Current Eye Research, 2015; 40(7): 744–751 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.956371
ORIGINAL ARTICLE
Topographical Correlation Between Macular Layer Thickness and Clockwise Circumpapillary Retinal Nerve Fiber Layer Sectors in Patients with Normal Tension Glaucoma Kazuko Omodaka1, Yu Yokoyama1, Yukihiro Shiga1, Maki Inoue1, Seri Takahashi1, Satoru Tsuda1, Kazuichi Maruyama1 and Toru Nakazawa1,2,3 1
Department of Ophthalmology, 2Department of Advanced Ophthalmic Medicine, and 3Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
ABSTRACT Purpose: To define topographical areas of the macula in optical coherence tomography (OCT) scans by identifying regions in which macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (mGCL + IPL) thickness was highly correlated with clockwise circumpapillary RNFL (cpRNFL) thickness in patients with normal tension glaucoma (NTG). Methods: This study included 101 eyes of 101 patients with mild or moderate NTG. CpRNFL, mRNFL, and mGCL + IPL thickness were assessed with spectral-domain OCT (3D OCT-2000). The region of interest (6 6 mm square) was centered on the fovea and layer thickness was measured at each point on a 10 10 grid. Spearman’s rank correlation coefficient was determined between each temporal clockwise sector (7, 8, 9, 10, 11 o’clock) of the cpRNFL and each grid point in the mRNFL and mGCL + IPL. Grid points were defined as correlated to specific clockwise sectors when the correlation coefficient was more than 0.4. To validate the areas comprised by these points, they were superimposed on a swept-source OCT image (12 9 mm, EnView software, Topcon) showing the anatomical trajectory of nerve fiber defects. Results: Macular areas with a high correlation coefficient (r 0.4, p50.05) to clockwise cpRNFL were identified. The number of grid points in the mRNFL and mGCL + IPL correlated to specific clockwise cpRNFL sectors was, respectively, 40 and 18 (7 o’clock), 41 and 22 (8), 33 and 44 (9), 39 and 39 (10), and 18 and 19 (11) (r = 0.40–0.79). Interestingly, the distribution of mRNFL sectors closely matched the RNFL defects in the OCT image, although the mGCL + IPL sectors differed and were closer to the fovea than the mRNFL sectors. Conclusion: The identification of these topographical macular areas, and the different layouts in the mRNFL and the mGCL + IPL, may increase the accuracy of clinical research on NTG. Keywords: Circumpapillary retinal nerve fiber layer thickness, macular, normal tension glaucoma, optical coherent tomography
INTRODUCTION
serious issue in countries with an aging population, as glaucoma progresses with age.3 In Asia, normal tension glaucoma (NTG) is the most common type of primary open angle glaucoma (POAG).4–6 In NTG, the main treatment for glaucoma, lowering intraocular pressure (IOP), is of more limited efficacy, increasing the importance of detecting structural
Glaucoma is characterized by glaucomatous optic neuropathy and a corresponding progressive degeneration of retinal ganglion cells (RGCs). It is now the second highest cause of blindness worldwide.1,2 Visual impairment due to glaucoma is becoming a
Received 5 May 2014; revised 13 June 2014; accepted 16 August 2014; published online 5 September 2014 Correspondence: Toru Nakazawa, Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. Tel: +81-22-717-7294. Fax: +81-22-717-7298. E-mail: [email protected]
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Topographical Correlation of OCT Macular Map 745 and/or functional progression in these patients. This poses a challenge, as NTG progresses more slowly than OAG or exfoliation glaucoma (EXG)7 and thus requires a more sensitive method of detecting progression. An additional challenge in tracking the progression of NTG is that it causes significantly more damage to the fixation point than other forms of glaucoma8,9, but the Humphrey field analyzer (HFA) 24-2 SITA program is less sensitive in this area. This is due to RGC redundancy and the small number of test points within the macular area. Another challenge is posed by myopia, one of the major risk factors for POAG.10 In NTG patients with myopia, the disc is tilted temporally, making temporal rim recognition and the evaluation of cupping very difficult. Furthermore, macular lesions are often present in NTG. As we have previously demonstrated, the myopic disc type is more common in patients with NTG11,12 and glaucoma patients with decreased visual acuity,13 when patients are classified by optic disc type according to Nicolela’s method.14,15 In Japan, there is a high prevalence of myopia, which is associated with a high prevalence of myopia in NTG patients. The overall prevalence of myopia (spherical equivalent 5 1 D) in the Japanese population is 41.8%, and of these, 8.2% have high myopia (spherical equivalent 5 5 D).16 By contrast, the prevalence of myopia in the United States, Western Europe, and Australia is approximately 16% to 27%, and the prevalence of high myopia is 2.8% to 4.5%.17,18 Overall, therefore, it is clear that macular evaluation is an increasingly important part of NTG management, especially in regions of the world where myopia and NTG are more common. These challenges in glaucoma assessment may best be met by new techniques relying on optical coherence tomography (OCT). This is a powerful tool that has seen an increasing role in routine examinations due to its well-established advantages in detecting early glaucoma compared to techniques such as fundus photography and HRT II. Recently, the development of spectral-domain (SD) OCT and improved segmentation algorithms has enabled us to separately measure and quantify each retinal layer in the macula. Quantifying the thickness of the macular retinal nerve fiber layer (mRNFL) and ganglion cell layer plus inner plexiform layer (mGCL + IPL) is especially helpful in the diagnosis of early glaucoma.19 Research based on layer segmentation has led to the understanding that glaucomatous damage to the macula is common even in the early stages of the disease.20 Additionally, Lisboa et al.21 found that circumpapillary RNFL thickness (cpRNFL) is also a good indicator of preperimetric glaucoma and suggested that it may be more accurate than OCT measurements of the ONH or macula. This may be due in part to the macula being less involved in the process of !
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glaucomatous damage than the cpRNFL. Nevertheless, parameters of the cpRNFL and the macula have both become routinely used as diagnostic instruments in glaucoma detection and follow-up, and both have useful roles. A greater understanding of the correlation between cpRNFL and topographical macular parameters, i.e. in different regions of the retina, would therefore be of significant clinical value. The purpose of this study was therefore to determine the topographical correlation of mRNFL and mGCL + IPL thickness to clockwise cpRNFL thickness in patients with NTG. Our results suggested that areas of high correlation closely coincided with the layout of the retinal nerve tract in patients with NTG.
MATERIALS AND METHODS Inclusion Criteria This was a retrospective, cross-sectional study including 101 eyes of 101 Japanese patients (mean age: 59.4 ± 14.7 years, 40 male and 61 female) with mild or moderate NTG (mean deviation (MD) measured with the HFA = 12.0 dB). The inclusion criteria were a diagnosis of NTG with untreated IOP less than 22 mmHg, spherical equivalent refractive error of 4 8.00 diopters (i.e. excluding patients with high myopia), and a glaucomatous visual field according to the Anderson-Patella classification. The exclusion criteria were (1) decimal VA 50.3, (2) the presence of macular disease such as premacular fibrosis, macular hole, and age-related macular degeneration, (3) concomitant ocular disease, (4) systemic disease affecting the visual field, and (5) cataract progression. The characteristics of the participants are listed in Table 1.
OCT Examination Topographical macular maps of the mRNFL, mGCL + IPL and cpRNFL were made with 3D OCT-2000 software (ver. 8.00, Topcon Corporation, Tokyo, Japan). The maps were derived from macular TABLE 1. Clinical data of patients included in this study. Sex male: female, n (%) Age (years) Spherical equivalent (D) VA (logMAR, Decimal) MDHFA24-2 (dB) IOP (mmHg) cpRNFLT (mm)
40(40%): 61(60%) 59.4 ± 14.7 2.9 ± 2.5 0.06 ± 0.10 (1.18 ± 0.23) 4.3 ± 3.1 13.5 ± 3.1 89.1 ± 12.5
VA, visual acuity; MD, mean deviation; HFA, Humphrey field analyzer; IOP, intraocular pressure; cpRNFL, circumpapillary retinal nerve fiber layer thickness.
746 K. Omodaka et al. cube scans of a 6 6 mm square area of the retina centered on the fovea, corresponding to the central 20 degrees of the macula. One hundred points from a 10 10 grid were used for the analysis. Scans were excluded if the image quality was less than 70 or if segmentation in the images was inaccurate. A swept-source OCT image (DRI OCT-1, 12 9 mm, EnView software, Topcon) that showed the anatomical trajectory of nerve fiber defects by flattening the inner limiting membrane (ILM) was also used. Macular areas comprised by points identified in our analysis as having a high correlation coefficient (40.4) were superimposed on this image to validate the correlation.
Statistical Analysis The correlation of cpRNFL thickness in each temporal clockwise sector (i.e. the 7, 8, 9, 10, and 11 o’clock sectors) to mRNFL and mGCL + IPL thickness in each grid point was determined with Spearman’s
rank correlation coefficient. Macular grid points were defined as highly correlated with clockwise cpRNFL sectors when the correlation coefficient was more than 0.4.
RESULTS Figure 1 shows the correlation coefficient for each mRNFL grid point to cpRNFL in the five temporal clockwise cpRNFL sectors. For each of the 7, 8, 10, and 11 o’clock sectors (shown in Figure 1A, B, D, and E, respectively), there was a corresponding contiguous arc-shaped area in which each mRNFL grid point had a high correlation coefficient (r = 0.4, p50.05). The arcshaped area with the highest correlation coefficient (r40.6) to the 9 o’clock sector was mainly 4–8 degrees superior and nasal to the fixation point (Figure 1C). The mRNFL area highly correlated to the 11 o’clock sector was located in the upper margin of the map. Reflecting the anatomical trajectory of the nerve fiber layer, the mRNFL areas correlated to the 7 and
FIGURE 1. The distribution of mRNFL grid points with a high correlation coefficient (40.4) to the clockwise cpRNFL sectors at 7, 8, 9, 10, and 11 o’clock (A, B, C, D, and E, respectively). Correlated points are highlighted in gray, with darker shades indicating a higher correlation coefficient. (F) Scatter blot graph showing the correlation between cpRNFL thickness and mRNFL thickness in the grid points with the highest correlation coefficients (r = 0.79, 9 rows from left and 10 rows from top, in Figure 1A). Current Eye Research
Topographical Correlation of OCT Macular Map 747
FIGURE 2. The distribution of mGCL + IPL grid points with a high correlation coefficient (40.4) to the clockwise cpRNFL sectors at 7, 8, 9, 10, and 11 o’clock (A, B, C, D, and E, respectively). Correlated points are highlighted in gray, with darker shades indicating a higher correlation coefficient. (F) Scatter blot graph showing the correlation between cpRNFL thickness and mGCL + IPL thickness in the grid points with the highest correlation coefficients (r = 0.70, 5 rows from left and 2 rows from top, in Figure 2D).
8 o’clock sectors were located in the lower hemifield and the areas correlated to the 10 and 11 o’clock sectors were located in the upper hemifield. Respectively, 40, 41, 33, 39, and 18 mRNFL grid points were highly correlated to the 7, 8, 9, 10, and 11 o’clock cpRNFL sectors (r = 0.40–0.79). Figure 1(F) shows a scatter blot graph indicating the correlation between cpRNFL thickness and mRNFL thickness in the grid points with the highest correlation coefficients (r = 0.79, 9 rows from left and 10 rows from top, in Figure 1A). Figure 2 shows the correlation coefficient for each grid point from the mGCL + IPL scan to the five temporal clockwise cpRNFL sectors. Once again, the grid points with a high correlation coefficient (r = 0.4, p50.05) to the 7, 8, 10, and 11 o’clock sectors (Figure 2A, B, D, and E, respectively) had a contiguous arc-shaped pattern. The area with the highest coefficient correlation (r40.6) to the 9 o’clock sector was mainly located 2–8 degrees superior to the fixation point (Figure 2C). The areas most !
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highly correlated to the 7 and 8 o’clock sectors overlapped and were within 6 degrees below the fixation point (Figure 2A and B). Respectively, 18, 22, 44, 39, and 19 mGCL + IPL grid points were highly correlated to the 7, 8, 9, 10, and 11 o’clock cpRNFL sectors (r = 0.40–0.70). Figure 2(F) shows a scatter blot graph indicating the correlation between cpRNFL thickness and mGCL + IPL thickness in the grid points with the highest correlation coefficients (r = 0.70, 5 rows from left and 2 rows from top, in Figure 2D). To confirm that the statistical analysis of correlated areas matched real RNFL defects, mRNFL and mGCL + IPL grids with the correlated points highlighted were superimposed onto DRI-OCT images of RNFL defects (Figure 3). The highly correlated mRNFL areas closely matched the RNFL defects visible in the OCT image (Figure 3). However, the mGCL + IPL areas (Figure 2) tend to be located closer to the fovea than the observed RNFL defects, and overall, were not closely matched.
748 K. Omodaka et al.
FIGURE 3. Macular maps with correlated areas highlighted superimposed onto an OCT image showing RNFL defects. The underlying OCT image was corrected in EnView software by flattening it with relative to the inner limiting membrane (ILM).
DISCUSSION In this study, we investigated the regional topographical correlation between OCT measurements of retinal thickness in a grid of test points in the macula in the mRNFL and mGCL + IPL and in clockwise sectors in
the temporal cpRNFL (at 7–11 o’clock) in patients with NTG. We identified distinctive arc-shaped areas in the mRNFL that were highly correlated to corresponding cpRNFL sectors. Moreover, these areas corresponded to observable defects in the retinal nerve tract. In addition, we identified areas of the mGCL + IPL Current Eye Research
Topographical Correlation of OCT Macular Map 749 that were highly correlated to clockwise sectors of the cpRNFL, and found that they were distinct from the mRNFL areas. The focus of our investigation was the structural relationship between the cpRNFL and macula, which we examined with a statistical analysis of OCT measurements of these two areas. In a previous study of NTG patients, Garway-Heath et al. established the anatomical relationship between regional visual field sensitivity, measured with the HFA 24-2 program, and RNFL defects in the optic nerve head, identified with fundus photography.22 In another study of eyes with glaucoma, Kanamori et al. examined in detail the regional relationship between OCT-measured RNFL thickness and visual field sensitivity.23 These past studies suggest that the prospects for study might have included a comparison of regional visual field sensitivity measured with the HFA 10-2 program and OCT macular maps. However, such a method of quantifying the relationship between structure and function in the macula has a number of important disadvantages, which are related to the phenomena of RGC redundancy24 and RGC displacement25 in the macula. Our comparison of the anatomical relationship between the macular and disc areas, in which we compared the OCT-measured thickness of the cpRNFL and in the macular map, minimized these biases. We found that the areas of high correlation in the mRNFL were horizontally asymmetrical (as can be seen by comparing Figure 1A and E or B and D). Specifically, the lower areas of high correlation (7 and 8 o’clock) were relatively closer to the macula than the upper sectors (10 and 11 o’clock). This asymmetrical distribution is consistent with previous reports.22,23 The location of the macula is inferior to the horizontal line and the anatomical trajectory of the retinal nerve fibers is therefore naturally asymmetrical.20 Furthermore, the map of corresponding locations in the retina and optic nerve head is influenced by axial length26 and, in this study, average spherical equivalence was 2.9 ± 2.5 D. Therefore, the high number of myopic patients in this study also likely contributed to the clearly asymmetrical shape of the correlated areas we observed. Interestingly, the areas of high correlation in the mRNFL and mGCL + IPL did not completely overlap, with the mGCL + IPL areas being closer to the macula. The RGC displacement25, a phenomenon that has previously been demonstrated in the macula, is an insufficient explanation. RGC displacement exists within 7.2 degrees of the macula and arises from the anatomical offset of RGCs from the photoreceptors that provide their input. Taking into account the projection of the retinal nerve fibers from the cell bodies, this implies that near the optic nerve head, the mRNFL should undergo damage over a wider area than the mGCL + IPL. However, while our results for !
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the 9 o’clock sector are consistent with these theoretical wider damages in mRNFL, the discrepancies in the other sectors are not. An alternative explanation is that statistical limitations related to the structure of the mGCL + IPL led to high correlation values near the fovea. The mGCL + IPL is thicker in this area than in the periphery, and furthermore, the range of variation in the peripheral mGCL + IPL is small. Areas of the mGCL + IPL outside the central 7.2 degrees of the macula with near-normal sensitivity do not markedly differ in thickness with areas of the GCL + IPL with severe visual loss.27 Thus, the discrepancies we found between the mRNFL and mGCL + IPL in the areas that were correlated to sectoral cpRNFL thickness may be considered unsurprising. Although fundus photography allows us to readily identify the location of RNFL defects, defects in the mGCL + IPL are harder to see. This study is therefore the first to describe a method of identifying mGCL + IPL structural areas, by determining which areas are most highly correlated to the cpRNFL. The thresholds from visual field testing should also reflect in situ damage to the RGCs (in the GCL + IPL) but they are believed to be independent of the thickness of the overlying retinal nerve fibers, which comprise the RNFL. Moreover, the information we have revealed on this displacement may assist clinicians to interpret OCT results from the macula. The OCT evaluation for central area of the macula is important for good visual acuity. We found that the areas in the mRNFL and mGCL + IPL correlated to the 9 o’clock cpRNFL sector were shifted to the upper area of the macular map, as we had expected (Figures 1C and 2C). In particular, the correlation coefficient in the central four grid points was not high. This may be due to the thinness of the mRNFL and mGCL + IPL in these central 4 degrees, in addition to the effect of RGC displacement.25 It may therefore improve the accuracy of the results to exclude these grid points from the examination. We previously reported that the NTG patients with decreased visual acuity often had decreased tissue blood flow (represented by filling defects) in the temporal optic disc.13 Recently, NTG patients with stronger fluctuations in ocular perfusion pressure (OPP) have been shown to have more significant progression of visual field loss in the central 10 degrees.28,29 Thus, it is important to develop new OCT methods of screening for glaucomatous damage in the macula caused by abnormal blood flow. The main finding of this study was the identification of important areas of the macula associated with areas of the optic disc, made by performing a statistical analysis of clockwise sectors of the cpRNFL and a grid of measurement points in the macula. These areas of the macula may help to diagnose glaucoma and to detect glaucoma progression, and may be most useful in a cluster analysis.
750 K. Omodaka et al. Recently, Kanamori et al.30 showed that analyzing abnormal OCT parameters in clusters of grid points in the macula was a reliable method of diagnosing early glaucoma. Thus, accurate information on the relationship between these grid points and the anatomical trajectory of the nerve fibers would be valuable addition to future strategies using macular maps to diagnose glaucoma and identify its structural progression, and should increase their sensitivity and specificity to glaucoma. This study had several limitations. First, the sample size was relatively small, affecting its statistical power to detect significant differences. Second, glaucoma is a heterogeneous disease, and aging or other indices, such as myopia and glaucoma stage, may have affected our results. To decrease the influence of these factors, we excluded glaucoma patients with high myopia (less than 8 diopter) or advanced glaucoma (MD 5 12 dB). Third, glaucoma patients with focal damage outside the macular area were outside the scope of this evaluation method. In conclusion, the macular areas identified here, and their differing characteristics in the mRNFL and mGCL + IPL, may help to increase the accuracy of clinical assessments of NTG, the major type of glaucoma in Asia.
ACKNOWLEDGEMENTS The authors thank Mr. Tim Hilts for editing this article and Dr. Masahiro Akiba for useful discussion.
DECLARATION OF INTEREST No authors have any financial disclosures. The authors report no conflict of interest. This article was supported in part by JST grant, JSPS KAKENHI Grant-in-Aid for Scientific Research (B), (T.N. 26293372), for Exploratory Research (T.N. 26670751), and by JST Center for Revitalization Promotion.
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ORIGINAL ARTICLE
Topographical Correlation Between Macular Layer Thickness and Clockwise Circumpapillary Retinal Nerve Fiber Layer Sectors in Patients with Normal Tension Glaucoma Kazuko Omodaka1, Yu Yokoyama1, Yukihiro Shiga1, Maki Inoue1, Seri Takahashi1, Satoru Tsuda1, Kazuichi Maruyama1 and Toru Nakazawa1,2,3 1
Department of Ophthalmology, 2Department of Advanced Ophthalmic Medicine, and 3Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
ABSTRACT Purpose: To define topographical areas of the macula in optical coherence tomography (OCT) scans by identifying regions in which macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (mGCL + IPL) thickness was highly correlated with clockwise circumpapillary RNFL (cpRNFL) thickness in patients with normal tension glaucoma (NTG). Methods: This study included 101 eyes of 101 patients with mild or moderate NTG. CpRNFL, mRNFL, and mGCL + IPL thickness were assessed with spectral-domain OCT (3D OCT-2000). The region of interest (6 6 mm square) was centered on the fovea and layer thickness was measured at each point on a 10 10 grid. Spearman’s rank correlation coefficient was determined between each temporal clockwise sector (7, 8, 9, 10, 11 o’clock) of the cpRNFL and each grid point in the mRNFL and mGCL + IPL. Grid points were defined as correlated to specific clockwise sectors when the correlation coefficient was more than 0.4. To validate the areas comprised by these points, they were superimposed on a swept-source OCT image (12 9 mm, EnView software, Topcon) showing the anatomical trajectory of nerve fiber defects. Results: Macular areas with a high correlation coefficient (r 0.4, p50.05) to clockwise cpRNFL were identified. The number of grid points in the mRNFL and mGCL + IPL correlated to specific clockwise cpRNFL sectors was, respectively, 40 and 18 (7 o’clock), 41 and 22 (8), 33 and 44 (9), 39 and 39 (10), and 18 and 19 (11) (r = 0.40–0.79). Interestingly, the distribution of mRNFL sectors closely matched the RNFL defects in the OCT image, although the mGCL + IPL sectors differed and were closer to the fovea than the mRNFL sectors. Conclusion: The identification of these topographical macular areas, and the different layouts in the mRNFL and the mGCL + IPL, may increase the accuracy of clinical research on NTG. Keywords: Circumpapillary retinal nerve fiber layer thickness, macular, normal tension glaucoma, optical coherent tomography
INTRODUCTION
serious issue in countries with an aging population, as glaucoma progresses with age.3 In Asia, normal tension glaucoma (NTG) is the most common type of primary open angle glaucoma (POAG).4–6 In NTG, the main treatment for glaucoma, lowering intraocular pressure (IOP), is of more limited efficacy, increasing the importance of detecting structural
Glaucoma is characterized by glaucomatous optic neuropathy and a corresponding progressive degeneration of retinal ganglion cells (RGCs). It is now the second highest cause of blindness worldwide.1,2 Visual impairment due to glaucoma is becoming a
Received 5 May 2014; revised 13 June 2014; accepted 16 August 2014; published online 5 September 2014 Correspondence: Toru Nakazawa, Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. Tel: +81-22-717-7294. Fax: +81-22-717-7298. E-mail: [email protected]
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Topographical Correlation of OCT Macular Map 745 and/or functional progression in these patients. This poses a challenge, as NTG progresses more slowly than OAG or exfoliation glaucoma (EXG)7 and thus requires a more sensitive method of detecting progression. An additional challenge in tracking the progression of NTG is that it causes significantly more damage to the fixation point than other forms of glaucoma8,9, but the Humphrey field analyzer (HFA) 24-2 SITA program is less sensitive in this area. This is due to RGC redundancy and the small number of test points within the macular area. Another challenge is posed by myopia, one of the major risk factors for POAG.10 In NTG patients with myopia, the disc is tilted temporally, making temporal rim recognition and the evaluation of cupping very difficult. Furthermore, macular lesions are often present in NTG. As we have previously demonstrated, the myopic disc type is more common in patients with NTG11,12 and glaucoma patients with decreased visual acuity,13 when patients are classified by optic disc type according to Nicolela’s method.14,15 In Japan, there is a high prevalence of myopia, which is associated with a high prevalence of myopia in NTG patients. The overall prevalence of myopia (spherical equivalent 5 1 D) in the Japanese population is 41.8%, and of these, 8.2% have high myopia (spherical equivalent 5 5 D).16 By contrast, the prevalence of myopia in the United States, Western Europe, and Australia is approximately 16% to 27%, and the prevalence of high myopia is 2.8% to 4.5%.17,18 Overall, therefore, it is clear that macular evaluation is an increasingly important part of NTG management, especially in regions of the world where myopia and NTG are more common. These challenges in glaucoma assessment may best be met by new techniques relying on optical coherence tomography (OCT). This is a powerful tool that has seen an increasing role in routine examinations due to its well-established advantages in detecting early glaucoma compared to techniques such as fundus photography and HRT II. Recently, the development of spectral-domain (SD) OCT and improved segmentation algorithms has enabled us to separately measure and quantify each retinal layer in the macula. Quantifying the thickness of the macular retinal nerve fiber layer (mRNFL) and ganglion cell layer plus inner plexiform layer (mGCL + IPL) is especially helpful in the diagnosis of early glaucoma.19 Research based on layer segmentation has led to the understanding that glaucomatous damage to the macula is common even in the early stages of the disease.20 Additionally, Lisboa et al.21 found that circumpapillary RNFL thickness (cpRNFL) is also a good indicator of preperimetric glaucoma and suggested that it may be more accurate than OCT measurements of the ONH or macula. This may be due in part to the macula being less involved in the process of !
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glaucomatous damage than the cpRNFL. Nevertheless, parameters of the cpRNFL and the macula have both become routinely used as diagnostic instruments in glaucoma detection and follow-up, and both have useful roles. A greater understanding of the correlation between cpRNFL and topographical macular parameters, i.e. in different regions of the retina, would therefore be of significant clinical value. The purpose of this study was therefore to determine the topographical correlation of mRNFL and mGCL + IPL thickness to clockwise cpRNFL thickness in patients with NTG. Our results suggested that areas of high correlation closely coincided with the layout of the retinal nerve tract in patients with NTG.
MATERIALS AND METHODS Inclusion Criteria This was a retrospective, cross-sectional study including 101 eyes of 101 Japanese patients (mean age: 59.4 ± 14.7 years, 40 male and 61 female) with mild or moderate NTG (mean deviation (MD) measured with the HFA = 12.0 dB). The inclusion criteria were a diagnosis of NTG with untreated IOP less than 22 mmHg, spherical equivalent refractive error of 4 8.00 diopters (i.e. excluding patients with high myopia), and a glaucomatous visual field according to the Anderson-Patella classification. The exclusion criteria were (1) decimal VA 50.3, (2) the presence of macular disease such as premacular fibrosis, macular hole, and age-related macular degeneration, (3) concomitant ocular disease, (4) systemic disease affecting the visual field, and (5) cataract progression. The characteristics of the participants are listed in Table 1.
OCT Examination Topographical macular maps of the mRNFL, mGCL + IPL and cpRNFL were made with 3D OCT-2000 software (ver. 8.00, Topcon Corporation, Tokyo, Japan). The maps were derived from macular TABLE 1. Clinical data of patients included in this study. Sex male: female, n (%) Age (years) Spherical equivalent (D) VA (logMAR, Decimal) MDHFA24-2 (dB) IOP (mmHg) cpRNFLT (mm)
40(40%): 61(60%) 59.4 ± 14.7 2.9 ± 2.5 0.06 ± 0.10 (1.18 ± 0.23) 4.3 ± 3.1 13.5 ± 3.1 89.1 ± 12.5
VA, visual acuity; MD, mean deviation; HFA, Humphrey field analyzer; IOP, intraocular pressure; cpRNFL, circumpapillary retinal nerve fiber layer thickness.
746 K. Omodaka et al. cube scans of a 6 6 mm square area of the retina centered on the fovea, corresponding to the central 20 degrees of the macula. One hundred points from a 10 10 grid were used for the analysis. Scans were excluded if the image quality was less than 70 or if segmentation in the images was inaccurate. A swept-source OCT image (DRI OCT-1, 12 9 mm, EnView software, Topcon) that showed the anatomical trajectory of nerve fiber defects by flattening the inner limiting membrane (ILM) was also used. Macular areas comprised by points identified in our analysis as having a high correlation coefficient (40.4) were superimposed on this image to validate the correlation.
Statistical Analysis The correlation of cpRNFL thickness in each temporal clockwise sector (i.e. the 7, 8, 9, 10, and 11 o’clock sectors) to mRNFL and mGCL + IPL thickness in each grid point was determined with Spearman’s
rank correlation coefficient. Macular grid points were defined as highly correlated with clockwise cpRNFL sectors when the correlation coefficient was more than 0.4.
RESULTS Figure 1 shows the correlation coefficient for each mRNFL grid point to cpRNFL in the five temporal clockwise cpRNFL sectors. For each of the 7, 8, 10, and 11 o’clock sectors (shown in Figure 1A, B, D, and E, respectively), there was a corresponding contiguous arc-shaped area in which each mRNFL grid point had a high correlation coefficient (r = 0.4, p50.05). The arcshaped area with the highest correlation coefficient (r40.6) to the 9 o’clock sector was mainly 4–8 degrees superior and nasal to the fixation point (Figure 1C). The mRNFL area highly correlated to the 11 o’clock sector was located in the upper margin of the map. Reflecting the anatomical trajectory of the nerve fiber layer, the mRNFL areas correlated to the 7 and
FIGURE 1. The distribution of mRNFL grid points with a high correlation coefficient (40.4) to the clockwise cpRNFL sectors at 7, 8, 9, 10, and 11 o’clock (A, B, C, D, and E, respectively). Correlated points are highlighted in gray, with darker shades indicating a higher correlation coefficient. (F) Scatter blot graph showing the correlation between cpRNFL thickness and mRNFL thickness in the grid points with the highest correlation coefficients (r = 0.79, 9 rows from left and 10 rows from top, in Figure 1A). Current Eye Research
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FIGURE 2. The distribution of mGCL + IPL grid points with a high correlation coefficient (40.4) to the clockwise cpRNFL sectors at 7, 8, 9, 10, and 11 o’clock (A, B, C, D, and E, respectively). Correlated points are highlighted in gray, with darker shades indicating a higher correlation coefficient. (F) Scatter blot graph showing the correlation between cpRNFL thickness and mGCL + IPL thickness in the grid points with the highest correlation coefficients (r = 0.70, 5 rows from left and 2 rows from top, in Figure 2D).
8 o’clock sectors were located in the lower hemifield and the areas correlated to the 10 and 11 o’clock sectors were located in the upper hemifield. Respectively, 40, 41, 33, 39, and 18 mRNFL grid points were highly correlated to the 7, 8, 9, 10, and 11 o’clock cpRNFL sectors (r = 0.40–0.79). Figure 1(F) shows a scatter blot graph indicating the correlation between cpRNFL thickness and mRNFL thickness in the grid points with the highest correlation coefficients (r = 0.79, 9 rows from left and 10 rows from top, in Figure 1A). Figure 2 shows the correlation coefficient for each grid point from the mGCL + IPL scan to the five temporal clockwise cpRNFL sectors. Once again, the grid points with a high correlation coefficient (r = 0.4, p50.05) to the 7, 8, 10, and 11 o’clock sectors (Figure 2A, B, D, and E, respectively) had a contiguous arc-shaped pattern. The area with the highest coefficient correlation (r40.6) to the 9 o’clock sector was mainly located 2–8 degrees superior to the fixation point (Figure 2C). The areas most !
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highly correlated to the 7 and 8 o’clock sectors overlapped and were within 6 degrees below the fixation point (Figure 2A and B). Respectively, 18, 22, 44, 39, and 19 mGCL + IPL grid points were highly correlated to the 7, 8, 9, 10, and 11 o’clock cpRNFL sectors (r = 0.40–0.70). Figure 2(F) shows a scatter blot graph indicating the correlation between cpRNFL thickness and mGCL + IPL thickness in the grid points with the highest correlation coefficients (r = 0.70, 5 rows from left and 2 rows from top, in Figure 2D). To confirm that the statistical analysis of correlated areas matched real RNFL defects, mRNFL and mGCL + IPL grids with the correlated points highlighted were superimposed onto DRI-OCT images of RNFL defects (Figure 3). The highly correlated mRNFL areas closely matched the RNFL defects visible in the OCT image (Figure 3). However, the mGCL + IPL areas (Figure 2) tend to be located closer to the fovea than the observed RNFL defects, and overall, were not closely matched.
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FIGURE 3. Macular maps with correlated areas highlighted superimposed onto an OCT image showing RNFL defects. The underlying OCT image was corrected in EnView software by flattening it with relative to the inner limiting membrane (ILM).
DISCUSSION In this study, we investigated the regional topographical correlation between OCT measurements of retinal thickness in a grid of test points in the macula in the mRNFL and mGCL + IPL and in clockwise sectors in
the temporal cpRNFL (at 7–11 o’clock) in patients with NTG. We identified distinctive arc-shaped areas in the mRNFL that were highly correlated to corresponding cpRNFL sectors. Moreover, these areas corresponded to observable defects in the retinal nerve tract. In addition, we identified areas of the mGCL + IPL Current Eye Research
Topographical Correlation of OCT Macular Map 749 that were highly correlated to clockwise sectors of the cpRNFL, and found that they were distinct from the mRNFL areas. The focus of our investigation was the structural relationship between the cpRNFL and macula, which we examined with a statistical analysis of OCT measurements of these two areas. In a previous study of NTG patients, Garway-Heath et al. established the anatomical relationship between regional visual field sensitivity, measured with the HFA 24-2 program, and RNFL defects in the optic nerve head, identified with fundus photography.22 In another study of eyes with glaucoma, Kanamori et al. examined in detail the regional relationship between OCT-measured RNFL thickness and visual field sensitivity.23 These past studies suggest that the prospects for study might have included a comparison of regional visual field sensitivity measured with the HFA 10-2 program and OCT macular maps. However, such a method of quantifying the relationship between structure and function in the macula has a number of important disadvantages, which are related to the phenomena of RGC redundancy24 and RGC displacement25 in the macula. Our comparison of the anatomical relationship between the macular and disc areas, in which we compared the OCT-measured thickness of the cpRNFL and in the macular map, minimized these biases. We found that the areas of high correlation in the mRNFL were horizontally asymmetrical (as can be seen by comparing Figure 1A and E or B and D). Specifically, the lower areas of high correlation (7 and 8 o’clock) were relatively closer to the macula than the upper sectors (10 and 11 o’clock). This asymmetrical distribution is consistent with previous reports.22,23 The location of the macula is inferior to the horizontal line and the anatomical trajectory of the retinal nerve fibers is therefore naturally asymmetrical.20 Furthermore, the map of corresponding locations in the retina and optic nerve head is influenced by axial length26 and, in this study, average spherical equivalence was 2.9 ± 2.5 D. Therefore, the high number of myopic patients in this study also likely contributed to the clearly asymmetrical shape of the correlated areas we observed. Interestingly, the areas of high correlation in the mRNFL and mGCL + IPL did not completely overlap, with the mGCL + IPL areas being closer to the macula. The RGC displacement25, a phenomenon that has previously been demonstrated in the macula, is an insufficient explanation. RGC displacement exists within 7.2 degrees of the macula and arises from the anatomical offset of RGCs from the photoreceptors that provide their input. Taking into account the projection of the retinal nerve fibers from the cell bodies, this implies that near the optic nerve head, the mRNFL should undergo damage over a wider area than the mGCL + IPL. However, while our results for !
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the 9 o’clock sector are consistent with these theoretical wider damages in mRNFL, the discrepancies in the other sectors are not. An alternative explanation is that statistical limitations related to the structure of the mGCL + IPL led to high correlation values near the fovea. The mGCL + IPL is thicker in this area than in the periphery, and furthermore, the range of variation in the peripheral mGCL + IPL is small. Areas of the mGCL + IPL outside the central 7.2 degrees of the macula with near-normal sensitivity do not markedly differ in thickness with areas of the GCL + IPL with severe visual loss.27 Thus, the discrepancies we found between the mRNFL and mGCL + IPL in the areas that were correlated to sectoral cpRNFL thickness may be considered unsurprising. Although fundus photography allows us to readily identify the location of RNFL defects, defects in the mGCL + IPL are harder to see. This study is therefore the first to describe a method of identifying mGCL + IPL structural areas, by determining which areas are most highly correlated to the cpRNFL. The thresholds from visual field testing should also reflect in situ damage to the RGCs (in the GCL + IPL) but they are believed to be independent of the thickness of the overlying retinal nerve fibers, which comprise the RNFL. Moreover, the information we have revealed on this displacement may assist clinicians to interpret OCT results from the macula. The OCT evaluation for central area of the macula is important for good visual acuity. We found that the areas in the mRNFL and mGCL + IPL correlated to the 9 o’clock cpRNFL sector were shifted to the upper area of the macular map, as we had expected (Figures 1C and 2C). In particular, the correlation coefficient in the central four grid points was not high. This may be due to the thinness of the mRNFL and mGCL + IPL in these central 4 degrees, in addition to the effect of RGC displacement.25 It may therefore improve the accuracy of the results to exclude these grid points from the examination. We previously reported that the NTG patients with decreased visual acuity often had decreased tissue blood flow (represented by filling defects) in the temporal optic disc.13 Recently, NTG patients with stronger fluctuations in ocular perfusion pressure (OPP) have been shown to have more significant progression of visual field loss in the central 10 degrees.28,29 Thus, it is important to develop new OCT methods of screening for glaucomatous damage in the macula caused by abnormal blood flow. The main finding of this study was the identification of important areas of the macula associated with areas of the optic disc, made by performing a statistical analysis of clockwise sectors of the cpRNFL and a grid of measurement points in the macula. These areas of the macula may help to diagnose glaucoma and to detect glaucoma progression, and may be most useful in a cluster analysis.
750 K. Omodaka et al. Recently, Kanamori et al.30 showed that analyzing abnormal OCT parameters in clusters of grid points in the macula was a reliable method of diagnosing early glaucoma. Thus, accurate information on the relationship between these grid points and the anatomical trajectory of the nerve fibers would be valuable addition to future strategies using macular maps to diagnose glaucoma and identify its structural progression, and should increase their sensitivity and specificity to glaucoma. This study had several limitations. First, the sample size was relatively small, affecting its statistical power to detect significant differences. Second, glaucoma is a heterogeneous disease, and aging or other indices, such as myopia and glaucoma stage, may have affected our results. To decrease the influence of these factors, we excluded glaucoma patients with high myopia (less than 8 diopter) or advanced glaucoma (MD 5 12 dB). Third, glaucoma patients with focal damage outside the macular area were outside the scope of this evaluation method. In conclusion, the macular areas identified here, and their differing characteristics in the mRNFL and mGCL + IPL, may help to increase the accuracy of clinical assessments of NTG, the major type of glaucoma in Asia.
ACKNOWLEDGEMENTS The authors thank Mr. Tim Hilts for editing this article and Dr. Masahiro Akiba for useful discussion.
DECLARATION OF INTEREST No authors have any financial disclosures. The authors report no conflict of interest. This article was supported in part by JST grant, JSPS KAKENHI Grant-in-Aid for Scientific Research (B), (T.N. 26293372), for Exploratory Research (T.N. 26670751), and by JST Center for Revitalization Promotion.
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