Features of idiopathic and intermediate uveitis– associated epiretinal membranes on OCT and multi-color imaging

BACKGROUND To characterize the morphologic features of idiopathic epiretinal membrane (iERM) and subtle intermediate uveitis-associated epiretinal membrane (IU-ERM) using optical coherence tomography (OCT) with multi-color imaging. METHODS Forty-three eyes of 36 patients diagnosed as iERM and IU-ERM by fundus examination and ultrasound biomicroscopy were underwent multi-color scanning laser ophthalmoscopy imaging using a Heidelberg Spectralis HRA+OCT. Area and thickness of the ERM, central foveal thickness (CFT), and best-corrected visual acuity (BCVA) were compared between these two groups. RESULTS The ERM area of the IU-ERM group was larger than that of the iERM group (33.03 ± 14.62mm2 vs.13.03 ± 7.00 mm2, P<0.001). The ERM thickness of the IU-ERM group was also thicker than that of iERM group (20.14 ± 1.52 µm vs.17.92 ± 1.28 µm, P<0.001). The BCVA of the eyes with iERM was better (0.10 ± 0.18 vs.0.35 ± 0.28, P<0.001) and the CFT was thinner (217.66 ± 64.21 µm vs. 359.19 ± 128.72 µm, P = 0.002) compared to the IU-ERM group. CONCLUSION IU-ERM was larger and thicker than iERM. OCT with multi-color imaging could faciliate the assessment of ERM morphology, which might aid in differentiating IU-ERM from iERM. eyes of 36 patients diagnosed as iERM and subtle IU-ERM by fundus examination recruit in this cross-sectional observational study at to eyes of patients diagnosed with IU were IU-ERM group, and 15 eyes of 14 patients diagnosed were iERM goup. The diagnosis of IU in


Background
Epiretinal membranes (ERMs) are a common fundus finding which can lead to metamorphopsia, blurred vision, and eventually vision loss. [1,2] The causes of most idiopathic ERMs (iERMs) are not readily apparent. These iERMs have been theorized to the proliferation on the retinal surface and the cortical vitreous which is thought to serve as a scaffold. In other cases, ERMs develop secondary to other associated ocular pathologies such as retinal vascular disease, inflammation/uveitis, or surgery. [3-6] The wide availability of OCT has increased the detection of ERMs, as OCT can often reveal a subtle ERM which is asymptomatic and difficult to discern by biomiscroscopy. [7] iERMs are easy to distinguish from some secondary ERMs based on patients' history. While, intermediate uveitis-associated epiretinal membranes (IU-ERMs) in particular may be misdiagnosed as iERMs because the inflammatory disease may be mild or asymptomatic. [8,9] ERMs is a common complication of IU and can be detected in 39.6-57.0% of IU cases.[10, 11] The incidence of ERMs in IU cases increases with age in a 20-year study,[9] which coincides with the peak prevalence of iERMs observed in elderly individuals. [12] Patients initially thought to have iERMs in our study were noted on closer inspection to accompanied with cilliay body edema and / or exudation on ultrasound biomicroscopy (UBM), suggesting an underlying intermediate uveitis. As intermediate uveitis can have a chronic or relapsing/remitting course with associated ocular complications, distinguishing iERMs from IU-ERMs may be of clinical importance in these cases with subtle and un-diagnosed IU.
Since OCT B-scans do not appear to be effective for distinguishing iERMs from IU-ERMs, we wondered whether other imaging modalities could demonstrate differentiating features.
Recently, multi-color fundus imaging using a scanning laser ophthalmoscope (SLO) with three separate lasers (blue, green, infrared) has been suggested to better display the morphology and extent of ERM compared to traditional fundus photos and OCT B-scan. [13] In the present study, we sought to better characterize and compare the morphologic features of IU-ERMs and iERMs on multi-color imaging.

Methods
All study procedures adhered to the tenets of the Declaration of Helsinki and were approved by the investigational review board of Ehtics Committee of Zhongshan image were the key parameters used to facilitate a diagnosis of IU in these cases. [14] All patients were taken UBM examination to measure the thickness of ciliary body at a position 1 mm posterior to the scleral spur (CBT1). As the CBT1 may be altered in eyes with high myopia, high hypermetropia or narrow angle, such eyes were not enrolled in the study. Individuals with other ocular diseases including diabetic retinopathy, vascular occlusion, active or a history of definite uveitis, retinal detachment, or history of intraocular trauma, previous surgery, intraocular injection or laser treatment were also excluded from the study. Patients with severe cataract preventing high-quality of the retinal imaging were also excluded.

Measurement of vitreous cells
In accordance with Saito et al' s study, the presence of vitreous cells was also assessed on the OCT images. These vitreous cells were defined as hyperreflective dots in the vitreous which were larger and more reflective compared to the background speckle noise (Fig. 2). [14] Measurement of epiretinal membranes The macular of all eligible study eyes was captured the multi-color SLO images with 30 degree using a Spectralis HRA+OCT (Heidelberg Engineering, Germany). Structural OCT was also obtained using a 30 x 25 degree volume scan centered on the fovea with 31 horizontal B-scans 240 microns apart.
The multi-color imaging provided a good delineation of the boundaries of the ERM when compared with the flash white-light color photograph (Fig. 3A). The boundaries of the ERM were manually segmented using Image J (Fig. 3B). To further optimize the delineation of the ERM boundaries, the multi-color image was simultaneously correlated with OCT B scans at the corresponding locations, and then the ERM boundary was adjusted (Fig. 3C) based on the termination of the hyper-reflective line on the OCT. Following the manual delineation and adjustment, the ERM area (ERMA) was calculated. The representative multi-color images of ERMs from the two groups were shown in Figure 4.
In addition, the central thickness of ERM (ERMT) was also measured using image J by applying a grid composed of four concentric circles with the radii of 200 µm, 400 µm, 600 µm and 800 µm in the multi-color image. The grid was placed at the "center" of the ERM which was defined as the darkest point on the multi-color image ( Fig. 5A and 5B). The thickness of ERM was measured at the intersections between the circular grid lines and the OCT B-scans, amounting to a total of 29 points. The mean of these 29 measurements was taken to be the ERMT for subsequent analysis, and the central foveal thickness (CFT) was also measured.

Statistical analysIs
The data were statistically analyzed using a commercial analytical software program (SPSS 13.0; SPSS, Inc., Chicago, IL). All tests were two sided, and a P value less than 0.05 was considered statistically significant. Snellen BCVA was converted to logMAR value for statistical analysis. Two-sample independent t-test was used for the continuous variables.
Fisher exact test was used for the categorical variables. Mean ± SD was calculated for quantiative parameters. The correlation analysis was examined by Pearson correlation.

Results
Mean age of subjects was 64 years. The BCVA in the iERM group was better than the IU-ERM group (P 0.001), whereas there was no significant difference in age or gender of these two groups (Table 1). Six eyes were found hyperreflective dots in OCT images in IU-ERM group (Fig. 2).
Contrast with the flash white-light color photograph, the ERM in multi-color picture manifested as yellow-green area accompany with a clean, crisp outline. The darkest area of both the iERM and IU-ERM usually avoided the foveola.
Representative multi-color images of iERM and IU-ERM were shown in Figure 3. On the planar area measurement from multi-color imaging, the ERMA of the IU-ERM group was significantly larger than that of the iERM group (P 0.001, fig. 4C). In contrast, the average ERMT of the IU-ERM group was greater than that of the iERM group (P 0.001, fig.   5E). The CFT of iERM group was thinner than that of IU-ERM group (217.66 ± 64.21 µm vs. 359.19 ± 128.72 µm, P = 0.002).
On Pearson correlation analysis, BCVA was negatively correlated to CFT (t = 0.564; P 0.001), but was not related to the ERMA or the ERMT.

Discussion
In this study, we firstly evaluated the morphology of idiopathic and IU-associated ERMs on multi-color imaging and OCT. Multi-color images appeared to show superior visualization of the ERMs compared to the standard flash white-light color images of the retina, allowing more precise delineation of the transverse borders of the lesion.
Compared with iERMs, IU-ERMs were noted to be thicker and larger. This might be caused by the infiltration of inflamatory cells in IU eyes, [15] which can promote tissue proliferation. In the histological analysis of eyes with iERM, only abnormal migration of a few RPE and glial cells are observed. [15] This findings of subtantially larger ERMs in eyes with IU suggested that the underlying inflammatory (albeit possibly quiescent at any given time) might need to be considered in eyes which present with very extensive membranes.
Mean BCVA was also better and mean CFT was thinner in eyes with thinner ERMs.
Correlation analysis demonstrated that BCVA was negatively correlated with CFT, but did not vary according to the ERMA or the ERMT. The correlations between retinal thickness and BCVA have been well investigated in the setting of ERM. [16] In our study, we found that the thickest portion of the ERM did not coincide with the foveal center in most of the study eyes, which might be one reason why the BCVA did not correlate with the ERMT. We hypothesized that due to the normal point of tighter attachment between the posterior hyaloid and the retina in the foveola, the vitreous might separate from retina later in this area, preventing the growth of the ERM into this area during in the disease course. As a result, the ERM might have been thinner in the central macular area than other area. of recurrent ERM might suggest that other factors aside from the operation itself might be contributing to recurrence in these cases. We wondered whether the on-going subtle inflammation might be a contributor.
There was a limitation of the sample size is somewhat limited, particularly for eyes with idiopathic ERM in this study. Our study, however, was also the first to specifically describe differences between iERM and IU-ERM revealed by multi-color imaging.

Conclusion
In summary, multi-color imaging and OCT can be useful for more precisely mapping the morphology of ERMs, and the differences in ERM morphology might be helpful in aiding discrimination of the IU-ERM from the iERM. Consent for publication: All athours are consent for publication.
Availability of data and materials: Not applicable.
Competing interests: There are no competing interests in this study.   The delineation of ERM boundary in a patient's eye. In the flash white-light color photograph (A), the ERM is detectable, but its border was difficult to differentiate.
Multi-color scanning laser ophthalmoscopic (SLO) image of the same eye more clearly depicted the ERM. Dotted line illustrated the manually segmented borders (B). Side-by-side comparison with the multi-color image of the ERM, the underlying structural OCT B-scans allowed the segmentation to be slightly refined to achieve more precise delineation of the ERM boundary (C).

Supplementary Files
This is a list of supplementary files associated with the primary manuscript. Click to download. STROBE_checklist_cross-sectional.doc