Diabetic macular edema (DME) is the most common cause. Effect of Diabetic Macular Edema on Peripapillary Retinal Nerve Fiber Layer Thickness Profiles

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1 Retina Effect of Diabetic Macular Edema on Peripapillary Retinal Nerve Fiber Layer Thickness Profiles Duck Jin Hwang, 1,2 Eun Ji Lee, 1 Sang Yoon Lee, 3 Kyu Hyung Park, 1 and Se Joon Woo 1 1 Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea 2 HanGil Eye Hospital, Incheon, Korea 3 Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea Correspondence: Se Joon Woo, Department of Ophthalmology, Seoul National University Bundang Hospital, #300, Gumi-dong, Bundang-gu, Seongnam, Gyeonggi-do , Korea; sejoon1@snu.ac.kr. Submitted: December 16, 2013 Accepted: April 30, 2014 Citation: Hwang DJ, Lee EJ, Lee SY, Park KH, Woo SJ. Effect of diabetic macular edema on peripapillary retinal nerve fiber layer thickness profiles. Invest Ophthalmol Vis Sci. 2014;55: DOI: / iovs PURPOSE. To investigate both the effect of diabetic macular edema (DME) on measured peripapillary retinal nerve fiber layer (RNFL) thickness and the effect of intravitreal bevacizumab injection on RNFL thickness using spectral-domain optical coherence tomography (SD-OCT) in patients with diabetic retinopathy. METHODS. We compared the SD-OCT RNFL thickness profiles between eyes with and without DME (DME [n ¼ 42]; without DME [n ¼ 53]) and conducted an interventional study for evaluating the effect of DME on RNFL thickness. Six sectorial and the global RNFL (grnfl) thicknesses were compared between the two groups. To evaluate the intraindividual effect of DME on RNFL thickness, 1-month follow-up OCT data of 42 eyes that received an intravitreal bevacizumab injection were compared with preinjection data. RESULTS. The six sectorial and grnfl thicknesses were greater in the DME group than the non- DME group (P < 0.05). The grnfl thickness significantly correlated with the central foveal thickness (CFT) (R ¼ 0.470, P < 0.001) and total macular volume (R ¼ 0.786, P < 0.001). The 42 eyes that received intravitreal bevacizumab injections showed significant decreases of the CFT (P < 0.001) and grnfl thickness (P < 0.001) after injection. Additionally, the changes in macular thickness and RNFL thickness were significantly correlated (R ¼ 0.576, P < 0.001). CONCLUSIONS. The RNFL thickness was generally increased in patients with DME, and the increment correlated with the degree of macular edema. While long-lasting DME resulted in RNFL thickening in all sectors, short-term DME resolution mainly influenced the temporal and nasal RNFL thicknesses. Cautious interpretation is recommended for evaluation of glaucoma using RNFL thickness in diabetic patients, especially patients with DME. Keywords: diabetic macular edema, glaucoma, retinal nerve fiber layer thickness Diabetic macular edema (DME) is the most common cause of visual impairment and legal blindness in patients with diabetes mellitus (DM). 1 The pathogenesis of DME is rather complex and is still not fully understood. It occurs mainly because of disruption of the blood retinal barrier, which leads to increased fluid accumulation within the intraretinal layers of the macula. 2 Glaucoma is a progressive optic neuropathy characterized by progressive loss of retinal ganglion cells (RGC) and the retinal nerve fiber layer (RNFL) with or without associated visual field loss. 3 Because glaucomatous optic nerve damage is largely irreversible, early detection of the disease and its progression is crucial in glaucoma management. It has been shown that quantitative RNFL thickness measurement using optical coherence tomography (OCT) is a valuable tool for the early diagnosis of glaucoma 4,5 as well as for monitoring glaucoma progression. 6,7 With the advent of spectral-domain (SD)-OCT, which facilitates the segmentation of the retina and quantification of RNFL thickness with better resolution, it has been recently demonstrated that the sensitivity and specificity for diagnosis and progression detection can be significantly improved. 8,9 According to a few previous studies, 10,11 DME may affect other parts of the eye in addition to the macula. Funatsu et al. 10 reported that the vitreous vascular endothelial growth factor (VEGF) level was higher in subjects with DME compared to that in control subjects. Further, we previously reported that temporary macular edema after panretinal photocoagulation accompanied a transient increase in peripapillary RNFL thickness, 11 providing indirect evidence that DME may have an effect on RNFL thickness profiles. However, to the best of our knowledge, no prior study has addressed the possible effects of DME on the RNFL thickness assessment. Such information is clinically important because individuals with diabetes are at a higher risk of having glaucoma than people without diabetes: The rate of glaucoma was 7.8% in people with diabetes compared to 3.9% in nondiabetic individuals in a population-based study. 12 Therefore, the aim of this study was to compare the peripapillary RNFL thickness in diabetic patients with DME to that in patients without DME and to investigate whether the fluctuation in DME with intravitreal drug injections changes the peripapillary RNFL thickness parameters. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc. j ISSN:

2 Effect of DME on RNFL Profiles IOVS j July 2014 j Vol. 55 j No. 7 j 4214 METHODS Subjects We included 95 eyes of 95 patients (42 patients with DME and 53 age- and diabetes duration matched patients with diabetic retinopathy without DME) in this case-control study. We retrospectively reviewed the charts of patients diagnosed with diabetic retinopathy at the Seoul National University Bundang Hospital from September 2012 to February Patients who met the following inclusion criteria were included consecutively: (1) age greater than 30 years and (2) diagnosed with clinical evidence of diabetic retinopathy with/without DME. Diabetic macular edema was defined as a central foveal thickness (CFT) 350 lm on OCT. The major exclusion criteria were as follows: (1) history of or clinical evidence of glaucoma; (2) presence of vitreous hemorrhage; (3) presence of another retinal disease except for diabetic retinopathy, that is, other conditions that can cause macular thickening such as retinal vein occlusion, epiretinal membrane, or vitreomacular traction or age-related macular degeneration; (4) previous treatment for DME with focal/grid laser or intravitreal injection within 6 months; (5) history of panretinal photocoagulation; (6) any intraocular surgery within 6 months or previous pars plana vitrectomy; and (7) severe cataracts or media opacity, which could have an influence on performing OCT. All 42 eyes with DME received an intravitreal bevacizumab injection for the treatment of DME. To evaluate the intraindividual effect of DME on RNFL thickness, 42 eyes that received intravitreal bevacizumab injections for DME were retrospectively included in the interventional cohort study. The macular thickness and volume profiles of the retina and choroid were measured at baseline (preinjection) and 1 month after a single bevacizumab injection. When both eyes were eligible for the study, the eye with more severe DME was selected. Optical Coherence Tomography Scanning Protocols An SD-OCT examination with macular thickness mapping and circumpapillary RNFL thickness measurements was performed by using Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). The circumpapillary RNFL thickness was measured in six sectors: temporal (T, ), superior temporal (TS, ), superior nasal (NS, ), nasal (N, ), inferior nasal (NI, ), and inferior temporal (TI, ), together with the papillomacular bundle (PMB, 338 8; Spectralis Nsite Axonal Analytics Software; Heidelberg Engineering) thickness. The global RNFL thickness was obtained by averaging the total 3608 RNFL thicknesses. The RNFL thickness parameters were compared between the DME group and the non-dme group. In addition, the relationship between RNFL profiles and macular thickness was evaluated. All eyes with DME underwent Spectralis OCT before and after a single intravitreal injection of bevacizumab. A central volume scan with a 25-scan pattern and macular thickness map protocols was performed. The macular thickness maps were divided into nine sectors according to the Early Treatment Diabetic Retinopathy Study (ETDRS) layout, namely, the 1,000- lm central ring and each of the four quadrants of an inner ring and an outer ring. Additionally, a volumetric assessment of the central retinal structures consisting of 25 single horizontal axial scans was performed (scanning area: mm, centered at the fovea). The global RNFL thickness and the peripapillary RNFL thicknesses of the six sectors were compared between preand 1-month postinjection values. Intravitreal Injection Methods All injections were performed within 1 week after performance of the OCT examination. Under topical anesthesia with proparacaine (0.5%) eye drops, the bulbar conjunctiva and fornices were rinsed with 5% povidone-iodine, followed by application of a sterile drape and lid speculum. After applying a drop of 5% povidone-iodine, 1.25 mg (0.05 ml) bevacizumab was injected via the pars plana. The needle was removed carefully, and the injection site was compressed with a sterile cotton applicator to prevent reflux. Antibiotic eye drops were applied four times per day for 3 days after the injection. Ethics Statement The study was approved by the institutional review board of Seoul National University Bundang Hospital, and the study was carried out in accordance with the tenets of the Declaration of Helsinki. Statistical Analysis Statistical analyses were performed using a commercially available software package (IBM SPSS Statistics 18; SPSS, Inc., Chicago, IL, USA). In the comparative study, significant differences in the CFT and macular volume between the DME and non-dme groups were evaluated using the independent t-test and the Mann-Whitney test for parametric and nonparametric data, respectively. Additionally, the relationship between the RNFL thickness profiles and macular thickness was evaluated by Pearson s correlation analysis. In the interventional cohort study, significant differences between baseline and 1 month after intravitreal bevacizumab injection were evaluated using the paired t-test. Continuous variables are presented as the mean 6 standard deviation. Statistical significance was defined as P < RESULTS The baseline characteristics of 95 patients with diabetic retinopathy are summarized in Table 1. The mean age was years; the mean DM duration was years; and the averaged hemoglobin A1c (HbA1c) level was %. The mean 6 standard deviation of the visual acuity, converted to the logarithm of the minimal angle of resolution (logmar), was in the DME group and in the non-dme group (P < 0.001). No statistically significant differences in age, sex, DM duration, history of hypertension, HbA1c, baseline IOP, or refractive errors were observed (all P > 0.05). The CFT was 73.4% thicker in the DME group ( lm) than in the non-dme group ( lm, P < 0.001). Significant differences in RNFL thickness profiles were found between the DME and non-dme groups (Table 1, Figs. 1, 2). The global RNFL thickness was 37.4% greater in the DME group ( lm) compared to the non-dme group ( lm, P < 0.001). Further, the RNFL thickness of all six sectors was greater in the DME group than in the non-dme group (P < 0.001). The difference in RNFL thickness was largest in the temporal sector (46.4 lm), followed by the nasal (40.9 lm), superior nasal (36.3 lm), inferior nasal (32.9 lm), superior temporal (32.12 lm), and inferior temporal (18.0 lm) sectors. The global RNFL thickness was significantly correlated with the CFT (R ¼ 0.470, P < 0.001) and total macular volume (R ¼ 0.786, P < 0.001) (Fig. 3). In 42 DME eyes that received a single intravitreal injection, significant decreases in the CFT ( lm, P < 0.001) and RNFL thickness ( lm, P < 0.001) were

3 Effect of DME on RNFL Profiles IOVS j July 2014 j Vol. 55 j No. 7 j 4215 TABLE 1. Comparison of Patients With Diabetic Retinopathy With and Without DME in the Case-Control Study Total, N ¼ 95 Eyes DME Group, N ¼ 42 Eyes Non-DME Group, N ¼ 53 Eyes DME/Non-DME Ratio, % P Value Base characteristics Age, y * Female (%) 43 (45.3) 23 (54.8) 20 (37.7) Male (%) 52 (54.7) 19 (45.2) 33 (62.3) DM duration, y * HTN, N (%) 37 (38.9) 18 (42.9) 19 (35.8) HbA1c, % * IOP, mm Hg * SE, diopters * VA, logmar <0.001* Macular thickness/volume Central foveal thickness, lm <0.001* Total macular volume, mm <0.001* RNFL thickness, lm Global <0.001* PMB * Temporal <0.001* Nasal <0.001* Superotemporal <0.001* Inferotemporal * Superonasal * Inferonasal <0.001* DME/non-DME ratio (%) indicates the value of parameters of the DME group/value of the parameters of the non-dme group. The values represent means 6 standard deviation. HTN, hypertension; SE, spherical equivalent; VA, visual acuity. * P values calculated by the independent t-test and the Mann-Whitney test for parametric and nonparametric data. P values calculated by Pearson s v 2 test. Values in bold are statistically significant (P < 0.05). FIGURE 1. Peripapillary RNFL thickness profiles measured by Spectralis OCT were compared between the DME group and the non-dme group. The DME group had higher thickness profiles in global RNFL thickness and total RNFL sectors (P < 0.05). The pre- and postinjection RNFL parameters of the DME group were higher compared to those of the non-dme group in total sectors. The reduction in the RNFL thickness after intravitreal bevacizumab injection was significant in the temporal and nasal sectors and the papillomacular bundle (PMB) (P < 0.05).

4 Effect of DME on RNFL Profiles IOVS j July 2014 j Vol. 55 j No. 7 j 4216 FIGURE 2. The non-dme group and DME group were compared as shown in Spectralis OCT RNFL profiles and macular thickness maps. (A) Case 1: 40-year-old man with proliferative diabetic retinopathy (PDR) without DME in whom the diabetes duration was 7 years and HbA1c was 11.3%. His RNFL thickness profile was normal. (B) Case 2: 68-year-old man with severe nonproliferative diabetic retinopathy with DME in whom the diabetes duration was 4 years and the HbA1c was 6.8%. The RNFL thicknesses of all sectors except for the superior nasal sector were thicker than the normal range. (C) The values before and after a single intravitreal bevacizumab injection were compared in the case 2 patient. The RNFL thicknesses of all six sectors and the macular thickness decreased 1 month after a single injection. observed 1 month after intravitreal bevacizumab injection. The mean CFT was lm before injection and decreased to lm at 1 month after injection (P < 0.001) (Table 2, Fig. 2). The total macular volume of all ETDRS subfields was decreased at 1 month after injection ( mm 3 ) compared with that before injection ( mm 3, P < 0.001). The global RNFL thicknesses at pre- and post injection were lm and lm, respectively (P < 0.001). The changes in the RNFL thicknesses of the temporal and nasal sectors were significant (Table 2, FIGURE 3. (A, B) Global RNFL thickness was significantly correlated with the central foveal thickness (CFT) and total macular volume. The total macular volume showed a stronger correlation with the global RNFL thickness (R ¼ 0.786, P < 0.001) than with the CFT (R ¼ 0.470, P < 0.001).

5 Effect of DME on RNFL Profiles IOVS j July 2014 j Vol. 55 j No. 7 j 4217 TABLE 2. Comparison Between Pre- and Postinjection Parameters for Central Foveal Thickness, Total Macular Volume, and RNFL Thickness Profiles in the Interventional Cohort Study Preinjection, N ¼ 42 Eyes Postinjection, N ¼ 42 Eyes Post-Pre ratio, % P Value* Macular thickness/volume Central foveal thickness, lm <0.001 Total macular volume, mm <0.001 RNFL thickness, lm Global <0.001 PMB Temporal Nasal Superior temporal Inferior temporal Superior nasal Inferior nasal Post-pre ratio (%) indicates postinjection value/preinjection value. * P values calculated using the paired t-test. Values in bold are statistically significant (P < 0.05). Fig. 1). A significant amount of reduction in the sectorial RNFL thickness was found in the temporal ( lm, P ¼ 0.012) and nasal ( lm, P ¼ 0.003) sectors, followed by the superior temporal ( lm, P ¼ 0.088), superior nasal ( lm, P ¼ 0.173), inferior nasal ( lm, P ¼ 0.058), and inferior temporal ( lm, P ¼ 0.651) sectors. The global RNFL thickness change after intravitreal bevacizumab injection was significantly correlated with the change in the mean CFT (R ¼ 0.576, P < 0.001) and total macular volume (R ¼ 0.634, P < 0.001) (Fig. 4). Significant differences in the RNFL thickness profiles were observed between the DME and non-dme groups even after a single intravitreal bevacizumab injection (Table 3, Fig. 1). DISCUSSION In the current study, we demonstrated a significant difference in the RNFL thickness profiles between the DME group and non-dme group. The RNFL thicknesses of all six sectors were greater in the DME group than in the non-dme group, and the average increase in thickness was 37.4%. Additionally, shortterm improvement of DME following a single intravitreal injection of bevacizumab significantly decreased temporal and nasal RNFL thicknesses. In summary, chronic DME had an effect on the overall RNFL thickness profiles and had an effect mainly on the temporal and nasal RNFL thicknesses and PMB thickness in the short term (1 month). It is well known that glaucomatous change is mainly associated with decrement in the superior temporal or inferior temporal RNFL thickness. 13 However, our results indicate that long-term sustained DME influences the increment of the superior or inferior RNFL thickness as well as the temporal or nasal RNFL thickness. Therefore, because the OCT RNFL thickness is greater in patients with DME, careful interpretation may be required when one is evaluating glaucomatous RNFL damage in those patients. The increment of RNFL thickness was significantly correlated with the severity of DME in the current study. The exact etiology for the change of RNFL thickness profiles in patients with DME remains unclear. Because the breakdown of the blood retinal barrier (BRB) is the final common pathway in the formation of DME, 14 it is possible that the breakdown of the inner BRB in RNFL causes RNFL edema, which then results in the increase of RNFL thickness. In addition, the reduction in RNFL thickness after intravitreal bevacizumab injection was largest in the temporal sector, which may be related to the change of macular tomography according to the resolution of macular edema. From our study results, we can hypothesize TABLE 3. Comparison Between the Parameters of the Non-DME Group and the Postinjection Parameters of the DME Group Non-DME Group, N ¼ 53 Eyes DME Group, Postinjection, N ¼ 42 Eyes DME/Non-DME Ratio, % P Value* Macular thickness/volume Central foveal thickness, lm <0.001 Total macular volume, mm <0.001 RNFL thickness, lm Global <0.001 PMB <0.001 Temporal <0.001 Nasal <0.001 Superior temporal Inferior temporal Superior nasal <0.001 Inferior nasal <0.001 DME/non-DME ratio (%) indicates the value of the postinjection parameters of the DME group/value of the parameters of the non-dme group. * P values calculated using the paired t-test. Values in bold are statistically significant (P < 0.05).

6 Effect of DME on RNFL Profiles IOVS j July 2014 j Vol. 55 j No. 7 j 4218 FIGURE 4. The change in central foveal thickness (A) and total macular volume (B) correlated significantly with the change in the RNFL thickness after a single intravitreal bevacizumab injection (R ¼ 0.576, P < 0.001; R ¼ 0.634, P < 0.001, respectively). that acute DME first results in temporal RNFL edema/ thickening, followed by or coincident with the increment of nasal RNFL thickness; in contrast, the RNFL edema diffuses into all peripapillary sectors in subacute or chronic DME, causing a generalized increase in RNFL thickness. It is possible that no changes of RNFL thickness actually occurred in DME and that this finding can be explained by factors such as scanning error, diurnal fluctuation in RNFL due to the effect of diabetes, or the repeatability or reproducibility of OCT. Therefore, we examined each of the OCT scans in an attempt to identify a specific RNFL layer that showed notable errors of automatic segmentation in measuring thickness in patients with DME. However, this was not found for any participants, and no segmentation errors were observed. To the best of our knowledge, the present study is the first clinical study to report the effect of DME on peripapillary RNFL thickness. We evaluated peripapillary RNFL thickness profiles to provide insights into the interpretation of RNFL parameters for the diagnosis of glaucoma and for the detection of its progression. Somfai et al. 15 reported that the RNFL layer showed no change in eyes with DME using the retinal layer segmentation method. However, these authors did not evaluate peripapillary RNFL thickness. Although several studies, 12,16 18 including a meta-analysis, 18 have shown an association between DM and glaucoma, and a clinic-based report 19 suggested that patients with diabetic retinopathy are more likely to have a thinner RNFL, no report has demonstrated the impact of DME on RNFL profiles for evaluating glaucoma. This issue should be taken into account when one is assessing the RNFL in patients with DME because many patients with diabetic retinopathy have DME, which can occur at any stage of nonproliferative and proliferative diabetic retinopathy, and because many patients with diabetes or diabetic retinopathy also may have glaucoma. 12 Although a definitive causal relationship between RNFL thickness and macular thickness has not been confirmed in diabetic retinopathy, we observed that the RNFL thickness tended to increase with an increase in DME in the current study. When a normal parameter in RNFL thickness is detected in a diabetic glaucoma patient or a diabetic patient with DME, the effect of DME on RNFL thickness profiles should be considered before progression of glaucomatous damage is precluded in these patients. We are aware that our study has several limitations. First, because this was a retrospective study enrolling patients visiting a single hospital, a selection bias inherent to retrospective studies may have been present. Second, the glaucoma evaluation is performed by combining various structural and functional tests, especially the visual field test; it does not rely solely on the RNFL thickness measurement. Thus, the absence of visual field test results is a study limitation with respect to the interpretation of the RNFL thickness data. Third, we evaluated the RNFL thickness parameters of patients who received intravitreal bevacizumab injections and correlated this result to the short-term effect of DME on RNFL thickness. From this result, we can obtain knowledge regarding the RNFL thickness change after the resolution of DME, but not after the development of DME. Thus, extrapolation of the RNFL thickness change during acute development of DME is a potential bias and must be confirmed in a prospective cohort study. Fourth, we did not take into account other factors that affect the peripapillary RNFL, such as a larger neuroretinal rim, shorter axial length, thicker subfoveal choroid, larger optic disc, and flatter anterior cornea. 20 Finally, although we showed that DME alters the RNFL thickness profile, we cannot be certain that the altered profiles are clinically significant. A quantitative analysis on the errors in glaucoma evaluation should be further elucidated in future clinical studies. In conclusion, RNFL thickness was generally increased in diabetic patients with DME, indicating that DME could mask the decrease in RNFL thickness, and this increment in RNFL thickness was significantly correlated with the severity of DME. Moreover, short-term DME changes mainly influenced the temporal and nasal RNFL thickness profiles. Although further studies will be required to confirm the clinical implications, we suggest that caution be used in interpretation of RNFL thickness parameters in diabetic patients with DME. Acknowledgments Supported by a grant (2012R1A2A2A ) funded by the National Research Foundation in Korea. The authors alone are responsible for the content and writing of the paper. Disclosure: D.J. Hwang, None; E.J. Lee, None; S.Y. Lee, None; K.H. Park, None; S.J. Woo, None

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