Photoreceptor Outer Segment Length: A Prognostic

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epiretinal membrane (ERM) using spectral domain (SD) optical coherence tomography .... defined as the midpoint of the rising intensity edge of the A-scan.
Photoreceptor Outer Segment Length: A Prognostic Factor for Idiopathic Epiretinal Membrane Surgery Akira Shiono, MD,1,* Jiro Kogo, MD, PhD,1,* Gerd Klose, PhD,2 Hiroyuki Takeda, MD, PhD,1 Hiroki Ueno, MD, PhD,1 Naoto Tokuda, MD, PhD,1 Jun Inoue, MD, PhD,1 Akiko Matsuzawa, MD, PhD,1 Naoyuki Kayama, MD, PhD,1 Satoki Ueno, MD, PhD,1 Hitoshi Takagi, MD, PhD1 Purpose: To investigate prognostic factors for visual improvement in patients undergoing vitrectomy for epiretinal membrane (ERM) using spectral domain (SD) optical coherence tomography (OCT). Design: Prospective cohort study. Participants: A total of 41 eyes of 38 patients. Methods: A total of 41 eyes of 38 patients with idiopathic ERM underwent ERM resection. Ophthalmic evaluations included best-corrected visual acuity (BCVA) and OCT parameters before and 1, 3, and 6 months after surgery. Correlations between OCT parameters and BCVA were assessed at each time point. Correlations between postoperative BCVA and preoperative factors were evaluated, including age, preoperative BCVA, photoreceptor outer segment (PROS) length, central foveal thickness (CFT), outer foveal thickness (OFT), and outer nuclear layer thickness (ONLT). The factors influencing postoperative BCVA were evaluated using multiple regression analysis. Main Outcome Measures: The BCVA at 6 months postoperatively. Results: The PROS length had the most significant correlation with BCVA at each time point (baseline: P ⫽ 0.0098, r ⫽ ⫺0.409; 1 month: P ⫽ 0.0002, r ⫽ ⫺0.586; 3 months: P ⬍ 0.0001, r ⫽ ⫺0.642; 6 months: P ⫽ 0.0002, r ⫽ ⫺0.577). The PROS length 1 month postoperatively was significantly decreased compared with that preoperatively (P ⫽ 0.0325), and the PROS length at 3 months recovered to the baseline length. Preoperative BCVA and PROS length were significantly correlated with postoperative BCVA at 6 months (P ⫽ 0.0055, r ⫽ 0.439 and P ⫽ 0.0089, r ⫽ ⫺0.414, respectively). Other parameters, including age, CFT, OFT, and ONLT, were not significantly correlated with postoperative BCVA. Multiple regression analysis showed that preoperative PROS length yielded the highest regression coefficient with postoperative BCVA (P ⫽ 0.0363, standard regression coefficient ⫽ ⫺0.335, overall R2 ⫽ 0.289). Conclusions: Imaging of PROS length with SD-OCT was found to be a good indicator of BCVA at each time point after surgery and a predictor of postoperative BCVA in patients with idiopathic ERM. The PROS length changes after surgery may indicate surgical injury and restoration of the macular outer layer. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;xx:xxx © 2012 by the American Academy of Ophthalmology.

Idiopathic epiretinal membrane (ERM) is a relatively common finding in older persons and may occur in the absence of ocular disease processes other than posterior vitreous detachment.1–5 Surgery for patients with ERM causing symptomatic visual disturbance is a standard treatment procedure.6 Despite successful ERM resection in the absence of significant complications, some cases show poor visual acuity (VA) that cannot be explained fully by the most significant prognostic factors, such as preoperative VA and duration of symptoms.7 Optical coherence tomography (OCT) is a well-established diagnostic and monitoring tool for vitreomacular disorders.8 Spectral domain (SD) OCT recently has improved the speed and sensitivity of the examination, providing high-resolution images of foveal micro© 2012 by the American Academy of Ophthalmology Published by Elsevier Inc.

structural features.9,10 Detailed information on macular morphology, such as the photoreceptor inner segment (IS)/ outer segment (OS) junction and external limiting membrane (ELM), can be obtained in SD-OCT. Some OCT studies in patients with ERM indicated prognostic factors, such as marked loss of the foveal contour, the presence or absence of cystoid macular edema, and the condition of the photoreceptor layer.11–15 However, these are not quantitative prognostic factors. Other studies evaluated other quantitative factors in eye disease. It was reported that photoreceptor outer segment (PROS) length was correlated with best-corrected VA (BCVA) in patients with diabetic macular edema.16 Other investigators suggested that the thickness, area, and volume of the outer layer were correlated ISSN 0161-6420/12/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.09.044

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Figure 1. A, Foveal spectral domain (SD) optical coherence tomography (OCT) parameters, outer nuclear layer thickness (ONLT), and central foveal thickness (CFT). B, Enlargement of OCT image is shown, demonstrating photoreceptor outer segment (PROS) length and outer foveal thickness (OFT). ELM ⫽ external limiting membrane; IS/OS ⫽ inner segment/outer segment; RPE ⫽ retinal pigment epithelium.

with BCVA in patients with dry age-related macular degeneration (AMD).17 Outer foveal thickness (OFT) and relative reflectivity of the outer nuclear layer (ONL) were associated with BCVA in patients with macular hole.18,19 The volume of the ONL was found to be associated with BCVA in patients with AMD.20 The aim of this study was to investigate the preoperative quantitative factors as shown in SD-OCT images that correlate with postoperative VA in patients who underwent ERM surgery.

Patients and Methods Thirty-eight patients (41 eyes) who underwent surgery for idiopathic ERM resection between June 2009 and November 2010 were enrolled in this study. The study was a consecutive prospective case study. All investigations adhered to the tenets of the Declaration of Helsinki. This study was approved by the institutional review board and ethics committee of St. Marianna University School of Medicine. Patients were followed up for at least 6 months postoperatively at St. Marianna University Hospital. Eyes with media opacities resulting in poor OCT signals were excluded. Eyes with secondary ERM caused by conditions such as diabetic retinopathy, venous occlusion, retinal detachment, uveitis, trauma, or other ocular pathologies that could have interfered with the functional results, especially patients with severe cataract of more than grade 3 nuclear sclerosis or cortical opacity, were excluded. Surgery consisted of 25-gauge transconjunctival sutureless vitrectomy and ERM peeling using an end-gripping forceps. Cataract surgery was performed in 33 eyes. Epiretinal membrane and internal limiting membrane (ILM) peeling were performed in all eyes with triamcinolone acetonide staining in 38 eyes and indocyanine green dye injection in 3 eyes. The BCVA and SD-OCT (Cirrus HD-OCT, Carl Zeiss Meditec, Inc., Dublin, CA) findings were investigated before and after surgery at 1, 3, and 6 months. The BCVA was converted to the logarithm of the minimal angle of resolution (logMAR) units for statistical analysis. We assessed the associations among preoperative parameters, including logMAR VA, age, central foveal thickness (CFT; the distance between the

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vitreoretinal surface and the retinal pigment epithelium [RPE] at the foveal center), OFT (the distance between the ELM and the RPE), PROS length (the distance between the IS/OS junction and the RPE), outer nuclear layer thickness (ONLT; the distance between the outer plexiform layer/ONL boundary and the ELM at the foveal center), and postoperative VA 6 months after surgery (Fig 1). The CFT and ONLT measurements were derived from the software (Cirrus 3.0; Carl Zeiss Meditec, Inc.) provided by the manufacturer. Detailed image analysis was performed in the outer layer. The central PROS length and OFT measurements at the foveal center were performed using Image J software V1.46 (National Institutes of Health, Bethesda, MD; available at http:// rsbweb.nih.gov) from July 2011 and were true to scale.21 Within this selected area, longitudinal reflectivity profiles, arranged in a cross-sectional parallel manner, were calculated (Fig 2). The OCT scans through the outer layer showed 3 clearly distinguishable, highly reflective bands (peak [P] 1–3; Fig 2C). These highly reflective bands represented the RPE (P1), IS/OS junction (P2), and ELM (P3). The PROS length (the distance between P1 and P2) and OFT (the distance between P1 and P3) measurements were performed on longitudinal reflectivity profiles. The central subfield (averaged distances over central foveal 1-mm lengths) PROS length and OFT measurements required additional analysis to obtain accurate median values in the subfield. The repeatability of this manual analysis was investigated using a subset of both 5 images of healthy eyes and 5 images of the study eyes. The 3-sigma repeatability of the image analysis was found to be no less than 2.8 ␮m. The patients were therefore examined with the Cirrus HD-OCT using 5-line or HD 5-line raster scans. The images of the central B-scan were exported from the instrument and further analyzed with a code written in the Octave mathematic programming language. The routine was developed for the automatic detection of the location of the highly reflective bands (ELM, IS/OS junction, and RPE) relative to the ILM. The images were low-pass filtered first to reduce the intrinsic noise. The routine then attempted to find the location of the outer bands automatically by determining the position of the highest intensity in each band. The position of the ILM was defined as the midpoint of the rising intensity edge of the A-scan when entering the retina. After determining the position of the respective bands in the image, the corresponding pixel differences

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Shiono et al 䡠 Photoreceptor Outer Segment Length in ERM

Figure 2. Data extraction from grayscale images. A, Complete 24-bit image of patients with epiretinal membrane. B, Enlarged extract from the outer layer in (A). Dashed line: Line scan from which the single reflectivity profile (C) was calculated. C, Three distinct peaks within the longitudinal reflectivity profile were easily detected. Reflectivity is in 0 to 255 levels of gray (x-axis); scan depth is micrometers (y-axis). D, Semiautomatic layer segmentation to calculate average separation in central 1-mm subfield.

can be rescaled as geometric differences. In addition to layer separation at a manually determined foveal position, averaged distances also were calculated for the central subfield (Fig 2D). To the best of our knowledge, none of the currently available OCT instruments have such an analysis of the geometry of various outer layers embedded; thus, means of external image analysis were used for that purpose. First, in the measurement procedure of PROS length and OFT, we assessed which had a stronger correlation with VA at each time point. Associations between OCT parameters and VA were assessed before and 1, 3, and 6 months after surgery. Furthermore, factors influencing postoperative VA were examined using multiple regression analysis. All statistical analyses were performed using StatView software (Abacus Concepts, Inc., Berkeley, CA, 1992). For primary analyses, the correlations between BCVA at each time point and preoperative parameters were investigated using the Spearman rank-correlation coefficient. Independent variables for multiple regression analysis were determined using stepwise selection. The Wilcoxon rank-sum test was used to compare pre- and postoperative BCVA and OCT parameters. P ⬍ 0.05 was considered to represent a statistically significant difference.

Results Baseline Characteristics Twelve of the 38 patients (32%) were men, and 26 (68%) were women. The mean age was 69 years. Preoperatively, 36 eyes (88%) were phakic and 5 eyes (12%) were pseudophakic with posterior chamber intraocular lenses. The ERM and ILM were resected successfully in all cases. Cataract surgery combined with vitrectomy was performed in 33 eyes. Vitrectomy alone was performed in 6 pseudophakic eyes and 2 eyes with clear lenses.

was 0.166 (20/27)⫾0.221, 0.075 (20/23)⫾0.155, and 0.063 (20/ 22)⫾0.131, respectively. Figure 3 (available at http://aaojournal. org) shows the clinical course of VA. The BCVA at 1 month postoperatively was not significantly different from that preoperatively (P ⫽ 0.402). However, the BCVA at 3 and 6 months postoperatively improved significantly compared with that preoperatively (P ⬍ 0.0001 and P ⬍ 0.0001, respectively).

Comparison of Central Values and Central Subfield Values in the Outer Layer Table 1 (available at http://aaojournal.org) shows comparisons of central values and central subfield values in the outer layer at each time point. The central PROS length and OFT were more highly correlated with VA than were the mean central subfield PROS length and OFT at each time point. Subsequent analyses of the central PROS length and OFT were performed on the basis of this result.

Correlation between Spectral Domain Optical Coherence Tomography Parameters and Best-Corrected Visual Acuity at Each Time Point Table 2 (available at http://aaojournal.org) shows correlations between the OCT parameters and the VA at each time point. The PROS length and OFT at baseline were significantly correlated with VA at baseline (PROS: P ⫽ 0.0098, r⫽– 0.409; OFT: P ⫽ 0.0263, r⫽– 0.351) and 1 month (PROS: P ⫽ 0.0002, r ⫽ ⫺0.586; OFT: P ⫽ 0.0035, r ⫽ ⫺0.461), 3 months (PROS: P ⬍ 0.0001, r ⫽ ⫺0.642; OFT: P ⫽ 0.0054, r ⫽ ⫺0.440), and 6 months (PROS: P ⫽ 0.0003, r ⫽ ⫺0.577; OFT: P ⫽ 0.0015, r ⫽ ⫺0.502) after surgery. The CFT and ONLT were not significantly correlated with VA at any time point. The PROS length showed the highest correlation with VA at each time point.

Time Course Change of Visual Acuity

Time Course of Changes in Photoreceptor Outer Segment Length and Outer Foveal Thickness

The mean logMAR BCVA at baseline was 0.183 (20/28)⫾0.169, and the mean logMAR BCVA at 1, 3, and 6 months after surgery

Changes in OCT parameters that were correlated with VA at each time point are shown in Figure 4 (available at http://aaojournal.org). The

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Ophthalmology Volume xx, Number x, Month 2012 PROS length 1 month after surgery was significantly decreased compared with that at baseline (P ⫽ 0.0328). However, PROS length 3 and 6 months after surgery was not significantly different from that at baseline (P ⫽ 0.7885). The OFT 1 month after surgery was significantly decreased compared with the baseline value (P ⫽ 0.0006), although OFT 3 and 6 months after surgery was not significantly different from the baseline value (P ⫽ 0.0538).

Factors Affecting Postoperative Best-Corrected Visual Acuity in Multiple Regression Analysis In multiple regression analysis, the model with the highest adjusted R2 was determined by stepwise selection (adjusted R2 ⫽ 0.232). The model R2 for this analysis was 0.289. In this model, PROS length had the most significant effect on VA 6 months after surgery (P ⫽ 0.0363; standard regression coefficient ⫽ ⫺0.335) (Table 3).

Correlations between preoperative parameters and BCVA 6 months after surgery are shown in Figure 5. The PROS length and VA before surgery were significantly correlated with BCVA at 6 months (P ⫽ 0.0055, r ⫽ 0.439 and P ⫽ 0.0089, r ⫽ ⫺0.414, respectively). The mean CFT, OFT, and ONLT before surgery were not significantly correlated with BCVA at 6 months (P ⫽ 0.7100, r ⫽ 0.59; P ⫽ 0.0600, r ⫽ ⫺0.297; and P ⫽ 0.8232, r ⫽ 0.131, respectively).

In this study, we demonstrated that PROS length was significantly correlated with BCVA at each postoperative time point examined. Furthermore, PROS length was most significantly correlated with VA 6 months postoperatively and was a potent predictor of visual prognosis in multiple regression analysis. These results suggest that PROS length is a novel parameter reflecting postoperative VA and predict-

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Figure 5. Linear regression and correlation analysis of preoperative parameters with postoperative visual acuity (VA). Spearman rank correlation coefficient (r) and P values for the slope of the regression line are noted. Postoperative best-corrected VA (BCVA) is the BCVA at 6 months after surgery. logMAR ⫽ logarithm of the minimal angle of resolution; PROS ⫽ photoreceptor outer segment.

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Shiono et al 䡠 Photoreceptor Outer Segment Length in ERM Table 3. Multiple Regression Analysis between Preoperative Parameters and Visual Acuity at 6 Months Preoperative Parameter PROS length Age Preoperative VA

P Value

Standard Regression Cefficient

0.0363 0.1441 0.1576

⫺0.335 0.208 0.223 Overall R2 ⫽ 0.289

PROS ⫽ photoreceptor outer segment; VA ⫽ visual acuity.

ing visual outcome after ERM surgery. Because of the relatively small number of investigated eyes, a nonoptimized analysis procedure, and a large remaining unexplained variation in the linear model, the work should be seen as an a preliminary step to derive a model eventually predicting the visual outcome after ERM surgery. For primary analysis, we compared the central value with central subfield values of the outer layer, including PROS length and OFT, because the outer layer is a very small segment. Forooghian et al16 suggested that the mean PROS length of the central foveal point was longer than that of the macula in patients with diabetic macular edema. They reported that PROS length in the foveal region seemed to be more highly correlated with VA than the overall PROS length of the macular. As a consequence, we measured the central and mean central subfield PROS length and OFT at the fovea in this study. Our results suggest that central PROS length and OFT are more highly correlated with VA than mean central subfield PROS length and OFT at each time point. Previous histologic studies of the human retina found a PROS length of 25 to 63 ␮m in the macula.22 A recent OCT-based approach demonstrated a mean cone OS length of 40.6 ␮m in the fovea of healthy individuals.23 Srinivasan et al23 found that the OS length at the foveal center was the thickest in the macular region and was a determinant of visual function. Our results showed that PROS length at the fovea was approximately 50 ␮m, which is longer than previously reported.16,24 This difference may have been due to the measurement procedure used and disease type studied. With regard to preoperative prognostic factors, Asaria et al7 reported that preoperative VA was a prognostic factor for visual outcome in patients with ERM. We also found a similar correlation of preoperative BCVA with postoperative visual outcome. However, our multiple regression analysis showed that preoperative PROS length has a higher correlation with visual outcome than preoperative VA. This suggests that PROS length is a better indicator of final visual outcome. Massin et al24 suggested that preoperative macular thickness correlated negatively with preoperative VA. However, postoperative VA did not correlate with postoperative macular thickness. In this study, the CFT was not significantly correlated with VA at any time point. Furthermore, preoperative CFT was not significantly correlated with postoperative VA. These results suggest that CFT is not a strong prognostic factor. Christensen et al19 reported that the relative reflectivity of the ONL was significantly correlated with VA 12 months

after surgery in patients with macular hole, whereas Kashani et al18 found that ONL volume was significantly correlated with VA in patients with AMD. On the basis of those reports, we speculated that the length of the ONL could be a good predictor of visual function in patients with ERM. However, ONLT was not correlated with VA at any time point in this study. However, this discrepancy between several other reports and the results of the present study could not be clarified. One possibility was that the measurement methods differed. We assessed the ONL on the basis of thickness, whereas Kashani et al18 assessed the ONL on the basis of reflection or volume. Another possibility is that the morphology of the ONL may not have a significant effect on visual function in patients with ERM because no exudative change from the vasculature or substantial repair process is observed in the macular hole in the ONL during the postoperative course of patients with ERM. Shimozono et al20 reported that postoperative OFT has a linear correlation with postoperative VA in patients with a closed macular hole. In our study, OFT was significantly correlated with VA at each time point, suggesting that OFT reflects visual function postoperatively. Although OFT and PROS length were estimated in similar regions, PROS was more strongly correlated with VA than was OFT in this study. Estimation of PROS length may be more accurate than estimation of OFT in predicting visual function because the visual substance is a complex of opsin and all-trans-retinal and is present in the outer segment.25 Another theory is that disruption of the photoreceptor arrangement may cause shortening of PROS length and OFT. Among several SD-OCT parameters examined in this study, including OFT, foveal macular thickness, ONLT, and PROS length, only PROS length and OFT correlated with VA at each time point, whereas the others did not. This suggests that the thickness of the photoreceptor layer is more important than the thickness of the inner layer. Several reports assessed the correlation between the IS/OS junction and the VA. Suh et al12 demonstrated a high correlation coefficient of the integrity of the IS/OS junction with postoperative VA. Inoue et al14 reported similar results. Ooka et al26 found that the preoperative lengths of the IS/OS junction and ELM defect were significantly correlated with foveal sensitivity 6 months after macular hole surgery. Wakabayashi et al27 reported that restoration of the foveal ELM in the early postoperative period helps predict subsequent restoration of the foveal photoreceptor layer and the potential for a better visual outcome. Shimozono et al28 reported that the status of the cone outer segment tips line is a prognostic factor for after ERM surgery. However, it was often difficult to accurately evaluate the integrity of the IS/OS junction and the condition of the cone outer segment tips line because of artifacts such as macular edema and cataract in patients with ERM. On the basis of our results, we believe that PROS length is more useful than the integrity of the IS/OS junction for quantitative evaluation of the photoreceptor layer. Postoperatively, changes in PROS length and OFT were similar over time. Decreases in PROS length and OFT were noted 1 month after surgery, and both parameters returned to preoperative values at 3 months. These results suggest

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Ophthalmology Volume xx, Number x, Month 2012 that the decrease in PROS length and OFT at 1 month is caused by a perioperative traumatic mechanism, such as postoperative inflammation or intraoperative injury, which reflects the extent of reversible damage to the photoreceptor layer. The results of the present study indicate that a duration of 3 months after surgery is required for the restoration of the photoreceptor layer. Shimoda et al29 reported that VA in patients with foveal detachment was significantly lower with a disrupted IS/OS line than with a continuous IS/OS line 6 months after surgery and that the IS/OS line gradually recovered postoperatively. We speculate that the changes in PROS length and OFT are probably the result of the restoration of the photoreceptor arrangement after reversible photoreceptor injury.

Study Limitations This study had certain limitations. There were a relatively small number of eyes, and the follow-up period was relatively short. In addition, the reproducibility of the grading of PROS length is most important. For the analysis we used 2 methods: (1) a semiautomated image analysis using a selfwritten algorithm to find the relevant retinal layers and their respective average separation in B-scan sections across the fovea and (2) a manual image analysis using the free available ImageJ software (National Institutes of Health) to determine the PROS length at the central foveal position. The second method determining the central PROS length eventually was used to determine the correlation with the BCVA. It is difficult to properly determine the reproducibility of our method because, for example, no appropriate set of repeat measurements was collected preoperatively. However, estimating the reproducibility of the PROS length measurement from the observed variance between the 3and 6-month time points, a larger 3-sigma uncertainty of approximately 12 ␮m is obtained, which would also explain more of the variation seen in the correlation. A proper assessment of the reproducibility is subject to future work attempting to arrive at a predictive model. Nevertheless, this study was the first to demonstrate that the determination of PROS length is useful clinically because it is an important structural feature that reflects visual function and predicts postoperative visual outcome in patients with ERM. In conclusion, the PROS length is a strong indicator of visual function and a prognostic factor for postoperative VA in patients with idiopathic ERM. Changes in PROS length during the postoperative course may be suggestive of surgical injury and the process of restoration of the photoreceptor layer.

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Footnotes and Financial Disclosures Originally received: March 8, 2012. Final revision: September 24, 2012. Accepted: September 25, 2012. Available online: ●●●.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.E-mail: [email protected]. Manuscript no. 2012-338.

1

Department of Ophthalmology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa, Japan.

2

Carl Zeiss Meditec Co., Ltd., Shinjuku-ku, Tokyo, Japan.

*Both authors (A.S. and J.K.) contributed equally to this work. Correspondence: Hitoshi Takagi, MD, PhD, Department of Ophthalmology, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku, Kawasaki, Kanagawa 216 8511 Japan.

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