Int Ophthalmol DOI 10.1007/s10792-014-9988-7
ORIGINAL PAPER
Correlation between the ganglion cell complex and structural measures of the optic disc and retinal nerve fiber layer in glaucoma Erica Bresciani-Battilana • Ivan C. Teixeira • Diego T. Q. Barbosa • Cristiano Caixeta-Umbelino • Maurı´cio D. Paolera • Niro Kasahara
Received: 25 December 2013 / Accepted: 8 August 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To correlate the ganglion cell complex (GCC) parameters with structural measures of the optic nerve head (ONH) and retinal nerve fiber layer (RNFL) as evaluated by Fourier-Domain optic coherence tomography (OCT). This retrospective study included patients with glaucoma, ocular hypertensive patients and glaucoma suspects who had previously undergone OCT examination with the RTVue-100. The parameters of GCC (average, superior, inferior, focal loss volume [FLV], global loss volume [GLV]) were correlated with the values of the ONH (cup volume, cup area, horizontal cup-to-disk ratio, vertical cup-to-disk ratio, and rim area) and RNFL (average, superior, and inferior) using Pearson’s correlation coefficient. The sample included 74 eyes of 37 patients. All correlations between GCC parameters and RNFL were strong (r [ 0.60). The correlation between GCC parameters and ONH were good for most parameters, except that for FLV and cup volume (r = 0.13), GLV and cup volume (r = 0.09),
Presented at the 10th European Glaucoma Society Congress, Copenhagen on June 17–22, 2012. E. Bresciani-Battilana I. C. Teixeira D. T. Q. Barbosa C. Caixeta-Umbelino M. D. Paolera N. Kasahara (&) Department of Ophthalmology, Irmandade da Santa Casa de Misericordia de Sao Paulo, Santa Casa de Sao Paulo School of Medical Sciences, Rua Sao Mauro, 292, Sao Paulo, SP 02526-050, Brazil e-mail: [email protected]; [email protected]
and GLV and cup area (r = 0.21). The GCC parameters can be used as structural measures of the glaucomatous optic neuropathy. Keywords Glaucoma Optic disk Retinal nerve fiber layer Ganglion cell complex
Introduction Primary open angle glaucoma (POAG) is a multifactorial optic neuropathy characterized by a progressive loss of retinal ganglion cells leading to irreversible visual impairment. Structural evaluation of the optic nerve head (ONH) and the retinal nerve fiber layer (RNFL) are surrogates of glaucoma evaluation and commonly used in clinical practice. Reports have suggested that macular thickness assessment could be a valuable measure of glaucomatous structural change, because glaucoma damage affects retinal ganglion cells, which are densely present in the macular region [1–3]. The ganglion cell complex (GCC) is a measure of the retinal ganglion cells in the macular region assessed by the Fourier-domain optic coherence tomography (OCT). The GCC encompasses three layers in the retina, the retinal nerve fiber layer made of the ganglion cell axons, the ganglion cell layer made of the ganglion cell bodies, and the inner-plexiform layer made of the ganglion cell dendrites. It has good diagnostic value to detect glaucoma and to differentiate between normal and glaucoma subjects [4–18].
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Apart from the diagnostic accuracy, little is known about the correlation between the GCC and other structural measurements used in glaucoma evaluation. Hence, the purpose of this study was to assess the correlation between the GCC parameters with structural measures of the ONH and the RNFL as evaluated by Fourier-domain OCT.
white, 8 were African Brazilian, 13 were mulatto and one was Asian. Mean age was 57.3 ± 10.1 years. Best corrected visual acuity was 20/20 on both eyes in all subjects. Fundus examination revealed no macular disease in all patients. Table 1 displays the demographic characteristic of the sample stratified by groups (glaucoma patients, suspects, and ocular hypertensives).
Materials and methods
Fourier-domain optic coherence tomography
Study population
The GCC images were retrieved from the RTVue-100 OCT (software version A4, 0, 5, 46; Optovue Inc, Freemont, CA) hard drive. The OCT image is acquired on a very fast rate (26,000 A-scan/second), with a frame rate of 256–4,096 A-scan/frame, and provides high tissue resolution (depth resolution of 5.0 lm and transverse resolution of 15 lm). The acquisition of images was done previously by a technician following standard procedure. After pharmacologic dilation, retinal ganglion cells in the macular region were assessed using the GCC scan protocol (MM7). Optic nerve head analysis and peripapillar RNFL thickness were measured employing the NHM4 (Nerve head map 4 mm diameter) scanning mode. The GCC scan covered a 7 9 7 mm scan area centered on the fovea. The NHM4 provides quantitative data on the optic disc rim and cup and measures RNFL thickness by recalculating data along a circle 3.45 mm in diameter around the optic disc, guided by a map created from en face imaging of 6 circular and 12 linear data inputs. Images with signal strength index (SSI) less than 40 or with overt misalignment of the surface detection algorithm on at least 10 % of consecutive A-scans or 15 % of cumulative A-scans or with overt decentration of the measurement circle location were excluded from the analysis.
This retrospective study included both patients with POAG and suspects older than 40 years of age of both genders, with 20/20 best corrected visual acuity, and any ethnicity. Subjects with cataracts or any other ocular disease and previous incision or laser surgery for glaucoma were not included in the study. Institution Board Review approved the study and the procedures followed adhered to the principles for medical research involving human subjects of the Declaration of Helsinki in 1964 (amended by the 59th WMA General Assembly, Seoul, Korea, October 2008). The charts of all eligible subjects were reviewed in order to verify if they fulfilled the inclusion criteria and all data for the study extracted by one of us. In order to be included in the study, POAG patients had to have typical optic disc damage (diffuse or localized rim thinning, enlarged cupping, disc hemorrhage, asymmetry in cup-to disc ratio 0.2 or greater between eyes) with corresponding visual field loss on a reliable perimetry exam (at least 3 adjacent points in an expected location of the central 24° field that have P \ 5 % on the pattern deviation plot, one of which with P \ 1 %; glaucoma hemifield test ‘‘outside normal limits’’; PSD with a P \ 5 %), intraocular pressure (IOP) higher than 21 mmHg (at the time of diagnosis on no medication) and open angles on gonioscopy. A reliable perimetry was an exam with less than 20 % fixation loss, and less than 33 % of both false negative and false positive. Glaucoma suspects comprised subjects with suspicious looking optic discs and normal visual fields as well as ocular hypertensive patients (IOP greater than 21 mmHg without typical optic disc damage). Thirty-seven subjects providing a sample of 74 eyes enrolled the study. Twenty-five patients were female (67.6 %) and 12 male (32.4 %). Fifteen patients were
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Statistical analysis Differences among the three groups were compared with the Fisher Exact test for categorical variables and the one-way analysis of variance (ANOVA) test for continuous variables. Pearson’s product moment correlation coefficients with 95 % confidence intervals (95 % CI) were calculated to quantify the linear relationship between the GCC parameters (average, superior, inferior, GLV [global loss volume], and FLV
Int Ophthalmol Table 1 Demographic characteristics of the sample
Variable
Glaucoma (n = 15)
Suspects (n = 12)
Ocular hypertensives (n = 10)
P value
Age
62.5 ± 9.2
M:F
5:10
51.8 ± 10.2
56.9 ± 8.9
0.020
4:8
3:7
0.874
white
7
3
5
black
3
4
1
mixed
4
5
4
asian
1
0
0
Ethnicity
0.503
Mean IOP OD 18.3 ± 2.1
14.5 ± 3.2
24.6 ± 2.8
0.219
19.2 ± 2.9
14.1 ± 3.4
25.1 ± 2.5
0.906
OD
0.8
0.6
0.3
0.000
OS
0.8
0.7
0.3
0.000
OS Median CD
Mean MD M male; F female; IOP intraocular pressure; CD cup-to-disc ratio; MD mean deviation: PSD pattern standard deviation; OD right eye; OS left eye
Table 2 Comparison of the ganglion cell complex parameters amongst groups
GCC ganglion cell complex; FLV focal loss volume; GLV global loss volume
OD
-7.8 ± 2.7
-1.7 ± 0.5
-0.2 ± 0.1
0.020
OS
-7.3 ± 2.6
-1.9 ± 0.6
-0.3 ± 0.1
0.008
Mean PSD OD
5.3 ± 2.2
2.1 ± 0.4
1.2 ± 0.6
0.449
OS
5.4 ± 2.6
2.5 ± 0.5
1.4 ± 0.7
0.893
GCC parameters
Glaucoma (n = 30 eyes)
Suspects (n = 24 eyes)
Ocular hypertensives (n = 20 eyes)
P value
GCC average
72.7 ± 11.4
89.2 ± 2.3
98.3 ± 3.7
0.911
GCC superior
73.2 ± 10.7
89.2 ± 2.7
99.7 ± 7.3
0.713
GCC inferior FLV
72.2 ± 12.7 5.5 ± 4.3
89.0 ± 3.0 0.7 ± 0.2
97.2 ± 5.1 0.1 ± 0.1
0.000 0.000
GLV
18.8 ± 12.6
6.0 ± 4.4
5.1 ± 3.7
0.645
[focal loss volume]) with ONH parameters (rim area, vertical cup-to-disc ratio, horizontal cup-to-disc ratio, cup area, and cup volume) and peripapillar RNFL measures (average RNFL, superior average and inferior average). We have selected those parameters with corresponding locations in the eye anatomy, e.g. superior GCC with superior RNFL, average GCC with average RNFL and so on. Statistical significance was set at P \ 0.05 and all analyses were done with MedCalcÒ software, version 9.3.7.0 (MedCalc Software bvba, Belgium).
respectively, stratified by group (glaucoma patients, suspects and ocular hypertensives). The correlation between GCC parameters and the RNFL measurements are depicted on Table 5. All correlations were good and achieved statistical significance. Table 6 displays the correlation between GCC parameters and the ONH measurements. Except for the correlation between FLV and cup volume (P = 0.251), GLV and cup volume (P = 0.418), and GLV and cup area (P = 0.06), all correlations were good.
Results
Discussion
Tables 2, 3, and 4 show raw data for GCC parameters, RNFL parameters, and ONH measurements,
The results of this study revealed that most of GCC parameters have a strong correlation both with ONH
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Int Ophthalmol Table 3 Comparison of the retinal nerve fiber layer (RNFL) measurements amongst groups
RNFL parameter
Glaucoma (n = 30 eyes)
Suspects (n = 24 eyes)
Ocular hypertensives (n = 20 eyes)
P value
RNFL average
74.7 ± 10.9
98.9 ± 3.4
113.3 ± 7.6
0.009
RNFL superior
75.0 ± 12.2
99.4 ± 4.7
114.1 ± 11.5
0.030
RNLF retinal nerve fiber layer
RNFL inferior
74.4 ± 10.7
98.4 ± 6.4
112.6 ± 7.3
0.908
Table 4 Comparison of the optic nerve head measurements amongst groups
ONH parameters
Glaucoma (n = 30 eyes)
Suspects (n = 24 eyes)
Ocular hypertensives (n = 20 eyes)
P value
ONH optic nerve head; CD cup-to-disc ratio
Cup volume
0.5 ± 0.2
0.3 ± 0.1
0.0 ± 0.0
0.000
Horizontal CD
0.9 ± 0.0
0.7 ± 0.0
0.3 ± 0.1
0.000
Vertical CD Rim area
0.8 ± 0.1 0.4 ± 0.2
0.7 ± 0.1 0.8 ± 0.0
0.4 ± 0.2 1.5 ± 0.3
0.000 0.000
Cup area
1.7 ± 0.3
0.9 ± 0.1
0.2 ± 0.1
0.000
Table 5 Correlation between the ganglion cell complex parameters and the retinal nerve fiber layer measurements r Avg and RNFL_avg
95 % CI 0.813
0.718 to 0.878
Table 6 Correlation between the ganglion cell complex parameters and optic nerve head measurements
P value
r
0.000
FLV and cup vol
0.135
95 % CI
P value
-0.096 to 0.352
0.251
Sup and RNFL_sup
0.745
0.622 to 0.832
0.000
FLV and cup area
0.311
0.089 to 0.504
0.006
Inf and RNFL_inf
0.824
0.734 to 0.886
0.000
GLV and cup vol
0.095
-0.135 to 0.317
0.418
FLV and RNFL_avg
-0.685
-0.790 to -0.542
0.000
GLV and cup area
0.219
-0.009 to 0.426
0.060
GLV and RNFL_avg
-0.848
-0.902 to -0.769
0.000
FLV and CD hor
0.265
0.039 to 0.465
0.022
FLV and CD ver
0.402
0.191 to 0.577
0.0004
GLV and CD hor
0.267
0.041 to 0.467
0.021
GLV and CD ver
0.419
0.211 to 0.591
0.0002
Avg and CD hor Avg and CD ver
-0.262 -0.402
-0.463 to -0.036 -0.577 to -0.191
0.023 0.0004
Avg average; Sup superior; Inf inferior; FLV focal loss volume; GLV global loss volume; RNFL retinal nerve fiber layer; 95 % CI 95 % confidence interval
and RNFL measurements. We have decided to correlate GCC parameters with those of ONH and RNFL that would most closely match the anatomic relationship between them, e.g., the superior GCC with the superior RNFL and the average GCC with ONH rim area. The correlation with inferior GCC and superior RNFL would most probably reveal no correlation. Even though, some parameters did not show correlation; there was a trend towards correlation between GCC GLV and ONH cup area that fail to reach statistical significance. We found no correlation between GCC GLV and FLV with ONH cup volume. GLV and FLV are parameters that provide quantitative measures for the amount of significant GCC loss [19]. GLV measures the average amount of GCC loss over the entire GCC map whereas FLV measures the average amount of focal loss over the entire GCC map. FLV detects focal loss using a pattern deviation map to
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Avg and rim area
0.583
0.409 to 0.716
0.0000
FLV and rim area
-0.374
-0.555 to -0.159
0.001
GLV and rim area
-0.539
-0.683 to -0.354
0.0001
FLV focal loss volume; GLV global loss volume; Avg average; vol volume; CD cup-to-disc ratio; hor horizontal; ver vertical; 95 % CI: 95 % confidence interval
correct for overall absolute changes and will best detect local ganglion cell loss. On the other hand, GLV will best detect diffuse ganglion cell loss. Tan et al. have found that both FLV and GLV are better than average GCC thickness to differentiate normal from glaucomatous eyes [19]. The optic disc cup is a central depression in the optic nerve head devoid of neuroretinal tissue. In glaucoma neuropathy, the loss of retinal ganglion cells leads to enlargement of the cup and, at the same time, posterior bowing of the lamina cribrosa
Int Ophthalmol
which is unrelated to cell loss, renders the cup to become deeper. Hence, cup volume is a component of the structural measurement that is not related to ganglion cells number only and, to some extent, explains the lack of correlation with GLV and FLV in this study. We have found a strong correlation between GCC and RNFL parameters. The GCC parameters are obtained with the MM7 protocol centered 1 mm temporal to the fovea. It uses one horizontal line with a 7 mm scan length (934 A scans) followed by 15 vertical lines with a 7 mm scan length and 0.5 mm interval (800 A scans). The GCC thickness is measured from the internal limiting membrane to the inner plexiform layer boundary. In this study, the RNFL thickness was determined by the nerve head map 4 mm diameter (NHM4) mode, which measures RNFL thickness by recalculating data along a 3.45 mm diameter circle around the optic disc using a map created from en face imaging utilizing six circular scans ranging from 2.5 to 4.0 mm in diameter (587 or 775 A scans each) and 12 linear data inputs (3.4 mm length, 452 A scans each). They essentially measure the same tissue thickness using the same technology in different locations. The superior GCC is a measure of the RNFL located at the superior aspect of the tissue in the macula area, whereas the RNFLsuperior is a measure of the tissue in the superior aspect of the peripapillary ring. Hence, a strong correlation between them might have been anticipated. GCC is probably advantageous over RNFL in that the former is able to detect pre-perimetric glaucoma specially GLV and FLV parameters [13]. The GCC analysis adds another important piece of structural information for a full glaucoma evaluation. Previous studies had suggested that imaging of the macula for glaucoma was promising [1–3]. These studies, however, used a time domain OCT, which has a slower scan speed as compared to the Fourierdomain OCT (400 A scans/sec for the Time Domain and 26000 A scans/sec for Fourier-domain) and a lower depth resolution (10 micron depth resolution for time-domain as compared 5 micron resolution for Fourier-domain). The limited depth resolution for the time domain OCT allowed only for measurement of full macula thickness and was not able to differentiate specific layers. Conversely, the Fourier-domain OCT allows for specific segmentation of tissue structures and only the retinal layers associated with the ganglion
cells can be evaluated. This segmentation method of the ganglion cell complex targets the layers directly associated with the ganglion cells. This study has some shortcomings. The sample size was relatively small and we have used both eyes of the same patient. That was done in order to increase the analysis power. Besides the sample included a heterogeneous group of glaucoma patients, ocular hypertensive and glaucoma suspects who were not evenly distributed. In glaucoma, ONH parameters and RNFL measurements are clinically used for diagnosis, staging and monitoring disease so that, assuming that GCC has displayed a strong correlation with both ONH parameters and RNFL measurements in this study, we believe that GCC parameters can be used as an additional structural parameter in the management of glaucoma. However, more studies with larger cohorts of patients are necessary to support the use of GCC parameters in the evaluation of glaucoma patients. Acknowledgments submission.
No financial support was received for this
Conflict of interest None of the authors has conflict of interest with the submission.
References 1. Wollstein G, Ishikawa H, Wang J et al (2005) Comparison of three optical coherence tomography scanning areas for detection of glaucomatous damage. Am J Ophthalmol 139:39–43 2. Medeiros FA, Zangwill LM, Bowd C et al (2005) Evaluation of retinal nerve fiber layer, optic nerve head, and macular thickness measurements for glaucoma detection using optical coherence tomography. Am J Ophthalmol 139:44–55 3. Ishikawa H, Stein DM, Wollstein G et al (2005) Macular segmentation with optical coherence tomography. Invest Ophthalmol Vis Sci 46:2012–2017 4. Kim NR, Lee ES, Seong GJ et al (2010) Structure-function relationship and diagnostic value of macular ganglion cell complex measurement using Fourier-Domain OCT in glaucoma. Invest Ophthalmol Vis Sci 51:4646–4651 5. Mori S, Hangai M, Sakamoto A, Yoshimura N (2010) Spectral-domain optical coherence tomography measurement of macular volume for diagnosing glaucoma. J Glaucoma 19:528–534 6. Garas A, Vargha P, Hollo G (2011) Diagnostic accuracy of nerve fiber layer, macular thickness and optic disc measurements made with the RTVue-100 optical coherence tomography to detect glaucoma. Eye 25:57–65
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Int Ophthalmol 7. Takagi ST, Kita Y, Yagi F, Tomita G (2011) Macular retinal ganglion cell complex damage in the apparently normal visual field of glaucomatous eyes with hemifield defects. J Glaucoma 21:318–325 8. Kita Y, Kita R, Nitta A et al (2011) Glaucomatous eye macular ganglion cell complex thickness and its relation to temporal circumpapillary retinal nerve fiber layer thickness. Jp J Ophthalmol 55:228–234 9. Kim NR, Hong S, Kim JH et al (2013) Comparison of macular ganglion cell complex thickness by FourierDomain OCT in normal tension glaucoma and primary open-angle glaucoma. J Glaucoma 22:133–139 10. Sevim MS, Buttanri B, Acar BT et al (2013) Ability of Fourier-domain optical coherence tomography to detect retinal ganglion cell complex atrophy in glaucoma patients. J Glaucoma 22:542–549 11. Schulze A, Lamparter J, Pfeiffer N et al (2011) Diagnostic ability of retinal ganglion cell complex, retinal nerve fiber layer, and optic nerve head measurements by Fourierdomain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 249:1039–1045 12. Chen J, Huang H, Wang M et al (2012) Fourier domain OCT measurement of macular, macular ganglion cell complex, and peripapillary RNFL thickness in glaucomatous Chinese eyes. Eur J Ophthalmol 22:972–979 13. Arintawati P, Sone T, Akita T et al (2013) The applicability of ganglion cell complex parameters determined from SD-
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OCT images to detect glaucomatous eyes. J Glaucoma 22:713–718 Kita Y, Kita R, Takeyama A et al (2013) Ability of optical coherence tomography-determined ganglion cell complex thickness to total retinal thickness ratio to diagnose glaucoma. J Glaucoma 22:757–762 Morooka S, Hangai M, Nukada M et al (2012) Wide 3-dimensional macular ganglion cell complex imaging with spectral-domain optical coherence tomography in glaucoma. Invest Ophthalmol Vis Sci 53:4805–4812 Na JH, Kook MS, Lee Y, Baek S (2012) Structure-function relationship of the macular visual field sensitivity and the ganglion cell complex thickness in glaucoma. Invest Ophthalmol Vis Sci 53:5044–5051 Firat PG, Doganay S, Demirel EE, Colak C (2013) Comparison of ganglion cell and retinal nerve fiber layer thickness in primary open-angle glaucoma and normal tension glaucoma with spectral-domain OCT. Graefes Arch Clin Exp 251:831–838 Sung MS, Kang BW, Kim HG et al (2013) Clinical validity of macular ganglion cell complex by spectral domainoptical coherence tomography in advanced glaucoma. J Glaucoma. doi:10.1097/IJG.0b013e318279c932 Tan O, Chopra V, Lu ATH et al (2009) Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography. Ophthalmology 116:2305–2314
ORIGINAL PAPER
Correlation between the ganglion cell complex and structural measures of the optic disc and retinal nerve fiber layer in glaucoma Erica Bresciani-Battilana • Ivan C. Teixeira • Diego T. Q. Barbosa • Cristiano Caixeta-Umbelino • Maurı´cio D. Paolera • Niro Kasahara
Received: 25 December 2013 / Accepted: 8 August 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To correlate the ganglion cell complex (GCC) parameters with structural measures of the optic nerve head (ONH) and retinal nerve fiber layer (RNFL) as evaluated by Fourier-Domain optic coherence tomography (OCT). This retrospective study included patients with glaucoma, ocular hypertensive patients and glaucoma suspects who had previously undergone OCT examination with the RTVue-100. The parameters of GCC (average, superior, inferior, focal loss volume [FLV], global loss volume [GLV]) were correlated with the values of the ONH (cup volume, cup area, horizontal cup-to-disk ratio, vertical cup-to-disk ratio, and rim area) and RNFL (average, superior, and inferior) using Pearson’s correlation coefficient. The sample included 74 eyes of 37 patients. All correlations between GCC parameters and RNFL were strong (r [ 0.60). The correlation between GCC parameters and ONH were good for most parameters, except that for FLV and cup volume (r = 0.13), GLV and cup volume (r = 0.09),
Presented at the 10th European Glaucoma Society Congress, Copenhagen on June 17–22, 2012. E. Bresciani-Battilana I. C. Teixeira D. T. Q. Barbosa C. Caixeta-Umbelino M. D. Paolera N. Kasahara (&) Department of Ophthalmology, Irmandade da Santa Casa de Misericordia de Sao Paulo, Santa Casa de Sao Paulo School of Medical Sciences, Rua Sao Mauro, 292, Sao Paulo, SP 02526-050, Brazil e-mail: [email protected]; [email protected]
and GLV and cup area (r = 0.21). The GCC parameters can be used as structural measures of the glaucomatous optic neuropathy. Keywords Glaucoma Optic disk Retinal nerve fiber layer Ganglion cell complex
Introduction Primary open angle glaucoma (POAG) is a multifactorial optic neuropathy characterized by a progressive loss of retinal ganglion cells leading to irreversible visual impairment. Structural evaluation of the optic nerve head (ONH) and the retinal nerve fiber layer (RNFL) are surrogates of glaucoma evaluation and commonly used in clinical practice. Reports have suggested that macular thickness assessment could be a valuable measure of glaucomatous structural change, because glaucoma damage affects retinal ganglion cells, which are densely present in the macular region [1–3]. The ganglion cell complex (GCC) is a measure of the retinal ganglion cells in the macular region assessed by the Fourier-domain optic coherence tomography (OCT). The GCC encompasses three layers in the retina, the retinal nerve fiber layer made of the ganglion cell axons, the ganglion cell layer made of the ganglion cell bodies, and the inner-plexiform layer made of the ganglion cell dendrites. It has good diagnostic value to detect glaucoma and to differentiate between normal and glaucoma subjects [4–18].
123
Int Ophthalmol
Apart from the diagnostic accuracy, little is known about the correlation between the GCC and other structural measurements used in glaucoma evaluation. Hence, the purpose of this study was to assess the correlation between the GCC parameters with structural measures of the ONH and the RNFL as evaluated by Fourier-domain OCT.
white, 8 were African Brazilian, 13 were mulatto and one was Asian. Mean age was 57.3 ± 10.1 years. Best corrected visual acuity was 20/20 on both eyes in all subjects. Fundus examination revealed no macular disease in all patients. Table 1 displays the demographic characteristic of the sample stratified by groups (glaucoma patients, suspects, and ocular hypertensives).
Materials and methods
Fourier-domain optic coherence tomography
Study population
The GCC images were retrieved from the RTVue-100 OCT (software version A4, 0, 5, 46; Optovue Inc, Freemont, CA) hard drive. The OCT image is acquired on a very fast rate (26,000 A-scan/second), with a frame rate of 256–4,096 A-scan/frame, and provides high tissue resolution (depth resolution of 5.0 lm and transverse resolution of 15 lm). The acquisition of images was done previously by a technician following standard procedure. After pharmacologic dilation, retinal ganglion cells in the macular region were assessed using the GCC scan protocol (MM7). Optic nerve head analysis and peripapillar RNFL thickness were measured employing the NHM4 (Nerve head map 4 mm diameter) scanning mode. The GCC scan covered a 7 9 7 mm scan area centered on the fovea. The NHM4 provides quantitative data on the optic disc rim and cup and measures RNFL thickness by recalculating data along a circle 3.45 mm in diameter around the optic disc, guided by a map created from en face imaging of 6 circular and 12 linear data inputs. Images with signal strength index (SSI) less than 40 or with overt misalignment of the surface detection algorithm on at least 10 % of consecutive A-scans or 15 % of cumulative A-scans or with overt decentration of the measurement circle location were excluded from the analysis.
This retrospective study included both patients with POAG and suspects older than 40 years of age of both genders, with 20/20 best corrected visual acuity, and any ethnicity. Subjects with cataracts or any other ocular disease and previous incision or laser surgery for glaucoma were not included in the study. Institution Board Review approved the study and the procedures followed adhered to the principles for medical research involving human subjects of the Declaration of Helsinki in 1964 (amended by the 59th WMA General Assembly, Seoul, Korea, October 2008). The charts of all eligible subjects were reviewed in order to verify if they fulfilled the inclusion criteria and all data for the study extracted by one of us. In order to be included in the study, POAG patients had to have typical optic disc damage (diffuse or localized rim thinning, enlarged cupping, disc hemorrhage, asymmetry in cup-to disc ratio 0.2 or greater between eyes) with corresponding visual field loss on a reliable perimetry exam (at least 3 adjacent points in an expected location of the central 24° field that have P \ 5 % on the pattern deviation plot, one of which with P \ 1 %; glaucoma hemifield test ‘‘outside normal limits’’; PSD with a P \ 5 %), intraocular pressure (IOP) higher than 21 mmHg (at the time of diagnosis on no medication) and open angles on gonioscopy. A reliable perimetry was an exam with less than 20 % fixation loss, and less than 33 % of both false negative and false positive. Glaucoma suspects comprised subjects with suspicious looking optic discs and normal visual fields as well as ocular hypertensive patients (IOP greater than 21 mmHg without typical optic disc damage). Thirty-seven subjects providing a sample of 74 eyes enrolled the study. Twenty-five patients were female (67.6 %) and 12 male (32.4 %). Fifteen patients were
123
Statistical analysis Differences among the three groups were compared with the Fisher Exact test for categorical variables and the one-way analysis of variance (ANOVA) test for continuous variables. Pearson’s product moment correlation coefficients with 95 % confidence intervals (95 % CI) were calculated to quantify the linear relationship between the GCC parameters (average, superior, inferior, GLV [global loss volume], and FLV
Int Ophthalmol Table 1 Demographic characteristics of the sample
Variable
Glaucoma (n = 15)
Suspects (n = 12)
Ocular hypertensives (n = 10)
P value
Age
62.5 ± 9.2
M:F
5:10
51.8 ± 10.2
56.9 ± 8.9
0.020
4:8
3:7
0.874
white
7
3
5
black
3
4
1
mixed
4
5
4
asian
1
0
0
Ethnicity
0.503
Mean IOP OD 18.3 ± 2.1
14.5 ± 3.2
24.6 ± 2.8
0.219
19.2 ± 2.9
14.1 ± 3.4
25.1 ± 2.5
0.906
OD
0.8
0.6
0.3
0.000
OS
0.8
0.7
0.3
0.000
OS Median CD
Mean MD M male; F female; IOP intraocular pressure; CD cup-to-disc ratio; MD mean deviation: PSD pattern standard deviation; OD right eye; OS left eye
Table 2 Comparison of the ganglion cell complex parameters amongst groups
GCC ganglion cell complex; FLV focal loss volume; GLV global loss volume
OD
-7.8 ± 2.7
-1.7 ± 0.5
-0.2 ± 0.1
0.020
OS
-7.3 ± 2.6
-1.9 ± 0.6
-0.3 ± 0.1
0.008
Mean PSD OD
5.3 ± 2.2
2.1 ± 0.4
1.2 ± 0.6
0.449
OS
5.4 ± 2.6
2.5 ± 0.5
1.4 ± 0.7
0.893
GCC parameters
Glaucoma (n = 30 eyes)
Suspects (n = 24 eyes)
Ocular hypertensives (n = 20 eyes)
P value
GCC average
72.7 ± 11.4
89.2 ± 2.3
98.3 ± 3.7
0.911
GCC superior
73.2 ± 10.7
89.2 ± 2.7
99.7 ± 7.3
0.713
GCC inferior FLV
72.2 ± 12.7 5.5 ± 4.3
89.0 ± 3.0 0.7 ± 0.2
97.2 ± 5.1 0.1 ± 0.1
0.000 0.000
GLV
18.8 ± 12.6
6.0 ± 4.4
5.1 ± 3.7
0.645
[focal loss volume]) with ONH parameters (rim area, vertical cup-to-disc ratio, horizontal cup-to-disc ratio, cup area, and cup volume) and peripapillar RNFL measures (average RNFL, superior average and inferior average). We have selected those parameters with corresponding locations in the eye anatomy, e.g. superior GCC with superior RNFL, average GCC with average RNFL and so on. Statistical significance was set at P \ 0.05 and all analyses were done with MedCalcÒ software, version 9.3.7.0 (MedCalc Software bvba, Belgium).
respectively, stratified by group (glaucoma patients, suspects and ocular hypertensives). The correlation between GCC parameters and the RNFL measurements are depicted on Table 5. All correlations were good and achieved statistical significance. Table 6 displays the correlation between GCC parameters and the ONH measurements. Except for the correlation between FLV and cup volume (P = 0.251), GLV and cup volume (P = 0.418), and GLV and cup area (P = 0.06), all correlations were good.
Results
Discussion
Tables 2, 3, and 4 show raw data for GCC parameters, RNFL parameters, and ONH measurements,
The results of this study revealed that most of GCC parameters have a strong correlation both with ONH
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Int Ophthalmol Table 3 Comparison of the retinal nerve fiber layer (RNFL) measurements amongst groups
RNFL parameter
Glaucoma (n = 30 eyes)
Suspects (n = 24 eyes)
Ocular hypertensives (n = 20 eyes)
P value
RNFL average
74.7 ± 10.9
98.9 ± 3.4
113.3 ± 7.6
0.009
RNFL superior
75.0 ± 12.2
99.4 ± 4.7
114.1 ± 11.5
0.030
RNLF retinal nerve fiber layer
RNFL inferior
74.4 ± 10.7
98.4 ± 6.4
112.6 ± 7.3
0.908
Table 4 Comparison of the optic nerve head measurements amongst groups
ONH parameters
Glaucoma (n = 30 eyes)
Suspects (n = 24 eyes)
Ocular hypertensives (n = 20 eyes)
P value
ONH optic nerve head; CD cup-to-disc ratio
Cup volume
0.5 ± 0.2
0.3 ± 0.1
0.0 ± 0.0
0.000
Horizontal CD
0.9 ± 0.0
0.7 ± 0.0
0.3 ± 0.1
0.000
Vertical CD Rim area
0.8 ± 0.1 0.4 ± 0.2
0.7 ± 0.1 0.8 ± 0.0
0.4 ± 0.2 1.5 ± 0.3
0.000 0.000
Cup area
1.7 ± 0.3
0.9 ± 0.1
0.2 ± 0.1
0.000
Table 5 Correlation between the ganglion cell complex parameters and the retinal nerve fiber layer measurements r Avg and RNFL_avg
95 % CI 0.813
0.718 to 0.878
Table 6 Correlation between the ganglion cell complex parameters and optic nerve head measurements
P value
r
0.000
FLV and cup vol
0.135
95 % CI
P value
-0.096 to 0.352
0.251
Sup and RNFL_sup
0.745
0.622 to 0.832
0.000
FLV and cup area
0.311
0.089 to 0.504
0.006
Inf and RNFL_inf
0.824
0.734 to 0.886
0.000
GLV and cup vol
0.095
-0.135 to 0.317
0.418
FLV and RNFL_avg
-0.685
-0.790 to -0.542
0.000
GLV and cup area
0.219
-0.009 to 0.426
0.060
GLV and RNFL_avg
-0.848
-0.902 to -0.769
0.000
FLV and CD hor
0.265
0.039 to 0.465
0.022
FLV and CD ver
0.402
0.191 to 0.577
0.0004
GLV and CD hor
0.267
0.041 to 0.467
0.021
GLV and CD ver
0.419
0.211 to 0.591
0.0002
Avg and CD hor Avg and CD ver
-0.262 -0.402
-0.463 to -0.036 -0.577 to -0.191
0.023 0.0004
Avg average; Sup superior; Inf inferior; FLV focal loss volume; GLV global loss volume; RNFL retinal nerve fiber layer; 95 % CI 95 % confidence interval
and RNFL measurements. We have decided to correlate GCC parameters with those of ONH and RNFL that would most closely match the anatomic relationship between them, e.g., the superior GCC with the superior RNFL and the average GCC with ONH rim area. The correlation with inferior GCC and superior RNFL would most probably reveal no correlation. Even though, some parameters did not show correlation; there was a trend towards correlation between GCC GLV and ONH cup area that fail to reach statistical significance. We found no correlation between GCC GLV and FLV with ONH cup volume. GLV and FLV are parameters that provide quantitative measures for the amount of significant GCC loss [19]. GLV measures the average amount of GCC loss over the entire GCC map whereas FLV measures the average amount of focal loss over the entire GCC map. FLV detects focal loss using a pattern deviation map to
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Avg and rim area
0.583
0.409 to 0.716
0.0000
FLV and rim area
-0.374
-0.555 to -0.159
0.001
GLV and rim area
-0.539
-0.683 to -0.354
0.0001
FLV focal loss volume; GLV global loss volume; Avg average; vol volume; CD cup-to-disc ratio; hor horizontal; ver vertical; 95 % CI: 95 % confidence interval
correct for overall absolute changes and will best detect local ganglion cell loss. On the other hand, GLV will best detect diffuse ganglion cell loss. Tan et al. have found that both FLV and GLV are better than average GCC thickness to differentiate normal from glaucomatous eyes [19]. The optic disc cup is a central depression in the optic nerve head devoid of neuroretinal tissue. In glaucoma neuropathy, the loss of retinal ganglion cells leads to enlargement of the cup and, at the same time, posterior bowing of the lamina cribrosa
Int Ophthalmol
which is unrelated to cell loss, renders the cup to become deeper. Hence, cup volume is a component of the structural measurement that is not related to ganglion cells number only and, to some extent, explains the lack of correlation with GLV and FLV in this study. We have found a strong correlation between GCC and RNFL parameters. The GCC parameters are obtained with the MM7 protocol centered 1 mm temporal to the fovea. It uses one horizontal line with a 7 mm scan length (934 A scans) followed by 15 vertical lines with a 7 mm scan length and 0.5 mm interval (800 A scans). The GCC thickness is measured from the internal limiting membrane to the inner plexiform layer boundary. In this study, the RNFL thickness was determined by the nerve head map 4 mm diameter (NHM4) mode, which measures RNFL thickness by recalculating data along a 3.45 mm diameter circle around the optic disc using a map created from en face imaging utilizing six circular scans ranging from 2.5 to 4.0 mm in diameter (587 or 775 A scans each) and 12 linear data inputs (3.4 mm length, 452 A scans each). They essentially measure the same tissue thickness using the same technology in different locations. The superior GCC is a measure of the RNFL located at the superior aspect of the tissue in the macula area, whereas the RNFLsuperior is a measure of the tissue in the superior aspect of the peripapillary ring. Hence, a strong correlation between them might have been anticipated. GCC is probably advantageous over RNFL in that the former is able to detect pre-perimetric glaucoma specially GLV and FLV parameters [13]. The GCC analysis adds another important piece of structural information for a full glaucoma evaluation. Previous studies had suggested that imaging of the macula for glaucoma was promising [1–3]. These studies, however, used a time domain OCT, which has a slower scan speed as compared to the Fourierdomain OCT (400 A scans/sec for the Time Domain and 26000 A scans/sec for Fourier-domain) and a lower depth resolution (10 micron depth resolution for time-domain as compared 5 micron resolution for Fourier-domain). The limited depth resolution for the time domain OCT allowed only for measurement of full macula thickness and was not able to differentiate specific layers. Conversely, the Fourier-domain OCT allows for specific segmentation of tissue structures and only the retinal layers associated with the ganglion
cells can be evaluated. This segmentation method of the ganglion cell complex targets the layers directly associated with the ganglion cells. This study has some shortcomings. The sample size was relatively small and we have used both eyes of the same patient. That was done in order to increase the analysis power. Besides the sample included a heterogeneous group of glaucoma patients, ocular hypertensive and glaucoma suspects who were not evenly distributed. In glaucoma, ONH parameters and RNFL measurements are clinically used for diagnosis, staging and monitoring disease so that, assuming that GCC has displayed a strong correlation with both ONH parameters and RNFL measurements in this study, we believe that GCC parameters can be used as an additional structural parameter in the management of glaucoma. However, more studies with larger cohorts of patients are necessary to support the use of GCC parameters in the evaluation of glaucoma patients. Acknowledgments submission.
No financial support was received for this
Conflict of interest None of the authors has conflict of interest with the submission.
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