Epiretinal membrane (ERM) is a common vitreoretinal disorder1 that is characterized by tangential traction, which may induce morphological abnormalities and circulatory disturbances in the foveal and/or perifoveal area.2,3 Vertical traction can also contribute to the architectural changes by causing increased retinal thickness and cystoid macular edema. These changes eventually lead to a decrease in visual acuity (VA) and/or metamorphopsia that may benefit from surgical intervention.4
Optical coherence tomography angiography (OCTA) is a novel, noninvasive imaging technique that allows for the acquisition of high-resolution depth-resolved images of the retinal vascular layers.5 Though fluorescein angiography can identify the superficial capillary plexus (SCP),6 OCTA can visualize blood vessels at various depth-resolved levels, including the deep capillary plexus (DCP) and choroicapillaries. In addition, OCTA appears to better delineate the complexities of the vessels at the edge of the foveal avascular zone (FAZ).
Fundus photography or multicolor scanning laser imaging of the macula can typically show vessel distortion and optical membrane density in eyes with ERM. We have previously shown that multicolor imaging (MCI) provided better delineation of membrane with a higher detection of retinal surface striae than conventional fundus photography, likely because of the use of monochromatic laser imaging in wavelengths which reflects well from the retinal surface.7 We have observed some architectural changes on the perifoveal capillary network causing apparent distortion of FAZ in eyes with ERMs. Herein, we wish to determine whether there is a correlation between morphological changes and density of the ERM graded by MCI. On the other hand, despite presence of prior studies showing a decrease in foveal capillary plexus — particularly in the DCP — in the literature,8,9 the association between membrane density and foveal changes in the perifoveal capillary distribution is unknown.
Patients and Methods
This was a retrospective, observational case series including patients with a diagnosis of ERM and healthy subjects as control group at the Department of Ophthalmology, Jacobs Retina Center, Shiley Eye Institute, University of California San Diego, between September 2016 and February 2017. The study was approved by the institutional review board of University of California San Diego and complied with the Health Insurance Portability and Accountability Act, and the protocol adheres to the tenets of the Declaration of Helsinki. Written informed consent was obtained for each patient prior to acquiring OCTA images.
Healthy control subjects with best-corrected VA (BCVA) of 20/20 and without a history of any systemic and ophthalmological diseases were selected from a normative database from our department.
All participants underwent a comprehensive ophthalmological examination including BCVA using Early Treatment Diabetic Retinopathy Study charts, slit-lamp examination, dilated fundus examination through 20 Diopter lens by indirect ophthalmoscopy. The diagnosis of ERM was made clinically by the same clinician (WRF) in all patients and was confirmed with multimodal imaging. Data including BCVA, age, gender, presence of systemic diseases were retrieved from the charts. Presence and duration of symptoms were also noted.
All participants underwent multimodal imaging including MCI using scanning laser ophthalmoscopy, spectral-domain optical coherence tomography (SD-OCT), fundus fluorescein angiography (Spectralis; Heidelberg Engineering, Heidelberg, Germany), and OCTA (Optovue, Fremont, CA) after optimal dilation of pupils.
Assessment of OCTA images: This OCTA system (RTVue XR Avanti, version 2016.2.0.35; Optovue, Fremont, CA) uses split-spectrum amplitude decorrelation angiography algorithm and operates at 70,000 A-scans per second to acquire OCTA volumes consisting of 304 × 304 A-scans. Orthogonal registration and merging of two consecutive scans were used to obtain OCTA volume scans over a central 3 mm × 3 mm area. OCTA images of the superficial and deep capillary networks were generated separately using the automated software algorithm. Based on these default settings, the boundaries of superficial network extended from 3 μm below the internal limiting membrane to 16 μm below the inner plexiform layer. The deep capillary network extended from 16 μm to 69 μm below the inner plexiform layer. Poor quality images with segmentation errors, motion artifacts, or low signal strength index (< 50) were excluded.
Each scan was automatically segmented by the OCTA device. After checking the accuracy of segmentation of retinal layers, images with SCP were saved as Tagged Image File Format (TIFF) files and transferred to an open-source image-processing program, ImageJ (National Institutes of Health, Bethesda, MD). We defined a foveal eccentricity index as the longest diameter of the FAZ/shortest diameter, measured on the superficial slabs of the OCTA.10 When the fovea was fully vascularized (ie, the FAZ disappeared), the FAZ index was considered as zero. The presence of vessel crossing through the fovea was also noted.
Evaluation of ERM density on MCI: ERM on MCI was defined as a green-yellow superficial structure with attendant retinal stria.7 In order to quantify the ERM, first identifying features of the patients were removed from the original images by an independent observer and images were saved as TIFF format. Then, an Early Treatment Diabetic Retinopathy Study (ETDRS) grid with 1 mm inner diameter and 3 mm outer diameter was displayed on the MCI by paying attention to the alignment of the center of grid with the center of presumed fovea on MCI. At the final step, density of the membrane was quantified using a grading scale ranging from 0 to 3. Score was given based on the visibility of underlying chorioretinal structures and vessels as follows: 0 = chorioretinal structures are clearly visible; 1 = partially visible; and 2 = not visible, retinal structures obscured. This scoring was done for both the central fovea (within 1 mm of an ETDRS circle) and each para-foveal quadrant, including the temporal, nasal, superior, and inferior quadrants, within 3 mm of an ETDRS circle. The sum of grading score of each zone was considered as the total membrane density score (Figure 1A).
(A) demonstrates an Early Treatment Diabetic Retinopathy Study circle overlay with a 1-mm inner diameter. The total membrane score is 5 (2 for each horizontal quadrant, 1 for the inferior quadrant, and 0 for the superior quadrant). In the optical coherence tomography angiography (OCTA) image, the foveal avascular zone (FAZ) is absent, totally vascularized (B). The FAZ change is also apparent in fundus angiography, seen as an oblique slit running toward the inferior-nasal macula (C). The spectral-domain OCT image cutting through the center of fovea shows loss of foveal pit with some thickening of the central fovea secondary to the epiretinal membrane (D). Note, the signal strength index of the OCTA image is 62 despite duplication of some retinal vessels.
SD-OCT scan assessment: For each study eye, a 6-mm × 6-mm macular cube scan was performed using the fast scanning mode comprising at least 25 horizontal B-scans, each made up of 512 A-scans. Horizontal and vertical scans cutting through the fovea were also obtained. In a B-scan, the foveal center point thickness (FCP), the vertical distance between the innermost retina and the retinal pigment epithelium (Bruch's complex), was measured manually in both axes using the caliper function of the device, and the average thickness was obtained for the statistical analysis. Central macular thickness (CMT) (mean retinal thickness within the central 1 mm) was measured using the SD-OCT volumetric map. Additionally, the status of foveal contour was graded as normal or minimally elevated, flat, or evaginated based on the status of foveal pit.
All scans were analyzed by two experienced retina specialists at different sessions, and the agreement between the graders was obtained. The agreement between the graders for FAZ eccentricity index and density of the membrane were high (intraclass correlation coefficient [ICC] = 0.87 and ICC = 0.92, respectively) in randomly selected images.
Continuous parameters were presented as mean and standard deviation (SD), and categorical variables were reported as percentages (%). BCVA was converted to logarithm of the minimum angle resolution (logMAR) for the statistical analysis. Spearman's correlation was used to assess the correlation between FAZ eccentricity index and membrane density score, SD-OCT parameters, or BCVA. A P value of less than .05 was considered statistically significant. All statistical analyses were carried out using SPSS 24.0 (SPSS Inc., Chicago, IL).
Seventy-nine eyes of 70 patients were enrolled the study, including 52 eyes of 43 patients with ERM and 27 eyes of 27 healthy subjects as control group. There was no significant difference in the mean age of participants between the ERM group (67.28 ± 10.51 years) and the control group (61.10 ± 15.02 years) (P = .109). The signal strength of OCTA images reviewed was similar across the groups (66.34 ± 13.34 in ERM eyes and 68.78 ± 15.08 in healthy subjects) (P = .48).
Among 52 eyes with ERM, 31 eyes (59.61%) had some morphological FAZ changes. Seven eyes (13.46%) showed full vascularization of the FAZ (Figure 1). Sixteen eyes (30.76%) demonstrated some decrease in FAZ circularity (Figure 2). Presence of a vessel crossing through the FAZ (five of 52; 9.61%), and elongation of FAZ along the horizontal or vertical axes (three of 52; 5.76%) (Figure 3) were the other observed morphological changes of FAZ in patients with ERM.
The panel shows the images of a patient who underwent multimodal imaging for an epiretinal membrane. The patient has some retinal stria over the macula on the multicolor image (A) with a small foveal avascular zone on the superficial slab of the optical coherence tomography angiography (OCTA) image (B). The vertical spectral-domain OCT scan reveals thickening of inner retinal layers with elevated, corrugated foveal contour (C).
Multimodal imaging (A–D) in a patient with pseudohole secondary to epiretinal membrane (ERM). Multicolor image (A) demonstrates a hole appearance with some surface folds, which are mostly located in the vertical axis. A superficial slab of the optical coherence tomography angiography (OCTA) shows elongation of the foveal avascular zone along the vertical axis (B). Spectral-domain OCT image reveals multiple intraretinal cysts and schisis with ERM (C).
When looking at the quantitative structural changes by multimodal imaging modalities, the ERM density score on MCI was 5.0 ± 2.87 (range: 1.0–10.0). On SD-OCT, not surprisingly, the ERM group had a thicker mean FCP thickness and CMT compared to healthy subjects (P < .001 for both variables). The FAZ eccentricity index on OCTA was 0.84 ± 0.46 (range: 0.0–1.86) in eyes with ERM and 0.98 ± 0.07 (range: 0.96–1.02) in the control subjects, respectively; the difference in the mean FAZ index between the two groups was statistically significant (P = .02). Quantitative measurements of the SD-OCT and OCTA parameters are presented in Table 1.
Clinical and Imaging Characteristics of the Participants
The correlation plots for the FAZ eccentricity index and SD-OCT parameters or ERM density are given in Figure 4. There was a negative significant correlation between FAZ eccentricity index and CMT (correlation coefficient [CC] = −0.30; P = .04) (Figure 1A). FAZ index was also negatively correlated with FCP thickness (CC = −0.192, P = .17) (Figure 1B) and ERM density (CC = −0.182, P = .19) (Figure 1C).
The correlation plots for the foveal avascular zone (FAZ) eccentricity index and quantitative measurements of epiretinal membrane (ERM) by spectral-domain optical coherence tomography or multicolor imaging. Scatter plot demonstrating a significant negative correlation between the FAZ index and central macular thickness (A) (P = .04). A negative correlation between FAZ index and foveal center point thickness (P = .17) is illustrated in B. (C) Image shows a negative correlation between FAZ index and ERM density score (P = .19).
The mean BCVA was 0.20 ± 0.24 logMAR (± Snellen Equivalent, 20/30) (range: 1.10–0.00, logMAR; ± Snellen Equivalent, 20/250–20/20) in eyes with ERM at presentation. Of 52 eyes with ERM, 65.38% (34 eyes) had visual symptoms, including decreased or blurry vision (19 of 34; 55.88%) for a mean of 18.43 weeks ± 20.0 weeks and metamorphopsia (15 of 34; 44.11%) for a mean of 15.6 weeks ± 21.50 weeks.
In this study, after confirming the accuracy of segmentation of retinal layers on OCTA slabs, we show that ERM can cause foveal remodeling including full or partial vascularization of fovea, decrease in size of the FAZ, or elongation of the FAZ along horizontal or vertical axes. We observed that as the CMT increased, the FAZ appeared to be smaller and more vascularized. It is more likely that the vascularized fovea is due to contraction of the FAZ by the ERM. These vessels are not “new” vessels; rather, they are the same existing vessels that are pulled in. We used the FAZ eccentricity index as a surrogate of FAZ distortion secondary to tractional forces and showed that membrane density may be negatively correlated with FAZ eccentricity index (non-significant), which may indicate that the denser the membrane, the more irregular and smaller the FAZ.
Romano et al.8 showed that both the area of superficial and deep vascular plexus decreased in patients with idiopathic ERM compared to healthy eyes, whereas diabetic ERM eyes demonstrated a significant decrease in only deep vascular plexus. Following the membrane peeling, diabetic eyes showed a significant increase in the mean deep vascular plexus area. The authors concluded that impaired diabetic perifoveal capillary plexus may be more sensitive to the iatrogenic damage induced on the Müller cells by internal limiting membrane peeling. In another study with seven eyes, the irregular focal hypofluorescent areas seen in FA corresponded to the locations of absent or low flow signals in the DCP.9 However, the SCP did not exhibit any sign of nonperfusion. Though presence of abovementioned studies showing that the DCP was more prone to tractional forces secondary to ERM, we evaluated FAZ changes on SCP rather than DCP due to the fact that ill-defined DCP would not yield accurate assessment of FAZ.10
The FAZ, which is thought to be related to minimizing light scatter and maximizing light sensitivity, may show individual variation regarding the shape and size. Although having intact and regular FAZ is essential for optimal VA, there have been some reports showing the abnormality of FAZ in healthy subjects with normal VA.12 Recently, Cicinelli et al.13 reported a case series with macular-foveal capillaries in patients with a variety of retinal disorders such as retinal vein occlusion, macular pucker, and age-related macular degeneration. The authors concluded that complete absence of the FAZ or only partial vascularity may complicate different retinal abnormalities or represent a coincidental retinal finding. In our case series, we identified five cases with a crossing vessel through the FAZ. This finding might be related to pseudo-crossing secondary to mechanical traction due to ERM.
In conclusion, structural changes in the FAZ in eyes with ERM may have a wide range of FAZ eccentricity index in comparison to healthy subjects. Our data demonstrate that as the central macula thickens due to ERM, the FAZ becomes less circular and shows variety of changes, including full or partial vascularization, decrease in size, or elongation along the axis where the tractional forces are more prominent.
- Ng CH, Cheung N, Wang JJ, et al. Prevalence and risk factors for epiretinal membranes in a multi-ethnic United States population. Ophthalmology. 2011;118(4):694–699. doi:10.1016/j.ophtha.2010.08.009 [CrossRef]
- Yagi T, Sakata K, Funatsu H, Noma H, Yamamoto K, Hori S. Macular microcirculation in patients with epiretinal membrane before and after surgery. Graefes Arch Clin Exp Ophthalmol. 2012;250(6):931–934. doi:10.1007/s00417-011-1838-y [CrossRef]
- Kadonosono K, Itoh N, Nomura E, Ohno S. Capillary blood flow velocity in patients with idiopathic epiretinal membranes. Retina. 1999;19(6):536–539. doi:10.1097/00006982-199919060-00010 [CrossRef]
- Ichikawa Y, Imamura Y, Ishida M. Metamorphopsia and tangential retinal displacement after epiretinal membrane surgery. Retina. 2017;37(4):673–679 doi:10.1097/IAE.0000000000001232 [CrossRef]
- Samara WA, Shahlaee A, Adam MK, et al. Quantification of diabetic macular ischemia using optical coherence tomography angiography and its relationship with visual acuity. Ophthalmology. 2017;124(2):235–244. doi:10.1016/j.ophtha.2016.10.008 [CrossRef]
- Spaide RF, Klancnik JM Jr., Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015;133(1):45–50. doi:10.1001/jamaophthalmol.2014.3616 [CrossRef]
- Kilic Muftuoglu I, Bartsch DU, Barteselli G, Gaber R, Nezgoda J, Freeman WR. Visualization of macular pucker by multicolor scanning laser imaging. Retina. 2018;38(2):352–358. doi:10.1097/IAE.0000000000001525 [CrossRef]
- Romano MR, Cennamo G, Schiemer S, Rossi C, Sparnelli F, Cennamo G. Deep and superficial OCT angiography changes after macular peeling: Idiopathic vs diabetic epiretinal membranes. Graefes Arch Clin Exp Ophthalmol. 2017;255(4):681–689. doi:10.1007/s00417-016-3534-4 [CrossRef]
- Lin TC, Chung YC, Lin CY, Lee FL, Chen SJ. Focal nonperfusion of deep retinal capillary plexus in eyes with epiretinal membranes revealed by optical coherence tomography angiography. Ophthalmic Surg Lasers Imaging Retina. 2016;47(5):404–409. doi:10.3928/23258160-20160419-02 [CrossRef]
- Shahlaee A, Pefkianaki M, Hsu J, Ho AC. Measurement of foveal avascular zone dimensions and its reliability in healthy eyes using optical coherence tomography angiography. Am J Ophthalmol. 2016; 161: 50–55.e1. doi:10.1016/j.ajo.2015.09.026 [CrossRef]
- Olson E. Particle shape factors and their use in image analysis–part 1: Theory. Journal of GxP Compliance. 2011;15:85–96.
- Al-Sheikh M, Falavarjani KG, Tepelus TC, Sadda SR. Quantitative comparison of swept-source and spectral-domain oct angiography in healthy eyes. Ophthalmic Surg Lasers Imaging Retina. 2017;48(5):385–391. doi:10.3928/23258160-20170428-04 [CrossRef]
- Cicinelli Mv, Carnevali A, Rabiolo A, et al. Clinical spectrum of macular-foveal capillaries evaluated with optical coherence tomography angiography. Retina. 2017;37(3):436–443. doi:10.1097/IAE.0000000000001199 [CrossRef]
Clinical and Imaging Characteristics of the Participants
|ERM Group||Control Group||P|
|Number of Eyes||52||27|
|Axial Length, mm||23.56 ± 0.78||23.97 ± 0.54||.32|
|Lens Status, Phakia, Number||24 (46.15%)||11 (40.74%)||.14|
|Foveal Center Point Thickness, μm (Range)||304.27 ± 88.0 (180.0–587.0)||223.0 ± 25.95 (182.0–286.0)||< .001|
|Central Macular Thickness, μm (Range)||366.78 ± 75.97 (263.0–563.0)||268.95 ± 21.71 (238.0–307.0)||< .001|
|Foveal Contour on SD-OCT|
| Normal or minimally elevated||24 (46.15%)||27 (100%)||.004|
| Flat||17 (32.69%)||—|
| Evaginated||11 (21.15)||—|
|Foveal Avascular Zone Eccentricity Index on OCTA||0.84 ± 0.46 (0.0–1.86)||0.98 ± 0.07 (0.85–1.12)||.02|