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Detection of Functional Change in Preperimetric and Perimetric Glaucoma Using 10-2 Matrix Perimetry
Accepted Manuscript Detection of functional change in preperimetric and perimetric glaucoma using 10-2 Matrix Perimetry Kyoung In Jung, M.D., Ph.D., Chan Kee Park, M.D., Ph.D. PII:
S0002-9394(17)30302-1
DOI:
10.1016/j.ajo.2017.07.007
Reference:
AJOPHT 10205
To appear in:
American Journal of Ophthalmology
Received Date: 21 December 2016 Revised Date:
4 July 2017
Accepted Date: 7 July 2017
Please cite this article as: Jung KI, Park CK, Detection of functional change in preperimetric and perimetric glaucoma using 10-2 Matrix Perimetry, American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2017.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Detection of functional change in preperimetric and perimetric glaucoma using 10-2 Matrix Perimetry Abstract
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Purpose: To evaluate an effective functional strategy for detecting glaucomatous damage of the macula in preperimetric to perimetric glaucoma Design: Cross-sectional study Methods: Preperimetric glaucoma patients (n=102) and perimetric glaucoma patients (n=88) with isolated paracentral scotoma or combined paracentral scotoma were enrolled in this study. Global and sectoral mean sensitivities (MS) were evaluated using 10-2 standard automated perimetry (SAP) with a stimulus of sizes III (0.43° diameter), V (1.72°), and 10-2 matrix perime try with a stimulus of 2°. Ganglion cell-inner plexiform layer (GCIPL) was measured using spectral domain optical coherence tomography. Results: The percentage of significantly depressed VF points < 5% and < 1% in the pattern deviation plot was higher with FDT 10-2 than with SAP 10-2 III in patients with preperimetric glaucoma (both P<0.001). Using FDT 10-2 tests, the structurefunction correlation was superior to SAP 10-2 (III or V) both in preperimetric and perimetric glaucoma. Topographic structure-function relationships for each VF test were more favorable with the FDT 10-2 test. The preperimetric glaucoma patients showing VF abnormalities on FDT 10-2 or SAP 10-2 (III) showed thinner average, minimum, superior, inferior and inferotemporal GCIPL thicknesses than in those without VF abnormalities (all P<0.05). Conclusions: FDT 10-2 was found to detect functional damage of the macula early in preperimetric glaucoma, and perform better than with SAP 10-2 (size III or V) from preperimetric to perimetric glaucoma in the structure-function relationship. FDT 10-2 can be considered a useful tool to detect glaucomatous damage of the macula early and appropriately.
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ACCEPTED MANUSCRIPT Detection of functional change in preperimetric and perimetric glaucoma using 10-2 Matrix Perimetry
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Kyoung In Jung, M.D., Ph.D., Chan Kee Park, M.D., Ph.D. Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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* Address correspondence and reprint requests to: Chan Kee Park: Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea 222 Banpo-daero, Seocho-ku, Seoul 137-701, Korea Tel.: 82-2-2258-6199, Fax: 82-2-599-7405 E-mail: [email protected]
Short title: 10-2 Matrix perimetry and glaucomatous damage of the macula
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Each of the coauthors has seen and agreed with each of the changes made to this manuscript in the revision.
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Supplemental Material available at AJO.com
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ACCEPTED MANUSCRIPT Introduction
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Early detection of glaucomatous damage of the macula is critical because central vision is clinically important in reading and driving. 1-3 There are more retinal ganglion cells (RGCs) located in the macular area than in the peripheral retina. 4 However, only 12 test points of the standard automated perimetry (SAP) 24-2 test fall within the central 10° visual field (VF), where more than 30% of RGCs are located.5 In the 24-2 VF test, the stimulus has a diameter of 0.43° and test points are 6° apart. Therefore, it is difficult for the SAP 24-2 test to thoroughly cover the macular region and evaluate structural glaucomatous damage in this area. In the 10-2 SAP (2°grid), the test points are more closely spaced than in the 24-2 SAP. The 10-2 VF test is less likely to miss paracentral defects with more detailed spatial information than the 24-2 VF test.5-7 For example, some patients with macular glaucomatous damage identified with both the 10-2 VF test and optical coherence tomography (OCT) were classified as normal with 24-2 SAP alone.8 In another report, 22.7% of eyes classified as normal on the 24-2 test showed VF defects on the 10-2 test.9 Matrix frequency doubling technology (FDT) perimetry is claimed to be more useful in detecting the onset of early glaucomatous VF defects compared to SAP10-13, although this remains controversial.14, 15 Previously, we reported that topographic structure-function relationships are favorable only with FDT 24, and not with SAP 242, in glaucoma patients with parafoveal scotoma which inevitably was associated with macular damage.16 FDT 10-2, with more closely spaced test points than FDT 24-2, may also be a good candidate for effective functional strategy when evaluating macular glaucomatous damage. Given these findings, we hypothesized that FDT 10-2 might satisfactorily reflect macular glaucomatous structural damage. In this study, FDT 10-2 was compared with the conventional SAP 10-2 in terms of early detection of macular damage in glaucoma patients. The size of the stimulus target differs between FDT 10-2 (2°) and conventional SAP 10-2 (Goldmann size III, 0.43°). W e additionally included the SAP 10-2 using Goldmann size V (1.72°) as well as conve ntional SAP 10-2 (0.43°) in the comparison of FDT 10-2 with SAP 10-2 to remove the effects of different target size in each VF test.
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ACCEPTED MANUSCRIPT Methods Subjects
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This cross-sectional study was approved by the Institutional Review Board of the Catholic University of Korea, Seoul, Korea, and followed the tenets of the Declaration of Helsinki. Patients with glaucoma that met inclusion criteria were consecutively included from all patients examined for glaucoma at the glaucoma clinic of Seoul St. Mary’s Hospital between January 2016 and June 2016. Informed consent was obtained from all the patients. Inclusion criteria were best-corrected visual acuity of 20/40 or better, axial length within 27 mm, and a normal open angle. Patients with uveitis or diseases that might affect the peripapillary or macular areas, or unreliable VF tests were excluded. When both eyes met the inclusion criteria, one eye per individual was randomly selected for the study. Classification of the Groups by Visual Field Defects
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A glaucomatous VF defect was defined as a cluster of 3 or more points with a P value <5%, one of which had a P value of < 1% on the pattern deviation plot. Eyes with the presence of a glaucomatous optic disc, such as diffuse or focal rim thinning, notching, or retinal nerve fiber layer defect without (preperimetric glaucoma) or with corresponding glaucomatous VF damage on SAP 24-2, including paracentral scotoma (perimetric glaucoma), were enrolled in this study. One glaucoma specialist (K.I.J.) determined paracentral scotoma based on pattern deviation probability plots in the SITA 24-2 test. Paracentral scotoma was defined as a single glaucomatous VF defect within twelve points of a central 10° radius in one hemifield (Fig. 1). Amongst all perimetric glaucoma patients with paracentral scotoma, sub-analysis was performed for patients with isolated paracentral scotoma (the isolated paracentral scotoma group) with mean deviation (MD) > -10 dB. If glaucoma patients with paracentral scotoma had VF defects in both the central 10° and peripheral nasal fields or an area other than central or in both superior and inferior hemifields, they were assigned to the combined paracentral scotoma group, not the isolated paracentral scotoma group. Comparisons among VF tests was performed on three groups of subjects: the preperimetric group, the isolated paracentral scotoma group, and the combined paracentral scotoma group. Measurements
All patients underwent a complete ophthalmic examination, including slit-lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, axial length measurement, central corneal thickness measurement, and dilated fundus biomicroscopy. Stereoscopic optic disc photography was also performed on all subjects. Optical Coherence Tomography Spectral-domain OCT imaging was performed using Cirrus HD-OCT version 6.0 (Carl Zeiss Meditec, Inc.). Using a macular cube scan, the ganglion cell-inner plexiform layer (GCIPL) thickness was obtained. The protocol for GCIPL thickness
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has previously been described in detail.17, 18 Ganglion cell analysis software was used to measure the average, minimum, and sectoral (superior, superotemporal, superonasal, inferior, inferotemporal, and inferonasal) GCIPL thicknesses in a 14.13mm2 elliptical annulus with vertical inner and outer radii of 0.5 and 2.0 mm, respectively, and horizontal inner and outer radii of 0.6 and 2.4 mm, respectively. RNFL thickness was determined using the optic Disc Cube 200 x 200 scan mode. Poor-quality images with signal strength less than 6 were discarded. OCT was performed on the day SAP 24-2 was done.
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Visual Field Testing All patients received 24-2 and 10-2 SAP with a Humphrey field analyzer (Carl Zeiss Meditec, Dublin, CA). Goldmann size III targets with diameters of 0.43° used the Swedish interactive threshold algorithm (SITA) standard program (SAP 10-2 III). Sizes V targets with diameters of 1.72° were utiliz ed with the FASTPAC algorithm (SAP 10-2 V) because the SITA program was unavailable for these sizes. FDT perimetry was performed using the 10-2 program with 2° stimuli, a spatial frequency of 0.5 cycles/deg, and a temporal frequency of 12 Hz with the FDT Humphrey Matrix (Carl Zeiss Meditec). VF sensitivity was evaluated using the logarithmic dB [10 × log(1/Lambert)] scale in SAP 10-2 and logarithmic dB [20 x log (1/Michelson contrast)] in FDT 10-2. Reliable tests were defined as <15% fixation losses, false positives, or false negatives. The second VF test was done if the first one was not reliable. All patients underwent SAP 24-2 initially. Other VF tests were performed in random order within 3 months.
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Analysis
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MD, PSD, and the abnormal points: SAP III vs FDT MD and pattern standard deviation (PSD) were compared between SAP 10-2 (III) and FDT 10-2. MD and PSD were not available for 10-2 SAP with size V stimuli. On the pattern deviation plot, the percentages of significantly depressed VF points at P < 0.05 and P < 0.01 were evaluated using SAP 10-2 (size III) and FDT 10-2.
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Structure-Function Relationship: SAP III vs SAP V vs FDT Overall and sectoral mean sensitivity (MS) were evaluated on threshold printouts in VF tests. Overall MS is calculated as the mean of VF sensitivities in the 68 points in 10-2 SAP and the 44 points in 10-2 FDT. The relationship between global MS and average GCIPL thickness was evaluated. Sixty-eight VF test points on 10-2 SAP and 44 VF test points on 10-2 FDT were assigned to superotemporal, inferotemporal, superonasal, and inferonasal sectors by adapting the Garway-Heath map designed for 24-2 SAP (Figure 1).19 Superotemporal and inferotemporal GCIPL thicknesses were used for the superotemporal and inferotemporal topographical structurefunction relationship, respectively. For superonasal and inferonasal sectors, the sum of the superior and superonasal GCIPL thicknesses and the sum of the inferior and inferonasal GCIPL thicknesses was employed, respectively. GCIPL thickness in preperimetric glaucoma: SAP III vs FDT Average and sectoral GCIPL thickness was compared between the subgroups according to the presence of visual field defects in preperimetric glaucoma. A visual field defect was defined as the presence of points at P < 0.01 on the pattern
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deviation plot in FDT 10-2 or SAP 10-2 using size III. Receiver operating characteristic (ROC) curves and area under the receiver operating characteristic (AUC) curves were built with continuous categories obtained from the GCIPL thicknesses in order to determine the discriminatory capabilities between preperimetric glaucoma patients with abnormalities on VF 10-2 and those without. For AUCs, abnormalities on VF 10-2 were defined as points at P < 0.01 on the pattern deviation plot both in FDT 10-2 or SAP 10-2 III. In all analyses, P < 0.05 indicated statistical significance.
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Statistics Differences between the SAP 10-2 (III) and FDT 10-2 were evaluated by a paired t test. Correlations between VF parameters and GCIPL variables were assessed based on Pearson’s correlation coefficients. To compare the correlation between VF tests, a Hotelling-Williams test was used. With regard to Pearson’s correlation coefficients, the correction was not done for multiple comparisons because this study was an explorative trial and to minimize the risk of type II errors. SPSS software (ver. 17.0; SPSS Inc., Chicago, IL) was used for all statistical analyses.
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Summary of Overall Study Design At first, conventional SAP 10-2 using size III and FDT 10-2 were compared in their ability to detect early functional loss using the significantly depressed points in the pattern deviation plot in patients with preperimetric glaucoma and perimetric glaucoma with paracentral scotoma. Secondly, the structure-function relationship was investigated using conventional SAP 10-2 III, SAP 10-2 V and FDT 10-2 in patients with preperimetric glaucoma and perimetric glaucoma with paracentral scotoma. Third, we also determined the characteristics of GCIPL thickness in preperimetric glaucoma patients with abnormalities on 10-2 VF tests.
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Results
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Data from 102 patients with preperimetric glaucoma, 45 patients with isolated paracentral scotoma, and 43 patients with combined paracentral scotoma were analyzed. Demographics of each group are shown in Table 1. The MD of SAP 24-2 was -1.0±1.3 in the preperimetric glaucoma patients, -2.4±1.9 in the isolated paracentral scotoma patients, -5.6±3.6 in the combined paracentral scotoma patients (P<0.001).
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MD, PSD, and the abnormal points: SAP III vs FDT The MD of FDT 10-2 was lower than that of SAP 10-2 III in patients with preperimetric glaucoma, with isolated paracentral scotoma, and with combined paracentral scotoma (P <0.001, <0.001, 0.003, respectively). The PSD was greater in FDT 10-2 than in SAP 10-2 III in preperimetric glaucoma (P<0.001), but the reverse was noted in glaucoma patients with combined paracentral scotoma (P=0.015). In glaucoma patients with isolated paracentral scotoma, the PSD showed no significant difference between FDT 10-2 and SAP 10-2 III (P=0.202). The percentage of total VF points that were significantly depressed by < 5% and < 1% in the pattern deviation plot was higher in FDT 10-2 than in SAP 10-2 III in patients with preperimetric glaucoma (P<0.001, both; Fig.2). A total of 67 eyes (65.7%) had depressed points < 1% both in FDT 10-2 and SAP 10-2 III (Fig.3). Structure-Function Relationship: SAP III vs SAP V vs FDT
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Global The global structure-function relationship is shown in Fig.4. In preperimetric glaucoma, the average GCIPL thickness had a positive correlation with MS in SAP 10-2 III (r=0.292, P=0.004) and FDT 10-2 (r=0.288, P=0.004), but not with SAP 10-2 V (r=0.088, P=0.389). SAP 10-2 III and FDT 10-2 revealed stronger correlations than SAP 10-2 V (P=0.026, 0.030, respectively). In glaucoma with an isolated paracentral scotoma, the correlation between average GCIPL thickness and MS in VF 10-2 was significant in SAP 10-2 V (r=0.437, P=0.003) and FDT 10-2 (r=0.496, P=0.001), but not in SAP 10-2 III (r=0.276, P=0.070). In glaucoma patients with a combined paracentral scotoma, all VF showed a positive correlation with average GCIPL thickness (SAP 10-2 III, r=0.377, P=0.014; SAP 10-2 V, r=0.389, P=0.011; FDT 10-2, r=0.704, P<0.001). In the comparison between each VF test, FDT 10-2 revealed a higher correlation than SAP 10-2 III or V (P<0.001, both). Topographic In preperimetric glaucoma, SAP 10-2 III and FDT 10-2 showed a significant correlation between the sectoral GCIPL thickness and the corresponding MS in all sectors (SAP III, r=0.252-0.372, all P<0.02; FDT 10-2, r=0.303-0.449, all P<0.01; Table 2). In SAP 10-2 V, the topographic structure-function correlation was significant only in the superotemporal sector (r=0.209, P=0.040). FDT 10-2 showed significantly higher correlations on two sectors in comparison with SAP 10-2 V. In patients with an isolated paracentral scotoma, SAP 10-2 V and FDT 10-2 exhibited a positive correlation between the sectoral GCIPL thickness and the corresponding MS in all sectors (SAP 10-2 V, r=0.372-0.526, all P<0.02; FDT 10-2,
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r=0.444-0.691, all P<0.01). In SAP 10-2 III, the topographic structure-function correlation was significant only in the inferotemporal and inferonasal sectors (r=0.465, P=0.002; r=0.499, P=0.001, respectively). FDT 10-2 showed a higher correlation between the inferotemporal or superonasal GCIPL thickness and the corresponding MS compared to SAP 10-2 III (P=0.002, 0.023, respectively), and between the inferotemporal GCIPL thickness and the corresponding MS compared to SAP 10-2 V (P=0.04). In glaucoma patients with a combined paracentral scotoma, the structure-function relationship was significant in all sectors using SAP 10-2 III, SAP 10-2 V, or FDT 102. The correlations between the inferotemporal, superonasal, and inferonasal sectors and the corresponding VF sensitivities were greater in FDT 10-2 than in SAP 10-2 III or V (all P <0.02).
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GCIPL thickness in preperimetric glaucoma: SAP III vs FDT The preperimetric glaucoma patients showing a VF abnormality on FDT 10-2 showed thinner average, minimum, superior, inferior, and inferotemporal GCIPL thicknesses than those without a VF abnormality (P=0.032, 0.001, 0.041, 0.017, 0.006, respectively; Table 3). Average, minimum, superior, inferonasal, inferior, inferotemporal, and superotemporal GCIPL thicknesses were thinner in eyes with a VF defect on SAP 10-2 III compared to those without a VF defect (P=0.005, <0.001, 0.044, 0.010, 0.003, 0.002, 0.023, respectively). Among GCIPL parameters, minimum (AUC, 0.635; 95% CI, 0.521-0.749) and inferior (AUC, 0.637; 95% CI, 0.522-0.751) GCIPL thicknesses had the largest AUC for discriminating the presence of a VF 10-2 defect in preperimetric glaucoma. (Supplemental table 1; Supplemental Material available at AJO.com).
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A representative case A 52-year-old female showed a localized RNFL defect and thin GCIPL thickness at the inferior and inferotemporal sectors (Fig.5). No definitive VF defect was shown in SAP 24-2 and SAP 10-2 III. On FDT 10-2 testing, a superior paracentral VF defect was distinct, corresponding to a thin inferior GCIPL thickness
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ACCEPTED MANUSCRIPT Discussion
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In this study, FDT 10-2 detected macular damage earlier than SAP 10-2 III in preperimetric glaucoma. In terms of topographic structure-function relationship, FDT 10-2 also performed better than SAP 10-2 III or SAP 10-2 V from preperimetric glaucoma to perimetric glaucoma. Patients who presented with an abnormality on FDT 10-2 or SAP 10-2 III were more likely to be associated with a thinner GCIPL thickness than those without an abnormality on VF 10-2 tests. Earlier detection of macular damage with SAP 10-2 compared to SAP 24-2 has been reported in several studies on glaucoma because VF test points are more densely located.6-8 In 10-2 VF tests, more closely spaced test points can lead to good sampling of the macular area. However, even the conventional 10-2 SAP using the stimulus with a diameter of 0.43° only tests ab out 3.14 % ([π {0.43°/2 2 x 68]/[π X10°x10°] x 100) of the total area within 10° and th erefore a substantial amount of macular area may be missed (about 97%). The 10-2 FDT tests employ a target of 2°, which is larger than size III (0.43°) commonly used in SAP 10-2. An untested area can be smaller in the FDT than in the SAP with a stimulus of sizes III because the larger stimulus is used in the FDT. A target of 2° in FDT 10-2 is similar to a size V stimulus (1.72°) in SAP. In this study, FDT 10-2 wa s compared with the SAP 10-2 both by size III and V stimuli because the difference between SAP 10-2 and FDT 102 could be attributable to the stimulus size or different stimulus characteristics itself.
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Preperimetric Glaucoma The proportion of depressed < 5% and < 1% points in the pattern deviation plot were greater in FDT 10-2 than in SAP 10-2 III in preperimetric glaucoma (P<0.001). That is, it seemed that FDT 10-2 was able to detect glaucomatous macular damage earlier than SAP 10-2 III. Using the topographic structure-function relationship, inferotemporal GCIPL thickness showed a better correlation with FDT 10-2 than with SAP 10-2 III or V in preperimetric glaucoma. Eyes with abnormal points on FDT 10-2 showed a thinner GCIPL thickness than those without. This finding supports the hypothesis that abnormalities in FDT 10-2 are definitely related to structural glaucomatous loss in the macular area. The ROC for the common VF defects in FDT 10-2 and SAP 10-2 III was significant for minimum and inferior GCIPL thicknesses. Therefore, functional analysis of macular damage from FDT 10-2 or SAP 10-2 III may be helpful for preperimetric glaucoma patients with thin minimum and inferior GCIPL thicknesses.
Perimetric Glaucoma Topographic structure-function relationships for each VF test were more favorable with the FDT 10-2 test than SAP 10-2 III or V also in perimetric glaucoma. Good structure-function relationship of FDT 10-2 may not confirm that it is the best VF test because of inaccuracy of the structure and functional assessments and dissimilar measurement scales across FDT and SAP. However, MD, PSD, or pattern standard deviation map were not available for 10-2 SAP with size V stimuli. Therefore, the structure-function relationship was used in this study to compare each VF test including SAP 10-2 V. At least, FDT 10-2 tests can be considered a good functional strategy to detect glaucomatous damage of the macula also in perimetric glaucoma.
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Why did the FDT 10-2 perform well in preperimetric and perimetric glaucoma? SAP size V did not perform well in patients with preperimetric glaucoma in terms of the structure-function relationship. This could be explained by the fact that the larger stimulus target was found to decrease the depth of the defect and the ability to detect VF damage,20 even though a large stimulus such as size V has been found to have better test-retest variability and greater effective dynamic range than size III.21, 22 Therefore, the superior ability of FDT 10-2 in detecting early macular glaucomatous damage did not seem to be attributed to just the larger target size. The different stimulus characteristics between FDT and SAP may result in dissimilar responses from the retina and brain, and hence different VF sensitivities. The superior performance of FDT compared to SAP in glaucoma patients with paracentral scotoma might be due to the low redundancy of the magnocellular ganglion cells.23, 24 However, Swanson et al. recently reported that the conventional size III perimetric stimulus was more effective than the frequency-doubling stimulus in preferentially stimulating magnocellular ganglion cells compared with parvocellular ganglion cells in primates.25 The further studies are needed to investigate the precise underlying mechanism and the functional characteristics with regard to SAP and FDT.
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A comparison to a previous study In terms of the comparison between FDT 10-2 and SAP 10-2 III, Sun et al. reported that the average perimetric loss was comparable for FDT 10-2 and SAP 102 III in perimetric glaucoma (mean 24-2 SAP MD= -8.92±7.9 dB).26 Their study is in accordance with our study regarding some aspects of perimetric glaucoma. In perimetric glaucoma with combined paracentral scotoma (mean 24-2 SAP MD=5.6±3.6 dB), MD was lower in FDT 10-2 but PSD were higher in SAP 10-2. The proportion of depressed points on the pattern deviation plot differed between FDT 10-2 and SAP 10-2 III only in preperimetric glaucoma whereas they were similar between VFs in perimetric glaucoma. Given these findings, overall perimetric loss seemed to be similar between FDT 10-2 and SAP 10-2 III in perimetric glaucoma.
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Study Limitations There are several limitations in this study. First, SAP 10-2 III or V uses a 2°x 2° grid constantly with a total of 68 test points. In FDT 10-2, a 2° grid is used within a central 5° of VF, and a 3 ° grid outside a central 5° of VF, yielding a total of 44 test points. However, FDT 10-2 performed well in detecting macular damage in preperimetric glaucoma even though there were fewer test points than in SAP 10-2. Second, SAP 10-2 using size V was performed with a FASTPAC algorithm since the SITA program was unavailable for size V stimuli and test time was shorter than standard threshold tests without significant deterioration in the detection of VF defects.27 One report found that an intra-test variance was greater with the FASTPAC algorithm than with the standard full-threshold strategy. However, the FASTPAC algorithm was used for size V SAP 10-2 in this study. Size V has been found to have better test-retest variability than size III.22 Therefore, decreased variability using size V might offset the intra-test variance when using the FASTPAC program. Third, for the topographic structure-function relationship, FDT 10-2 presented a more favorable correlation with the GCIPL thickness than SAP 10-2 III or V in perimetric glaucoma with combined paracentral scotoma. However, glaucoma
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ACCEPTED MANUSCRIPT patients with combined paracentral scotoma had an average MD of -5.6±3.6 dB. These results should be interpreted with caution because the positive results with FDT may not be generalizable to advanced glaucoma.
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Conclusions To the best our knowledge, there have been no prior reports on the ability of the FDT 10-2 test in detecting glaucomatous damage in preperimetric glaucoma. FDT 10-2 was found to detect functional damage early in preperimetric glaucoma, and perform better than SAP 10-2 tests from preperimetric to perimetric glaucoma as a functional assessment of glaucoma. FDT 10-2 tests can be considered a functional strategy especially if preperimetric glaucoma patients present with thin GCIPL thickness.
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ACCEPTED MANUSCRIPT Acknowledgements
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A. Funding/support: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C1940). The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. B. All authors declare that no competing interests exist with the funder.
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ACCEPTED MANUSCRIPT References
1. Kolker AE. Visual prognosis in advanced glaucoma: a comparison of medical and surgical therapy for retention of vision in 101 eyes with advanced glaucoma. Trans Am Ophthalmol Soc 1977;75:539-555.
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2. Coeckelbergh TR, Brouwer WH, Cornelissen FW, Van Wolffelaar P, Kooijman AC. The effect of visual field defects on driving performance: a driving simulator study. Arch Ophthalmol 2002;120(11):1509-1516.
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3. Fujita K, Yasuda N, Oda K, Yuzawa M. [Reading performance in patients with central visual field disturbance due to glaucoma]. Nippon Ganka Gakkai Zasshi 2006;110(11):914-918. 4. Curcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol 1990;300(1):5-25.
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5. Park SC, Kung Y, Su D, et al. Parafoveal scotoma progression in glaucoma: Humphrey 10-2 versus 24-2 visual field analysis. Ophthalmology 2013;120(8):15461550. 6. Hangai M, Ikeda HO, Akagi T, Yoshimura N. Paracentral scotoma in glaucoma detected by 10-2 but not by 24-2 perimetry. Jpn J Ophthalmol 2014;58(2):188-196.
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7. Traynis I, De Moraes CG, Raza AS, Liebmann JM, Ritch R, Hood DC. Prevalence and nature of early glaucomatous defects in the central 10 degrees of the visual field. JAMA Ophthalmol 2014;132(3):291-297.
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8. Grillo LM, Wang DL, Ramachandran R, et al. The 24-2 Visual Field Test Misses Central Macular Damage Confirmed by the 10-2 Visual Field Test and Optical Coherence Tomography. Transl Vis Sci Technol 2016;5(2):15.
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9. Hayashi K, Araie M, Konno S, Tomidokoro A. Correlation of macular ganglion cell complex thickness with frequency-doubling technology perimetry in open-angle glaucoma with hemifield defects. J Glaucoma 2015. 10. Landers J, Goldberg I, Graham S. A comparison of short wavelength automated perimetry with frequency doubling perimetry for the early detection of visual field loss in ocular hypertension. Clin Experiment Ophthalmol 2000;28(4):248252. 11. Sample PA, Bosworth CF, Blumenthal EZ, Girkin C, Weinreb RN. Visual function-specific perimetry for indirect comparison of different ganglion cell populations in glaucoma. Invest Ophthalmol Vis Sci 2000;41(7):1783-1790. 12. Sample PA, Medeiros FA, Racette L, et al. Identifying glaucomatous vision loss with visual-function-specific perimetry in the diagnostic innovations in glaucoma study. Invest Ophthalmol Vis Sci 2006;47(8):3381-3389.
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13. Racette L, Medeiros FA, Zangwill LM, Ng D, Weinreb RN, Sample PA. Diagnostic accuracy of the Matrix 24-2 and original N-30 frequency-doubling technology tests compared with standard automated perimetry. Invest Ophthalmol Vis Sci 2008;49(3):954-960.
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14. Patel A, Wollstein G, Ishikawa H, Schuman JS. Comparison of visual field defects using matrix perimetry and standard achromatic perimetry. Ophthalmology 2007;114(3):480-487.
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15. Redmond T, O'Leary N, Hutchison DM, Nicolela MT, Artes PH, Chauhan BC. Visual field progression with frequency-doubling matrix perimetry and standard automated perimetry in patients with glaucoma and in healthy controls. JAMA Ophthalmol 2013;131(12):1565-1572.
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16. Jung KI, Kang MK, Choi JA, Shin HY, Park CK. Structure-Function Relationship in Glaucoma Patients With Parafoveal Versus Peripheral Nasal Scotoma. Invest Ophthalmol Vis Sci 2016;57(2):420-428. 17. Mwanza JC, Oakley JD, Budenz DL, Chang RT, Knight OJ, Feuer WJ. Macular ganglion cell-inner plexiform layer: automated detection and thickness reproducibility with spectral domain-optical coherence tomography in glaucoma. Invest Ophthalmol Vis Sci 2011;52(11):8323-8329.
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18. Shin HY, Park HY, Jung KI, Park CK. Comparative study of macular ganglion cell-inner plexiform layer and peripapillary retinal nerve fiber layer measurement: structure-function analysis. Invest Ophthalmol Vis Sci 2013;54(12):7344-7353. 19. Garway-Heath DF, Holder GE, Fitzke FW, Hitchings RA. Relationship between electrophysiological, psychophysical, and anatomical measurements in glaucoma. Invest Ophthalmol Vis Sci 2002;43(7):2213-2220.
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20. Wilensky JT, Mermelstein JR, Siegel HG. The use of different-sized stimuli in automated perimetry. Am J Ophthalmol 1986;101(6):710-713.
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21. Wall M, Woodward KR, Doyle CK, Zamba G. The effective dynamic ranges of standard automated perimetry sizes III and V and motion and matrix perimetry. Arch Ophthalmol 2010;128(5):570-576. 22. Wall M, Woodward KR, Doyle CK, Artes PH. Repeatability of automated perimetry: a comparison between standard automated perimetry with stimulus size III and V, matrix, and motion perimetry. Invest Ophthalmol Vis Sci 2009;50(2):974-979. 23. Anderson AJ, Johnson CA. Mechanisms isolated by frequency-doubling technology perimetry. Invest Ophthalmol Vis Sci 2002;43(2):398-401. 24. Leeprechanon N, Giangiacomo A, Fontana H, Hoffman D, Caprioli J. Frequency-doubling perimetry: comparison with standard automated perimetry to detect glaucoma. Am J Ophthalmol 2007;143(2):263-271.
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25. Swanson WH, Sun H, Lee BB, Cao D. Responses of primate retinal ganglion cells to perimetric stimuli. Invest Ophthalmol Vis Sci 2011;52(2):764-771. 26. Sun H, Dul MW, Swanson WH. Linearity can account for the similarity among conventional, frequency-doubling, and gabor-based perimetric tests in the glaucomatous macula. Optom Vis Sci 2006;83(7):455-465.
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27. Mills RP, Barnebey HS, Migliazzo CV, Li Y. Does saving time using FASTPAC or suprathreshold testing reduce quality of visual fields? Ophthalmology 1994;101(9):1596-1603.
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-Figure legends-
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Fig. 1 Topographic structure-function correspondence map according to GarwayHeath et al19. Sixty-eight VF test points on 10-2 standard automated perimetry (left) and 44 VF test points on 10-2 FDT (middle) were assigned to superotemporal, inferotemporal, superonasal, and inferonasal sectors (right). GCIPL, ganglion cell-inner plexiform layer; I, inferior; IN, inferonasal; IT, inferotemporal; S, superior; SN, superonasal; ST, superotemporal
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Fig. 2 The proportion of abnormal points significantly depressed by <5% and <1% in the pattern deviation plot. The percentage of points significantly depressed by <5% (upper row) and <1% (lower row) was greater using FDT 10-2 than with SAP 10-2 III in patients with preperimetric glaucoma (both P<0.001).
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Fig.3 Correspondence between 10-2 standard automated perimetry and 10-2 frequency doubling technology test. There were 67 patients (65.7%) showing depressed points < 1% both in FDT 10-2 and SAP 10-2 III among subjects with preperimetric glaucoma (n=102). Four patients (3.9%) showed depressed points < 1% only in SAP 10-2 III, and 31 patients (30.4%) exhibited abnormal points only in FDT 10-2.
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Fig. 4 Structure-function relationship between average Ganglion cell-inner plexiform layer (GCIPL) thickness and global mean sensitivity on 10-2 visual field tests. FDT 10-2 revealed a better correlation than SAP 10-2 V (P=0.030) in patients with preperimetric glaucoma. In glaucoma patients with combined paracentral scotoma, FDT 10-2 performed more favorably than SAP 10-2 III or SAP 10-2 V (both P<0.001).
Fig. 5 Representative case. A 52-year-old female exhibited a localized retinal nerve fiber layer defect (top left). Ganglion cell-inner plexiform layer (GCIPL) thickness of the inferior and inferotemporal sectors was thinner in the thickness parameter, and abnormal at < 1% level compared to normative data on a deviation map (top middle). Standard automated perimetry (SAP) 24-2 showed no abnormality (top right). SAP 10-2 III did not display any visual field defects (bottom left). A frequency doubling technology 10-2 test showed a superior paracentral scotoma corresponding to an inferior localized retinal nerve fiber layer defect and thin GCIPL thickness (bottom right).
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Combined paracentral scotoma (n=43)
P value
52.2±12.6 34/68 540.0±33.1
Isolated paracentral scotoma (n=45) 56.0±12.6 18/27 537.5±35.0
54.3±9.7 12/31 546.6±25.1
0.204 0.484 0.422
-2.4±3.3
-1.5±2.7
-1.5±2.7
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Table 1. Characteristics of glaucoma patients
24.7±1.7
24.2±1.3
24.2±1.4
0.086
75.3±8.9
69.1±11.0
67.7±9.2
<0.001
-1.0±1.3
-2.4±1.9
-5.6±3.6
<0.001
1.7±0.6
4.3±2.1
8.0±3.5
<0.001
0.120
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Age (years) Male/Female Central corneal thickness (µm) Spherical equivalent (diopter) Axial length (mm) Average GCIPL thickness (µm) SAP 24-2 MD (dB) SAP 24-2 PSD (dB)
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Parameter
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MD, mean deviation; PSD, pattern standard deviation; SAP, standard automated perimetry Continuous variables are expressed as n (percentage), mean ± standard deviation, or percentage.
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0.267 0.455 0.282 0.499 0.372 0.526 0.419* 0.508 0.444 0.691†‡ 0.567† 0.654
0.083 0.002 0.067 0.001 0.014 <0.001 0.005 0.001 0.003 <0.001 <0.001 <0.001
Combined paracentral scotoma
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ST IT SN IN SAP ST 10-2 (V) IT SN IN FDT ST 10-2 IT SN IN
P value 0.312 0.002 0.256 0.011 0.252* 0.013 0.372* <0.001 0.209 0.040 0.156 0.127 -0.006 0.951 0.170 0.097 0.324 0.001 0.449†‡ <0.001 0.303‡ 0.003 0.342 0.001 r
Isolated paracentral scotoma P value r
r
P value
0.559 0.407 0.538 0.467 0.570 0.473 0.550 0.429 0.648 0.739†‡ 0.710†‡ 0.724†‡
<0.001 0.008 <0.001 0.002 <0.001 0.002 <0.001 0.005 <0.001 <0.001 <0.001 <0.001
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SAP 10-2 (III)
Preperimetric
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SDOCT GCIPL Sector
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FDT, frequency doubling technology; GCIPL, Ganglion cell-inner plexiform layer; SAP, standard automated perimetry; SD-OCT, spectral domain optical coherence tomography The cells of statistically significant values (P < 0.05) are highlighted. r=Pearson’s correlation coefficient * Statistically significant difference with P<0.05 between SAP 10-2 (III) and SAP 10-2 (V) † Statistically significant difference with P<0.05 between SAP 10-2 (III) and FDT 10-2 ‡ Statistically significant difference with P<0.05 between SAP 10-2 (V) and FDT 10-2
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75.9±9.4
79.4±9.6
0.141
69.7±10.1 71.3±10.4
75.8±10.5 78.4±8.9
0.017 0.006
74.4±11.0
78.0±8.6
0.168
P value
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0.032 0.001 0.041 0.339
P value
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Average (µm) Minimum (µm) Superior (µm) Superonasal (µm) Inferonasal (µm) Inferior (µm) Inferotemporal (µm) Superotemporal (µm)
Visual field defect (-) (n =21) 79.0±8.9 74.8±10.3 80.0±9.4 81.8±9.4
SAP 10-2 (III) Visual Visual field field defect (+) defect (-) (n =51 ) (n =46) 72.9±7.7 77.9±9.5 63.7±10.0 72.3±10.0 74.0±10.4 78.1±9.7 78.1±9.1 81.6±11.9
0.005 <0.001 0.044 0.105
74.3±9.1
79.3±9.3
0.010
68.1±9.8 69.8±9.6
74.3±10.3 76.3±10.5
0.003 0.002
72.9±8.1
77.7±12.3
0.023
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GCIPL thickness
FDT 10-2 Visual field defect (+) (n =81 ) 74.3±8.7 65.8±10.2 74.8±10.2 79.3±10.9
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FDT, frequency doubling technology; GCIPL, Ganglion cell-inner plexiform layer; SAP, standard automated perimetry
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S0002-9394(17)30302-1
DOI:
10.1016/j.ajo.2017.07.007
Reference:
AJOPHT 10205
To appear in:
American Journal of Ophthalmology
Received Date: 21 December 2016 Revised Date:
4 July 2017
Accepted Date: 7 July 2017
Please cite this article as: Jung KI, Park CK, Detection of functional change in preperimetric and perimetric glaucoma using 10-2 Matrix Perimetry, American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2017.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Detection of functional change in preperimetric and perimetric glaucoma using 10-2 Matrix Perimetry Abstract
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Purpose: To evaluate an effective functional strategy for detecting glaucomatous damage of the macula in preperimetric to perimetric glaucoma Design: Cross-sectional study Methods: Preperimetric glaucoma patients (n=102) and perimetric glaucoma patients (n=88) with isolated paracentral scotoma or combined paracentral scotoma were enrolled in this study. Global and sectoral mean sensitivities (MS) were evaluated using 10-2 standard automated perimetry (SAP) with a stimulus of sizes III (0.43° diameter), V (1.72°), and 10-2 matrix perime try with a stimulus of 2°. Ganglion cell-inner plexiform layer (GCIPL) was measured using spectral domain optical coherence tomography. Results: The percentage of significantly depressed VF points < 5% and < 1% in the pattern deviation plot was higher with FDT 10-2 than with SAP 10-2 III in patients with preperimetric glaucoma (both P<0.001). Using FDT 10-2 tests, the structurefunction correlation was superior to SAP 10-2 (III or V) both in preperimetric and perimetric glaucoma. Topographic structure-function relationships for each VF test were more favorable with the FDT 10-2 test. The preperimetric glaucoma patients showing VF abnormalities on FDT 10-2 or SAP 10-2 (III) showed thinner average, minimum, superior, inferior and inferotemporal GCIPL thicknesses than in those without VF abnormalities (all P<0.05). Conclusions: FDT 10-2 was found to detect functional damage of the macula early in preperimetric glaucoma, and perform better than with SAP 10-2 (size III or V) from preperimetric to perimetric glaucoma in the structure-function relationship. FDT 10-2 can be considered a useful tool to detect glaucomatous damage of the macula early and appropriately.
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ACCEPTED MANUSCRIPT Detection of functional change in preperimetric and perimetric glaucoma using 10-2 Matrix Perimetry
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Kyoung In Jung, M.D., Ph.D., Chan Kee Park, M.D., Ph.D. Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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* Address correspondence and reprint requests to: Chan Kee Park: Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea 222 Banpo-daero, Seocho-ku, Seoul 137-701, Korea Tel.: 82-2-2258-6199, Fax: 82-2-599-7405 E-mail: [email protected]
Short title: 10-2 Matrix perimetry and glaucomatous damage of the macula
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Each of the coauthors has seen and agreed with each of the changes made to this manuscript in the revision.
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Supplemental Material available at AJO.com
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ACCEPTED MANUSCRIPT Introduction
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Early detection of glaucomatous damage of the macula is critical because central vision is clinically important in reading and driving. 1-3 There are more retinal ganglion cells (RGCs) located in the macular area than in the peripheral retina. 4 However, only 12 test points of the standard automated perimetry (SAP) 24-2 test fall within the central 10° visual field (VF), where more than 30% of RGCs are located.5 In the 24-2 VF test, the stimulus has a diameter of 0.43° and test points are 6° apart. Therefore, it is difficult for the SAP 24-2 test to thoroughly cover the macular region and evaluate structural glaucomatous damage in this area. In the 10-2 SAP (2°grid), the test points are more closely spaced than in the 24-2 SAP. The 10-2 VF test is less likely to miss paracentral defects with more detailed spatial information than the 24-2 VF test.5-7 For example, some patients with macular glaucomatous damage identified with both the 10-2 VF test and optical coherence tomography (OCT) were classified as normal with 24-2 SAP alone.8 In another report, 22.7% of eyes classified as normal on the 24-2 test showed VF defects on the 10-2 test.9 Matrix frequency doubling technology (FDT) perimetry is claimed to be more useful in detecting the onset of early glaucomatous VF defects compared to SAP10-13, although this remains controversial.14, 15 Previously, we reported that topographic structure-function relationships are favorable only with FDT 24, and not with SAP 242, in glaucoma patients with parafoveal scotoma which inevitably was associated with macular damage.16 FDT 10-2, with more closely spaced test points than FDT 24-2, may also be a good candidate for effective functional strategy when evaluating macular glaucomatous damage. Given these findings, we hypothesized that FDT 10-2 might satisfactorily reflect macular glaucomatous structural damage. In this study, FDT 10-2 was compared with the conventional SAP 10-2 in terms of early detection of macular damage in glaucoma patients. The size of the stimulus target differs between FDT 10-2 (2°) and conventional SAP 10-2 (Goldmann size III, 0.43°). W e additionally included the SAP 10-2 using Goldmann size V (1.72°) as well as conve ntional SAP 10-2 (0.43°) in the comparison of FDT 10-2 with SAP 10-2 to remove the effects of different target size in each VF test.
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ACCEPTED MANUSCRIPT Methods Subjects
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This cross-sectional study was approved by the Institutional Review Board of the Catholic University of Korea, Seoul, Korea, and followed the tenets of the Declaration of Helsinki. Patients with glaucoma that met inclusion criteria were consecutively included from all patients examined for glaucoma at the glaucoma clinic of Seoul St. Mary’s Hospital between January 2016 and June 2016. Informed consent was obtained from all the patients. Inclusion criteria were best-corrected visual acuity of 20/40 or better, axial length within 27 mm, and a normal open angle. Patients with uveitis or diseases that might affect the peripapillary or macular areas, or unreliable VF tests were excluded. When both eyes met the inclusion criteria, one eye per individual was randomly selected for the study. Classification of the Groups by Visual Field Defects
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A glaucomatous VF defect was defined as a cluster of 3 or more points with a P value <5%, one of which had a P value of < 1% on the pattern deviation plot. Eyes with the presence of a glaucomatous optic disc, such as diffuse or focal rim thinning, notching, or retinal nerve fiber layer defect without (preperimetric glaucoma) or with corresponding glaucomatous VF damage on SAP 24-2, including paracentral scotoma (perimetric glaucoma), were enrolled in this study. One glaucoma specialist (K.I.J.) determined paracentral scotoma based on pattern deviation probability plots in the SITA 24-2 test. Paracentral scotoma was defined as a single glaucomatous VF defect within twelve points of a central 10° radius in one hemifield (Fig. 1). Amongst all perimetric glaucoma patients with paracentral scotoma, sub-analysis was performed for patients with isolated paracentral scotoma (the isolated paracentral scotoma group) with mean deviation (MD) > -10 dB. If glaucoma patients with paracentral scotoma had VF defects in both the central 10° and peripheral nasal fields or an area other than central or in both superior and inferior hemifields, they were assigned to the combined paracentral scotoma group, not the isolated paracentral scotoma group. Comparisons among VF tests was performed on three groups of subjects: the preperimetric group, the isolated paracentral scotoma group, and the combined paracentral scotoma group. Measurements
All patients underwent a complete ophthalmic examination, including slit-lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, axial length measurement, central corneal thickness measurement, and dilated fundus biomicroscopy. Stereoscopic optic disc photography was also performed on all subjects. Optical Coherence Tomography Spectral-domain OCT imaging was performed using Cirrus HD-OCT version 6.0 (Carl Zeiss Meditec, Inc.). Using a macular cube scan, the ganglion cell-inner plexiform layer (GCIPL) thickness was obtained. The protocol for GCIPL thickness
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has previously been described in detail.17, 18 Ganglion cell analysis software was used to measure the average, minimum, and sectoral (superior, superotemporal, superonasal, inferior, inferotemporal, and inferonasal) GCIPL thicknesses in a 14.13mm2 elliptical annulus with vertical inner and outer radii of 0.5 and 2.0 mm, respectively, and horizontal inner and outer radii of 0.6 and 2.4 mm, respectively. RNFL thickness was determined using the optic Disc Cube 200 x 200 scan mode. Poor-quality images with signal strength less than 6 were discarded. OCT was performed on the day SAP 24-2 was done.
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Visual Field Testing All patients received 24-2 and 10-2 SAP with a Humphrey field analyzer (Carl Zeiss Meditec, Dublin, CA). Goldmann size III targets with diameters of 0.43° used the Swedish interactive threshold algorithm (SITA) standard program (SAP 10-2 III). Sizes V targets with diameters of 1.72° were utiliz ed with the FASTPAC algorithm (SAP 10-2 V) because the SITA program was unavailable for these sizes. FDT perimetry was performed using the 10-2 program with 2° stimuli, a spatial frequency of 0.5 cycles/deg, and a temporal frequency of 12 Hz with the FDT Humphrey Matrix (Carl Zeiss Meditec). VF sensitivity was evaluated using the logarithmic dB [10 × log(1/Lambert)] scale in SAP 10-2 and logarithmic dB [20 x log (1/Michelson contrast)] in FDT 10-2. Reliable tests were defined as <15% fixation losses, false positives, or false negatives. The second VF test was done if the first one was not reliable. All patients underwent SAP 24-2 initially. Other VF tests were performed in random order within 3 months.
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Analysis
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MD, PSD, and the abnormal points: SAP III vs FDT MD and pattern standard deviation (PSD) were compared between SAP 10-2 (III) and FDT 10-2. MD and PSD were not available for 10-2 SAP with size V stimuli. On the pattern deviation plot, the percentages of significantly depressed VF points at P < 0.05 and P < 0.01 were evaluated using SAP 10-2 (size III) and FDT 10-2.
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Structure-Function Relationship: SAP III vs SAP V vs FDT Overall and sectoral mean sensitivity (MS) were evaluated on threshold printouts in VF tests. Overall MS is calculated as the mean of VF sensitivities in the 68 points in 10-2 SAP and the 44 points in 10-2 FDT. The relationship between global MS and average GCIPL thickness was evaluated. Sixty-eight VF test points on 10-2 SAP and 44 VF test points on 10-2 FDT were assigned to superotemporal, inferotemporal, superonasal, and inferonasal sectors by adapting the Garway-Heath map designed for 24-2 SAP (Figure 1).19 Superotemporal and inferotemporal GCIPL thicknesses were used for the superotemporal and inferotemporal topographical structurefunction relationship, respectively. For superonasal and inferonasal sectors, the sum of the superior and superonasal GCIPL thicknesses and the sum of the inferior and inferonasal GCIPL thicknesses was employed, respectively. GCIPL thickness in preperimetric glaucoma: SAP III vs FDT Average and sectoral GCIPL thickness was compared between the subgroups according to the presence of visual field defects in preperimetric glaucoma. A visual field defect was defined as the presence of points at P < 0.01 on the pattern
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deviation plot in FDT 10-2 or SAP 10-2 using size III. Receiver operating characteristic (ROC) curves and area under the receiver operating characteristic (AUC) curves were built with continuous categories obtained from the GCIPL thicknesses in order to determine the discriminatory capabilities between preperimetric glaucoma patients with abnormalities on VF 10-2 and those without. For AUCs, abnormalities on VF 10-2 were defined as points at P < 0.01 on the pattern deviation plot both in FDT 10-2 or SAP 10-2 III. In all analyses, P < 0.05 indicated statistical significance.
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Statistics Differences between the SAP 10-2 (III) and FDT 10-2 were evaluated by a paired t test. Correlations between VF parameters and GCIPL variables were assessed based on Pearson’s correlation coefficients. To compare the correlation between VF tests, a Hotelling-Williams test was used. With regard to Pearson’s correlation coefficients, the correction was not done for multiple comparisons because this study was an explorative trial and to minimize the risk of type II errors. SPSS software (ver. 17.0; SPSS Inc., Chicago, IL) was used for all statistical analyses.
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Summary of Overall Study Design At first, conventional SAP 10-2 using size III and FDT 10-2 were compared in their ability to detect early functional loss using the significantly depressed points in the pattern deviation plot in patients with preperimetric glaucoma and perimetric glaucoma with paracentral scotoma. Secondly, the structure-function relationship was investigated using conventional SAP 10-2 III, SAP 10-2 V and FDT 10-2 in patients with preperimetric glaucoma and perimetric glaucoma with paracentral scotoma. Third, we also determined the characteristics of GCIPL thickness in preperimetric glaucoma patients with abnormalities on 10-2 VF tests.
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Results
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Data from 102 patients with preperimetric glaucoma, 45 patients with isolated paracentral scotoma, and 43 patients with combined paracentral scotoma were analyzed. Demographics of each group are shown in Table 1. The MD of SAP 24-2 was -1.0±1.3 in the preperimetric glaucoma patients, -2.4±1.9 in the isolated paracentral scotoma patients, -5.6±3.6 in the combined paracentral scotoma patients (P<0.001).
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MD, PSD, and the abnormal points: SAP III vs FDT The MD of FDT 10-2 was lower than that of SAP 10-2 III in patients with preperimetric glaucoma, with isolated paracentral scotoma, and with combined paracentral scotoma (P <0.001, <0.001, 0.003, respectively). The PSD was greater in FDT 10-2 than in SAP 10-2 III in preperimetric glaucoma (P<0.001), but the reverse was noted in glaucoma patients with combined paracentral scotoma (P=0.015). In glaucoma patients with isolated paracentral scotoma, the PSD showed no significant difference between FDT 10-2 and SAP 10-2 III (P=0.202). The percentage of total VF points that were significantly depressed by < 5% and < 1% in the pattern deviation plot was higher in FDT 10-2 than in SAP 10-2 III in patients with preperimetric glaucoma (P<0.001, both; Fig.2). A total of 67 eyes (65.7%) had depressed points < 1% both in FDT 10-2 and SAP 10-2 III (Fig.3). Structure-Function Relationship: SAP III vs SAP V vs FDT
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Global The global structure-function relationship is shown in Fig.4. In preperimetric glaucoma, the average GCIPL thickness had a positive correlation with MS in SAP 10-2 III (r=0.292, P=0.004) and FDT 10-2 (r=0.288, P=0.004), but not with SAP 10-2 V (r=0.088, P=0.389). SAP 10-2 III and FDT 10-2 revealed stronger correlations than SAP 10-2 V (P=0.026, 0.030, respectively). In glaucoma with an isolated paracentral scotoma, the correlation between average GCIPL thickness and MS in VF 10-2 was significant in SAP 10-2 V (r=0.437, P=0.003) and FDT 10-2 (r=0.496, P=0.001), but not in SAP 10-2 III (r=0.276, P=0.070). In glaucoma patients with a combined paracentral scotoma, all VF showed a positive correlation with average GCIPL thickness (SAP 10-2 III, r=0.377, P=0.014; SAP 10-2 V, r=0.389, P=0.011; FDT 10-2, r=0.704, P<0.001). In the comparison between each VF test, FDT 10-2 revealed a higher correlation than SAP 10-2 III or V (P<0.001, both). Topographic In preperimetric glaucoma, SAP 10-2 III and FDT 10-2 showed a significant correlation between the sectoral GCIPL thickness and the corresponding MS in all sectors (SAP III, r=0.252-0.372, all P<0.02; FDT 10-2, r=0.303-0.449, all P<0.01; Table 2). In SAP 10-2 V, the topographic structure-function correlation was significant only in the superotemporal sector (r=0.209, P=0.040). FDT 10-2 showed significantly higher correlations on two sectors in comparison with SAP 10-2 V. In patients with an isolated paracentral scotoma, SAP 10-2 V and FDT 10-2 exhibited a positive correlation between the sectoral GCIPL thickness and the corresponding MS in all sectors (SAP 10-2 V, r=0.372-0.526, all P<0.02; FDT 10-2,
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r=0.444-0.691, all P<0.01). In SAP 10-2 III, the topographic structure-function correlation was significant only in the inferotemporal and inferonasal sectors (r=0.465, P=0.002; r=0.499, P=0.001, respectively). FDT 10-2 showed a higher correlation between the inferotemporal or superonasal GCIPL thickness and the corresponding MS compared to SAP 10-2 III (P=0.002, 0.023, respectively), and between the inferotemporal GCIPL thickness and the corresponding MS compared to SAP 10-2 V (P=0.04). In glaucoma patients with a combined paracentral scotoma, the structure-function relationship was significant in all sectors using SAP 10-2 III, SAP 10-2 V, or FDT 102. The correlations between the inferotemporal, superonasal, and inferonasal sectors and the corresponding VF sensitivities were greater in FDT 10-2 than in SAP 10-2 III or V (all P <0.02).
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GCIPL thickness in preperimetric glaucoma: SAP III vs FDT The preperimetric glaucoma patients showing a VF abnormality on FDT 10-2 showed thinner average, minimum, superior, inferior, and inferotemporal GCIPL thicknesses than those without a VF abnormality (P=0.032, 0.001, 0.041, 0.017, 0.006, respectively; Table 3). Average, minimum, superior, inferonasal, inferior, inferotemporal, and superotemporal GCIPL thicknesses were thinner in eyes with a VF defect on SAP 10-2 III compared to those without a VF defect (P=0.005, <0.001, 0.044, 0.010, 0.003, 0.002, 0.023, respectively). Among GCIPL parameters, minimum (AUC, 0.635; 95% CI, 0.521-0.749) and inferior (AUC, 0.637; 95% CI, 0.522-0.751) GCIPL thicknesses had the largest AUC for discriminating the presence of a VF 10-2 defect in preperimetric glaucoma. (Supplemental table 1; Supplemental Material available at AJO.com).
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A representative case A 52-year-old female showed a localized RNFL defect and thin GCIPL thickness at the inferior and inferotemporal sectors (Fig.5). No definitive VF defect was shown in SAP 24-2 and SAP 10-2 III. On FDT 10-2 testing, a superior paracentral VF defect was distinct, corresponding to a thin inferior GCIPL thickness
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In this study, FDT 10-2 detected macular damage earlier than SAP 10-2 III in preperimetric glaucoma. In terms of topographic structure-function relationship, FDT 10-2 also performed better than SAP 10-2 III or SAP 10-2 V from preperimetric glaucoma to perimetric glaucoma. Patients who presented with an abnormality on FDT 10-2 or SAP 10-2 III were more likely to be associated with a thinner GCIPL thickness than those without an abnormality on VF 10-2 tests. Earlier detection of macular damage with SAP 10-2 compared to SAP 24-2 has been reported in several studies on glaucoma because VF test points are more densely located.6-8 In 10-2 VF tests, more closely spaced test points can lead to good sampling of the macular area. However, even the conventional 10-2 SAP using the stimulus with a diameter of 0.43° only tests ab out 3.14 % ([π {0.43°/2 2 x 68]/[π X10°x10°] x 100) of the total area within 10° and th erefore a substantial amount of macular area may be missed (about 97%). The 10-2 FDT tests employ a target of 2°, which is larger than size III (0.43°) commonly used in SAP 10-2. An untested area can be smaller in the FDT than in the SAP with a stimulus of sizes III because the larger stimulus is used in the FDT. A target of 2° in FDT 10-2 is similar to a size V stimulus (1.72°) in SAP. In this study, FDT 10-2 wa s compared with the SAP 10-2 both by size III and V stimuli because the difference between SAP 10-2 and FDT 102 could be attributable to the stimulus size or different stimulus characteristics itself.
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Preperimetric Glaucoma The proportion of depressed < 5% and < 1% points in the pattern deviation plot were greater in FDT 10-2 than in SAP 10-2 III in preperimetric glaucoma (P<0.001). That is, it seemed that FDT 10-2 was able to detect glaucomatous macular damage earlier than SAP 10-2 III. Using the topographic structure-function relationship, inferotemporal GCIPL thickness showed a better correlation with FDT 10-2 than with SAP 10-2 III or V in preperimetric glaucoma. Eyes with abnormal points on FDT 10-2 showed a thinner GCIPL thickness than those without. This finding supports the hypothesis that abnormalities in FDT 10-2 are definitely related to structural glaucomatous loss in the macular area. The ROC for the common VF defects in FDT 10-2 and SAP 10-2 III was significant for minimum and inferior GCIPL thicknesses. Therefore, functional analysis of macular damage from FDT 10-2 or SAP 10-2 III may be helpful for preperimetric glaucoma patients with thin minimum and inferior GCIPL thicknesses.
Perimetric Glaucoma Topographic structure-function relationships for each VF test were more favorable with the FDT 10-2 test than SAP 10-2 III or V also in perimetric glaucoma. Good structure-function relationship of FDT 10-2 may not confirm that it is the best VF test because of inaccuracy of the structure and functional assessments and dissimilar measurement scales across FDT and SAP. However, MD, PSD, or pattern standard deviation map were not available for 10-2 SAP with size V stimuli. Therefore, the structure-function relationship was used in this study to compare each VF test including SAP 10-2 V. At least, FDT 10-2 tests can be considered a good functional strategy to detect glaucomatous damage of the macula also in perimetric glaucoma.
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Why did the FDT 10-2 perform well in preperimetric and perimetric glaucoma? SAP size V did not perform well in patients with preperimetric glaucoma in terms of the structure-function relationship. This could be explained by the fact that the larger stimulus target was found to decrease the depth of the defect and the ability to detect VF damage,20 even though a large stimulus such as size V has been found to have better test-retest variability and greater effective dynamic range than size III.21, 22 Therefore, the superior ability of FDT 10-2 in detecting early macular glaucomatous damage did not seem to be attributed to just the larger target size. The different stimulus characteristics between FDT and SAP may result in dissimilar responses from the retina and brain, and hence different VF sensitivities. The superior performance of FDT compared to SAP in glaucoma patients with paracentral scotoma might be due to the low redundancy of the magnocellular ganglion cells.23, 24 However, Swanson et al. recently reported that the conventional size III perimetric stimulus was more effective than the frequency-doubling stimulus in preferentially stimulating magnocellular ganglion cells compared with parvocellular ganglion cells in primates.25 The further studies are needed to investigate the precise underlying mechanism and the functional characteristics with regard to SAP and FDT.
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A comparison to a previous study In terms of the comparison between FDT 10-2 and SAP 10-2 III, Sun et al. reported that the average perimetric loss was comparable for FDT 10-2 and SAP 102 III in perimetric glaucoma (mean 24-2 SAP MD= -8.92±7.9 dB).26 Their study is in accordance with our study regarding some aspects of perimetric glaucoma. In perimetric glaucoma with combined paracentral scotoma (mean 24-2 SAP MD=5.6±3.6 dB), MD was lower in FDT 10-2 but PSD were higher in SAP 10-2. The proportion of depressed points on the pattern deviation plot differed between FDT 10-2 and SAP 10-2 III only in preperimetric glaucoma whereas they were similar between VFs in perimetric glaucoma. Given these findings, overall perimetric loss seemed to be similar between FDT 10-2 and SAP 10-2 III in perimetric glaucoma.
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Study Limitations There are several limitations in this study. First, SAP 10-2 III or V uses a 2°x 2° grid constantly with a total of 68 test points. In FDT 10-2, a 2° grid is used within a central 5° of VF, and a 3 ° grid outside a central 5° of VF, yielding a total of 44 test points. However, FDT 10-2 performed well in detecting macular damage in preperimetric glaucoma even though there were fewer test points than in SAP 10-2. Second, SAP 10-2 using size V was performed with a FASTPAC algorithm since the SITA program was unavailable for size V stimuli and test time was shorter than standard threshold tests without significant deterioration in the detection of VF defects.27 One report found that an intra-test variance was greater with the FASTPAC algorithm than with the standard full-threshold strategy. However, the FASTPAC algorithm was used for size V SAP 10-2 in this study. Size V has been found to have better test-retest variability than size III.22 Therefore, decreased variability using size V might offset the intra-test variance when using the FASTPAC program. Third, for the topographic structure-function relationship, FDT 10-2 presented a more favorable correlation with the GCIPL thickness than SAP 10-2 III or V in perimetric glaucoma with combined paracentral scotoma. However, glaucoma
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Conclusions To the best our knowledge, there have been no prior reports on the ability of the FDT 10-2 test in detecting glaucomatous damage in preperimetric glaucoma. FDT 10-2 was found to detect functional damage early in preperimetric glaucoma, and perform better than SAP 10-2 tests from preperimetric to perimetric glaucoma as a functional assessment of glaucoma. FDT 10-2 tests can be considered a functional strategy especially if preperimetric glaucoma patients present with thin GCIPL thickness.
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A. Funding/support: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C1940). The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. B. All authors declare that no competing interests exist with the funder.
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1. Kolker AE. Visual prognosis in advanced glaucoma: a comparison of medical and surgical therapy for retention of vision in 101 eyes with advanced glaucoma. Trans Am Ophthalmol Soc 1977;75:539-555.
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2. Coeckelbergh TR, Brouwer WH, Cornelissen FW, Van Wolffelaar P, Kooijman AC. The effect of visual field defects on driving performance: a driving simulator study. Arch Ophthalmol 2002;120(11):1509-1516.
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3. Fujita K, Yasuda N, Oda K, Yuzawa M. [Reading performance in patients with central visual field disturbance due to glaucoma]. Nippon Ganka Gakkai Zasshi 2006;110(11):914-918. 4. Curcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol 1990;300(1):5-25.
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5. Park SC, Kung Y, Su D, et al. Parafoveal scotoma progression in glaucoma: Humphrey 10-2 versus 24-2 visual field analysis. Ophthalmology 2013;120(8):15461550. 6. Hangai M, Ikeda HO, Akagi T, Yoshimura N. Paracentral scotoma in glaucoma detected by 10-2 but not by 24-2 perimetry. Jpn J Ophthalmol 2014;58(2):188-196.
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7. Traynis I, De Moraes CG, Raza AS, Liebmann JM, Ritch R, Hood DC. Prevalence and nature of early glaucomatous defects in the central 10 degrees of the visual field. JAMA Ophthalmol 2014;132(3):291-297.
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8. Grillo LM, Wang DL, Ramachandran R, et al. The 24-2 Visual Field Test Misses Central Macular Damage Confirmed by the 10-2 Visual Field Test and Optical Coherence Tomography. Transl Vis Sci Technol 2016;5(2):15.
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9. Hayashi K, Araie M, Konno S, Tomidokoro A. Correlation of macular ganglion cell complex thickness with frequency-doubling technology perimetry in open-angle glaucoma with hemifield defects. J Glaucoma 2015. 10. Landers J, Goldberg I, Graham S. A comparison of short wavelength automated perimetry with frequency doubling perimetry for the early detection of visual field loss in ocular hypertension. Clin Experiment Ophthalmol 2000;28(4):248252. 11. Sample PA, Bosworth CF, Blumenthal EZ, Girkin C, Weinreb RN. Visual function-specific perimetry for indirect comparison of different ganglion cell populations in glaucoma. Invest Ophthalmol Vis Sci 2000;41(7):1783-1790. 12. Sample PA, Medeiros FA, Racette L, et al. Identifying glaucomatous vision loss with visual-function-specific perimetry in the diagnostic innovations in glaucoma study. Invest Ophthalmol Vis Sci 2006;47(8):3381-3389.
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13. Racette L, Medeiros FA, Zangwill LM, Ng D, Weinreb RN, Sample PA. Diagnostic accuracy of the Matrix 24-2 and original N-30 frequency-doubling technology tests compared with standard automated perimetry. Invest Ophthalmol Vis Sci 2008;49(3):954-960.
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14. Patel A, Wollstein G, Ishikawa H, Schuman JS. Comparison of visual field defects using matrix perimetry and standard achromatic perimetry. Ophthalmology 2007;114(3):480-487.
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15. Redmond T, O'Leary N, Hutchison DM, Nicolela MT, Artes PH, Chauhan BC. Visual field progression with frequency-doubling matrix perimetry and standard automated perimetry in patients with glaucoma and in healthy controls. JAMA Ophthalmol 2013;131(12):1565-1572.
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16. Jung KI, Kang MK, Choi JA, Shin HY, Park CK. Structure-Function Relationship in Glaucoma Patients With Parafoveal Versus Peripheral Nasal Scotoma. Invest Ophthalmol Vis Sci 2016;57(2):420-428. 17. Mwanza JC, Oakley JD, Budenz DL, Chang RT, Knight OJ, Feuer WJ. Macular ganglion cell-inner plexiform layer: automated detection and thickness reproducibility with spectral domain-optical coherence tomography in glaucoma. Invest Ophthalmol Vis Sci 2011;52(11):8323-8329.
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18. Shin HY, Park HY, Jung KI, Park CK. Comparative study of macular ganglion cell-inner plexiform layer and peripapillary retinal nerve fiber layer measurement: structure-function analysis. Invest Ophthalmol Vis Sci 2013;54(12):7344-7353. 19. Garway-Heath DF, Holder GE, Fitzke FW, Hitchings RA. Relationship between electrophysiological, psychophysical, and anatomical measurements in glaucoma. Invest Ophthalmol Vis Sci 2002;43(7):2213-2220.
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20. Wilensky JT, Mermelstein JR, Siegel HG. The use of different-sized stimuli in automated perimetry. Am J Ophthalmol 1986;101(6):710-713.
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21. Wall M, Woodward KR, Doyle CK, Zamba G. The effective dynamic ranges of standard automated perimetry sizes III and V and motion and matrix perimetry. Arch Ophthalmol 2010;128(5):570-576. 22. Wall M, Woodward KR, Doyle CK, Artes PH. Repeatability of automated perimetry: a comparison between standard automated perimetry with stimulus size III and V, matrix, and motion perimetry. Invest Ophthalmol Vis Sci 2009;50(2):974-979. 23. Anderson AJ, Johnson CA. Mechanisms isolated by frequency-doubling technology perimetry. Invest Ophthalmol Vis Sci 2002;43(2):398-401. 24. Leeprechanon N, Giangiacomo A, Fontana H, Hoffman D, Caprioli J. Frequency-doubling perimetry: comparison with standard automated perimetry to detect glaucoma. Am J Ophthalmol 2007;143(2):263-271.
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25. Swanson WH, Sun H, Lee BB, Cao D. Responses of primate retinal ganglion cells to perimetric stimuli. Invest Ophthalmol Vis Sci 2011;52(2):764-771. 26. Sun H, Dul MW, Swanson WH. Linearity can account for the similarity among conventional, frequency-doubling, and gabor-based perimetric tests in the glaucomatous macula. Optom Vis Sci 2006;83(7):455-465.
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27. Mills RP, Barnebey HS, Migliazzo CV, Li Y. Does saving time using FASTPAC or suprathreshold testing reduce quality of visual fields? Ophthalmology 1994;101(9):1596-1603.
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-Figure legends-
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Fig. 1 Topographic structure-function correspondence map according to GarwayHeath et al19. Sixty-eight VF test points on 10-2 standard automated perimetry (left) and 44 VF test points on 10-2 FDT (middle) were assigned to superotemporal, inferotemporal, superonasal, and inferonasal sectors (right). GCIPL, ganglion cell-inner plexiform layer; I, inferior; IN, inferonasal; IT, inferotemporal; S, superior; SN, superonasal; ST, superotemporal
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Fig. 2 The proportion of abnormal points significantly depressed by <5% and <1% in the pattern deviation plot. The percentage of points significantly depressed by <5% (upper row) and <1% (lower row) was greater using FDT 10-2 than with SAP 10-2 III in patients with preperimetric glaucoma (both P<0.001).
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Fig.3 Correspondence between 10-2 standard automated perimetry and 10-2 frequency doubling technology test. There were 67 patients (65.7%) showing depressed points < 1% both in FDT 10-2 and SAP 10-2 III among subjects with preperimetric glaucoma (n=102). Four patients (3.9%) showed depressed points < 1% only in SAP 10-2 III, and 31 patients (30.4%) exhibited abnormal points only in FDT 10-2.
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Fig. 4 Structure-function relationship between average Ganglion cell-inner plexiform layer (GCIPL) thickness and global mean sensitivity on 10-2 visual field tests. FDT 10-2 revealed a better correlation than SAP 10-2 V (P=0.030) in patients with preperimetric glaucoma. In glaucoma patients with combined paracentral scotoma, FDT 10-2 performed more favorably than SAP 10-2 III or SAP 10-2 V (both P<0.001).
Fig. 5 Representative case. A 52-year-old female exhibited a localized retinal nerve fiber layer defect (top left). Ganglion cell-inner plexiform layer (GCIPL) thickness of the inferior and inferotemporal sectors was thinner in the thickness parameter, and abnormal at < 1% level compared to normative data on a deviation map (top middle). Standard automated perimetry (SAP) 24-2 showed no abnormality (top right). SAP 10-2 III did not display any visual field defects (bottom left). A frequency doubling technology 10-2 test showed a superior paracentral scotoma corresponding to an inferior localized retinal nerve fiber layer defect and thin GCIPL thickness (bottom right).
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Combined paracentral scotoma (n=43)
P value
52.2±12.6 34/68 540.0±33.1
Isolated paracentral scotoma (n=45) 56.0±12.6 18/27 537.5±35.0
54.3±9.7 12/31 546.6±25.1
0.204 0.484 0.422
-2.4±3.3
-1.5±2.7
-1.5±2.7
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Table 1. Characteristics of glaucoma patients
24.7±1.7
24.2±1.3
24.2±1.4
0.086
75.3±8.9
69.1±11.0
67.7±9.2
<0.001
-1.0±1.3
-2.4±1.9
-5.6±3.6
<0.001
1.7±0.6
4.3±2.1
8.0±3.5
<0.001
0.120
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Age (years) Male/Female Central corneal thickness (µm) Spherical equivalent (diopter) Axial length (mm) Average GCIPL thickness (µm) SAP 24-2 MD (dB) SAP 24-2 PSD (dB)
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Parameter
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MD, mean deviation; PSD, pattern standard deviation; SAP, standard automated perimetry Continuous variables are expressed as n (percentage), mean ± standard deviation, or percentage.
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0.267 0.455 0.282 0.499 0.372 0.526 0.419* 0.508 0.444 0.691†‡ 0.567† 0.654
0.083 0.002 0.067 0.001 0.014 <0.001 0.005 0.001 0.003 <0.001 <0.001 <0.001
Combined paracentral scotoma
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ST IT SN IN SAP ST 10-2 (V) IT SN IN FDT ST 10-2 IT SN IN
P value 0.312 0.002 0.256 0.011 0.252* 0.013 0.372* <0.001 0.209 0.040 0.156 0.127 -0.006 0.951 0.170 0.097 0.324 0.001 0.449†‡ <0.001 0.303‡ 0.003 0.342 0.001 r
Isolated paracentral scotoma P value r
r
P value
0.559 0.407 0.538 0.467 0.570 0.473 0.550 0.429 0.648 0.739†‡ 0.710†‡ 0.724†‡
<0.001 0.008 <0.001 0.002 <0.001 0.002 <0.001 0.005 <0.001 <0.001 <0.001 <0.001
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SAP 10-2 (III)
Preperimetric
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FDT, frequency doubling technology; GCIPL, Ganglion cell-inner plexiform layer; SAP, standard automated perimetry; SD-OCT, spectral domain optical coherence tomography The cells of statistically significant values (P < 0.05) are highlighted. r=Pearson’s correlation coefficient * Statistically significant difference with P<0.05 between SAP 10-2 (III) and SAP 10-2 (V) † Statistically significant difference with P<0.05 between SAP 10-2 (III) and FDT 10-2 ‡ Statistically significant difference with P<0.05 between SAP 10-2 (V) and FDT 10-2
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75.9±9.4
79.4±9.6
0.141
69.7±10.1 71.3±10.4
75.8±10.5 78.4±8.9
0.017 0.006
74.4±11.0
78.0±8.6
0.168
P value
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0.032 0.001 0.041 0.339
P value
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Average (µm) Minimum (µm) Superior (µm) Superonasal (µm) Inferonasal (µm) Inferior (µm) Inferotemporal (µm) Superotemporal (µm)
Visual field defect (-) (n =21) 79.0±8.9 74.8±10.3 80.0±9.4 81.8±9.4
SAP 10-2 (III) Visual Visual field field defect (+) defect (-) (n =51 ) (n =46) 72.9±7.7 77.9±9.5 63.7±10.0 72.3±10.0 74.0±10.4 78.1±9.7 78.1±9.1 81.6±11.9
0.005 <0.001 0.044 0.105
74.3±9.1
79.3±9.3
0.010
68.1±9.8 69.8±9.6
74.3±10.3 76.3±10.5
0.003 0.002
72.9±8.1
77.7±12.3
0.023
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GCIPL thickness
FDT 10-2 Visual field defect (+) (n =81 ) 74.3±8.7 65.8±10.2 74.8±10.2 79.3±10.9
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FDT, frequency doubling technology; GCIPL, Ganglion cell-inner plexiform layer; SAP, standard automated perimetry
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