was conducted. Prior to the initiation of the study, approval was obtained from the Institutional Review Board of the medical school. A query of the billing records database cross-referencing cases of uveitis (ICD-9 codes 363.00–364.99) and macular edema (ICD-9 code 362.53) was performed in order to identify cases of uveitic macular edema. Additionally, all spectral-domain OCTs (Heidelberg Spectralis; Heidelberg Engineering, Vota, California, USA) of patients with diagnosis codes 363.00–364.99 were reviewed in order to ensure complete identification of uveitic macular edema cases. The data collection period spanned from September 2008, when spectral-domain OCT capability was obtained, until December 2011, and all patients meeting the criteria were included. All spectral-domain OCT measurements were performed on the Heidelberg Spectralis machine using volume scans and registration between scans. Macular edema was diagnosed based on spectral-domain OCT findings. Patients with choroidal neovascularization with associated retinal edema were excluded. Only de-identified, HIPAA-compliant data were entered into the database for statistical analysis.
Data Collection and Outcome Measures
Uveitic macular edema patients were identified, and all OCTs of both eyes were reviewed, confirming the presence or absence of an epiretinal membrane, which was defined as a thin, smooth hyper-reflective layer between the neural retina and the vitreous ( Figure ). The first visit at which uveitic macular edema was identified (macular edema “presentation” or baseline visit) was used to categorize patients and eyes as either having or not having an epiretinal membrane. All available cross-sections of the macula at the baseline visit were scored independently by the same 2 investigators (B.L. and P.P.). At the end of this initial data collection phase, the investigators reviewed together any OCT on which there was initial disagreement regarding epiretinal membrane status and thereby reached a consensus interpretation for all OCTs. In many cases, the epiretinal membrane was attached at multiple focal points to the underlying internal limiting membrane, creating hyporeflective spaces between the epiretinal membrane and internal limiting membrane, and producing numerous folds or wrinkles along the internal limiting membrane. Therefore, the epiretinal membranes were scored as either associated with retinal surface wrinkling or not associated with wrinkling by the same 2 investigators. Central subfield thickness, as recorded by the Spectralis OCT, and best-corrected visual acuity data were recorded at presentation and at 3 months and 6 months after presentation. Only the available data for each patient were used, and those patients who did not complete both a 3- and 6-month follow-up visit by the end of the data collection period were noted as having only partial follow-up. A central subfield retinal thickness of 315 μm or greater as calculated by the Spectralis OCT was used to identify macular edema. The presence of cystoid spaces also was noted.
For the analysis of outcomes, resolution of macular edema was defined as a decrease in macular thickness to a normal level (<315 μm). Improvement in edema was defined as achieving at least a 20% reduction in macular thickness or resolution of edema if a less than 20% decrease led to a macular thickness of less than 315 μm. LogMAR transformation was used to determine mean acuities and converted back to Snellen acuities for reporting purposes. Previously described logMAR equivalents for hand motion or count fingers acuities were used where necessary. In addition, the percentage of patients with acuities at traditional benchmark thresholds (20/200 or worse and 20/40 or better) were recorded at baseline, 3 months, and 6 months. Months elapsed since the diagnosis of uveitis; patient sex, age, and race; presence or absence of subretinal fluid; treatment regimen (regional corticosteroids, oral corticosteroids, immunomodulatory therapy, or combination regional and oral corticosteroids); and anatomic location of uveitis (anterior, intermediate, anterior and intermediate, posterior, or panuveitis) also were noted and accounted for as potential confounders.
Statistical Analysis
Eyes without an epiretinal membrane served as the control group for comparisons to (1) eyes with an epiretinal membrane without surface wrinkling and (2) eyes with an epiretinal membrane with surface wrinkling. Eyes with an epiretinal membrane without and with surface wrinkling were also compared. Central subfield thickness and logMAR visual acuity were related to the presence or absence of the epiretinal membrane type using mixed analysis of variance (ANOVA) models, stratified by visit. The correlation between eyes in the same patient was accounted for by these models. The binary outcomes of improvement and resolution of macular edema were related to presence or absence of an epiretinal membrane (without or with wrinkling) using log-binomial regression models. Similar to the mixed ANOVA models, this method accounts for the correlation between measurements taken from 2 eyes of the same patient. The parameters of these models were estimated using generalized estimating equations methods. Patient characteristics on categorical and continuous variables were compared between epiretinal membrane groups using χ 2 and Wilcoxon tests, respectively. SAS 9.2 (SAS Institute Inc, Cary, North Carolina, USA) was used to conduct all analyses. No correction was made for multiple comparisons, and all hypothesis testing was conducted at the 5% level. Since the median ages of patients with and without an epiretinal membrane were significantly different, all analyses of the impact of epiretinal membranes on outcomes were age adjusted.
Results
Characteristics of the Patient Population
Table 1 outlines the general characteristics and demographics of the study population. Seventy-seven patients with uveitic macular edema were identified. There were 10 different uveitic diagnoses, the most frequent one of which was intermediate uveitis, non–pars planitis type, present in 26%. Of these 77 patients, 59 (76.6%) had an epiretinal membrane in at least 1 eye, and 18 (23.4%) did not have an epiretinal membrane in either eye. Patients with an eye with an epiretinal membrane either without (median, 55 years, P = .01 vs eyes without an epiretinal membrane) or with surface wrinkling (median, 63 years, P = .0005 vs eyes without an epiretinal membrane) were significantly older than those without an epiretinal membrane (median, 40.5 years). No other significant differences among the 3 groups in patient characteristics at presentation were identified.
| Characteristic | All Patients | No Epiretinal Membrane | Epiretinal Membrane, No Wrinkling | P Value a | Epiretinal Membrane With Wrinkling | P Value a | P Value b |
|---|---|---|---|---|---|---|---|
| Number of patients | 77 | 18 | 33 | 26 | |||
| Percent of population | 100 | 23.4 | 42.8 | 33.8 | |||
| Age (y) | .01 | .0005 | .09 | ||||
| Median | 55 | 40.5 | 55 | 63 | |||
| Interquartile range | 41–66 | 28–48 | 42–65 | 51–68 | |||
| Sex (%) | .24 | 1.0000 | .20 | ||||
| Male | 43 | 50 | 33 | 50 | |||
| Female | 57 | 50 | 67 | 50 | |||
| Race (%) | .25 | .66 | .94 | ||||
| White, non-Hispanic | 70 | 56 | 76 | 73 | |||
| Hispanic | 9 | 11 | 9 | 8 | |||
| African American | 17 | 28 | 12 | 15 | |||
| Other | 3 | 6 | 0 | 4 | |||
| Months since uveitis diagnosis | .21 | .07 | .63 | ||||
| Median | 23 | 10.5 | 20 | 24 | |||
| Interquartile range | 5–56 | 3–36 | 4–84 | 7–60 | |||
| Anatomic type of uveitis (%) | .83 | .76 | .34 | ||||
| Anterior | 16 | 11 | 21 | 12 | |||
| Intermediate | 22 | 22 | 27 | 15 | |||
| Anterior & intermediate | 23 | 28 | 24 | 19 | |||
| Posterior | 22 | 17 | 15 | 35 | |||
| Panuveitis | 17 | 22 | 12 | 19 | |||
| Macular edema | |||||||
| Bilateral macular edema (%) | 35 | 39 | 30 | .53 | 38 | .98 | .51 |
| Patients with subretinal fluid in at least 1 eye (%) | 40 | 61 | 36 | .09 | 31 | .65 |
a P value comparing patients in group to those with uveitic macular edema without an epiretinal membrane.
b P value comparing patients with uveitic macular edema, an epiretinal membrane, and surface wrinkling to those with an epiretinal membrane without surface wrinkling.
Epiretinal Membrane, Macular Thickness, and Visual Acuity at Presentation
Table 2 details the pairwise comparisons of eyes without an epiretinal membrane at presentation, with an epiretinal membrane without surface wrinkling at presentation, and with an epiretinal membrane and surface wrinkling at presentation. There were no significant differences in mean central subfield retinal thickness among the 3 groups; mean central subfield retinal thickness ± standard errors were: 420 ± 25 μm for eyes without an epiretinal membrane; 401 ± 21 μm for eyes with an epiretinal membrane without surface wrinkling ( P = .55 vs eyes without an epiretinal membrane); and 442 ± 24 μm for eyes with an epiretinal membrane with surface wrinkling ( P = .52 vs eyes without an epiretinal membrane). Mean Snellen acuities were 20/59 for eyes without an epiretinal membrane; 20/64 for eyes with an epiretinal membrane without surface wrinkling ( P = .37 vs eyes without an epiretinal membrane); and 20/109 for eyes with an epiretinal membrane and surface wrinkling ( P = .61 vs eyes without an epiretinal membrane). However, the percentage of eyes with presenting visual acuities 20/200 or worse appeared to be greater among those with an epiretinal membrane with surface wrinkling than among those without an epiretinal membrane. The percentages of eyes with 20/200 or worse acuity at presentation were: eyes without an epiretinal membrane, 16%; eyes with an epiretinal membrane without surface wrinkling, 13% ( P = .36 vs eyes without an epiretinal membrane); and eyes with an epiretinal membrane with surface wrinkling, 38% ( P = .02 vs eyes without an epiretinal membrane).
| Characteristic | Eyes Without an Epiretinal Membrane | Eyes With an Epiretinal Membrane Without Wrinkling | Mean Difference/Risk Ratio a | P Value a | Eyes With An Epiretinal Membrane and Wrinkling | Mean Difference/Risk Ratio a | P Value a | Mean Difference/Risk Ratio b | P Value b |
|---|---|---|---|---|---|---|---|---|---|
| Number of eyes | 32 | 38 | 34 | ||||||
| Central subfield thickness (μm) | |||||||||
| Mean | 420 | 401 | −18 | .55 | 442 | 23 | .52 | 41 | .19 |
| Standard error | 25 | 21 | [−78, 42] | 24 | [−47, 93] | [−21, 103] | |||
| Cystoid spaces (%) | 44 | 63 | 1.34 [0.81–2.23] | .25 | 56 | 1.13 [0.65, 1.95] | .66 | 0.84 [0.58, 1.22] | .36 |
| Visual acuity (logMAR) | |||||||||
| Mean | 0.444 | 0.52 | 0.077 | .37 | 0.73 | 0.287 | .08 | 0.210 | .15 |
| Standard error | 0.116 | 0.10 | [−0.215, 0.369] | 0.11 | [−0.040, 0.614] | [−0.079, 0.498] | |||
| Mean Snellen acuity | 20/59 | 20/64 | 20/109 | ||||||
| 20 /40 or better (%) | 53 | 42 | 0.75 [0.45, 1.27] | .29 | 35 | 0.66 [0.36–1.24] | .20 | 0.88 [0.48, 1.62] | .69 |
| 20/200 or worse (%) | 16 | 13 | 1.88 [0.49, 7.25] | .36 | 38 | 4.08 [1.23,13.55] | .02 | 2.18 [0.99, 4.81] | .06 |
a Numbers in brackets are 95% confidence intervals. P values are for comparison between eyes in group to those with uveitic macular edema without an epiretinal membrane.
b P values are for comparison between eyes with uveitic macular edema, an epiretinal membrane, and surface wrinkling to those with an epiretinal membrane without surface wrinkling.
Epiretinal Membrane and Response to Treatment
Patients with an epiretinal membrane and those without an epiretinal membrane underwent similar treatment regimens. Between the 2 groups, there was no significant difference in the percentage of patients receiving regional (periocular or intravitreal) corticosteroids (19% for those without an epiretinal membrane vs 25% for those with an epiretinal membrane, P = .74), oral corticosteroids (63% for those without an epiretinal membrane vs 63% for those with an epiretinal membrane, P = .96), immunosuppression (50% for those without an epiretinal membrane vs 45% for those with an epiretinal membrane, P = .78), or combination regional and oral corticosteroids (13% for those without an epiretinal membrane vs 22% for those with an epiretinal membrane, P = .49).
The response to therapy of eyes with uveitic macular edema is detailed in Table 3 . At the 3-month follow-up visit, the mean central subfield retinal thickness ± the standard errors were: eyes without an epiretinal membrane, 360 ± 15 μm; eyes with an epiretinal membrane without surface wrinkling, 332 ± 13 μm ( P = .14 vs eyes without an epiretinal membrane); and eyes with an epiretinal membrane with surface wrinkling, 392 ± 16 μm ( P = .15 vs eyes without an epiretinal membrane). At the 6-month follow-up visit, the mean central subfield retinal thickness ± the standard errors were: eyes without an epiretinal membrane, 338 ± 23 μm; eyes with an epiretinal membrane without surface wrinkling, 332 ± 20 μm ( P = .88 vs eyes without an epiretinal membrane); and eyes with an epiretinal membrane with surface wrinkling, 405 ± 22 μm ( P = .05 vs eyes without an epiretinal membrane). Among eyes with an epiretinal membrane, at 3 and 6 months, eyes with wrinkling consistently had a thicker central subfield retinal thickness than eyes without wrinkling ( P = .004 and P = .02, respectively). At 3 and 6 months follow-up, eyes with an epiretinal membrane and surface wrinkling consistently had worse visual acuities than the other groups. At 3 months, the mean Snellen visual acuities were: eyes without an epiretinal membrane, 20/35; eyes with an epiretinal membrane without surface wrinkling, 20/47 ( P = .18 vs eyes without an epiretinal membrane); and eyes with an epiretinal membrane with surface wrinkling, 20/94 ( P = .002 vs eyes without an epiretinal membrane and P = .01 vs eyes with an epiretinal membrane without surface wrinkling). At 6 months, the mean Snellen visual acuities were: eyes without an epiretinal membrane, 20/36; eyes with an epiretinal membrane without surface wrinkling, 20/46 ( P = .55 vs eyes without an epiretinal membrane); and eyes with an epiretinal membrane with surface wrinkling, 20/110 ( P = .02 vs eyes without an epiretinal membrane and P = .04 vs eyes with an epiretinal membrane without surface wrinkling). These differences in mean acuities are attributable in part to a greater percentage of eyes with acuities of 20/200 or worse at the 3- and 6-month follow-up visits. The percentages of eyes with 20/200 or worse acuity at the 3-month visit were: eyes without an epiretinal membrane, 4%; eyes with an epiretinal membrane without surface wrinkling, 9% ( P = .35 vs eyes without an epiretinal membrane); and eyes with an epiretinal membrane with surface wrinkling, 37% ( P = .02 vs eyes without an epiretinal membrane and P = .03 vs eyes with an epiretinal membrane without surface wrinkling). The percentages of eyes with 20/200 or worse acuity at the 6-month visit were: eyes without an epiretinal membrane, 5%; eyes with an epiretinal membrane without surface wrinkling, 6% ( P = .95 vs eyes without an epiretinal membrane); and eyes with an epiretinal membrane with surface wrinkling, 39% ( P = .02 vs eyes without an epiretinal membrane and P = .06 vs eyes with an epiretinal membrane without surface wrinkling).
