Abstract
Objectives
To investigate the changes in the temporal vascular angles after epiretinal membrane (ERM) surgery and utilize the angles to predict visual outcomes.
Methods
A total of 168 eyes from 84 patients with unilateral ERM who underwent vitrectomy were enrolled from a single institution. The angles of temporal venous (anglevein) and arterial arcades (angleartery) were measured on fundus photographs. The relationships between the angles and the best-corrected visual acuity (BCVA) were explored and multivariable logistic models and receiver operating characteristic (ROC) curves were analyzed to identify the factors that predicted visual outcomes.
Results
At baseline, both angleartery and anglevein were narrower in the eyes with ERM than the fellow eyes (p < 0.001 and 0.007) but had no correlation with the baseline BCVA (p = 0.754 and 0.804). Postoperatively, the angleartery and anglevein significantly widened (both p < 0.001) and a greater BCVA improvement was associated with a greater widening of the angleartery (p = 0.029) and anglevein (p = 0.050). Multivariable logistic analyses found a narrower baseline angleartery compared to the fellow eye had a higher chance for BCVA improvement ≧ 2 lines (Odds ratio = 0.97; 95% CI, 0.94–0.99; p = 0.016). ROC curve showed the baseline difference in the angleartery between bilateral eyes predicted BCVA improvement ≧ 2 lines (area under the curve = 0.74; p = 0.035), and a 0.73 sensitivity and 0.80 specificity with a cut-off value of −27.19 degrees.
Conclusions
The retinal vascular angles widened after ERM surgery and the fundus photograph-derived angles may serve as a highly-accessible biomarker to predict postoperative visual outcomes.
Subject terms: Predictive markers, Predictive markers
Introduction
Epiretinal membrane (ERM) is a common vitreoretinal disorder characterized by fibrocellular proliferation on the inner retinal surface and vitreomacular interface [1–3]. ERM has been reported to be mostly asymptomatic and non-progressive, where the majority of patients do not require immediate intervention [3–5]. However, decreased visual acuity, metamorphopsia, or aniseikonia can ensue, particularly when significant retinal traction is present [3]. For those patients, surgical intervention is considered [3, 6]. However, the visual outcomes do not always reach satisfactory visual recovery. Despite numerous studies attempting to identify predictive factors, the results were not consistent [7–10]. Therefore, it is essential to identify who and when will benefit from surgical intervention.
Since the tractional force to the retina is the hallmark of ERM, and the traction may cause retinal structural disruption and result in significant visual loss [11], we were eager to quantify this force and use it as an indicator of the severity of ERM. While it is impossible to noninvasively measure the traction directly, previous investigations had observed that the tractional on the inner retina caused dragging and distortion of the retinal vessels and that the angle between the temporal vascular arcades became narrower in eyes with ERM [11–13].
Based on the above studies, we hypothesize that the temporal vascular arcades angle represents the tractional force of the ERM to the inner retina, and the change of this angle may correlate to the change in vision after ERM surgery. Thus, the aim of this study was to identify the prognostic factors that could predict postoperative functional outcomes in eyes with ERM and whether the colour fundus photographs-based temporal vascular arcades angles could serve as a novel biomarker for ERM surgery.
Methods
Study design and patients
The study was a retrospective, nonrandomized, interventional case series in Linkou Chang Gung Memorial Hospital, Taiwan. The study was approved by the Institutional Review Board (No. 202101136B0) and adhered to the tenets of the Declaration of Helsinki.
Patients who were phakic and presented with unilateral idiopathic or secondary ERM and underwent pars plana vitrectomy (PPV) between January 2015 and December 2017 were enrolled. Patients who were followed for less than 12 months, with a history of eye trauma, previous intraocular surgery, intermediate or advanced age-related macular degeneration, macular geographic atrophy, retinal detachment, choroidal neovascularization, central serous chorioretinopathy, macular hole, retinal vascular occlusions, glaucoma or optic neuropathy were excluded. High myopia was defined as an eye with an axial length of 26.5 mm or more.
Surgical intervention
All patients underwent standard 23-gauge three-port PPV using the Constellation Vision System (Alcon, Fort Worth, Texas, USA) by a single experienced surgeon (C.-C. Lai). Core vitrectomy was followed by macular ERM removal and internal limiting membrane (ILM) peeling. To enhance visualization of the ERM and ILM, triamcinolone acetonide and 1 mg/mL ICG (Diagnogreen Injection, Daiichi Pharmaceutical, Tokyo, Japan) were spread inside the vitreous cavity before peeling. After the removal of the membranes, fluid–air exchange was done and all patients were instructed to maintain a prone position for 2 days postoperatively. Subsequent phacoemulsification with posterior chamber intraocular lens implantation was performed in eyes that developed significant cataracts during the study period.
Ophthalmic examinations
Complete ophthalmic examinations were performed in all patients in their eyes with ERM and their contralateral healthy eye at preoperative baseline, postoperative 1–3 months (defined as the early postoperative period), and postoperative 6–12 months (defined as the late postoperative period). The ophthalmic examinations included best-corrected visual acuity (BCVA) and intraocular pressure measurement, slit-lamp biomicroscopy, binocular indirect ophthalmoscopy, colour fundus photography (Nonmyd α -DIII; KOWA, Tokyo, Japan), and spectral-domain optical coherence tomography (SD-OCT) (Spectralis HRA-OCT system; Heidelberg Engineering, Heidelberg, Germany).
Optical coherence tomography analysis
Using the OCT slabs, the preoperative ERM stage was classified based on the ectopic inner foveal layer (EIFL) ERM staging system proposed by Govetto et al. [14]. In brief, EIFL stage 1 was defined as the presence of foveal depression with negligible morphologic or anatomic disruption. Eyes with EIFL stage 2 presented with stretching of the outer nuclear layer and loss of foveal depression while all retinal layers could still be clearly identified. EIFL stages 3 and 4 were characterized by the presence of a continuous EIFL anomalously crossing the central foveal area. The difference between EIFL stages 3 and 4 lied in the morphology of the retinal layers: the layers could still be clearly identified in EIFL stage 3 and were significantly distorted/disorganized in EIFL stage 4. Central foveal thickness (CFT) was measured by the in-built automated thickness map. Ellipsoid zone (EZ) disruption was defined as a discontinuous inner segment/outer segment band in the foveal region.
Definitions and measurement of the temporal vascular angles
The included angles of supratemporal and the infratemporal major vascular arcades were measured by using colour fundus photographs and ImageJ software (version 1.53, National Institutes of Health, Bethesda, MD; available at: http://imagej.nih.gov/ij/) (Fig. 1). To measure the included angles, firstly, a best-fit inner circle was drawn along the optic disc margin by employing the “fit circle” function in Image J. Then, an outer circle was drawn by sharing the same centre of circle with the inner circle and using four times the diameter of this inner circle. Next, the two major supratemporal and infratemporal retinal vascular arcades were identified by their widest retinal vessel diameters compared with the nearby vessels. The intersection points between supratemporal arterial arcade and the inner and outer circles were regarded as points A1 and A2, respectively (Fig. 1A). The intersection points between the infratemporal arterial arcade, and the inner and outer circles were defined as points A3 and A4. With these reference points, lines could be drawn between A1-A2 and A3-A4. The extension of these connection lines could form an included angle which was defined as the temporal retinal arterial angle (angleartery). By the same fashion, the included angle of the major temporal venous arcades (anglevein) could be identified and measured (Fig. 1B). The angleartery and anglevein were calculated preoperatively and at the early and late postoperative stages (Fig. 1C, D).
Fig. 1. Definition and measurement of temporal retinal vascular angle.
A The inner circle was drawn along the border of the optic disc, and the outer circle was drawn 4 times the diameter of the inner circle. The intersection points between supratemporal/infratemporal arterial arcades and inner/outer circles were marked as points A1 through A4. By drawing lines between A1-A2 and A3-A4, respectively, the temporal retinal arterial angle (angleartery) can be measured. B Similarly, the angle between the intersections points (V1 through V4) of the temporal venous arcade was defined as anglevein. C, D After membrane peeling, the postoperative angleartery and anglevein became wider.
In addition to the above angles, the difference in the angles between the eye with ERM and the contralateral fellow eyes was calculated by subtracting the angle of the fellow eye from the angle of the eye with ERM. For example, the angleartery difference between the eye with ERM and the fellow eye (Δangleartery (ou)) was calculated by subtracting the angleartery of the fellow eye from the angleartery of the eye with ERM. The anglevein difference between the eye with ERM and the fellow eye (Δanglevein (ou)) was obtained by the same method.
Statistical analysis
All analyses were performed using SPSS version 26.0 (SPSS Inc., Chicago, IL). The continuous variables were recorded as mean ± standard deviations and the categorical variables as percentages. For statistical analysis, the decimal BCVA was converted to a logarithm of the minimum angle of resolution (logMAR). Differences in categorical variables among the three groups were calculated by the Fisher’s-Exact test. The McNemar test was used to compare the proportion of categorical variables before and after surgery. Wilcoxon signed ranks test was carried out to compare BCVA and temporal vascular angles in eyes with ERM or their fellow eyes at different periods. Kruskal-Wallis test and post hoc analyses using Dunn’s test were conducted to evaluate the significant difference in BCVA and temporal vascular angle in the three groups, respectively. Spearman’s test was applied for determining the correlation between changes of vascular angle and BCVA improvement. In order to predict the functional outcomes, multivariable logistic regression models were established with the backwards method, and a receiver operating characteristic (ROC) curve was generated. A P-value less than 0.05 was considered statistically significant.
Results
Eighty-four phakic patients with unilateral ERMs who underwent vitrectomy with membrane peeling were enrolled. The baseline demographics of the study population are summarized in Table 1. The mean age of the patients was 61.7 ± 6.4 years (range 41–73 years). Thirteen patients (16%) had diabetes mellitus and 24 (29%) had hypertension. According to the EIFL staging system, 7, 45, and 32 patients were categorized as EIFL stages 2, 3, and 4, respectively. There was no significant difference in the demographics of patients in various EIFL stages.
Table 1.
Demographics and clinical characteristics of patients with unilateral epiretinal membrane.
| All (n = 84) | EIFL Stage 2 (n = 7) | EIFL Stage 3 (n = 45) | EIFL Stage 4 (n = 32) | P-valuea | |
|---|---|---|---|---|---|
| Age, years, mean ± SD | 61.7 ± 6.4 | 61.3 ± 2.2 | 61.6 ± 1.6 | 61.5 ± 1.2 | 0.788b |
| Sex, female, n (%) | 46 (55) | 2 (29) | 24 (53) | 20 (63) | 0.253c |
| Diabetes mellitus, n (%) | 13 (16) | 1 (14) | 8 (18) | 4 (13) | 0.818c |
| Hypertension, n (%) | 24 (29) | 3 (43) | 14 (31) | 7 (22) | 0.466c |
| Right eye, n (%) | 47 (56) | 3 (43) | 29 (64) | 15 (47) | 0.238c |
| High myopiaf, n (%) | 12 (14) | 3(43) | 6 (13) | 3 (1) | 0.094 |
| Phakic lens status, n (%) | |||||
| Preoperative | 84 (100) | 7 (100) | 45 (100) | 32 (100) | NA |
| Early postoperative | 82 (98) | 6 (86) | 44 (98) | 32 (100) | 0.082c |
| Late postoperative | 44 (52) | 4 (57) | 24 (53) | 16 (50) | 0.972c |
| CFT, μm, mean ± SD | |||||
| Preoperative | 528.88 ± 107.48 | 404.86 ± 12.28A | 511.47 ± 15.12B | 578.91 ± 17.09C | <0.001b |
| Early postoperative | 379.38 ± 51.83d | 326.57 ± 16.94A | 378.89 ± 7.73AB | 389.13 ± 8.43B | 0.016b |
| Late postoperative | 389.94 ± 81.12d | 334.71 ± 19.08A | 376.33 ± 8.02AB | 421.16 ± 18.59B | 0.010b |
| EZ disruption, n (%) | |||||
| Preoperative | 33 (39) | 1 (14) | 13 (29) | 19 (59) | 0.010c |
| Early postoperative | 12 (14)e | 1 (14) | 3 (7) | 8 (25) | 0.079c |
| Late postoperative | 10 (12)e | 1 (14) | 2 (4) | 7 (22) | 0.067c |
EIFL Ectopic inner foveal layer, ERM Epiretinal membrane, CFT Central foveal thickness, EZ Ellipsoid zone, Early and late postoperative periods were defined as postoperative 1–3 months and 6–12 months, respectively, NA Not applicable.
A–CData denote by the same uppercase superscript letters are not statistically significantly different (P ≥ 0.05 by Kruskal-Wallis test).
dDenotes that the value of CFT in early postoperative compared with preopeative data is statistically significant (P < 0.01). Likewise, the value of CFT in late postoperative compared with preopeative data is statistically significant (P < 0.01).
eMcNemar test while comparing postoperative data with preoperative data. Both P-value were < 0.001 in early and late postoperative periods.
fDefined as an axial length of 26.5 mm or more.
Optical coherence tomography features and functional outcomes
At baseline, the mean BCVA of eyes with ERM was 0.65 ± 0.37 logMAR and was significantly worse in EIFL stage 4 eyes when compared to EIFL stage 2 or 3 eyes (p < 0.001; Table 2). After vitrectomy and membrane peeling, the overall BCVA significantly improved to 0.54 ± 0.41 logMAR (p = 0.006) and 0.34 ± 0.31 logMAR (p < 0.001) in early and late postoperative periods, respectively. The final BCVA was comparable across different EIFL stages, indicating more improvement after surgery in the EIFL stage 4 eyes (p = 0.003).
Table 2.
Changes in visual acuity and angles of temporal vascular arcades after vitrectomy and membrane peeling.
| Eyes with ERM (n = 84) | P-Valuea | EIFL Stage 2 (n = 7) | EIFL Stage 3 (n = 45) | EIFL Stage 4 (n = 32) | P-valueb | |
|---|---|---|---|---|---|---|
| BCVA, logMAR | ||||||
| Preop | 0.65 ± 0.37 | - | 0.42 ± 0.06A | 0.56 ± 0.06A | 0.83 ± 0.06B | <0.001* |
| Early postop | 0.54 ± 0.41 | 0.006* | 0.43 ± 0.24 | 0.51 ± 0.42 | 0.62 ± 0.44 | 0.212 |
| Late postop | 0.34 ± 0.31 | <0.001* | 0.35 ± 0.06 | 0.31 ± 0.04 | 0.37 ± 0.06 | 0.594 |
| Change in BCVA, logMAR | ||||||
| Early postop | −0.11 ± 0.41 | - | -0.08 ± 0.29 | −0.05 ± 0.45 | −0.20 ± 0.36 | 0.158 |
| Late postop | −0.32 ± 0.42 | - | -0.08 ± 0.08A | −0.25 ± 0.07A | −0.46 ± 0.06B | 0.003* |
| Anglevein | ||||||
| Preop | 96.68 ± 20.61 | - | 93.12 ± 17.22 | 95.31 ± 21.38 | 99.34 ± 20.33 | 0.588 |
| Early postop | 103.74 ± 19.52 | <0.001* | 95.45 ± 17.12 | 102.26 ± 20.15 | 107.64 ± 18.77 | 0.238 |
| Late postop | 105.79 ± 19.42 | <0.001* | 95.42 ± 16.19 | 104.27 ± 20.33 | 110.21 ± 18.01 | 0.133 |
| Change in Anglevein | ||||||
| Early postop | 7.08 ± 5.69 | - | 2.39 ± 2.11A | 7.43 ± 5.12B | 8.30 ± 5.63B | 0.007* |
| Late postop | 9.13 ± 7.21 | - | 2.80 ± 2.04A | 9.43 ± 6.69B | 10.87 ± 6.95B | 0.002* |
| Angleartery | ||||||
| Preop | 85.72 ± 15.54 | - | 92.51 ± 10.22 | 85.08 ± 14.84 | 85.08 ± 17.39 | 0.437 |
| Early postop | 93.69 ± 13.79 | <0.001* | 95.94 ± 6.91 | 92.91 ± 13.26 | 94.31 ± 15.73 | 0.797 |
| Late postop | 95.43 ± 13.71 | <0.001* | 98.60 ± 9.87 | 94.17 ± 13.05 | 96.49 ± 15.38 | 0.560 |
| Change in Angleartery | ||||||
| Early postop | 8.00 ± 6.04 | - | 4.69 ± 3.53A | 8.00 ± 5.93A,B | 9.22 ± 5.83B | 0.042* |
| Late postop | 13.16 ± 7.21 | - | 6.09 ± 3.21 | 9.32 ± 6.09 | 11.41 ± 7.36 | 0.069 |
Data are presented as the mean ± SD.
Anglevein: angle of temporal venous arcades; Angleartery: angle of temporal arterial arcades; Δanglevein (ou): difference of anglevein between eyes with ERM and their fellow eyes; Δangleartery (ou): difference of angleartery between eyes with ERM and their fellow eyes, ERM Epiretinal membrane, EIFL Ectopic inner foveal layer, preop Preoperative, BCVA Best-corrected visual acuity, logMAR logarithm of the minimum angle of resolution; Early postop: at 1–3 months postoperatively; Late postop: at 6–12 months postoperatively.
*Statistically significant P value.
aWilcoxon signed ranks test while comparing preoperative and postoperative data.
bKruskal-Wallis test and post hoc tests comparing EIFL stage 2, 3, and 4 were performed by Dunn’s test. A,BData denote by the same uppercase superscript letters are not statistically significantly different (P ≥ 0.05 by Kruskal-Wallis test).
The initial mean CFT was 528.88 ± 107.48 μm and increased with higher EIFL stages (p < 0.001; Table 1). After surgery, CFT decreased in the early (379.38 ± 51.83 μm, p < 0.001) and late (389.94 ± 81.12 μm) postoperative periods, and advanced EIFL stages had higher CFT (p = 0.016 and p = 0.010, respectively). While worse preoperative BCVA was associated with greater CFT, r = 0.371, p < 0.001), postoperative BCVA showed no correlation (in early postoperative period: p = 0.300; in late postoperative period: p = 0.533). Among the eyes, 33 eyes (39.3%) displayed EZ disruption at baseline, and were more common in advanced EIFL stages (p < 0.001; Table 1). The presence of EZ disruption at baseline (p < 0.001) and early postoperative periods was negatively associated with BCVA (p = 0.002).
Dynamics of the vascular angles and its association with EIFL stages
The mean overall baseline anglevein was 96.68 ± 20.61 degrees and was comparable in different EIFL stages (p = 0.588; Table 2). After vitrectomy and membrane peeling, the anglevein significantly widened to 103.74 ± 19.52 and 105.79 ± 19.42 degrees in the early and late postoperative periods, respectively (both p < 0.001). The postoperative mean anglevein was comparable in each EIFL stage, but further calculations of the mean changes in anglevein showed that the change was significantly more in higher EIFL stages (in the late postoperative period: 10.87 ± 6.95 degrees in stage 4 eyes, 9.43 ± 6.69 in stage 3, and 2.80 ± 2.04 in stage 2; p = 0.002).
Regarding the angleartery, the mean overall preoperative angleartery was 85.72 ± 15.54 degrees and was comparable in different EIFL stages (p = 0.437; Table 2). After surgery, similar to the changes noted in the venous arcades, the angleartery also significantly widened to 93.69 ± 13.79 degrees in the early postoperative period (p < 0.001) and 95.43 ± 13.71 degrees in the late postoperative period (p < 0.001). The change in the angleartery in the early postoperative period was significantly more in EIFL stage 3 (8.00 ± 5.93 degrees) and stage 4 eyes (9.22 ± 5.83 degrees) when compared to the stage 2 eyes (4.69 ± 3.53 degrees; p = 0.042).
Furthermore, the postoperative change in angleartery (13.16 ± 7.21 degrees) was greater than anglevein (9.13 ± 7.21 degrees) in the late postoperative period (p = 0.039), showing that the arterial arcades moved more than the venous arcades. The above data demonstrate the dynamic change of temporal venous and arterial arcades after surgery, likely related to the release of the traction forces after the peeling of the membranes.
The difference in the vascular angles in bilateral eyes
When compared to the fellow eyes (105.07 ± 19.36 degrees), the mean preoperative anglevein was significantly narrower in the eyes with ERM (96.68 ± 20.61 degrees; Δanglevein (ou): −8.41 ± 25.66 degrees; p = 0.007; Table 3). Similarly, the mean preoperative angleartery was also significantly narrower when compared to the fellow eyes (85.72 ± 15.54 degrees vs. 99.19 ± 17.21 degrees; Δangleartery (ou): −13.49 ± 17.92 degrees; p < 0.001).
Table 3.
The difference in temporal vascular arcades in the eyes with epiretinal membrane and their fellow eyes.
| All (n = 84) | P-valuea | EIFL Stage 2 (n = 7) | EIFL Stage 3 (n = 45) | EIFL Stage 4 (n = 32) | P-valueb | |
|---|---|---|---|---|---|---|
| Δanglevein (ou) | ||||||
| Preop | −8.41 ± 25.66 | _ | −5.26 ± 7.32 | −14.32 ± 3.88 | −0.79 ± 4.38 | 0.098 |
| Early postop | −1.55 ± 24.51 | <0.001* | −2.19 ± 6.43 | −7.50 ± 3.70 | 6.96 ± 4.15 | 0.071 |
| Late postop | 0.69 ± 24.78 | <0.001* | 1.12 ± 6.19 A | −5.91 ± 3.78AB | 10.37 ± 4.02B | 0.023* |
| Δangleartery (ou) | ||||||
| Preop | −13.49 ± 17.92 | _ | −0.37 ± 4.51 | −14.16 ± 2.59 | −15.42 ± 3.36 | 0.093 |
| Early postop | −5.77 ± 16.86 | <0.001* | 2.97 ± 5.55 | −6.18 ± 2.46 | −7.09 ± 3.13 | 0.311 |
| Late postop | −3.43 ± 16.92 | <0.001* | 6.89 ± 6.26 | −4.22 ± 2.38 | −4.58 ± 3.18 | 0.236 |
Data are presented as the mean ± SD.
Anglevein: Angle of temporal venous arcades; Angleartery: Angle of temporal arterial arcades; Δanglevein (ou): Difference of anglevein between eyes with ERM and their fellow eyes; Δangleartery (ou): Difference of angleartery between eyes with ERM and their fellow eyes, BCVA Best-corrected visual acuity, ERM Epiretinal membrane, EIFL Ectopic inner foveal layer, LogMAR Logarithm of the minimum angle of resolution; Early postop: at 1–3 months postoperatively; Late postop: at 6–12 months postoperatively.
*Statistically significant P-value.
A,BData denoted by the same uppercase superscript letters in rows are not significantly different from each other (P ≥ 0.05 by Kruskal–Wallis test).
After vitrectomy and peeling surgery, the difference in anglevein between bilateral eyes (Δanglevein (ou)) had become significantly smaller (p < 0.001; Table 3). The Δanglevein (ou) decreased from −8.41 ± 25.66 degrees to −1.55 ± 24.51 degrees at the early postoperative period (p < 0.001) and 0.69 ± 24.78 degrees at the late postoperative period (p < 0.001). In different EIFL subgroups, the Δanglevein (ou) was not significantly different at baseline and the early postoperative period; but in the late postoperative period, the Δanglevein (ou) had increased to 10.37 ± 4.02 degrees in EIFL stage 4 eyes, which was significantly different from −1.12 ± 6.19 in EIFL stage 2 eyes (p = 0.023).
Similar to anglevein data, the difference in angleartery between bilateral eyes (Δangleartery (ou)) also had become significantly smaller after surgery (p < 0.001; Table 3). The Δangleartery (ou) decreased from −13.49 ± 17.92 degrees before the operation to −5.77 ± 16.86 and −3.43 ± 16.92 degrees at early and late postoperative periods, respectively (both p < 0.001). Different to what we observed in Δanglevein (ou), the Δangleartery (ou) was not significantly different among the EIFL subgroups throughout the study period.
The above findings implicated that the temporal vascular arcades angles were initially significantly narrower in the eyes with ERM when compared to their fellow eyes, but the difference decreased after vitrectomy. Interestingly, in the eyes with EIFL stage 4 ERM, their anglevein widened up remarkably after vitrectomy and had become even wider than the fellow eyes.
The associations between vascular angles and the functional outcomes
The pre-and postoperative mean anglevein, angleartery, Δanglevein (ou), and Δangleartery (ou) were not correlated with the EIFL stages or the BCVA either at the baseline or early and late postoperative periods (all p > 0.05; Kruskal-Wallis test). The magnitude of widening in angleartery and anglevein postoperatively, however, was correlated with BCVA improvement (in the early postoperative period: p = 0.029 and 0.050, respectively; in the late postoperative period: p = 0.277 and 0.003 respectively, Spearman’s test).
In order to predict the functional outcomes, logistic models were constructed using preoperative variables (Table 4). The univariate logistic model showed that males (p = 0.061), a history of hypertension (p = 0.046), and greater preoperative angleartery (p = 0.055) and Δangleartery (ou) (i.e., smaller difference in angleartery between bilateral eyes; p = 0.030) were associated with a lower chance of BCVA improvement of 2 lines or more after surgery. A further multivariable logistic model was constructed and confirmed that males, a history of hypertension, and a greater preoperative Δangleartery(ou) contributed to a significantly lower chance of achieving BCVA improvement ≧2 lines postoperatively (Odds ratios=0.419, 0.365, and 0.971, respectively; p = 0.034, 0.025, and 0.016, respectively).
Table 4.
Logistic regression analysis for factors associated with BCVA improvement of 2 lines or more after vitrectomy in eyes with ERM.
| Univariate analysis | Multivariable analysisa | |||
|---|---|---|---|---|
| Predictor | OR (95% CI) | P Value | OR (95% CI) | P-value |
| Age | 0.1947 (0.880, 1.019) | 0.142 | N.S. | |
| Male | 0.419 (0.169, 1.039) | 0.061 | 0.341 (0.126, 0.920) | 0.034* |
| Diabetes mellitus | 0.591 (0.173, 2.024) | 0.402 | N.S. | |
| Hypertension | 0.365 (0.136, 0.982) | 0.046* | 0.288 (0.097, 0.853) | 0.025* |
| EIFL staging | ||||
| Stage 2 | Reference | N.S. | ||
| Stage 3 | 1.174 (0.483, 2.854) | 0.724 | N.S. | |
| Stage 4 | 1.382 (0.551, 3.471) | 0.491 | N.S. | |
| Central foveal thickness | 1.000 (0.996, 1.004) | 0.988 | N.S. | |
| Ellipsoid zone disruption | ||||
| No | Reference | N.S. | ||
| Yes | 0.896 (0.361, 2.220) | 0.812 | N.S. | |
| Preop BCVA, logMAR | 1.549 (0.393, 6.102) | 0.532 | N.S. | |
| Preop anglevein in eyes with ERM | 1.008 (0.986, 1.030) | 0.492 | N.S. | |
| Preop angleartery in eyes with ERM | 0.971 (0.942, 1.001) | 0.055 | N.S. | |
| Preop Δanglevein (ou) | 0.996 (0.979, 1.014) | 0.658 | N.S. | |
| Preop Δangleartery (ou) | 0.971 (0.945, 0.997) | 0.030* | 0.965 (0.938, 0.994) | 0.016* |
Anglevein: angle of temporal venous arcades; Angleartery: angle of temporal arterial arcades; Δanglevein (ou): angle difference in the venous arcades between eyes with epiretinal membrane and their fellow eyes; Δangleartery (ou): angle difference in arterial arcade between eyes with epiretinal membrane and their fellow eyes, EIFL Ectopic inner foveal layer, ERM Epiretinal membrane, Preop Preoperative, N.S. Not selected.
*Statistically significant P-value.
aAll variables were entered into multivariable logistic regression models with the backwards method to explore independent predictors for best-corrected visual acuity improvement of 2 lines or more at postoperative 6−12 months.
Lastly, the ROC analysis demonstrated that by utilizing the preoperative Δangleartery (ou), the determination of whether BCVA improvement ≥ 2 lines postoperatively could be achieved reached an area under the curve of 0.736 (p = 0.035; Supplementary Fig. 1). By using a cut-off value of −27.19 degrees in Δangleartery (ou), the prediction of BCVA improvement ≥ 2 lines postoperatively had a sensitivity of 0.73 and specificity of 0.80. These results implied a possible new biomarker in predicting the functional outcomes after surgery — if the angleartery in the eye with ERM is narrower than the fellow eye of 27 degrees or more, one can expect a high chance of reaching significant BCVA improvement postoperatively.
Discussion
This retrospective study demonstrated that in the eyes with ERM, the temporal retinal vascular arcades angles were narrower than their contralateral healthy eyes. After ERM surgery, both arterial and venous arcades widened, and a greater improvement in BCVA was positively associated with a greater widening of arterial and venous arcades. Furthermore, this study identified a narrower preoperative arterial arcades angle as a predictor for significant functional improvement after ERM surgery.
Several OCT parameters have been assessed as prognostic factors, including EIFL presence, CFT, and EZ disruption [14–20], all indicating poorer functional outcomes [14–19]. Nevertheless, consensus on the most reliable indicator is lacking, and results have been inconsistent [9, 14–18, 21, 22]. In the current study, we observed that eyes with higher EIFL stages had poorer baseline visual acuity and greater postoperative visual acuity improvements; nevertheless, no correlation existed between the final BCVA and EIFL stages. EIFL staging system is a subjective grading that has an inherent limitation in discrepancies among graders. Our findings aligned with previous studies, showing that CFT correlated positively with preoperative BCVA but lacked correlation with postoperative BCVA [22, 23]. The presence of EZ disruption was linked to worse BCVA both at baseline and after surgery [22, 24], and CFT and EZ disruption were notably more prevalent in higher EIFL stages [24]. However, the multivariate analysis in the current study indicated that neither CFT nor EZ presence contributed to final visual improvement. These OCT parameters rely on high-quality OCT imaging; thus, difficulties may ensue particularly when the retinal structure is severely altered and the patients’ vision or ability of fixation is poor [25]. Therefore, more objective and less complex biomarkers could be helpful in predicting visual outcomes.
ERM tractional force exerted on the inner retina may drag the retinal vessels toward the macular regions, causing distortion and displacement of the vessels [12, 13, 25, 26]. HK Yang et al. first observed that the angle between the superior and inferior major arcades was narrower in eyes with ERMs than their normal fellow eyes and became wider postoperatively [12]. However, they only analysed the venous arcades and did not explore the relationship between the vascular angles and visual function. Nagura et al. [13] measured the arterial arcades angle and also observed that the angle was narrower than their fellow eyes, and demonstrated a positive correlation between the angle and BCVA. Nevertheless, they focused solely on arterial arcades and did not look into the postoperative changes [13].
We address the above-mentioned knowledge gap by analyzing both the arterial and venous angles pre-and postoperatively and comparing them with fellow eyes to reduce the inter-individual differences. Both the retinal artery and vein shared the same characteristics of narrower vascular arcades in eyes with ERM, demonstrating that the tractional force had dragged temporal retinal arcades toward the macular region. After ERM surgery, the arcades angles widened owing to the relief of tractional forces and restoration of the retinal structure [16]. In concordance with HK Yang et al. [12], no significant difference in mean vascular angles, baseline BCVA, and final BCVA was noted in the current study. Yet, the postoperative BCVA improvement was positively associated with the widening of angles, implying that the mobility of retinal arcades is an indicator of inner retinal traction in eyes with ERM and a potential biomarker of functional recovery.
Interestingly, the arterial arcades widened more than the venous arcades after surgery in the current study. There is a space lacking the complicated capillary network around the retinal arterioles but not around the venules [27], potentially giving more room for the arteries to move. In addition, in the vicinity around the optic nerve head, the lumen diameter of the arteries is significantly smaller than the veins, resulting in a relatively smaller volume of arterial retinal blood flow [28]. We speculated that the arteries are thus more susceptible to displacement than the veins when subjected to the same tractional force. The above anatomical variations may have contributed to the difference that we observed between the arterial and the venous arcades and implied that the arterial arcades are a more sensitive proxy for ERM traction.
Using the arterial angle difference between both eyes, we identified that a narrower arterial in the eyes with ERM was a predictor of significant BCVA improvement after surgery, particularly when the difference was greater than 27.19 degrees. The advantage of utilizing arterial angles as a predictor is that it is entirely objective and could possibly be calculated automatically by artificial intelligence [29, 30]. Moreover, the advancement in portable or cellphone-based fundus cameras has made fundus photography more accessible and potentiates continuous home monitoring in a telemedicine approach [31, 32].
Male patients and a history of hypertension were also found to be predictive of poor visual outcomes. Hypertension may lead to vascular changes including lumen narrowing, vessel wall stiffness, focal ischemia, and irreversible retinopathy [33]. Furthermore, studies have found that compared to males, females have thinner retinal thickness and worse baseline BCVA when ERM developed [9, 34, 35]. We speculated that the thinner retinal thickness in females was prone to structural alteration by ERM traction, leading to a worse baseline vision and more room for improvement after ERM surgery.
There were limitations to this study. This was a retrospective study with a small number of EIFL stage 2 eyes. The initial manual drawing of the inner circle could potentially introduce subjective errors. Artificial intelligence assistance may enable more objective measurements in future studies. We did not categorize primary and secondary ERMs because oftentimes it is not possible to reliably differentiate the two. This approach may ensue bias but provides a broader generalizability of the study results. Also, we included highly myopic eyes (n = 12 [14%]). The longer axial length of the highly myopic eyes might affect the projection of the retinal images when taking fundus photographs and lead to variations in the retinal vascular angle [36]. Nevertheless, we addressed this concern by calculating the angle difference between ERM eyes and their respective fellow eyes, which all had myopia; and the change of angles within the same eye before and after the ERM surgery. This strategy should have decreased the impact of this issue.
In conclusion, the present study demonstrated that the temporal vascular arcades in eyes with ERM were narrower than the healthy fellow eyes and widened after ERM surgery. The arterial arcade was a more sensitive proxy for ERM traction and could serve as a potential biomarker for postoperative visual outcomes. The proposed colour fundus-based biomarker is totally objective and can be obtained quickly, cheaply, non-invasively, and even remotely in home-based settings.
Summary
What was known before
While surgical intervention is considered for symptomatic epiretinal membrane (ERM), postoperative visual recovery outcomes vary.
Despite the identification of several predictive factors, there is currently a lack of objective biomarkers to predict postoperative visual function.
What this study adds
The retinal vascular arcades were narrower in the eyes with ERM and widened after membrane peeling surgery.
The postoperative widening of the arcades was associated with visual gain and the change in the arterial arcade angle could serve as a predictive biomarker.
The fundus photography-based biomarker is objective, highly accessible, and low-cost, and brings the possibility for further telemedicine and home-monitoring approaches to evaluate and follow up on the highly prevalent epiretinal membrane condition.
Supplementary information
Author contributions
HDC, YCC: writing the manuscript, analysing the results, and interpreting the data. EYCK, YHC, LL, KJC, YSH, ANC, WCW, CCL: data collection. HDC, YCC, PYW: data processing. HDC, YCC: conception and design of the work. All authors approved the final manuscript.
Data availability
Data supporting the findings of the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Hung-Da Chou, Yu-Chieh Chang.
Supplementary information
The online version contains supplementary material available at 10.1038/s41433-023-02776-6.
References
- 1.Smiddy WE, Maguire AM, Green WR, Michels RG, de la Cruz Z, Enger C, et al. Idiopathic epiretinal membranes. Ultrastructural characteristics and clinicopathologic correlation. Ophthalmology. 1989;96:811–20. doi: 10.1016/S0161-6420(89)32811-9. [DOI] [PubMed] [Google Scholar]
- 2.Kim JH, Kim YM, Chung EJ, Lee SY, Koh HJ. Structural and functional predictors of visual outcome of epiretinal membrane surgery. Am J Ophthalmol. 2012;153:103–10. doi: 10.1016/j.ajo.2011.06.021. [DOI] [PubMed] [Google Scholar]
- 3.Fung AT, Galvin J, Tran T. Epiretinal membrane: A review. Clin Exp Ophthalmol. 2021;49:289–308. doi: 10.1111/ceo.13914. [DOI] [PubMed] [Google Scholar]
- 4.Chen X, Klein KA, Shah CP, Heier JS. Progression to Surgery for Patients With Idiopathic Epiretinal Membranes and Good Vision. Ophthalmic Surg Lasers Imaging Retin. 2018;49:S18–22. doi: 10.3928/23258160-20180814-03. [DOI] [PubMed] [Google Scholar]
- 5.Dawson SR, Shunmugam M, Williamson TH. Visual acuity outcomes following surgery for idiopathic epiretinal membrane: an analysis of data from 2001 to 2011. Eye (London) 2014;28:219–24. doi: 10.1038/eye.2013.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Matoba R, Morizane Y. Surgical Treatment of Epiretinal Membrane. Acta Med Okayama. 2021;75:403–13. doi: 10.18926/AMO/62378. [DOI] [PubMed] [Google Scholar]
- 7.Miliatos I, Lindgren G. Epiretinal membrane surgery evaluated by subjective outcome. Acta Ophthalmol. 2017;95:52–9. doi: 10.1111/aos.13001. [DOI] [PubMed] [Google Scholar]
- 8.Scheerlinck LM, van der Valk R, van Leeuwen R. Predictive factors for postoperative visual acuity in idiopathic epiretinal membrane: a systematic review. Acta Ophthalmol. 2015;93:203–12. doi: 10.1111/aos.12537. [DOI] [PubMed] [Google Scholar]
- 9.Coppola M, Brambati M, Cicinelli MV, Marchese A, Zanzottera EC, Peroglio Deiro A, et al. The visual outcomes of idiopathic epiretinal membrane removal in eyes with ectopic inner foveal layers and preserved macular segmentation. Graefes Arch Clin Exp Ophthalmol. 2021;259:2193–201. doi: 10.1007/s00417-021-05102-6. [DOI] [PubMed] [Google Scholar]
- 10.Feng J, Yang X, Xu M, Wang Y, Shi X, Zhang Y, et al. Association of Microvasculature and Macular Sensitivity in Idiopathic Macular Epiretinal Membrane: Using OCT Angiography and Microperimetry. Front Med (Lausanne) 2021;8:655013. doi: 10.3389/fmed.2021.655013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Weinberger D, Stiebel-Kalish H, Priel E, Barash D, Axer-Siegel R, Yassur Y. Digital red-free photography for the evaluation of retinal blood vessel displacement in epiretinal membrane. Ophthalmology. 1999;106:1380–3. doi: 10.1016/S0161-6420(99)10164-7. [DOI] [PubMed] [Google Scholar]
- 12.Yang HK, Kim SJ, Jung YS, Kim KG, Kim JH, Yu HG. Improvement of horizontal macular contraction after surgical removal of epiretinal membranes. Eye (London) 2011;25:754–61. doi: 10.1038/eye.2011.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Nagura K, Inoue T, Zhou HP, Obata R, Asaoka R, Arasaki R, et al. Association between retinal artery angle and visual function in eyes with idiopathic epiretinal membrane. Transl Vis Sci Technol. 2021;10:35. doi: 10.1167/tvst.10.9.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Govetto A, Lalane RA, 3rd, Sarraf D, Figueroa MS, Hubschman JP. Insights into epiretinal membranes: presence of ectopic inner foveal layers and a new optical coherence tomography staging scheme. Am J Ophthalmol. 2017;175:99–113. doi: 10.1016/j.ajo.2016.12.006. [DOI] [PubMed] [Google Scholar]
- 15.Govetto A, Virgili G, Rodriguez FJ, Figueroa MS, Sarraf D, Hubschman JP. Functional and anatomical significance of the ectopic inner foveal layers in eyes with idiopathic epiretinal membranes: surgical results at 12 months. Retina. 2019;39:347–57. doi: 10.1097/IAE.0000000000001940. [DOI] [PubMed] [Google Scholar]
- 16.González-Saldivar G, Berger A, Wong D, Juncal V, Chow DR. Ectopic Inner Foveal Layer Classification Scheme Predicts Visual Outcomes After Epiretinal Membrane Surgery. Retina. 2020;40:710–7. doi: 10.1097/IAE.0000000000002486. [DOI] [PubMed] [Google Scholar]
- 17.Mavi Yildiz A, Avci R, Yilmaz S. The predictive value of ectopic inner retinal layer staging scheme for idiopathic epiretinal membrane: surgical results at 12 months. Eye (Lond) 2021;35:2164–72. doi: 10.1038/s41433-021-01429-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Kim BH, Kim DI, Bae KW, Park UC. Influence of postoperative ectopic inner foveal layer on visual function after removal of idiopathic epiretinal membrane. PLoS One. 2021;16:e0259388. doi: 10.1371/journal.pone.0259388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Mahmoudzadeh R, Israilevich R, Salabati M, Hsu J, Garg SJ, Regillo CD, et al. Pars plana vitrectomy for idiopathic epiretinal membrane: oct biomarkers of visual outcomes in 322 Eyes. Ophthalmol Retin. 2022;6:308–17. doi: 10.1016/j.oret.2021.10.008. [DOI] [PubMed] [Google Scholar]
- 20.Kunavisarut P, Supawongwattana M, Patikulsila D, Choovuthayakorn J, Watanachai N, Chaikitmongkol V, et al. Idiopathic epiretinal membranes: visual outcomes and prognostic factors. Turk J Ophthalmol. 2022;52:109–18. doi: 10.4274/tjo.galenos.2021.09258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lee MW, Jung I, Song YY, Baek SK, Lee YH. Long-term outcome of epiretinal membrane surgery in patients with internal limiting membrane dehiscence. J Clin Med. 2020;9:2470. doi: 10.3390/jcm9082470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Jeon S, Jung B, Lee WK. Long-term prognostic factors for visual improvement after epiretinal membrane removal. Retina. 2019;39:1786–93. doi: 10.1097/IAE.0000000000002211. [DOI] [PubMed] [Google Scholar]
- 23.Zhmurin R, Grajewski L, Krause L. Influence of preoperative foveal layers’ Thickness on Visual Function and Macular Morphology by Phacovitrectomy for Epiretinal Membrane. J Ophthalmol. 2022;2022:1895498. doi: 10.1155/2022/1895498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Doguizi S, Sekeroglu MA, Ozkoyuncu D, Omay AE, Yilmazbas P. Clinical significance of ectopic inner foveal layers in patients with idiopathic epiretinal membranes. Eye (Lond) 2018;32:1652–60. doi: 10.1038/s41433-018-0153-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kaplan RI, Chen M, Gupta M, Rosen RB. Impact of automated OCT in a high-volume eye urgent care setting. BMJ Open Ophthalmol. 2019;4:e000187. doi: 10.1136/bmjophth-2018-000187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Gupta P, Sadun AA, Sebag J. Multifocal retinal contraction in macular pucker analyzed by combined optical coherence tomography/scanning laser ophthalmoscopy. Retina. 2008;28:447–52. doi: 10.1097/IAE.0b013e318160a754. [DOI] [PubMed] [Google Scholar]
- 27.Mase T, Ishibazawa A, Nagaoka T, Yokota H, Yoshida A. Radial peripapillary capillary network visualized using wide-field montage optical coherence tomography angiography. Invest Ophthalmol Vis Sci. 2016;57:504–10. doi: 10.1167/iovs.15-18877. [DOI] [PubMed] [Google Scholar]
- 28.Iwase T, Ra E, Yamamoto K, Kaneko H, Ito Y, Terasaki H. Differences of retinal blood flow between arteries and veins determined by laser speckle flowgraphy in healthy subjects. Med (Baltim) 2015;94:e1256. doi: 10.1097/MD.0000000000001256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Matsopoulos GK, Asvestas PA, Delibasis KK, Mouravliansky NA, Zeyen TG. Detection of glaucomatous change based on vessel shape analysis. Comput Med Imaging Graph. 2008;32:183–92. doi: 10.1016/j.compmedimag.2007.11.003. [DOI] [PubMed] [Google Scholar]
- 30.Liu R, Li Q, Xu F, Wang S, He J, Cao Y, et al. Application of artificial intelligence-based dual-modality analysis combining fundus photography and optical coherence tomography in diabetic retinopathy screening in a community hospital. Biomed Eng Online. 2022;21:47. doi: 10.1186/s12938-022-01018-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Rodenbeck SJ, Mackay DD. Examining the ocular fundus in neurology. Curr Opin Neurol. 2019;32:105–10. doi: 10.1097/WCO.0000000000000637. [DOI] [PubMed] [Google Scholar]
- 32.Beduk T, Beduk D, Hasan MR, Guler Celik E, Kosel J, Narang J, et al. Smartphone-Based Multiplexed Biosensing Tools for Health Monitoring. Biosens (Basel) 2022;12:583. doi: 10.3390/bios12080583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Fraser-Bell S, Symes R, Vaze A. Hypertensive eye disease: a review. Clin Exp Ophthalmol. 2017;45:45–53. doi: 10.1111/ceo.12905. [DOI] [PubMed] [Google Scholar]
- 34.Wagner-Schuman M, Dubis AM, Nordgren RN, Lei Y, Odell D, Chiao H, et al. Race- and sex-related differences in retinal thickness and foveal pit morphology. Invest Ophthalmol Vis Sci. 2011;52:625–34. doi: 10.1167/iovs.10-5886. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Kashani AH, Zimmer-Galler IE, Shah SM, Dustin L, Do DV, Eliott D, et al. Retinal thickness analysis by race, gender, and age using Stratus OCT. Am J Ophthalmol. 2010;149:496–502. doi: 10.1016/j.ajo.2009.09.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Asano S, Yamashita T, Asaoka R, Fujino Y, Murata H, Terasaki H, et al. Retinal vessel shift and its association with axial length elongation in a prospective observation in Japanese junior high school students. PLoS One. 2021;16:e0250233. doi: 10.1371/journal.pone.0250233. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Data Availability Statement
Data supporting the findings of the current study are available from the corresponding author on reasonable request.