Inclusion and Exclusion Criteria

The authors reviewed the entire UCLA Optovue database of patients (1,848 patients and 3,696 eyes) who underwent en face OCT angiography (OCTA) to identify en face OCT cases of EVG. In total, en face OCT scans from 1,298 patients (and 2,476 eyes), imaged using the Optovue device (Avanti RTVue XR; Optovue, Fremont, California, USA) between January 1, 2014, and August 30, 2019, as part of the standard retinal evaluation (with D.S.) at the Stein Eye Institute, were included in the initial review. Inclusion criteria were en face OCT scans of sufficient quality (quality index of 4 or greater) with signal strength index (SSI) of 50 or greater. Eyes were excluded if they possessed any retinal pathology that would predispose them to the development of secondary ERM including any history of retinal procedures (cryotherapy, laser photocoagulation, or photodynamic therapy) or retinal surgery (eg, pars plana vitrectomy) and any evidence of retinal vein occlusion, diabetic retinopathy, retinitis pigmentosa, tumor, uveitis, trauma, peripheral retinal holes, retinal tears, retinal detachments, and choroidal hemorrhages. Scans with blinking or motion artifacts limiting evaluation and analysis of EVG were excluded. A thorough chart review was performed to determine the retinal diagnosis for exclusion. Relevant demographic information, specifically age, sex, and phakic status, were collected.

Image Acquisition and Protocols

All eyes underwent imaging using spectral domain-OCT (SD-OCT) and OCTA (Avanti RTVue XR; Optovue; or Spectralis HRA + OCT; Heidelberg Engineering, Germany). Patients underwent both high-definition and non-high-definition 6 × 6-mm volume scans using the Optovue device to produce both registered cross-sectional B-scan and en face OCT. Those images were analyzed for the presence and localization of EVG and ERMs.

Presence and grading of PVD was performed on the basis of evaluation of OCT B-scans through the fovea and optic discs acquired from both the Optovue and Heidelberg systems. In some cases, additional B-scan imaging was performed using the Topcon system (Topcon 50DX; Topcon, Inc., Oakland, New Jersey, USA) to confirm PVD status.

All scans were initially evaluated for the presence of EVG, ERM, and presence and grade of PVD by the first author (C.G.). Presence of the EVG was confirmed by a second independent grader (D.W., F.G., K.T., A.A.). Presence of ERM and presence and grade of PVD were confirmed by a second independent grader (D.W., F.G., A.A.). Any discrepancies among graders were adjudicated by the senior investigator (D.S.).

Definitions and Grading Scheme of EVG, Contractile ERM, and PVD

Optimal identification of EVG was performed using customized segmentation aligned to the ILM with a 9-µm offset. The lower segmentation border was aligned 3 µm anterior to the retinal nerve fiber layer (RNFL), and the upper segmentation border was positioned 9 µm anterior to the lower segmentation line toward the vitreous side. Any abnormal segmentations were manually corrected. This customized slab segmentation of 9-µm thickness was chosen to reduce the light-reflecting signal from the RNFL on en face OCT images and to optimally highlight the EVG lesion.

The presence of a hyper-reflective band, corresponding to the EVG, at the innermost level of the retina was confirmed by using the registered cross-sectional OCT B-scan.

By contrast, a contractile ERM was characterized by the presence of epiretinal membrane causing tangential retinal traction. Identification of a contractile ERM was defined as a hyper-reflective lesion anterior to the RNFL on OCT B-scan showing hyporeflective spaces between the lesion and the inner retina and causing wrinkling or corrugation of the inner retina. With en face OCT, contractile ERMs appeared as central plaque-like hyper-reflective lesions associated with radiating hyporeflective striae corresponding to the wrinkling or irregularity of the inner retinal surface. Further confirmation was obtained by evaluating the OCTA scans, which demonstrated distortion of the retina vasculature.

The presence of PVD was assessed using the OCT B-scan through the fovea and optic disc or evaluating the OCT volume scan through the macula and optic disc. Grading was performed as previously described as follows and was defined as: grade 1: detachment of the posterior hyaloid from the macula on either side of the fovea; grade 2: detachment of the posterior hyaloid from the macula on both sides of the fovea; grade 3: detachment of the posterior hyaloid from the fovea; grade 4: detachment of the posterior hyaloid from the fovea and the optic nerve.

Image Processing and Analysis: Quantitative Analysis of the Normal ILM and EVG

The 6 × 6-mm multimodal dataset from the Optovue machine was exported to ImageJ 1.51m9 version software (National Institutes of Health, Bethesda, Maryland, USA) ( Figure 1 ). The 6 × 6-mm en face structural OCT was cropped within ImageJ, with the resulting image measured as 600 × 600 pixels. The scale was set for 100 pixels/mm for all images.

OCT segmentation and image processing for identification and analysis of EVG. En face OCT (A) with default SCP segmentation shows remarkable hyper-reflective perivascular plaque-like lesions. Registered OCT cross-sectional B-scan illustrates corresponding band-like hyper-reflective lesions at the level of the ILM (arrows) (B) Note the absence of a hypo-reflective pre-retinal space underneath the lesions. En face OCT and cross-sectional B-scan (C and D., respectively) with a customized segmentation aligned to the ILM positioned 3 µm toward the vitreous with a 9-µm offset more effectively highlights the perivascular plaques and their dendritic or filamentous extensions, the morphology of which is consistent with previous scanning electron microscopy descriptions of EVG. Corresponding en face OCTA (E) with default SCP segmentation was inverted and transposed on top of the en face OCT (F) to neutralize hyper-reflective artifact from the vasculature. This composite image was then converted to an 8-bit gray scale and a threshold was derived for EVG to calculate the total surface area and percentage of surface area (G). This image was then inverted to calculate the total surface area and percentage of surface area of the background ILM (H). EVG = epivascular glia; ILM = internal limiting membrane; OCT = optical coherence tomography angiography; SCP = superficial capillary plexus.

Artifacts from vessels were removed by using the cropped OCTA image. Vasculature on the default superficial capillary segmentation was isolated, selected, inverted, and overlaid on the en face OCT. This allowed for normalization and removal of the hyper-reflectivity corresponding to the retinal vasculature. Images were then binarized and converted to an 8-bit grayscale (with a total of 256 shades, where 0 = pure black and 255 = pure white for thresholding).

Threshold reflectivity was performed on the aforementioned customized segmented cropped en face OCT images that were corrected for vascular artifacts ( Figure 1 , F). This segmentation allowed for specific isolation of EVG ( Figure 1 , G). The mean EVG brightness was measured by averaging the rectangular regions of interest (0.001 mm ² ) that were placed on 3 different regions of the EVG.

The mean EVG brightness was used as the threshold cutoff to select the EVG lesion. Using ImageJ software, selected EVG lesions were then measured for average reflectivity and total surface area (mm ² ) of the EVG ( Figure 1 , G). For normal ILM reflectivity measurements, the inverse selection threshold was applied ( Figure 1 , H). The percentages of surface area of the EVG lesions were calculated as total surface areas of the EVG lesion divided by the total surface areas of the 6 × 6-mm scan (36 mm ² ).

Presence of Contractile ERM in Patients With and Without EVG

To determine whether contractile ERMs occurred more frequently in patients with EVG, the presence of contractile ERMs associated with EVGs were compared to those in a randomly selected, age- and sex-matched cohort. Specifically, from the cohort of patients without EVG, 161 patients were randomly selected to match the age and sex distribution of the EVG cohort. Then we compared the percentages of contractile ERMs present in patients with EVG relative to those without EVG.

Statistical Analysis

Analysis was performed using R version 3.6.3 software (R Foundation for Statistical Computing, Vienna, Austria). Mean ± standard deviation or numerical counts with percentages were presented for interval and ordinal or categorical variables, respectively. The χ ² test was used for parametric categorical or ordinal variables while the Fisher exact test was used for nonparametric categorical or ordinal variables. For parametric interval variables, paired or nonpaired t -tests were used when samples were paired or not paired, respectively. For inter-grader analysis, Cohen’s kappa results were obtained. The generalized estimating equation (GEE) regression model was used to assess an association between the presence of EVG and age, PVD status, and phakia with correction of bilateral eye enrollment. A P value of <.05 was considered statistically significant.

Demographics of the Total Cohort and Subgroup of Patients With and Without EVG

Using the Optovue database at UCLA, the en face imaging of 1,848 patients (3,696 eyes) were evaluated to identify cases with EVG. Of these, 1,298 patients (or 2,476 eyes) met the inclusion and exclusion criteria and were analyzed ( Table 1 ). EVG was present in 161 eyes from 119 patients, and EVG was absent in 2,315 eyes of 1,179 patients. Assessment of agreement between graders for the presence of EVG showed a kappa value of 0.8 (95% confidence interval [CI]: 0.7 – 0.9; P <.01; with an overall agreement of 87.0%). EVGs were bilateral in 35% and unilateral in 65% of patients. The calculated prevalence was 161 of 2,476 eyes (6.5%) and 119 of 1,298 patients (9.2%) in this cohort. The mean age of all patients was 58.7 years ± 24.6 years old (range: 3.0 – 100.0 years). Patients with EVG (mean: 79.3 ± 10.7 years old; range: 38.0 – 100.0 years old) were significantly older than patients without EVG (mean: 55.9 ± 24.6 years old; range: 3.0 – 98.0 years old; P < .001). There were no differences pertaining to sex ( P = .10) or eye laterality ( P = .75) between patients with and without EVG. Patients with EVG were more commonly pseudophakic (98 of 161; 60.9%) compared to those without EVG (436 of 2,315; 18.8%; P <.001). GEE modeled for age and PVD status and controlled for bilateral eye involvement showed persistence of statistical significance of phakic status ( P <.001).

To further control for variability between age and sex, an age- and sex-matched cohort was randomly selected between patients with and without EVG. Patients with EVG were more likely to be pseudophakic (98 of 161; 60.9%) than patients without EVG (73 of 161; 45.3%; P = .005) ( Table 2 ).

TABLE 2

Comparison of Demographic and PVD Status Between Patients With and Without EVG With Random Age- and Sex-Matched Controls.

		Presence of EVG a	Absence of EVG b	P Value
Demographic Analysis
Average ± SD age (range), yrs		79.3 ± 10.7 (38.0 – 100.0)	78.9 ±10.6 (38.0 – 97.0)	.73
Gender	Females	64.0 (53.8)	79.0 (49.1)	.44
	Males	55.0 (46.2)	82.0 (50.9)
Eye	OD eyes	83.0 (51.6)	83.0 (51.6)	1.0
	OS eyes	78.0 (48.4)	78.0 (48.4)
Lens Status	Phakia eyes	63.0 (39.1)	88.0 (54.7)	.005 c
	Pseudophakia eyes	98.0 (60.9)	73.0 (45.3)
Presence of ERM, eyes (%)		71.0 (44.1)	30.0 (18.6)	<.001 c
PVD Analysis
Presence eyes		137.0 (95.1)	121.0 (84.1)	.002 c
Absence eyes		7.0 (4.9)	23.0 (15.9)
Grade 1 eyes		3.0 (2.1)	1.0 (0.7)	.62
Grade 2 eyes		4.0 (2.7)	6.0 (4.2)	.51
Grade 3 eyes		60.0 (41.7)	40.0 (27.8)	<.001 c
Grade 4 eyes		70.0 (48.6)	74.0 (51.4)	.64

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