Jpn J Ophthalmol (2013) 57:529–539 DOI 10.1007/s10384-013-0270-8
CLINICAL INVESTIGATION
Comparison of ability of time-domain and spectral-domain optical coherence tomography to detect diffuse retinal nerve fiber layer atrophy Ko Eun Kim • Seok Hwan Kim • Jin Wook Jeoung Ki Ho Park • Tae Woo Kim • Dong Myung Kim
•
Received: 27 February 2013 / Accepted: 21 June 2013 / Published online: 3 September 2013 Ó Japanese Ophthalmological Society 2013
Abstract Purpose Our aim was to evaluate and compare diagnostic capabilities of time-domain (Stratus) and spectral-domain (Cirrus) optical coherence tomography (OCT) to detect diffuse retinal nerve fiber layer (RNFL) atrophy. Methods This study assessed 101 eyes from 101 glaucoma patients with diffuse RNFL atrophy and 101 eyes from 101 age-matched healthy individuals. Two experienced glaucoma specialists graded red-free RNFL photographs of eyes with diffuse RNFL atrophy using a fourlevel grading system. The area under the receiver operating characteristic curves (AUC) of normal eyes was compared with that of eyes with diffuse atrophy. Sensitivity and specificity of each OCT device were calculated on the basis of its internal normative database.
Electronic supplementary material The online version of this article (doi:10.1007/s10384-013-0270-8) contains supplementary material, which is available to authorized users. K. E. Kim S. H. Kim J. W. Jeoung K. H. Park T. W. Kim D. M. Kim Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea K. E. Kim J. W. Jeoung K. H. Park D. M. Kim Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea S. H. Kim (&) Department of Ophthalmology, Seoul National University Boramae Hospital, 425 Shindaebang-dong, Dongjak-gu, Seoul 156-707, Korea e-mail:
[email protected] T. W. Kim Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea
Results The largest AUC for Stratus and Cirrus were obtained for average RNFL thicknesses (0.96 and 0.94, respectively). Comparison of the AUC with different RNFL atrophy grades revealed no significant difference between the two OCT devices. Using an internal normative database at a \5 % level, the overall sensitivity of Stratus ranged from 58.0 to 84.0 %, whereas that of Cirrus ranged from 75.0 to 87.0 %. According to the normative database, the highest Stratus sensitivity was obtained with the temporal–superior–nasal–inferior–temporal (TSNIT) thickness graph, and the highest Cirrus sensitivity with the TSNIT thickness graph and the deviation map. Conclusions The AUC obtained from Cirrus were comparable with those from Stratus. On the basis of their normative databases, these devices had similar diagnostic accuracy. Our results suggest that the diagnostic capabilities of the two instruments to detect diffuse RNFL atrophy are similar. Keywords Cirrus OCT Stratus OCT Diffuse retinal nerve fiber layer atrophy Glaucoma Diagnostic accuracy
Introduction Retinal nerve fiber layer (RNFL) atrophy is the first anatomic sign of optic nerve damage, and qualitative and quantitative RNFL evaluation is of great importance for diagnosing glaucomatous optic neuropathy [1–3]. Among the techniques used for RNFL evaluation, red-free RNFL photography provides a qualitative or semiquantitative reference for structural RNFL damage and is capable of detecting early glaucomatous changes. However, this
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technique has limitations, including subjective interpretation and the necessity for experienced photographers. An advanced, more objective and reproducible technology, namely, optical coherence tomography (OCT), has opened up an era of quantitative evaluation of RNFL thickness with high resolution in real time [4–8]. RNFL atrophy can be divided into diffuse atrophy and localized RNFL defects, the former of which is more common [9]. However, compared with localized RNFL defects, diffuse RNFL atrophy is more difficult to detect with red-free RNFL photographs and requires an experienced ophthalmologist [9]. This is a critical issue in clinical practice, because it is often difficult to discriminate normal eyes from eyes with diffuse atrophy by red-free RNFL photography. Moreover, glaucomatous optic disc changes may not be seen, or the visual field may be normal in eyes with mild diffuse atrophy, which might lead to overdiagnosis or underdiagnosis of glaucoma. Therefore, OCT, which measures RNFL thickness quantitatively, might be useful for discriminating normal eyes from those with diffuse atrophy. To date, several studies [2, 10, 11] have focused on the ability of OCT in eyes with a localized defect, but only limited information is available regarding the diagnostic accuracy of OCT for identifying diffuse RNFL atrophy. Our group reported that time-domain Stratus OCT RNFL thickness parameters show excellent quantitative correlation with the degree of diffuse RNFL atrophy [12]. We also reported that Stratus with a normative database can detect diffuse RNFL atrophy with moderate sensitivity and high specificity [13]. Recently, spectral-domain Cirrus OCT with more advanced and enhanced high-definition scans was introduced and provides data with maximum accuracy and precision [14, 15]. Several studies compared the diagnostic abilities of Cirrus and Stratus [14, 16–18]. However, there are no reports comparing the capabilities of these two devices to detect diffuse RNFL atrophy. Therefore, we compared the diagnostic abilities of Stratus and Cirrus to detect diffuse RNFL atrophy previously shown on red-free RNFL photography by comparing the various RNFL thickness parameters. We also evaluated the sensitivity and specificity of these two devices on the basis of their normative classifications.
Materials and methods This study is part of the Diffuse Atrophy Imaging Study, which enrolled glaucoma patients with diffuse RNFL atrophy and healthy controls from the Glaucoma Clinic of the Seoul National University Boramae Hospital. The study conformed to the Declaration of Helsinki and was approved by the Institutional Review Board of the Seoul
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National University Boramae Hospital. Informed consent was obtained from all participants. Study participants Participants were enrolled from January 2009 through December 2011 and underwent complete ophthalmologic examination, including visual acuity, manifest refraction, and intraocular pressure (IOP) measurements using Goldmann applanation tonometry, slit-lamp examination, gonioscopy, dilated fundus examination, color sequential stereo-disc photography, red-free RNFL photography (TRC-50IX; Topcon, Tokyo, Japan), Swedish interactive threshold algorithm (SITA) 30-2 perimetry (Humphrey Field Analyzer II; Carl Zeiss Meditec, Dublin, CA, USA), Cirrus high-definition (HD)-OCT (Carl Zeiss Meditec), and Stratus OCT (Carl Zeiss Meditec). All examinations were conducted within a 3-month period. All participants had a best-corrected visual acuity of 20/40 or better, spherical equivalent refractive error within ±5.00 D, astigmatism within ±3.00 D, open anterior chamber angle on gonioscopy, good-quality color-disc and red-free RNFL photographs, and reliable OCT and visual fields, which are described in greater detail below. Individuals with a history of ocular surgery other than simple cataract extraction were excluded. We also excluded all individuals with diseases that may cause nonglaucomatous RNFL damage (e.g., diabetic retinopathy, hypertensive retinopathy, retinal vascular occlusion, or ischemic optic neuropathy), other diseases that may affect the peripapillary area where OCT measurements are obtained (e.g., chorioretinal coloboma, peripapillary staphyloma, or large peripapillary atrophy), or diseases with secondary symptoms of elevated IOP (e.g., uveitis, trauma, ocular malignancy). All eyes with unreliable redfree RNFL photographs, OCT measurements, or visual fields were excluded. To be included in the study, patients were required to have diffuse RNFL atrophy clearly visible on red-free RNFL photography as evaluated by two blinded glaucoma specialists (SHK and JWJ). Eyes with diffuse RNFL atrophy were defined as those with a generalized loss of RNFL visibility on red-free RNFL photography in the upper or lower retina without localized wedge-shaped RNFL defects, regardless of their width [12, 13]. In individuals in whom both eyes were eligible for the study, only one eye was randomly chosen for inclusion. Age-matched healthy controls met the following criteria: healthy individuals with IOP B21 mmHg by Goldmann applanation tonometry, no history of elevated IOP, no evidence of glaucomatous optic neuropathy, no visible RNFL defect of any type on red-free RNFL photographs, and normal visual field determined by standard automatic
OCT in detecting diffuse atrophy
perimetry (SAP). Glaucomatous optic neuropathy was defined as increased cupping (cup-to-disc ratio [0.6); cup/ disc asymmetry of [0.2 between the study and fellow eye; rim thinning, notching, or excavation; and absence of a neurologic disorder that could affect the optic nerve. A normal visual field was defined as a mean deviation (MD) and pattern standard deviation (PSD) within 95 % confidence limits, an absence of a cluster of C3 points with a P value of \0.05 on the pattern deviation plot, and a glaucoma hemifield test (GHT) result within normal limits. Color-disc and red-free RNFL photography Color disc and red-free RNFL photographs were obtained using a fundus digital camera after complete dilation. Fiftydegree views of the fundus, carefully focused on the retina using the built-in split-line focusing device, were obtained and reviewed on an liquid crystal display (LCD) monitor [12, 13]. Good-quality photographs required a well-focused and evenly illuminated image. Two experienced glaucoma specialists (SHK and JWJ) graded all photographs. First, presence of a glaucomatous optic-disc appearance and diffuse atrophy was determined by a consensus between specialists in a blinded fashion. Two observers independently classified eyes into one of the following categories: normal; localized RNFL defect; diffuse atrophy; coexisting localized RNFL defect; and ambiguous information. When either observer identified the red-free RNFL photograph as indicating a localized RNFL defect, a coexisting localized RNFL defect, or ambiguous information, those individuals were excluded from further analysis. Only participants classified by both observers as being either normal or having diffuse atrophy were included in control and diffuse atrophy groups, respectively. Second, diffuse RNFL atrophy was graded by the same observers by assessing the red-free RNFL photographs in a blinded fashion. Using the semiquantitative RNFL grading method described by Quigley and colleagues [19], diffuse RNFL atrophy was divided into four groups according to brightness, texture, and covering of blood vessels by nerve fibers in the superior and inferior poles: D0 (no atrophy), D1(mild), D2 (moderate), and D3 (severe). A score of D0 indicated healthy nerve fibers, whereas a score of D3 indicated severe RNFL damage, with clearly visible blood vessels and no visible RNFL fibers. For each method, superior and inferior arcuate bundles were scored separately. Grading of diffuse RNFL atrophy was determined by agreement between the specialists. Any disagreements were resolved through discussion, and a third specialist (KHP) was consulted, if necessary. Our previous study proved considerable interobserver agreement for this assessment (j statistics = 0.760 and 0.777 for superior and inferior RNFL areas, respectively) [12, 13].
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Optical coherence tomography Details of the Stratus and Cirrus techniques are described elsewhere [12, 13, 16]. All images were acquired by a single, well-trained technician. Image quality of both OCT scans was evaluated by the specialists in a blinded fashion. Cirrus (software version 3.0) uses spectral-domain technology of an optic disc cube obtained from a 3D data set composed of 200 A scans from each of 200 B scans that cover a 6-mm2 area centered on the optic disc. After generating an RNFL thickness map from the cube data set, the software automatically determines the center of the disc and then positions a calculation circle, which is 3.46 mm in diameter from the cube data set, for RNFL thickness measurement [14, 15]. Using these data, Cirrus provides 12-clock-hour thickness, four-quadrant thickness, global 360° average thickness, and temporal–superior–nasal– inferior–temporal (TSNIT) thickness profiles. For each parameter, Cirrus software provides a classification (within normal limits, borderline, or outside normal limits) based on comparison with an internal normative database. A parameter is classified as outside normal limits if it falls below the 99 % confidence interval (CI) of the healthy, age-matched population. A borderline result indicates that the value is between the 95 and 99 % CI. Segments of the TSNIT thickness graph located below the yellow band (outside the 95 % normal limit) and in the red band (outside the 99 % normal limit) were defined as an OCT RNFL defect on TSNIT graphs at the 5 and 1 % levels, respectively. Only accurate images with a signal strength of C6 (10 = maximum), no overt misalignment, and no overt decentration of the measurement circle location were included. Cirrus also provides RNFL thickness deviation maps that apply the yellow and red colors of the agematched normative data to superpixels in which average thickness falls in 1–5 % and \1 % of normal distribution percentiles, respectively. The fast RNFL mode of Stratus, which consists of a series of three consecutive 3.46-mm-diameter circumpapillary scans with 256 A scans obtained over 1.92 s, was used to obtain RNFL thickness measurements. Data were averaged to yield 12-clock-hour thicknesses, four-quadrant thicknesses, and a global average RNFL thickness measurement. For each parameter, Stratus software provides a classification (within normal limits, borderline, or outside normal limits) based on comparison with an internal normative database. In addition, OCT RNFL defects on TSNIT graphs were defined in the same way as for Cirrus. Good-quality scans had to have well-focused images, presence of a centered circular ring around the optic disc, and signal strength of C6 (10 = maximum). For both instruments, the average, four-quadrant (temporal, superior, nasal, inferior), and 12-clock-hour RNFL thickness
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values and classification according to an internal normative database were used. Additionally, TSNIT thickness graphs from Cirrus and Stratus and RNFL deviation maps from Cirrus were included. Right-eye orientation was used to document all OCT data. For both the right and the left eye, 12 o’clock corresponded to the superior region, 3 o’clock to the nasal region, 6 o’clock to the inferior region, and 9 o’clock to the temporal region. For both OCT systems, normative classification consisted of three categories: normal (5th–100th percentiles, white or green on the RNFL thickness map), borderline (1st–5th percentiles, yellow), and abnormal (less than 1st percentile, red). In our study, white and green were regarded as normal and yellow and red as abnormal. A yellow or red display in the quadrants, clock-hour segments, or TSNIT thickness graphs was defined as detection of an RNFL defect when it corresponded to the location of the diffuse RNFL atrophy observed on the red-free RNFL photograph. On the RNFL thickness-deviation maps, radiating defects from the optic nerve head, shown in yellow (\5 % level) or red (\1 % level), were defined as abnormal, and the radiating defect corresponding to the location on the red-free RNFL photograph was defined as detection of diffuse RNFL atrophy. The minimum width of a defect on RNFL deviation maps should be larger than that of a major retinal vessel at a onedisc-diameter distance from the edge of the disc [16]. Visual-field test Visual-field testing was performed using the 30-2 SITA standard test of the Humphrey Field Analyzer. Glaucomatous visual-field loss was defined as the consistent presence of a cluster of three or more nonedge points on the pattern deviation plot, with a probability of occurrence in \5 % of the normal population (P \ 0.05), with one of these points having the probability of occurring in \1 % of the normal population (P \ 0.01) in one hemisphere, a PSD with P \ 0.05, or a GHT result outside normal limits. Visual-field defects had to be repeatable on at least two consecutive tests at two separate visits within 3 months. Visual fields were evaluated for reliability and excluded if either: (1) the false-positive or falsenegative rate was C33 %, or (2) the fixation loss was C20 %.
K. E. Kim et al.
normative database were used. For RNFL thickness data, the area under the receiver operating characteristic curves (AUC) were used to compare the abilities of Cirrus and Stratus to detect diffuse RNFL atrophy. After comparing the general ability of each OCT to distinguish between glaucoma patients and healthy controls, the AUC of diffuse RNFL atrophy subgroups was compared between D0 and D1; D1 and D2; and D2 and D3. Multiple comparisons of RNFL thickness were performed with the Bonferroni adjustment. The DeLong [20] method was used to compare the AUC. Sensitivity and specificity of each OCT were evaluated on the basis of the internal normative database at a\5 % level.
Results This study initially involved 384 eyes from 384 individuals enrolled during the enrollment period (221 glaucoma patients and 163 healthy controls). Of these 384 eyes, 11 with unacceptable Cirrus scans and 27 with unacceptable Stratus scans were excluded from further analysis, leaving a sample of 346 eyes from 346 individuals (199 glaucoma patients and 147 healthy controls). Of the 199 glaucomatous eyes from 199 glaucoma patients, 98 had localized or coexisting RNFL defects (75 eyes), ambiguous information (8 eyes), or poor-quality scans (15 eyes). They were consequently excluded from further analysis. Therefore, the study sample involved 101 eyes with diffuse RNFL atrophy and 147 healthy control eyes. Of the 147 healthy control eyes, 101 eyes from 101 individuals were age matched and selected for further analysis. Demographic and baseline characteristics Table 1 presents clinical characteristics of the study population. No significant differences in age, sex, refractive error, or IOP between glaucoma and control groups were found. The MD of the visual-field test was -0.7 ± 1.8 dB in control eyes and -9.0 ± 8.2 dB in glaucomatous eyes (Table 1). RNFL thickness parameters for Stratus and Cirrus in control eyes and in eyes with diffuse atrophy are shown in Online resource 1. Demographic images of red-free RNFL photography, perimetry, and two OCT devices are shown in Fig. 1.
Statistical analysis Student’s t tests and chi-square tests were used to compare demographic and clinical data, including age, sex, spherical equivalent, IOP, MD, and PSD of the visual test. Statistical analysis was performed using IBM SPSS Statistics (version 18.0; SPSS, Chicago, IL, USA) or MedCalc (MedCalc Software, Mariakerke, Belgium). A probability value\0.05 was considered significant. Quantitative RNFL thickness data and diagnostic classification based on the internal
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AUC for Stratus and Cirrus OCT for various RNFL thickness parameters Table 2 presents a comparison of the overall AUC of various OCT RNFL thickness parameters of control and glaucomatous eyes. Both Stratus and Cirrus achieved the highest AUC (0.96 and 0.94, respectively) on the average RNFL thickness. No significant difference in AUC was found between the devices (P = 0.282). In addition, by comparing the AUC of
OCT in detecting diffuse atrophy Table 1 Clinical characteristics of the study population
BCVA best-corrected visual acuity, IOP intraocular pressure * Student’s t test, ** chi-square test
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Normal control (n = 101)
Diffuse atrophy (n = 101)
P value
Age (years)
60.4 ± 10.3
61.3 ± 12.5
0.254*
Gender (M:F)
49:52
55:46
0.400**
BCVA (logMAR)
0.0 ± 0.1
0.1 ± 0.2
0.665*
Refraction (spherical equivalent, D)
-0.1 ± 2.3
-0.2 ± 2.4
0.241*
IOP without medication (mmHg)
13.9 ± 3.2
15.0 ± 4.0
0.180*
Humphrey C30-2 threshold visual field Mean deviation (dB)
-0.7 ± 1.8
-9.0 ± 8.2
\0.001*
Pattern standard deviation (dB)
1.8 ± 0.4
7.3 ± 4.6
\0.001*
Fig. 1 Demographic images of a case of diffuse retinal nerve fiber layer (RNFL) atrophy. a Red-free RNFL photography with severe inferior diffuse RNFL atrophy (D3). b Pattern deviation map of visual field showing superior hemifield defect corresponding to the inferior diffuse atrophy. c Deviation map of Cirrus optical coherence
tomography (OCT) indicating inferior diffuse atrophy. OCT images showing circumpapillary RNFL thickness for quadrants and clockhour segments and temporal–superior–nasal–inferior–temporal thickness graph of d Stratus and e Cirrus OCT
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Table 2 Area under the receiver operating characteristic curves for Stratus and Cirrus OCT in various parameters of retinal nerve fiber layer thickness Stratus OCT
Cirrus OCT
P value*
0.96 (0.94–0.98)
0.94 (0.91–0.97)
0.282
Superior Temporal
0.93 (0.89–0.96) 0.79 (0.73–0.86)
0.89 (0.84–0.93) 0.78 (0.71–0.84)
0.191 0.830
Inferior
0.95 (0.92–0.98)
0.92 (0.88–0.96)
0.230
Nasal
0.75 (0.68–0.81)
0.62 (0.54–0.69)
0.013
Average Quadrant
Clock-hour segment 12 superior
0.89 (0.85–0.94)
0.84 (0.79–0.90)
0.151
11
0.90 (0.85–0.94)
0.84 (0.78–0.90)
0.120
10
0.76 (0.69–0.83)
0.76 (0.69–0.83)
1.000
9 temporal
0.66 (0.59–0.74)
0.64 (0.56–0.71)
0.720
8
0.82 (0.76–0.88)
0.77 (0.71–0.84)
0.270
7
0.93 (0.89–0.96)
0.91 (0.87–0.95)
0.480
6 inferior
0.92 (0.89–0.96)
0.88 (0.84–0.93)
0.191
5
0.82 (0.77–0.88)
0.77 (0.71–0.84)
0.263
4
0.70 (0.63–0.77)
0.58 (0.50–0.66)
0.030
3 nasal
0.67 (0.60–0.74)
0.53 (0.44–0.61)
0.012
2 1
0.78 (0.72–0.84) 0.87 (0.82–0.92)
0.69 (0.61–0.76) 0.77 (0.70–0.83)
0.066 0.016
databases. Using the criterion of abnormality set at a \5 % level, the highest overall sensitivity for Stratus was 84.0 %, obtained using the TSNIT thickness; for Cirrus, this value was 87.0 % and was obtained using the TSNIT thickness and the deviation map. The overall sensitivity and specificity of Cirrus were comparable to those of Stratus. Diagnostic sensitivity and specificity of various OCT RNFL parameters for different grades of diffuse RNFL atrophy Table 5 shows sensitivity and specificity of the various OCT RNFL parameters based on their internal normative values for different grades of diffuse RNFL atrophy. For both OCT devices, sensitivity tended to increase in accordance with the severity of RNFL damage. For grade D1 atrophy, using a criterion of abnormal set at\5 %, Stratus and Cirrus sensitivity ranged from 12.2 to 43.5 % and from 9.6 to 54.8 %, respectively. For grade D2 atrophy, sensitivity ranged from 16.0 to 76.0 % for Stratus and from 15.0 to 90.9 % for Cirrus. For grade D3 atrophy, sensitivities of Stratus and Cirrus were 96.9 and 100 %, respectively.
Bonferroni correction was used for multiple comparisons, and the significant cutoff value was set as 0.003, 0.05 divided by 17
Discussion
OCT optical coherence tomography
The OCT technique has greatly improved, and Cirrus, a fourth-generation spectral domain OCT, is now widely used. Previous studies report that Cirrus is more reproducible, offers better scan quality, and has lower measurement variability than Stratus [16, 21–23]. Therefore, when compared with Stratus, Cirrus is expected to have a better diagnostic accuracy for detecting glaucoma; however, this is debatable. Some authors [14, 24] report that Cirrus shows better diagnostic capability than did Stratus. On the other hand, other groups show that Cirrus diagnostic accuracy is equivalent to that of Stratus [21, 23, 25]. In addition, to the best of our knowledge, no other study has investigated the diagnostic ability of Cirrus to evaluate diffuse RNFL atrophy. Therefore, this study was designed to evaluate and compare the diagnostic abilities of Stratus and Cirrus for detecting glaucoma in eyes with diffuse RNFL atrophy. Our results show that the diagnostic capabilities of these devices to discriminate between healthy eyes and eyes with diffuse RNFL atrophy do not differ significantly. We obtained several measures of diagnostic accuracy for detecting glaucoma in eyes with diffuse RNFL atrophy, including AUC analysis from RNFL thickness parameters. We found that the largest AUC of Stratus and Cirrus were obtained when using the average RNFL thickness (0.96 and 0.94, respectively) and that the AUC of Cirrus RNFL thickness parameters for detecting diffuse RNFL atrophy
* Comparison was performed using the method of DeLong
the RNFL thickness measurements in each of the four quadrants and in each of the 12-clock-hour sectors, no significant difference was found between devices. Comparison of AUC of OCT RNFL thickness parameters between Stratus and Cirrus for different grades of diffuse RNFL atrophy Table 3 shows the comparison between the AUC of OCT parameters of Stratus and Cirrus for different grades of diffuse RNFL atrophy. Superior and inferior RNFL areas were separately analyzed. Among the D0 and D1 subgroups in the superior and inferior RNFL areas, the AUC of Cirrus was comparable with that of Stratus, and no significant differences were found between devices. Comparisons of D1 and D2 and D2 and D3 in the superior and inferior RNFL areas revealed that the AUC did not differ significantly between devices. Overall sensitivity and specificity of Stratus and Cirrus OCT based on internal normative databases Table 4 presents the overall sensitivity and specificity of Stratus and Cirrus based on their internal normative
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0.94 (0.90–0.98)
Superior quadrant
0.89 (0.81–0.97)
0.92 (0.87–0.98)
Average
Inferior quadrant
Inferior diffuse RNFL atrophy
0.58 (0.38–0.78)
0.84 (0.73–0.95)
0.91 (0.83–1.00)
0.81 (0.65–0.97)
5
6
7
8
0.65 (0.47–0.82)
0.85 (0.75–0.96)
0.67 (0.52–0.83)
0.53 (0.34–0.73)
0.55 (0.38–0.72)
0.86 (0.74–0.98)
0.78 (0.63–0.92)
Cirrus
OCT optical coherence tomography, RNFL retinal nerve fiber layer
0.57 (0.38–0.76)
4
Clock hours
0.56 (0.44–0.69)
0.67 (0.55–0.78)
0.192
0.393
0.076
0.722
0.877
0.358
0.179
P
0.120
0.092 0.66 (0.51–0.81)
0.64 (0.49–0.79)
0.73 (0.59–0.86) 0.73 (0.59–0.86)
0.80 (0.67–0.93)
0.71 (0.57–0.85)
0.72 (0.57–0.86)
0.84 (0.73–0.94) 0.71 (0.57–0.85)
0.64 (0.49–0.79)
0.83 (0.72–0.94)
0.74 (0.60–0.87)
0.76 (0.58–0.94)
0.57 (0.38–0.76)
0.77 (0.61–0.92)
0.92 (0.81–1.00)
0.75 (0.56–0.94)
0.65 (0.46–0.85)
0.92 (0.83–1.00)
0.65 (0.47–0.83)
0.88 (0.77–0.99)
0.94 (0.86–1.00)
0.77 (0.59–0.95)
0.55 (0.30–0.79)
0.98 (0.94–1.00)
0.84 (0.68–0.99)
Cirrus
Stratus
0.69 (0.59–0.80)
2
0.136 0.109
0.900
0.78 (0.65–0.90)
0.73 (0.60–0.87)
Stratus
0.80 (0.70–0.90)
1
0.91 (0.85–0.97) 0.78 (0.70–0.87)
0.76 (0.65–0.87)
0.109
0.773
D1 (n = 19) vs D2 (n = 25)
0.96 (0.98–0.99) 0.87 (0.80–0.93)
11 12
0.88 (0.82–0.94)
0.92 (0.87–0.97)
D0 (n = 101) vs D1 (n = 19)
0.77 (0.66–0.89)
10
Clock hours
0.93 (0.89–0.98)
Average
Superior diffuse RNFL atrophy
Cirrus
Stratus
P
Stratus
Cirrus
D1 (n = 31) vs D2 (n = 22)
D0 (n = 101) vs D1 (n = 31)
0.552
0.259
0.758
0.883
0.530
0.269
0.507
P
0.631
0.451
0.640 0.841
0.448
0.560
0.918
P
0.56 (0.37–0.76)
0.62 (0.43–0.81)
0.74 (0.57–0.90) 0.74 (0.57–0.90)
0.61 (0.42–0.80)
0.68 (0.50–0.85)
0.77 (0.61–0.92)
Cirrus
0.71 (0.58–0.85)
0.82 (0.71–0.93)
0.86 (0.77–0.96)
0.80 (0.68–0.92)
0.63 (0.49–0.78)
0.89 (0.80–0.98)
0.81 (0.69–0.92)
Stratus
0.62 (0.47–0.78)
0.71 (0.58–0.85)
0.75 (0.64–0.88)
0.66 (0.52–0.80)
0.52 (0.37–0.68)
0.79 (0.67–0.91)
0.74 (0.61–0.87)
Cirrus
D2 (n = 25) vs D3 (n = 32)
0.60 (0.41–0.79)
0.71 (0.53–0.90)
0.79 (0.65–0.94) 0.79 (0.65–0.94)
0.65 (0.46–0.84)
0.77 (0.62–0.92)
0.81 (0.67–0.95)
Stratus
D2 (n = 22) vs D3 (n = 16)
Table 3 Comparison of the area under the receiver operating characteristic curves between Stratus and Cirrus OCT parameters for different grades of diffuse RNFL atrophy
0.384
0.217
0.172
0.143
0.313
0.187
0.433
P
0.772
0.505
0.347 0.651
0.769
0.442
0.710
P
OCT in detecting diffuse atrophy 535
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536 Table 4 Overall sensitivity and specificity with 95 % confidence intervals of Stratus and Cirrus OCT based on the internal normative database
K. E. Kim et al.
Stratus
Cirrus
Sensitivity (%)
Specificity (%)
Sensitivity (%)
Specificity (%)
5 % level
81.0 (71.9–88.2)
91.0 (83.6–95.8)
84.0 (75.3–90.6)
85.0 (76.5–91.4)
1 % level
68.0 (57.9–77.0)
100 (96.4–100)
72.0 (62.1–80.5)
99.0 (94.6–100)
5 % level
73.0 (63.2–81.4)
99.0 (94.6–100)
81.0 (71.9–88.2)
89.0 (81.2-94.4)
1 % level
63.0 (52.8–72.4)
100 (96.4–100)
72.0 (62.1–80.5)
100 (96.4–100)
5 % level
58.0 (47.7–67.8)
100 (96.4–100)
75.0 (65.3–83.1)
97.0 (91.5–99.4)
1 % level
42.0 (32.2–52.3)
100 (96.4–100)
53.0 (42.8–63.1)
85.7 (71.5–94.6)
93.0 (86.1–97.1) 100 (96.4–100)
87.0 (78.8–92.9) 75.0 (65.3–83.1)
80.0 (70.8–87.3) 97.0 (91.5–99.4)
C1 clock hour
C1 quadrant
Average
TSNIT thickness graph
OCT optical coherence tomography, TSNIT temporal– superior–nasal–inferior– temporal, RNFL retinal nerve fiber layer
5 % level 1 % level
84.0 (75.3–90.6) 68.0 (57.9–77.0)
RNFL deviation map 5 % level
NA
NA
87.0 (78.8–92.9)
82.0 (73.1–89.0)
1 % level
NA
NA
77.0 (67.5–84.8)
96.0 (90.1–98.9)
did not significantly differ from Stratus parameters. Leung and colleagues [22] report that the AUC of the average or superior RNFL thickness of Cirrus (AUC 0.963) and Stratus (AUC 0.956) were largest and that no significant differences were detected for glaucoma identification, which accords with our results. Other studies show similar diagnostic capabilities between the two devices, reporting that the highest AUC ranged from 0.829 to 0.934 for Stratus and from 0.837 to 0.953 for Cirrus [24, 26]. However, owing to the different disease severities, inclusion criteria, and techniques used in those previous studies, direct comparison with our results is limited. This study demonstrates sensitivity and specificity based on the classification of the internal normative database. Prior studies comparing sensitivities and specificities of Stratus and Cirrus based on their internal normative databases revealed variable results for detecting glaucoma. As the normative databases differ between the two instruments, this could have affected results based on the internal normative classification in different study settings. Sung and colleagues [14] report that overall sensitivity and specificity were higher with Cirrus in the normative classification of average RNFL thickness. However, other studies report that for detecting glaucoma, Cirrus sensitivity was equivalent to or slightly better than that of Stratus, whereas Cirrus specificity was similar to or worse than that of Stratus [16, 18, 27]. In our study, using an internal normative database with a criterion of abnormal set at \5 %, Stratus sensitivity and specificity ranged from 58.0 to 84.0 % and from 91 to 100 %, respectively, whereas Cirrus sensitivity and specificity ranged from 75 to 87 % and from 80 to 100 %, respectively, suggesting
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that the diagnostic abilities of Cirrus and Stratus are similar. Previous studies report that the diagnostic performance of an imaging device depends on the severity of glaucomatous damage. Medeiros and colleagues [25] report that the severity of visual-field damage significant influences the sensitivity of imaging devices. Our previous study [13] also demonstrates that Stratus sensitivity tended to increase with increasing severity of RNFL damage. Thus, to determine the effect produced by severity of glaucomatous damage, we classified glaucoma patients according to the grading of diffuse RNFL atrophy. Average RNFL thickness measured by OCT or MD values of SAP might be more globalized standards reflecting glaucoma severity. However, the main purpose of our study was to compare diagnostic abilities of Cirrus with Stratus in individuals with diffuse RNFL atrophy on red-free RNFL photography. For that purpose, we used the semiquantitative RNFL grading method described by Quigley and colleagues [19]. To prove that grading by red-free RNFL photography can also reflect the global severity of glaucoma, we evaluated MD values of glaucoma patients in subgroups D1, D2, and D3. In subgroups with superior diffuse RNFL atrophy, MD values were -5.2 ± 4.6 dB in D1, -10.8 ± 7.9 dB in D2, and -21.7 ± 6.7 dB in D3, indicating significant difference in severity among subgroups [P \ 0.001, one-way analysis of variance (ANOVA), and Tukey post hoc test]. Similar results were shown in subgroups with inferior diffuse RNFL atrophy: MD values were -3.4 ± 2.6 dB in D1, -6.9 ± 4.6 dB in D2, and -18.6 ± 7.8 dB in D3 (P \ 0.001, one-way ANOVA, and Tukey post hoc test). Taken together, these findings show that Cirrus sensitivity
95.2
12.2 15.2
43.5
18.5
7
8
97.0
100.0
94.0 100.0
94.0
100.0
20.5
51.5
20.5 18.3
18.3
43.5
92.8
91.3
85.0 90.1
90.1
91.0
28.0
72.0
20.0 76.0
16.0
76.0
Sensitivity (%)
100.0
100.0
93.2 100.0
92.4
92.4
Specificity (%)
OCT optical coherence tomography, RNFL retinal nerve fiber layer, Sup superior, Inf inferior
Sensitivity and specificity of OCT parameters were tested using the criterion of abnormal at the 5 % level
12.2
5 6 Inf
36.8
4
Clock hours
Inferior quadrant
Inferior diffuse RNFL atrophy
Specificity (%)
Specificity (%)
27.3
95.2
Sensitivity (%)
95.2
27.3
95.2
Sensitivity (%)
9.6
98.0
50.0
100.0
100.0
95.2
Stratus
97.0
19.4
99.0
72.7
54.5
72.7
Cirrus
19.4
2
100.0
25.8
96.0
99.0
96.0
Stratus
16.1
1
100.0
54.8
38.7
45.2
Grade D2 atrophy (n = 25)
29.0
12 Sup
97.0
100.0
97.0
Specificity (%)
Grade D1 atrophy (n = 19)
41.9
25.8
Clock hours 10
11
38.7
Superior quadrant
Superior diffuse RNFL atrophy
Sensitivity (%)
Sensitivity (%)
Sensitivity (%)
Specificity (%)
Stratus
Cirrus
Stratus Specificity (%)
Grade D2 atrophy (n = 22)
Grade D1 atrophy (n = 31)
36.0
80.0
36.0 84.0
15.0
85.0
Sensitivity (%)
Cirrus
18.2
45.5
54.6
90.9
59.1
86.4
Sensitivity (%)
Cirrus
88.0
92.1
88.0 92.1
91.0
96.0
Specificity (%)
94.1
94.1
94.1
98.1
98.1
94.1
Specificity (%)
Table 5 Diagnostic sensitivity and specificity of the various OCT RNFL parameters for different grades of diffuse RNFL atrophy
93.2
93.2
100.0
100.0
93.2
100.0
Specificity (%)
56.3
96.9
71.9 96.9
28.1
96.9
Sensitivity (%)
Stratus
100.0
95.0
100.0 100.0
95.0
100.0
Specificity (%)
Grade D3 atrophy (n = 32)
43.8
68.8
93.8
93.8
68.8
93.8
Sensitivity (%)
Stratus
Grade D3 atrophy (n = 16)
37.5
100.0
50.0 93.8
15.6
100.0
Sensitivity (%)
Cirrus
37.5
75.0
81.3
100.0
50.0
100.0
Sensitivity (%)
Cirrus
88.2
94.2
85.0 94.2
88.2
94.2
Specificity (%)
90.1
93.2
93.2
93.2
90.1
90.1
Specificity (%)
OCT in detecting diffuse atrophy 537
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538
increased with increasing severity of RNFL damage, even in groups based on the RNFL grading method. Therefore, Cirrus, with an internal normative database, should be interpreted with caution, especially in the early stage of glaucoma with diffuse RNFL atrophy. RNFL thickness is quite variable in healthy individuals, with approximately a twofold difference between the 5th and 95th percentiles of a normative database. Owing to intersubject variability, RNFL thickness measured by OCT in patients with early glaucoma, even though it is in a decreasing state, may be classified as ‘‘normal,’’ because it does not reach the 5th percentile cutoff. Although the ethnic distribution of the Cirrus internal normative database has changed compared with that of Stratus, Cirrus still uses a specific cutoff level, which is an unchanged major limitation. This may explain the relatively low sensitivity of Cirrus for detecting early glaucoma eyes with diffuse atrophy. Software that can assess the decreasing trend in RNFL thickness instead of making comparisons with a normative database may improve the diagnostic ability of Cirrus. In conclusion, this study shows that Stratus and Cirrus did not differ significantly in detecting diffuse RNFL atrophy based on RNFL thickness parameters as well as in comparison with the internal normative database. Our study also shows that Cirrus sensitivity is closely related to the severity of diffuse RNFL atrophy. Although the overall results obtained for the two devices seem comparable, this study deals only with their diagnostic capabilities to detect diffuse RNFL atrophy, and thus, the use of Cirrus OCT should not be overlooked. Further studies with a larger number of individuals and a more ethnically diverse population are warranted. Acknowledgments This study was supported by grant number 04-2012-1325 from the Seoul National University Hospital Research Fund.
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