Current Eye Research, Early Online, 1–9, 2015 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2015.1019003
ORIGINAL ARTICLE
Correlation Between Visual Function and Photoreceptor Integrity in Diabetic Macular Edema: Spectral-Domain Optical Coherence Tomography Yinchen Shen1,2, Kun Liu1 and Xun Xu1
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Department of Ophthalmology, Shanghai First People’s Hospital affiliated with Shanghai Jiao Tong University, Shanghai, People’s Republic of China and 2Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
ABSTRACT Purpose: To evaluate the relationship between visual function and (i) microstructural changes in the fovea of the inner segment-outer segment junction (IS/OS) and (ii) external limiting membrane (ELM) in diabetic macular edema (DME). Methods: We conducted a retrospective, observational, cross-sectional study of 40 DME patients (61 eyes), all of whom had been treated at Shanghai First People’s Hospital. Patients were divided into groups based on integrity of the IS/OS or ELM: IS/OS (+, ± and ) and ELM (+, ± and ). We performed best-corrected visual acuity (BCVA), MP1 microperimetry and spectral-domain optical coherence tomography (SD-OCT) on all patients. Several variables, including IS/OS and ELM integrity, central macular thickness (CMT) and central macular volume (CMV), were evaluated by two observers, each masked to patients’ BCVA. Main outcome measures included determination of the association of visual function with SD-OCT results. Results: Significant differences were found between IS/OS (+), IS/OS (±) and IS/OS ( ) groups in BCVA (66.88 ± 7.89, 51.60 ± 9.39, 32.64 ± 17.93 letters, p50.001); macular sensitivity (MS; 8.21 ± 2.91, 3.55 ± 2.75, 2.72 ± 1.86 dB, p50.001); fixation stability within 2 (82.09 ± 12.76, 66.43 ± 29.54, 33.73 ± 29.51%, p50.001); and % central fixation (74.87 ± 16.88, 61.39 ± 31.38, 31.64 ± 31.89%, p50.001); but no differences were found for CMT (p = 0.069) or CMV (p = 0.069). Results were similar for ELM groups. There were significant differences between ELM (+), ELM (±) and ELM ( ) groups in BCVA (64.16 ± 9.49, 50.44 ± 9.83, 32.73 ± 17.98 letters, p50.001); MS (7.54 ± 3.22, 3.38 ± 2.38, 2.20 ± 1.72 dB, p50.001); fixation stability within 2 (81.48 ± 15.26, 61.12 ± 31.63, 35.00 ± 29.07%, p50.001); and % central fixation (75.90 ± 17.33, 55.88 ± 30.94, 30.09 ± 33.00%, p50.001); but not for CMT (p = 0.216) or CMV (p = 0.202). There was a strong correlation (r = 0.881, p50.001) between ELM and IS/OS integrity for the same patient. Categories of IS/OS showed more severe changes than did those of ELM. Conclusions: Both IS/OS and ELM integrity correlated positively with visual function in DME patients. Further studies are needed to confirm and validate this relationship. Keywords: Diabetic macular edema, external limiting membrane, inner segment-outer segment junction, integrity of photoreceptor layer, microperimetry, optical coherence tomography
INTRODUCTION
suffer from poor vision. While central macular thickness (CMT) does not necessarily correlate with visual acuity (VA) in DME, VA is influenced by various other factors,2 suggesting that the relationship of variables other than CMT should be investigated.
Diabetic macular edema (DME) is a leading cause of severe visual loss in patients with diabetic retinopathy (DR).1 Even after complete resolution of the macular edema (ME), many patients still
Received 30 September 2013; revised 27 October 2014; accepted 7 February 2015; published online 20 April 2015 Correspondence: Kun Liu, Department of Ophthalmology, Shanghai First People’s Hospital affiliated with Shanghai Jiao Tong University, No. 100 Haining Road, Shanghai 200080, People’s Republic of China. E-mail: [email protected]
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Several recent studies of DME have described new assessment modalities, including optical coherence tomography (OCT), for microstructural visualization of the integrity of the inner segment-outer segment (IS/OS) junction, integrity of the external limiting membrane (ELM) and length of the outer nuclear layer (ONL).2–4 OCT is a non-invasive imaging modality that produces high-resolution, crosssectional images of ocular tissues.5 Compared to time-domain OCT (TD-OCT), spectral-domain OCT (SD-OCT) yields a higher degree of axial resolution and provides more detailed views of intraretinal structure, the IS/OS junction and ELM in particular.6 Such detailed views are critical, as disturbances of these layers reflect anatomical disruptions of the retinal photoreceptors.7 In the current study, our goal was to investigate the differences in best-corrected VA (BCVA), macular sensitivity (MS), fixation stability and fixation location according to changes in IS/OS and ELM lines, in patients with DME.
MATERIALS AND METHODS Patients This study adhered to the tenets of the Declaration of Helsinki and had the approval of the Ethics Committee of Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China. After a detailed explanation of the purpose of the study, all patients provided written consent. A total of 40 DME patients (61 eyes) were enrolled for analysis. Ten patients (16 eyes) were excluded from the analysis. All participants of this crosssectional study were recruited from the Department of Ophthalmology, Shanghai First People’s Hospital, Shanghai Jiao Tong University. Included in the study were patients with evidence of clinically significant macular edema (CSME), as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS),8 and an OCT retinal thickness of 250 mm in the central subfield. Excluded from the study were patients (i) who had prior surgeries (e.g. pars plana vitrectomy), intra-vitreal anti-VEGF drug therapy, or intra-vitreal triamcinolone acetonideta (IVTA) treatment; (ii) whose clinical histories may have caused macular thickening [e.g. uveitis, retinal venous occlusion, epiretinal membrane (ERM) and/or vitreomacular traction]; (iii) with other macular diseases (e.g. macular degeneration) or significant cataracts, any of which could result in poor OCT signals; and (iv) with renal insufficiency. All patients underwent comprehensive ophthalmologic examinations, including measurement of BCVA, slit-lamp biomicroscopy, color fundus photography, microperimetry and SD-OCT.
Patients’ ages, gender, insulin dependency, duration of diabetes, duration of DME, HbAlc and any prior treatments for DME were recorded. BCVA was measured using ETDRS charts. Figure 1 shows the flowchart of the study.
OCT OCT scans were obtained using an SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). Eyes were dilated before OCT examination. All OCT scans were centered on the fovea, using a centrally oriented internal fixation mark. OCT scans were conducted by the same operator. Horizontal and vertical SD-OCT foveal images were evaluated for each patient. CMT and central macular volume (CMV) within 1 mm of the central fovea were calculated automatically by the instrument. DME morphology, including IS/OS and ELM integrity, was also assessed within 1 mm of the central fovea. A disruption in IS/OS or ELM integrity was defined as loss of the back-reflection line. In our study, ELM status was classified as follows3: eyes with a complete ELM line at the fovea in both scans were classified as ELM (+); eyes with an interrupted ELM line in one or both scans were classified as ELM (±); and eyes with an undetectable ELM line at the fovea were classified as ELM ( ). Status of the IS/OS line was determined using the same criteria to obtain IS/OS (+), IS/OS (±) and IS/OS ( ). Two experienced graders (KL, YS), both of whom were masked to the BCVA status of each patient, classified the eyes independently. If there was a difference of opinion between the two observers, a senior ocular fundus specialist (XX) made the definitive determination. To demonstrate the status of IS/OS and ELM lines, Image J software (developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; http:// rsb.info.nih.gov/ij/index.html), which illustrates the strength of reflectivity of all layers in each stage of disease, was used (Figure 2).
Microperimetry Microperimetry was performed using an automated fundus-related microperimeter (MP1 Microperimeter; Nidek Technologies, Padova, Italy). The parameters are listed as follows: a fixation target consisting of a red cross, 2 in diameter; background illumination set at 1.27 cd/m2; and stimulus size Goldman III, with a 200 ms projection time. We chose a 4–2 staircase strategy. The starting stimulus light attenuation was set at 10 dB. Light stimuli were presented randomly during the examination, as in standard static perimetry. A false-positive test stimulus was projected onto the area of the optic nerve head to check for false-positive responses. All Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
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FIGURE 1 Flowchart.
subjects underwent microperimetry with dilated pupils. Retinal sensitivity was measured at 40 points (8 points at central 2 , 16 points at 6 and 16 points at 10 ). Values of mean retinal sensitivity (total and at 2, 6 and 10 ) and individual retinal sensitivity were assessed and analyzed. For the purpose of this study, arithmetic means of macular sensitivities of the eight points in the central 2 were used to evaluate visual function.9 In addition, two additional parameters, fixation stability and fixation location were compared between groups. Fixation stability was defined as the percentage of fixation points within 2 of center (fixation stability within 2 ). Fixation location, measured as % central fixation, was used to identify a chosen retinal locus and to describe whether it was centric, pericentric or eccentric.
Statistical Analyses Results are expressed as mean ± standard deviation (SD). A p value 50.05 was considered statistically significant. All statistical analyses were performed using SPSS software, version 13.0 (SPSS Inc., Chicago, IL). Data were analyzed by one-way analysis of !
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variance (ANOVA) when parametric analysis was possible. When data were non-parametric, the Kruskal–Wallis H-test was performed. Kappa coefficients were calculated as measures of reliability between two observers. Pearson correlation coefficients were used to analyze categories of IS/OS and ELM integrity for each patient.
RESULTS A total of 40 patients (61 eyes) with CSME were analyzed. Sixteen eyes of 10 patients were excluded from the analysis, and the main reasons were prior intra-vitreous anti-VEGF drug injection, vitreomacular traction and significant cataracts. Of the 40 patients included, 18 (45%) were women and 22 (55%) men (mean ages, 59.35 ± 8.86 years; range, 34–76 years). Patient characteristics are shown in Table 1. Blood pressure (BP) of each patient was under reasonable control, i.e. BP 5160/100 mmHg. Mean BCVAs were 54.44 ± 16.41 letters (range, 8–80 letters). The mean refractive status was 1.43 ± 2.93 D (range, 9.00 to +4.50 D). The mean CMT was 447.87 ± 144.31 mm (range, 241–989 mm). The mean
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FIGURE 2 IS/OS and ELM. The first column shows the color fundus photographs. The second column shows the SD-OCT scans across the fovea. The third column shows the quantification of reflectivity levels along the yellow vertical lines in the second column using gray-value measurement. (Top) IS/OS (+) and ELM (+). For gray-value measurements, the reflectivity peaks of the ELM and IS/ OS were intense. BCVA, 64 letters; MS, 9 dB. (Middle) IS/OS (±) and ELM (±). For gray-value measurements, the reflectivity peaks of the ELM and IS/OS were relatively faint. BCVA, 58 letters; MS, 4.5 dB. (Bottom) IS/OS ( ) and ELM ( ). For gray-value measurements, the reflectivity peaks of the ELM and IS/OS were invisible. BCVA, 35 letters; MS, 2 dB. TABLE 1 Clinical characteristics of all patients included in the study. Sex, n (%) Male Female Type of DM, n (%) Type 1 Type 2 Age (years) Range Mean ± SD Duration of DM (years) Range Mean ± SD HbAlc (%)
18 (45) 22 (55) 1 (2.5) 39 (97.5) 34–76 59.35 ± 8.86 1–32 13.87 ± 7.83 7.35 ± 1.13
CMV was 0.35 ± 0.11 mm3 (range, 0.19–0.78 mm3). Of the 61 eyes, 39 (64%) had cystoid ME and 22 (36%) had diffuse ME. Serous retinal detachment was present in 15 of 61 eyes (25%), nine (60%) from the cystoid ME group and six (40%) from the diffuse ME group. The MP-1 test was performed on 57 of 61 eyes
(93%); it could not be performed on four eyes due to severe fixation loss. The mean MS was 5.27 ± 3.60 dB (range, 0–14.25 dB).
Inter-Observer Consistency Patients were divided into groups based on IS/OS and ELM integrity (Figure 2). Kappa coefficients for observation of IS/OS and ELM integrity were 0.775 (p50.001) and 0.769 (p50.001), respectively, indicating good inter-observer consistencies.
Correlation Between Visual Function and ME A slight correlation was found between visual function and ME: for CMT and BCVA, r = 0.266 (p50.05); for BCVA and CMV, r = 0.266 (p50.05); for MS and CMT, r = 0.443 (p50.05); and for MS and CMV, r = 0.441 (p50.05). There was a relatively strong correlation between BCVA and MS: r = 0.640 (p50.001). Results are shown in Figure 3. Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
FIGURE 3 Correlation between visual function and ME. A mild correlation was found between visual function and ME. A: CMT and BCVA, r = 0.266 (p50.05); B: BCVA and CMV, r = 0.266 (p50.05); C: MS and CMT, r = 0.443 (p50.05); D: MS and CMV, r = 0.441 (p50.05). There was a relatively strong correlation between BCVA and MS (E), r = 0.640 (p50.001).
IS/OS and ELM Microstructure Versus Visual Function and ME Comparing visual function and extent of ME, we found significant differences between IS/OS (+), IS/OS (±) and IS/OS ( ) groups in BCVA (66.88 ± 7.89, 51.60 ± 9.39 and 32.64 ± 17.93 letters, respectively, p50.001); MS (8.21 ± 2.91, 3.55 ± 2.75 and 2.72 ± 1.86 dB, respectively, p50.001); fixation !
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stability within 2 (82.09 ± 12.76, 66.43 ± 29.54 and 33.73 ± 29.51%, respectively, p50.001); and % central fixation (74.87 ± 16.88, 61.39 ± 31.38 and 31.64 ± 31.89%, respectively, p50.001). There were, however, no significant differences in CMT (404.92 ± 100.49, 497.40 ± 170.83 and 432.91 ± 140.35 mm, respectively, p = 0.069) or CMV (0.32 ± 0.08, 0.39 ± 0.13 and 0.34 ± 0.11 mm3, respectively, p = 0.069; Figure 4). Results for ELM groups
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FIGURE 4 IS/OS integrity versus visual function and ME. Comparing visual function and extent of ME for all groups, we found that there were significant differences between IS/OS (+), IS/OS (±) and IS/OS ( ) groups in BCVA (66.88 ± 7.89, 51.60 ± 9.39 and 32.64 ± 17.93 letters, respectively, p50.001) (A) and MS (8.21 ± 2.91, 3.55 ± 2.75 and 2.72 ± 1.86 dB, respectively, p50.001) (B); fixation stability within 2 (82.09 ± 12.76, 66.43 ± 29.54 and 33.73 ± 29.51%, respectively, p50.001) (C); and % central fixation (74.87 ± 16.88, 61.39 ± 31.38 and 31.64 ± 31.89%, respectively, p50.001) (D). There was no significant differences in the CMT (404.92 ± 100.49, 497.40 ± 170.83 and 432.91 ± 140.35 mm, respectively, p = 0.069) (E) or CMV (0.32 ± 0.08, 0.39 ± 0.13 and 0.34 ± 0.11 mm3, respectively, p = 0.069) (F) (*p50.05).
were similar. Significant differences were found between ELM (+), ELM (±) and ELM ( ) groups in BCVA (64.16 ± 9.49, 50.44 ± 9.83 and 32.73 ± 17.98 letters, respectively, p50.001); MS (7.54 ± 3.22, 3.38 ± 2.38 and 2.20 ± 1.72 dB, respectively, p50.001); fixation stability within 2 (81.48 ± 15.26, 61.12 ± 31.63
and 35.00 ± 29.07%, respectively, p50.001); and % central fixation (75.90 ± 17.33, 55.88 ± 30.94 and 30.09 ± 33.00%, respectively, p50.001), but not in CMT (418.91 ± 126.08, 466.94 ± 126.94 and 500.91 ± 204.58 mm, respectively, p = 0. 216) or CMV (0.33 ± 0.10, 0.36 ± 0.10 and 0.39 ± 0.16 mm3, Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
FIGURE 5 ELM integrity versus visual function and ME. Comparing visual function and extent of ME, significant differences were found between ELM (+), ELM (±) and ELM ( ) groups in BCVA (64.16 ± 9.49, 50.44 ± 9.83 and 32.73 ± 17.98 letters, respectively, p50.001) (A) and MS (7.54 ± 3.22, 3.38 ± 2.38 and 2.20 ± 1.72 dB, respectively, p50.001) (B); fixation stability within 2 (81.48 ± 15.26, 61.12 ± 31.63 and 35.00 ± 29.07%, respectively, p50.001) (C); and % central fixation (75.90 ± 17.33, 55.88 ± 30.94 and 30.09 ± 33.00%, respectively, p50.001) (D), but not in CMT (418.91 ± 126.08, 466.94 ± 126.94 and 500.91 ± 204.58 mm, respectively, p = 0. 216) (E) or CMV (0.33 ± 0.10, 0.36 ± 0.10 and 0.39 ± 0.16 mm3, respectively, p = 0.202) (F) (*p50.05).
respectively, p = 0.202) (Figure 5). Furthermore, we found no significant differences in duration of DME for IS/OS (+), IS/OS (±) and IS/OS ( ) groups (1.58 ± 0.87, 1.92 ± 1.59 and 2.27 ± 1.92 years, respectively, p40.05) or for ELM (+), ELM (±) and ELM ( ) groups (1.51 ± 0.80, 2.19 ± 1.78 and 2.23 ± 1.94 years, !
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respectively, p40.05). Analysis of HbAlc showed no significant differences between IS/OS (+), IS/OS (±) and IS/OS ( ) groups (7.49 ± 0.99, 7.10 ± 1.16 and 7.52 ± 1.45%, respectively, p40.05) or between ELM (+), ELM (±) and ELM ( ) groups (7.37 ± 1.03, 7.04 ± 1.19 and 7.61 ± 1.40%, respectively, p40.05).
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TABLE 2 Correlation between the ELM and the IS/OS integrity.
ELM (+) ELM (±) ELM ( ) Total
IS/OS (+)
IS/OS (±)
IS/OS ( )
Total
25 0 0 25
7 17 1 25
0 1 10 11
32 18 11 61
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Correlation Between IS/OS and ELM Integrity The Pearson correlation coefficient was 0.881 (p50.001) for comparison of IS/OS and ELM integrity within the same patient. The correlation between ELM and IS/OS integrity for all 61 eyes is shown in Table 2. Integrities of ELM and IS/OS (all categories) were the same for 52 of 61 (85%) eyes. Generally, IS/OS disruption was more severe than that of the ELM. Intact ELMs were observed in 32 (52%) eyes, while only 25 (41%) of 61 eyes demonstrated intact IS/OS layers. For the most severe categories, i.e. IS/OS ( ) or ELM ( ), the percentages were equal (11 of 61 eyes, 18%).
DISCUSSION ME is a major cause of VA impairment in diabetic patients.10 CMT is a traditionally used parameter for measuring the severity of ME. However, the Diabetic Retinopathy Clinical Research Network stated that wide ranges in VA can be observed for any given degree of retinal edema.11 Reasons for limited VA include macular ischemia,12 photoreceptor dysfunction2 and accumulated subfoveal hard exudates.13 OCT is one of the new standard methods for quantifying and monitoring ME.14,15 Recent technological advances in OCT have led to a wealth of new information regarding photoreceptor microstructure, especially its correlation with visual functions in various diseases.16 In our study, two independent masked observers determined categories of IS/OS and ELM integrity. Their results showed excellent consistency, indicating that our method of evaluating IS/OS and ELM integrity provides reliable data for analyzing photoreceptor status. We found only a mild correlation between visual function and the extent of ME. Furthermore, IS/OS and ELM integrity showed a relatively weak correlation with CMT and CMV. However, differing photoreceptor integrities strongly influence BCVA, MS, fixation stability and fixation location. Interestingly, a recent study reported similar correlations between the photoreceptor layer and VA among patients with DME4 and implied that the extent of ME does not match the severity of visual dysfunction. Other factors, especially the integrity of the photoreceptors, are critical in the limited visual function of DME patients. Several recent studies have focused on photoreceptor integrity and VA in various retinopathies,
including AMD,17 DME2–4,18 and epiretinal membranes (ERM).7 The overall conclusion, and one that is in agreement with our findings, is that integrity of the ELM and IS/OS layers is more strongly correlated with BCVA than with CMT.7 The absence of ELM and IS/OS lines might represent cellular damage or cell death,19,20 either of which would explain the wide range of VA for a given degree of retinal edema. Currently, the general consensus is that photoreceptor layer integrity is closely related to parameters of visual function in DME. However, the relationship between the IS/OS and ELM lines has not been fully investigated. We found that IS/OS integrity is closely related to ELM integrity in the same person (r = 0.881, p50.001), indicating that these two layers are both reflective of the severity of photoreceptor damage. Interestingly, IS/OS groups had more severe damage than did the ELM groups, the ratios between groups being: IS/OS (+): IS/OS (±) = 25:25 eyes; ELM (+): ELM (±) = 32:18 eyes. We believe that the different sensitivities of photoreceptor layers to retinal damage are responsible for this distribution. It has been hypothesized that IS/OS is more sensitive to retinal damage than is ELM, and thus disrupted ELMs are able to withstand more severe retinal damage. For the most severe categories [IS/OS ( ) and ELM ( )], the percentage of severe damage was equal (11 eyes, 18%), reflecting the natural progression of DME. We suggest that IS/OS integrity is an indicator of ELM damage. The functional impact of DME is quantifiable by examining VA, despite the fact that VA is only one subjective parameter associated with macular function. In our study, microperimetry was performed to evaluate visual function in DME. Microperimetry provides an objective assessment of visual function at specific locations on the retina, independent of macular thickness.21 Moreover, this technique is valuable for predicting outcomes in DME.9 Our results show that MS closely correlates with both BCVA and photoreceptor layer morphology. Our findings correspond to those of Yohannan et al.22 who demonstrated that disruption of the IS/OS junction is correlated with a significant decrease in point sensitivity in DME eyes. To supplement microperimetry analysis, we have added several new parameters, i.e. fixation stability within 2 and % central fixation, to improve the evaluation of visual function in DME. Therefore, in addition to BCVA, we suggest that microperimetry, incorporating these two new parameters, be included as a standard test for visual function in patients with DME. Another feature of our study was the strict inclusion criteria for DME patients. In previous studies, patients with and without prior treatments were included, with no consideration for intrinsic damage so-produced to the IS/OS and ELM.2,3,15 Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
Consequently, to improve the accuracy of our study, our study excluded patients who had undergone previous treatments. However, heterogeneity was still observed within each group, since disrupted areas can differ in their lengths and locations. For example, similar disruptions in the fovea and foveola might have differing effects on the VA.23 The limits of this study were its retrospective design, cross-sectional nature and small sample size. Our results are preliminary and need further corroboration by larger sample studies. A longitudinal study would clarify the relationship of photoreceptor integrity with development of, and mechanisms involved in, DME. Thus, further prospective clinical trials for evaluation and treatment of DME are needed. In conclusion, integrity of IS/OS and ELM correlates with visual function in patients with DME. More studies are needed to confirm and validate this relationship.
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DECLARATION OF INTEREST 14.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This work was supported by a grant from the Major State Basic Research Development Program of China (973 Program) (No. 2011CB707500) and Shanghai Guide Fund for Medical Projects (No. 124119a9600). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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ORIGINAL ARTICLE
Correlation Between Visual Function and Photoreceptor Integrity in Diabetic Macular Edema: Spectral-Domain Optical Coherence Tomography Yinchen Shen1,2, Kun Liu1 and Xun Xu1
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1
Department of Ophthalmology, Shanghai First People’s Hospital affiliated with Shanghai Jiao Tong University, Shanghai, People’s Republic of China and 2Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
ABSTRACT Purpose: To evaluate the relationship between visual function and (i) microstructural changes in the fovea of the inner segment-outer segment junction (IS/OS) and (ii) external limiting membrane (ELM) in diabetic macular edema (DME). Methods: We conducted a retrospective, observational, cross-sectional study of 40 DME patients (61 eyes), all of whom had been treated at Shanghai First People’s Hospital. Patients were divided into groups based on integrity of the IS/OS or ELM: IS/OS (+, ± and ) and ELM (+, ± and ). We performed best-corrected visual acuity (BCVA), MP1 microperimetry and spectral-domain optical coherence tomography (SD-OCT) on all patients. Several variables, including IS/OS and ELM integrity, central macular thickness (CMT) and central macular volume (CMV), were evaluated by two observers, each masked to patients’ BCVA. Main outcome measures included determination of the association of visual function with SD-OCT results. Results: Significant differences were found between IS/OS (+), IS/OS (±) and IS/OS ( ) groups in BCVA (66.88 ± 7.89, 51.60 ± 9.39, 32.64 ± 17.93 letters, p50.001); macular sensitivity (MS; 8.21 ± 2.91, 3.55 ± 2.75, 2.72 ± 1.86 dB, p50.001); fixation stability within 2 (82.09 ± 12.76, 66.43 ± 29.54, 33.73 ± 29.51%, p50.001); and % central fixation (74.87 ± 16.88, 61.39 ± 31.38, 31.64 ± 31.89%, p50.001); but no differences were found for CMT (p = 0.069) or CMV (p = 0.069). Results were similar for ELM groups. There were significant differences between ELM (+), ELM (±) and ELM ( ) groups in BCVA (64.16 ± 9.49, 50.44 ± 9.83, 32.73 ± 17.98 letters, p50.001); MS (7.54 ± 3.22, 3.38 ± 2.38, 2.20 ± 1.72 dB, p50.001); fixation stability within 2 (81.48 ± 15.26, 61.12 ± 31.63, 35.00 ± 29.07%, p50.001); and % central fixation (75.90 ± 17.33, 55.88 ± 30.94, 30.09 ± 33.00%, p50.001); but not for CMT (p = 0.216) or CMV (p = 0.202). There was a strong correlation (r = 0.881, p50.001) between ELM and IS/OS integrity for the same patient. Categories of IS/OS showed more severe changes than did those of ELM. Conclusions: Both IS/OS and ELM integrity correlated positively with visual function in DME patients. Further studies are needed to confirm and validate this relationship. Keywords: Diabetic macular edema, external limiting membrane, inner segment-outer segment junction, integrity of photoreceptor layer, microperimetry, optical coherence tomography
INTRODUCTION
suffer from poor vision. While central macular thickness (CMT) does not necessarily correlate with visual acuity (VA) in DME, VA is influenced by various other factors,2 suggesting that the relationship of variables other than CMT should be investigated.
Diabetic macular edema (DME) is a leading cause of severe visual loss in patients with diabetic retinopathy (DR).1 Even after complete resolution of the macular edema (ME), many patients still
Received 30 September 2013; revised 27 October 2014; accepted 7 February 2015; published online 20 April 2015 Correspondence: Kun Liu, Department of Ophthalmology, Shanghai First People’s Hospital affiliated with Shanghai Jiao Tong University, No. 100 Haining Road, Shanghai 200080, People’s Republic of China. E-mail: [email protected]
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Several recent studies of DME have described new assessment modalities, including optical coherence tomography (OCT), for microstructural visualization of the integrity of the inner segment-outer segment (IS/OS) junction, integrity of the external limiting membrane (ELM) and length of the outer nuclear layer (ONL).2–4 OCT is a non-invasive imaging modality that produces high-resolution, crosssectional images of ocular tissues.5 Compared to time-domain OCT (TD-OCT), spectral-domain OCT (SD-OCT) yields a higher degree of axial resolution and provides more detailed views of intraretinal structure, the IS/OS junction and ELM in particular.6 Such detailed views are critical, as disturbances of these layers reflect anatomical disruptions of the retinal photoreceptors.7 In the current study, our goal was to investigate the differences in best-corrected VA (BCVA), macular sensitivity (MS), fixation stability and fixation location according to changes in IS/OS and ELM lines, in patients with DME.
MATERIALS AND METHODS Patients This study adhered to the tenets of the Declaration of Helsinki and had the approval of the Ethics Committee of Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai, China. After a detailed explanation of the purpose of the study, all patients provided written consent. A total of 40 DME patients (61 eyes) were enrolled for analysis. Ten patients (16 eyes) were excluded from the analysis. All participants of this crosssectional study were recruited from the Department of Ophthalmology, Shanghai First People’s Hospital, Shanghai Jiao Tong University. Included in the study were patients with evidence of clinically significant macular edema (CSME), as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS),8 and an OCT retinal thickness of 250 mm in the central subfield. Excluded from the study were patients (i) who had prior surgeries (e.g. pars plana vitrectomy), intra-vitreal anti-VEGF drug therapy, or intra-vitreal triamcinolone acetonideta (IVTA) treatment; (ii) whose clinical histories may have caused macular thickening [e.g. uveitis, retinal venous occlusion, epiretinal membrane (ERM) and/or vitreomacular traction]; (iii) with other macular diseases (e.g. macular degeneration) or significant cataracts, any of which could result in poor OCT signals; and (iv) with renal insufficiency. All patients underwent comprehensive ophthalmologic examinations, including measurement of BCVA, slit-lamp biomicroscopy, color fundus photography, microperimetry and SD-OCT.
Patients’ ages, gender, insulin dependency, duration of diabetes, duration of DME, HbAlc and any prior treatments for DME were recorded. BCVA was measured using ETDRS charts. Figure 1 shows the flowchart of the study.
OCT OCT scans were obtained using an SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). Eyes were dilated before OCT examination. All OCT scans were centered on the fovea, using a centrally oriented internal fixation mark. OCT scans were conducted by the same operator. Horizontal and vertical SD-OCT foveal images were evaluated for each patient. CMT and central macular volume (CMV) within 1 mm of the central fovea were calculated automatically by the instrument. DME morphology, including IS/OS and ELM integrity, was also assessed within 1 mm of the central fovea. A disruption in IS/OS or ELM integrity was defined as loss of the back-reflection line. In our study, ELM status was classified as follows3: eyes with a complete ELM line at the fovea in both scans were classified as ELM (+); eyes with an interrupted ELM line in one or both scans were classified as ELM (±); and eyes with an undetectable ELM line at the fovea were classified as ELM ( ). Status of the IS/OS line was determined using the same criteria to obtain IS/OS (+), IS/OS (±) and IS/OS ( ). Two experienced graders (KL, YS), both of whom were masked to the BCVA status of each patient, classified the eyes independently. If there was a difference of opinion between the two observers, a senior ocular fundus specialist (XX) made the definitive determination. To demonstrate the status of IS/OS and ELM lines, Image J software (developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; http:// rsb.info.nih.gov/ij/index.html), which illustrates the strength of reflectivity of all layers in each stage of disease, was used (Figure 2).
Microperimetry Microperimetry was performed using an automated fundus-related microperimeter (MP1 Microperimeter; Nidek Technologies, Padova, Italy). The parameters are listed as follows: a fixation target consisting of a red cross, 2 in diameter; background illumination set at 1.27 cd/m2; and stimulus size Goldman III, with a 200 ms projection time. We chose a 4–2 staircase strategy. The starting stimulus light attenuation was set at 10 dB. Light stimuli were presented randomly during the examination, as in standard static perimetry. A false-positive test stimulus was projected onto the area of the optic nerve head to check for false-positive responses. All Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
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FIGURE 1 Flowchart.
subjects underwent microperimetry with dilated pupils. Retinal sensitivity was measured at 40 points (8 points at central 2 , 16 points at 6 and 16 points at 10 ). Values of mean retinal sensitivity (total and at 2, 6 and 10 ) and individual retinal sensitivity were assessed and analyzed. For the purpose of this study, arithmetic means of macular sensitivities of the eight points in the central 2 were used to evaluate visual function.9 In addition, two additional parameters, fixation stability and fixation location were compared between groups. Fixation stability was defined as the percentage of fixation points within 2 of center (fixation stability within 2 ). Fixation location, measured as % central fixation, was used to identify a chosen retinal locus and to describe whether it was centric, pericentric or eccentric.
Statistical Analyses Results are expressed as mean ± standard deviation (SD). A p value 50.05 was considered statistically significant. All statistical analyses were performed using SPSS software, version 13.0 (SPSS Inc., Chicago, IL). Data were analyzed by one-way analysis of !
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variance (ANOVA) when parametric analysis was possible. When data were non-parametric, the Kruskal–Wallis H-test was performed. Kappa coefficients were calculated as measures of reliability between two observers. Pearson correlation coefficients were used to analyze categories of IS/OS and ELM integrity for each patient.
RESULTS A total of 40 patients (61 eyes) with CSME were analyzed. Sixteen eyes of 10 patients were excluded from the analysis, and the main reasons were prior intra-vitreous anti-VEGF drug injection, vitreomacular traction and significant cataracts. Of the 40 patients included, 18 (45%) were women and 22 (55%) men (mean ages, 59.35 ± 8.86 years; range, 34–76 years). Patient characteristics are shown in Table 1. Blood pressure (BP) of each patient was under reasonable control, i.e. BP 5160/100 mmHg. Mean BCVAs were 54.44 ± 16.41 letters (range, 8–80 letters). The mean refractive status was 1.43 ± 2.93 D (range, 9.00 to +4.50 D). The mean CMT was 447.87 ± 144.31 mm (range, 241–989 mm). The mean
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FIGURE 2 IS/OS and ELM. The first column shows the color fundus photographs. The second column shows the SD-OCT scans across the fovea. The third column shows the quantification of reflectivity levels along the yellow vertical lines in the second column using gray-value measurement. (Top) IS/OS (+) and ELM (+). For gray-value measurements, the reflectivity peaks of the ELM and IS/ OS were intense. BCVA, 64 letters; MS, 9 dB. (Middle) IS/OS (±) and ELM (±). For gray-value measurements, the reflectivity peaks of the ELM and IS/OS were relatively faint. BCVA, 58 letters; MS, 4.5 dB. (Bottom) IS/OS ( ) and ELM ( ). For gray-value measurements, the reflectivity peaks of the ELM and IS/OS were invisible. BCVA, 35 letters; MS, 2 dB. TABLE 1 Clinical characteristics of all patients included in the study. Sex, n (%) Male Female Type of DM, n (%) Type 1 Type 2 Age (years) Range Mean ± SD Duration of DM (years) Range Mean ± SD HbAlc (%)
18 (45) 22 (55) 1 (2.5) 39 (97.5) 34–76 59.35 ± 8.86 1–32 13.87 ± 7.83 7.35 ± 1.13
CMV was 0.35 ± 0.11 mm3 (range, 0.19–0.78 mm3). Of the 61 eyes, 39 (64%) had cystoid ME and 22 (36%) had diffuse ME. Serous retinal detachment was present in 15 of 61 eyes (25%), nine (60%) from the cystoid ME group and six (40%) from the diffuse ME group. The MP-1 test was performed on 57 of 61 eyes
(93%); it could not be performed on four eyes due to severe fixation loss. The mean MS was 5.27 ± 3.60 dB (range, 0–14.25 dB).
Inter-Observer Consistency Patients were divided into groups based on IS/OS and ELM integrity (Figure 2). Kappa coefficients for observation of IS/OS and ELM integrity were 0.775 (p50.001) and 0.769 (p50.001), respectively, indicating good inter-observer consistencies.
Correlation Between Visual Function and ME A slight correlation was found between visual function and ME: for CMT and BCVA, r = 0.266 (p50.05); for BCVA and CMV, r = 0.266 (p50.05); for MS and CMT, r = 0.443 (p50.05); and for MS and CMV, r = 0.441 (p50.05). There was a relatively strong correlation between BCVA and MS: r = 0.640 (p50.001). Results are shown in Figure 3. Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
FIGURE 3 Correlation between visual function and ME. A mild correlation was found between visual function and ME. A: CMT and BCVA, r = 0.266 (p50.05); B: BCVA and CMV, r = 0.266 (p50.05); C: MS and CMT, r = 0.443 (p50.05); D: MS and CMV, r = 0.441 (p50.05). There was a relatively strong correlation between BCVA and MS (E), r = 0.640 (p50.001).
IS/OS and ELM Microstructure Versus Visual Function and ME Comparing visual function and extent of ME, we found significant differences between IS/OS (+), IS/OS (±) and IS/OS ( ) groups in BCVA (66.88 ± 7.89, 51.60 ± 9.39 and 32.64 ± 17.93 letters, respectively, p50.001); MS (8.21 ± 2.91, 3.55 ± 2.75 and 2.72 ± 1.86 dB, respectively, p50.001); fixation !
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stability within 2 (82.09 ± 12.76, 66.43 ± 29.54 and 33.73 ± 29.51%, respectively, p50.001); and % central fixation (74.87 ± 16.88, 61.39 ± 31.38 and 31.64 ± 31.89%, respectively, p50.001). There were, however, no significant differences in CMT (404.92 ± 100.49, 497.40 ± 170.83 and 432.91 ± 140.35 mm, respectively, p = 0.069) or CMV (0.32 ± 0.08, 0.39 ± 0.13 and 0.34 ± 0.11 mm3, respectively, p = 0.069; Figure 4). Results for ELM groups
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FIGURE 4 IS/OS integrity versus visual function and ME. Comparing visual function and extent of ME for all groups, we found that there were significant differences between IS/OS (+), IS/OS (±) and IS/OS ( ) groups in BCVA (66.88 ± 7.89, 51.60 ± 9.39 and 32.64 ± 17.93 letters, respectively, p50.001) (A) and MS (8.21 ± 2.91, 3.55 ± 2.75 and 2.72 ± 1.86 dB, respectively, p50.001) (B); fixation stability within 2 (82.09 ± 12.76, 66.43 ± 29.54 and 33.73 ± 29.51%, respectively, p50.001) (C); and % central fixation (74.87 ± 16.88, 61.39 ± 31.38 and 31.64 ± 31.89%, respectively, p50.001) (D). There was no significant differences in the CMT (404.92 ± 100.49, 497.40 ± 170.83 and 432.91 ± 140.35 mm, respectively, p = 0.069) (E) or CMV (0.32 ± 0.08, 0.39 ± 0.13 and 0.34 ± 0.11 mm3, respectively, p = 0.069) (F) (*p50.05).
were similar. Significant differences were found between ELM (+), ELM (±) and ELM ( ) groups in BCVA (64.16 ± 9.49, 50.44 ± 9.83 and 32.73 ± 17.98 letters, respectively, p50.001); MS (7.54 ± 3.22, 3.38 ± 2.38 and 2.20 ± 1.72 dB, respectively, p50.001); fixation stability within 2 (81.48 ± 15.26, 61.12 ± 31.63
and 35.00 ± 29.07%, respectively, p50.001); and % central fixation (75.90 ± 17.33, 55.88 ± 30.94 and 30.09 ± 33.00%, respectively, p50.001), but not in CMT (418.91 ± 126.08, 466.94 ± 126.94 and 500.91 ± 204.58 mm, respectively, p = 0. 216) or CMV (0.33 ± 0.10, 0.36 ± 0.10 and 0.39 ± 0.16 mm3, Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
FIGURE 5 ELM integrity versus visual function and ME. Comparing visual function and extent of ME, significant differences were found between ELM (+), ELM (±) and ELM ( ) groups in BCVA (64.16 ± 9.49, 50.44 ± 9.83 and 32.73 ± 17.98 letters, respectively, p50.001) (A) and MS (7.54 ± 3.22, 3.38 ± 2.38 and 2.20 ± 1.72 dB, respectively, p50.001) (B); fixation stability within 2 (81.48 ± 15.26, 61.12 ± 31.63 and 35.00 ± 29.07%, respectively, p50.001) (C); and % central fixation (75.90 ± 17.33, 55.88 ± 30.94 and 30.09 ± 33.00%, respectively, p50.001) (D), but not in CMT (418.91 ± 126.08, 466.94 ± 126.94 and 500.91 ± 204.58 mm, respectively, p = 0. 216) (E) or CMV (0.33 ± 0.10, 0.36 ± 0.10 and 0.39 ± 0.16 mm3, respectively, p = 0.202) (F) (*p50.05).
respectively, p = 0.202) (Figure 5). Furthermore, we found no significant differences in duration of DME for IS/OS (+), IS/OS (±) and IS/OS ( ) groups (1.58 ± 0.87, 1.92 ± 1.59 and 2.27 ± 1.92 years, respectively, p40.05) or for ELM (+), ELM (±) and ELM ( ) groups (1.51 ± 0.80, 2.19 ± 1.78 and 2.23 ± 1.94 years, !
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respectively, p40.05). Analysis of HbAlc showed no significant differences between IS/OS (+), IS/OS (±) and IS/OS ( ) groups (7.49 ± 0.99, 7.10 ± 1.16 and 7.52 ± 1.45%, respectively, p40.05) or between ELM (+), ELM (±) and ELM ( ) groups (7.37 ± 1.03, 7.04 ± 1.19 and 7.61 ± 1.40%, respectively, p40.05).
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TABLE 2 Correlation between the ELM and the IS/OS integrity.
ELM (+) ELM (±) ELM ( ) Total
IS/OS (+)
IS/OS (±)
IS/OS ( )
Total
25 0 0 25
7 17 1 25
0 1 10 11
32 18 11 61
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Correlation Between IS/OS and ELM Integrity The Pearson correlation coefficient was 0.881 (p50.001) for comparison of IS/OS and ELM integrity within the same patient. The correlation between ELM and IS/OS integrity for all 61 eyes is shown in Table 2. Integrities of ELM and IS/OS (all categories) were the same for 52 of 61 (85%) eyes. Generally, IS/OS disruption was more severe than that of the ELM. Intact ELMs were observed in 32 (52%) eyes, while only 25 (41%) of 61 eyes demonstrated intact IS/OS layers. For the most severe categories, i.e. IS/OS ( ) or ELM ( ), the percentages were equal (11 of 61 eyes, 18%).
DISCUSSION ME is a major cause of VA impairment in diabetic patients.10 CMT is a traditionally used parameter for measuring the severity of ME. However, the Diabetic Retinopathy Clinical Research Network stated that wide ranges in VA can be observed for any given degree of retinal edema.11 Reasons for limited VA include macular ischemia,12 photoreceptor dysfunction2 and accumulated subfoveal hard exudates.13 OCT is one of the new standard methods for quantifying and monitoring ME.14,15 Recent technological advances in OCT have led to a wealth of new information regarding photoreceptor microstructure, especially its correlation with visual functions in various diseases.16 In our study, two independent masked observers determined categories of IS/OS and ELM integrity. Their results showed excellent consistency, indicating that our method of evaluating IS/OS and ELM integrity provides reliable data for analyzing photoreceptor status. We found only a mild correlation between visual function and the extent of ME. Furthermore, IS/OS and ELM integrity showed a relatively weak correlation with CMT and CMV. However, differing photoreceptor integrities strongly influence BCVA, MS, fixation stability and fixation location. Interestingly, a recent study reported similar correlations between the photoreceptor layer and VA among patients with DME4 and implied that the extent of ME does not match the severity of visual dysfunction. Other factors, especially the integrity of the photoreceptors, are critical in the limited visual function of DME patients. Several recent studies have focused on photoreceptor integrity and VA in various retinopathies,
including AMD,17 DME2–4,18 and epiretinal membranes (ERM).7 The overall conclusion, and one that is in agreement with our findings, is that integrity of the ELM and IS/OS layers is more strongly correlated with BCVA than with CMT.7 The absence of ELM and IS/OS lines might represent cellular damage or cell death,19,20 either of which would explain the wide range of VA for a given degree of retinal edema. Currently, the general consensus is that photoreceptor layer integrity is closely related to parameters of visual function in DME. However, the relationship between the IS/OS and ELM lines has not been fully investigated. We found that IS/OS integrity is closely related to ELM integrity in the same person (r = 0.881, p50.001), indicating that these two layers are both reflective of the severity of photoreceptor damage. Interestingly, IS/OS groups had more severe damage than did the ELM groups, the ratios between groups being: IS/OS (+): IS/OS (±) = 25:25 eyes; ELM (+): ELM (±) = 32:18 eyes. We believe that the different sensitivities of photoreceptor layers to retinal damage are responsible for this distribution. It has been hypothesized that IS/OS is more sensitive to retinal damage than is ELM, and thus disrupted ELMs are able to withstand more severe retinal damage. For the most severe categories [IS/OS ( ) and ELM ( )], the percentage of severe damage was equal (11 eyes, 18%), reflecting the natural progression of DME. We suggest that IS/OS integrity is an indicator of ELM damage. The functional impact of DME is quantifiable by examining VA, despite the fact that VA is only one subjective parameter associated with macular function. In our study, microperimetry was performed to evaluate visual function in DME. Microperimetry provides an objective assessment of visual function at specific locations on the retina, independent of macular thickness.21 Moreover, this technique is valuable for predicting outcomes in DME.9 Our results show that MS closely correlates with both BCVA and photoreceptor layer morphology. Our findings correspond to those of Yohannan et al.22 who demonstrated that disruption of the IS/OS junction is correlated with a significant decrease in point sensitivity in DME eyes. To supplement microperimetry analysis, we have added several new parameters, i.e. fixation stability within 2 and % central fixation, to improve the evaluation of visual function in DME. Therefore, in addition to BCVA, we suggest that microperimetry, incorporating these two new parameters, be included as a standard test for visual function in patients with DME. Another feature of our study was the strict inclusion criteria for DME patients. In previous studies, patients with and without prior treatments were included, with no consideration for intrinsic damage so-produced to the IS/OS and ELM.2,3,15 Current Eye Research
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Visual Function versus Photoreceptor Integrity in DME
Consequently, to improve the accuracy of our study, our study excluded patients who had undergone previous treatments. However, heterogeneity was still observed within each group, since disrupted areas can differ in their lengths and locations. For example, similar disruptions in the fovea and foveola might have differing effects on the VA.23 The limits of this study were its retrospective design, cross-sectional nature and small sample size. Our results are preliminary and need further corroboration by larger sample studies. A longitudinal study would clarify the relationship of photoreceptor integrity with development of, and mechanisms involved in, DME. Thus, further prospective clinical trials for evaluation and treatment of DME are needed. In conclusion, integrity of IS/OS and ELM correlates with visual function in patients with DME. More studies are needed to confirm and validate this relationship.
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DECLARATION OF INTEREST 14.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This work was supported by a grant from the Major State Basic Research Development Program of China (973 Program) (No. 2011CB707500) and Shanghai Guide Fund for Medical Projects (No. 124119a9600). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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