Hrev_master [page 38] [Eye Reports 2011; 1:e12] Optic disc parameters in manifest and suspected glaucoma Peter Wanger,1 Lucian Vancea,2 Lene Martin1,3 1Department of Clinical Neuroscience, Ophthalmology & Vision, Karolinska Institutet, Stockholm; 2Eye Clinic, Sundsvalls hospital, Sundsvall; 3Academy of Health and Welfare, Mälardalen University, Eskilstuna, Sweden Abstract Structure and function measurements are important in glaucoma management. Digital fundus photography has become a standard procedure and the Heidelberg Retina Tomograph (HRT), commonly used by glauco- ma specialists, provides a glaucoma probabili- ty score (GPS). The visual field index (VFI) is a novel statistic, aiming to facilitate follow-up of glaucoma patients. The aim of this study was to compare the results from the digital analysis of fundus photographs with HRT measurements including GPS and VFI in patients with ocular hypertension, suspect glaucoma or glaucoma, and if possible define an optic disc index, useful in glaucoma diagno- sis. Fifty-eight consecutive patients from a glaucoma service were included. Optic disc parameters (disc and cup areas) were meas- ured on digital fundus photographs, using a semi-automatic method, and compared with the GPS from the HRT and the VFI from stan- dard automated perimetry. A significant rela- tionship was observed between the GPS group classification (normal, borderline, or abnor- mal) and VFI classification (normal or abnor- mal), both when the GPS borderline group was regarded as normal (P = 0.0038 Fisher test) and as abnormal (P=0.0179, kappa = 0.33). No significant relationship was observed between VFI and optic disc parameters. The three- dimensional information in the GPS appears to be more related to visual function, as meas- ured by VFI, than the planimetric measures of the optic disc. Introduction Digital fundus cameras are a standard part of the ophthalmologic equipment, commonly used in screening for retinal disorders, such as age-related macular degeneration.1 Evaluation of the optic disc parameters on fundus photo- graphs is clinically relevant in glaucoma diag- nosis and follow-up2 and several algorithms have been evaluated for planimetric calcula- tion of optic nerve head parameters.3 Optic disc analysis can also be automatically per- formed with confocal scanning laser ophthal- moscopy4 using the Heidelberg Retinal Tomography, HRT (Heidelberg Engineering GmbH, Heidelberg, Germany). Recently, we developed a program which was designed to provide clinically relevant measures of optic disc parameters with a min- imum of user input.5 The program can be used directly on the acquired images, with the examined subject still available for re-exami- nation. In topographic analyses of the optic nerve the effect of disc size has to be taken into account.6 When calculating linear or area cup- to-disc ratios, small discs may be classified normal despite the presence of glaucoma and, vice versa, large discs may be falsely labelled as glaucomatous.7 Recently, a scoring system for evaluation of the optic disc in glaucoma was presented by the RAND study group8, which relied on estimation of both the cup-to- disc ratio and the disc size in order to over- come this drawback. The aim of this study was to compare the results from the digital analysis of fundus pho- tographs with HRT measurements including glaucoma probability score (GPS) and visual field index (VFI) in patients with ocular hyper- tension, suspect glaucoma, or glaucoma, and, if possible, define an optic disc index, useful in glaucoma diagnosis. Materials and Methods Subjects The patients were recruited from a glauco- ma service at a regional hospital. Inclusion cri- teria were as follows: primary open angle glau- coma (POAG), defined as intraocular pressure (IOP) >21 mmHg at two or more occasions AND either retinal nerve fiber layer (RNFL) defect or visual field (VF) defect, without other explanation, or both; suspected glaucoma, defined as either IOP >21 mmHg at two or more occasions OR either retinal RNFL defect or VF defect, without other explanation; ocular hypertension (OHT), defined as IOP >21 mmHg at two or more occasions with normal VF and no RNFL defect; and, normal tension glaucoma (NTG), defined as IOP <22 mmHg at two or more occasions AND either RNFL defect or VF defect, without other explanation, or both. Exclusion criteria were other disorders (such as optic nerve hypoplasia) that could influence the eye or vision and subjects with unreliable visual field results, defined accord- ing to the manufacturer’s manual. All patients had been examined at least twice at the glaucoma service and were sched- uled for follow-up. One eye from each of the 58 patients was randomly selected for analysis (Tables 1 and 2). All but 16 of the subjects had refraction within ± 3D (all refraction is expressed in spherical equivalent). One sub- ject had a hyperopia of +3.75D. The remaining subjects had moderate myopia (-3.5D to -6D; n=7) or high myopia (-6.75D to -14.75D; n=8). Methods All subjects underwent a standard clinical examination and visual field examination, using the Humphrey Visual Field Analyser (HFA), 24-2 Threshold test, Sita Fast (Carl Zeiss Meditec, Dublin, California, USA). Digital images of the optic nerve head (ONH) were obtained using the Heidelberg Retinal Tomography 3 (HRT3) (Heidelberg Engineering GmbH) and the Zeiss VISUPAC and FF 450plus telecentric fundus camera system (Carl Zeiss Meditec). Measurements of optic disc parame- ters were performed using the GPS calculations in the HRT. GPS makes a global assessment of the ONH by comparing the measured shape of the optic disc and the surrounding retina to a model for normal and glaucomatous optic nerves. The output of the program is a number between 0.00 and 1.00, which is classified as within normal limits (below 0.28), borderline (0.28 to 0.64) or outside normal limits (above 0.64).9 The quality of the images is evaluated by the HRT software and classified as excellent, very good, good, acceptable, poor or not usable (manufacturer’s manual). Only recordings with quality grade acceptable or better were used. The global GPS measure and the cup area (CA) measure were used. The Retinal Size Tool (RST) was used for measurements on the digital fundus photo- graphs.5 RST is a computer program developed in-house, that can be used on any digital fun- Eye Reports 2011; volume 1:e12 Correspondence: Lene Martin, Academy of Health and Welfare, Mälardalen University, PO Box 325, SE-631 05 Eskilstuna, Sweden. Tel. +46.161.532.02 - E-mail: lene.martin@mdh.se Key words: digital fundus photography, optic disc, heidelberg retina tomograph, glaucoma probabil- ity score, visual field index. Received for publication: 13 April 2011. Accepted for publication: 18 October 2011. This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BY- NC 3.0). ©Copyright P. Wanger et al., 2011 Licensee PAGEPress, Italy Eye Reports 2011; 1:e12 doi:10.4081/eye.2011.e12 Non -co mmerc ial us e o nly [Eye Reports 2011; 1:e12] [page 39] dus photograph where both the macula and the ONH are visible. Optic disc parameters, i.e. optic disc and cup, are assumed to be ellipti- cal,10 and the user marks the endpoints of their long and short diameters by mouse clicks. In order to compensate for differences in magni- fication due to camera and eye optics, the mac- ula-optic disc centre distance is used as refer- ence measure10-12 when converting pixel units to metric distance.5 This measure is reported to be quite constant among adults.13 The inter- operator agreement has been shown to be very good, both regarding disc and cup area (r=0.92 and 0.93, respectively).5 In the current study the cup area (CA), disc area (DA), and the quo- tient cup/disc area (CADA) were evaluated. The VFI14 in the HFA was used for compari- son with the structural measures. An HFA VFI >98% was regarded as a normal (Bengtsson, personal communication). The study was performed according to the Helsinki declaration and approved by the local ethical committee. Written informed consent was obtained from all patients prior to enrolment. Statistics For comparisons and correlations, the Fisher test, the Kruskall-Wallis non-parametric ANOVA-test and the Spearman Correlation test were used. Binary logistic regression was used in an attempt to define a diagnostic index based on the measurement on the fundus pho- tographs. Results Optic disc parameters in Heidelberg Retina Tomograph 3 and Retinal Size Tool Table 3 show the disc parameters in all sub- jects measured both with the RST (CA, DA, CADA) and the HRT GPS (CA). There was a strong correlation in the total group (r2=0.63; P<0.0001) between the CA measurements per- formed by the GPS and the RST, and no differ- ence in median value (0.46 in both measures). The CA’s were significantly smaller in the high myopes, measured both with RST (median 0.33; P<0.0001) and GPS (median 0.32; P=0.004). Nineteen patients out of 58 (33%) had nor- mal optic discs according to the GPS program; 12 were judged as borderline, and 27 as abnor- mal (example discs shown in Figure 1). In the 8 patients with high myopia, 7 were classified as normal and 1 as borderline. Table 4 shows the disc parameters, measured by RST, in the three GPS groups. A significant difference was found in CA and CADA between the normal group and both the borderline and the abnormal group and in DA between the normal and the abnormal group (Table 5). CADA correlated significantly, but weakly with GPS (r2=0.19, P<0.001). Optic disc parameters and humphrey visual field analyzer visual field index Eighteen patients out of 58 (31%) had nor- mal visual fields according to the VFI, and 40 had subnormal VFI values. In the 8 patients with high myopia, 5 had normal VFI values. Table 6 shows the relationship between HFA VFI and disc parameters in all patients. There Article Table 3. Median values for disc parameters in relation to the degree of myopia. All (n=58) High myopes (n=8) Non high myopes (n=50) Median RST DA (mm2) 2.17 (1.19-3.23) 1.64 (1.42-2.14) 2.22 (1.19-3.23) Median RST CA (mm2) 0.46 (0.12-1.89) 0.33 (0.12-0.41) 0.56 (0.12-1.89) Median RST CADA (mm2) 0.11 (0.04-0.20) 0.1 (0.05-0.19) 0.11 (0.04-0.20) Median HRT GPS CA (mm2) 0.46 (0.09-1.11) 0.32 (0.15-0.30) 0.48 (0.09- 1.11) RST, retinal size tool; DA, disc area; CA, cup area; CADA, cup/disc area quotient; HRT, Heidelberg retinal tomography; GPS, glaucoma probabil- ity score. Values in parentheses represent the range of values. Table 4. Median values for retinal size tool disc parameters and humphrey visual field analyzer visual field index in the three glaucoma probability score classification groups. GPS normal GPS borderline GPS abnormal Number of subjects 19 12 27 Median RST DA (mm2) 1.67 (1.19-3.02) 2.15 (1.31-2.68) 2.32 (1.38-3.23) Median RST CA (mm2) 0.31 (0.12-0.65) 0.59 (0.13-1.04) 0.63 (0.17-1.89) Median RST CADA (mm2) 0.16 (0.07-0.32) 0.28 (0.1-0.41) 0.28 (0.08-0.59) Median HFA VFI (%) 99 (65-100) 97.5 (80-100) 97 (65-99) RST, retinal size tool; GPS, glaucoma probability score; DA, disc area; CA, cup area; CADA, cup/disc area quotient; HFA, humphrey visual field analyzer; VFI, visual field index. Values in parentheses represent the range of values. Table 2. Diagnoses in the studied group. OHT POAG NTG Glaucoma Glaucoma Suspect secondary to secondary to glaucoma pseudoexfoliation pigmentary dispersion Number of subjects 7 13 10 15 3 10 Suspected glaucoma consisted of POAG, NTG, and pseudoexfoliative glaucoma. Table 1. Age, gender and refraction (spherical equivalent). Median age (range) 64 (30-85) Gender (female/male) 31/27 Median refraction (range) -0.63 (-14.5 to +3.75) Refraction expressed as spherical equivalent. Table 5. ANOVA P-values of comparisons between GPS classifications for cup area, disc area, and cup/disc area quotient. CA DA CADA GPS classification Normal vs borderline <0.05 >0.05 <0.05 Normal vs abnormal <0.001 <0.001 <0.01 Borderline vs abnormal >0.05 >0.05 >0.05 CA, cup area; DA, disc area; CADA, cup/disc area quotient; GPS, glaucoma probability score; VFI, visual field index. Table 6. Relationship between humphrey visual field analyzer visual field index and median disc parameters. VFI normal (>98%) VFI abnormal (<=98%) Number of subjects 18 40 Median DA (mm2) 2.01 (1.19-3.02) 2.21 (1.23-3.23) Median CA (mm2) 0.43 (0.12-0.96) 0.5 (0.12-1.89) Median CADA (mm2) 0.22 (0.07-0.4) 0.23 (0.07-0.59) Median HRT GPS CA (mm2) 0.17 (0.02-0.7) 0.64 (0.08-0.92)* VFI, visual field index; DA, disc area; CA, cup area; CADA, cup/disc area quotient; HRT, Heidelberg retinal tomography; GPS, glaucoma proba- bility score; *P=0.001. Values in parentheses represent the range of values. Non -co mmerc ial us e o nly [page 40] [Eye Reports 2011; 1:e12] was a significant difference between VFI in the GPS normal group compared with the GPS abnormal group (<0.05) (Table 7). The corre- lation between VFI and GPS score was weak (r2=0.083, P=0.027). Regarding classification, a significant relationship was observed between the GPS group classification (normal, borderline, or abnormal) and VFI classification (normal or abnormal), both when the GPS bor- derline group was regarded as normal and as abnormal (Tables 7 and 8). There was no cor- relation between CADA and VFI (r2=0.006, P = 0.56). A logistic regression equation based on DA and CADA did not discriminate between subjects with normal and abnormal VFI. Discussion Optic disc parameters in Heidelberg Retina Tomograph 3 and Retinal Size Tool and GPS classifications In a previous study, comparing disc meas- urements from RST and HRT3 in non-glauco- matous subjects, no significant difference between the measurements were found either in DA or in CA.5 This observation was con- firmed regarding CA in the current study of glaucoma subjects, but could not be confirmed regarding the DA, since the GPS program does not report this measure. It is well known that disc size influences the ability to classify the optic disc as normal or glaucomatous.6,8,9 This influence is true also for the HRT3 GPS classification.9 In the current study, the largest discs, median disc area of 2.32 mm2, were found in the GPS abnormal group, compared to median disc area of 2.15 mm2 in the GPS borderline group, and median disc area of 1.67 mm2 in the GPS normal group. For use in glaucoma management, the RAND system8 defines a score for the linear cup to disc ratio (CDR): score of 0 is CDR < 0.5, score 1 is CDR 0.5 to < 0.7, score 2 is CDR 0.7 to 0.9, and score 4 is CDR > 0.9, and the RAND system adjusts this score by subtracting one unit if the DA is ophthalmoscopically judged to be large and adding one unit if the DA is judged to be small. In the current study, which included patients with no or low degree of glaucomatous ON damage, binary logistic regression showed no significant effects of combining optic disc parameters for the iden- tification of eyes with abnormal VFI. Thus, the significant relationship between GPS and VFI appears to depend on the three-dimensional analysis of the neuro-retinal rim area per- formed by the HRT. A weakness in the RST method is that notching of the rim area is not visible in the measurement values. However, visual evaluation of the fundus photographs revealed notching in one eye only. The concor- dance between GPS and VFI in classification as normal and abnormal was moderate. Alencar, et al.15 reported that GPS values were predic- tive of conversion in a population of patients with suspected glaucoma. Thus, the combina- tion of GPS and VFI data may provide an easily analyzed basis for decision-making in glauco- ma management. Conclusions A statistically significant relationship was found between HRT GPS and HFA VFI, but not between optic disc parameters, obtained by planimetric measurements on digital fundus photographs. The three-dimensional informa- tion in the GPS appears to be more related to visual function, as measured by VFI, than the planimetric measures of the optic disc. References 1. Sheidow PT, Hooper P. Prospective evalua- tion of digital non-stereo color fundus pho- tography as a screening tool in age-related macular degeneration. Am J Ophthalmol 2005;139:455-61. 2. O'Leary N, Crabb DP, Mansberger SL, et al. Glaucomatous progression in series of stereoscopic photographs and Heidelberg retina tomograph images. Arch Ophthalmol 2010;128:560-8. 3. Laemmer R, Schroeder S, Martus P, et al. Quantification of neuroretinal rim loss using digital planimetry in long-term fol- low-up of normals and patients with ocular hypertension. J Glaucoma 2007;16:430-6. 4. Chauhan BC, Hutchison DM, Artes PH, et al. Optic disc progression in glaucoma: comparison of confocal scanning laser tomography to optic disc photographs in a prospective study. Invest Ophthalmol Vis Sci 2009;50:1682-91. 5. Bartling H, Wanger P, Martin L. Measure- ment of optic disc parameters on digital fundus photographs – algorithm develop- ment and evaluation. Acta Ophthalmol Scand 2008;86:837-41. 6. Heijl A, Mölder H. Optic disc diameter influences the ability to detect glaucoma- tous disc damage. Acta Ophthalmol (Copenh) 1993;71:122-9. 7. Hoesl LM, Mardin CY, Horn FK, et al. Influence of glaucomatous damage and optic disc size on glaucoma detection by scanning laser tomography. J Glaucoma 2009;18:385-9. 8. RAND Study Group. For which glaucoma suspects is it appropriate to initiate treat- Article Figure 1. Examples of optic discs with dif- ferent glaucoma probability score classifi- cations and visual field index findings. (A) Female born 1944, with OHT, GPS nor- mal, RST CA/DA 0.19,VFI 99%; (B) Male born 1938, with pseudoexfoliation, GPS borderline, RST CA/DA 0.22, VFI 93%; and (C) Male born 1948, with NTG, GPS abnormal, RST CA/DA 0.64, VFI 83%.OHT, ocular hypertension; GPS, glaucoma probability score; RST, Retinal Size Tool; CADA, cup/disc area quotient in mm2; VFI, visual field index; NTG, normal tension glaucoma. Table 8. Relationship between glaucoma prob- ability score (GPS) grouping and normal/ abnormal visual field index, when the GPS borderline group was regarded as abnormal. GPS normal GPS borderline or abnormal VFI >98 10 8 VFI <=98 9 31 GPS, glaucoma probability score; VFI, visual field index; P=0.0179 Fischer test; kappa = 0.33. A B C Table 7. Relationship between glaucoma prob- ability score (GPS) grouping and normal/ abnormal visual field index, when the GPS borderline group was regarded as normal. GPS normal or GPS abnormal borderline VFI > 98 15 3 VFI ≤=98 16 24 GPS, glaucoma probability score; VFI, visual field index; P, 0.0038 Fisher test; kappa = 0.36. Non -co mmerc ial us e o nly [Eye Reports 2011; 1:e12] [page 41] ment? Ophthalmology 2009;116:710-16. 9. Strouthidis NG, Garway-Heath DF. New developments in Heidelberg retina tomo- graph for glaucoma. Curr Opin Ophthalmol 2008;19:141-8. 10. Williams TD. Elliptical features of the human optic nerve head. Am J Optom Physiol Opt 1987;64:172-8. 11. Wakakura M, Alvarez E. A simple clinical method of assessing patients with optic nerve hypoplasia. The disc-macula dis- tance to disc diameter ratio (DM/DD). Acta Ophthalmol (Copenh) 1987;65:612-7. 12. Williams TD, Wilkingson JM. Position of the fovea centralis with respect to the optic nerve head. Optom Vis Sci 1992;69;369-77. 13. Mok KH, Lee VW. Disk-to-macula distance to disc-diameter ratio for optic disc size estimation. J Glaucoma 2002;11:392-5. 14. Bengtsson B, Heijl A. A visual field index for calculation of glaucoma rate of progres- sion. Am J Ophthalmol 2008;145:343-53. 15. Alencar LM, Bowd C, Weinreb RN, et al. Comparison of HRT-3 glaucoma probabili- ty score and subjective stereophotograph assessment for prediction of progression Article Non -co mmerc ial us e o nly