THE ABILITY OF THE HEIDELBERG RETINA TOMOGRAPH AND GDx TO DETECT PATIENTS WITH EARLY GLAUCOMA

ANNA J. KWARTZ, DAVID B. HENSON, A. FIONA SPENCER,

ROBERT A. HARPER and DAVID MCLEOD

Research Group in Eye and Vision Science, Royal Eye Hospital, School of Medicine, University of Manchester, Manchester, UK

Abstract

Purpose: To investigate the ability of the Heidelberg Retina Tomograph (HRT) and GDx to identify patients with early primary open-angle glaucoma. Methods: HRT and GDx measurements were taken from 19 patients who had recently developed repeatable perimetric defects (defined by the glaucoma hemifield test); optic nerve head characteristics were not used as diagnostic criteria. Imaging data were classified as abnormal if they fell beyond the 95% confidence interval of normality. HRT data took into account optic nerve head size (Moorfields’ regression analysis) and GDx data took into account the ‘number’, average thickness, ellipse modulation and total polar average. Results: The experimental group was aged 64.1 ± 9.4 years with early visual field loss (mean MD: -1.5 ± 1.6 dB). The sensitivity of HRT was 74% (95% CI: 54–93%). The sensitivity of the GDx ‘number’ was 16% (95% CI: 6–38%). Conclusions: HRT demonstrated better ability than GDx for detecting patients with early glaucomatous field defects. However, four patients (21%) were classified as being within normal limits by both instruments.

Introduction

The Heidelberg Retina Tomograph (HRT; Heidelberg Engineering, Germany) and GDx (Laser Diagnostic Technologies, Inc, San Diego, CA) both have the potential to provide useful clinical information to aid in the diagnosis of glaucoma. HRT is a confocal scanning laser ophthalmoscope, which provides a three-dimensional assessment of the optic disc, whilst GDx is a scanning laser polarimeter that estimates peripapillary retinal nerve fiber layer thickness. Within their clinical application, an area of fundamental interest is their diagnostic accuracy for detecting early glaucomatous optic neuropathy. HRT has the potential to perform this function, since it is widely accepted that the primary site of clinically detectable damage is the optic disc.1-3 GDx also has the theoretical ability to detect this stage of the condition be-

Address for correspondence: Anna Kwartz, MD, Academic Department of Ophthalmology, Royal Eye Hospital, Oxford Road, Manchester M13 9WH, UK. Email: anna.kwartz@man.ac.uk

Perimetry Update 2002/2003, pp. 299–307

Proceedings of the XVth International Perimetric Society Meeting, Stratford-upon-Avon, England, June 26–29, 2002

edited by David B. Henson and Michael Wall

© 2004 Kugler Publications, The Hague, The Netherlands

300 A.J. Kwartz et al.

cause detectable retinal nerve fiber loss can precede the development of visual field defects,4 with the loss of a significant proportion of retinal nerve fibers often occurring prior to the formation of statistically significant perimetric defects.5

Evaluation of previous research on the sensitivity and specificity of HRT and GDx is complicated by the selection of different levels of specificity. For the purposes of screening, it is generally accepted that high specificity is required when dealing with a low-prevalence disease (<1% of population >40 years of age have undetected glaucoma). Therefore, this study was chosen to set the cut-off criteria at the 95% confidence limit of normality.

In order to provide the instruments with a significant diagnostic challenge, the aim was to select a group of patients who had very recently developed detectable glaucomatous visual field defects; this is in contrast to other studies,6-10 in which the experimental groups included eyes with more advanced disease. The inclusion of more advanced cases will inflate sensitivity estimates.

Previous research has shown promising results for both instruments; however, some of these studies required significant amounts of supplementary analysis9,11,12 which would be difficult to incorporate within routine clinical practice. This paper reports on the diagnostic performance of the instruments in their standard mode, i.e., without any supplementary analysis. An example of the latter is the Moorfields’ regression analysis (MRA),13 which is an integral component of the HRT’s successor (HRT II) and has been shown to diagnose early glaucoma with a sensitivity and specificity of 84 and 96%, respectively, using the 99% prediction interval from the linear regression between optic disc area and the log of the neuro-retinal rim area. An example of supplementary data analysis is the GDx linear discriminant function.14

Methods

Patients were selected from those attending a large-scale longitudinal glaucoma study. Individuals were identified who had recently developed repeatable glaucomatous visual field defects, confirmed by two consecutive non-normal glaucoma hemifield test (GHT) results (borderline or outside normal limits).15 All perimetric tests were performed with the Humphrey 24-2 full threshold program and conformed to standard reliability levels (false positive and negative rates <33% and fixation losses <20%). Optic nerve head characteristics were not used for classification.16

At the examination session subsequent to perimetric conversion, five good quality images were obtained with HRT and GDx, the three best of which were used to compose a mean image. The decision that an image was of adequate quality, and the selection of the composite images for the mean, were the responsibility of the operator; this protocol was used to reflect, as closely as possible, the probable situation in a normal clinical environment. All operators were fully trained and highly experienced.

HRT data were analyzed with the MRA, with glaucoma being defined as a result exceeding the 95% confidence limit of normality. Four GDx parameters were investigated (the ‘number’, average thickness (AT), ellipse modulation (EM) and total polar average (TPA)). The relationship of AT, EM and TPA to the 95% confidence limit of the GDx internal normative database was noted. The 95% confidence limits for the

parameter the ‘number’ are not provided with the instrument. In order to overcome this problem, a sample of 44 normal control eyes was examined in order to derive estimates of the normal range of the ‘number’; this strategy was also applied to the other three GDx parameters. In addition, the ‘number’ was interpreted according to recommended guidelines,17 i.e., ≤ 30 is within normal limits, 31-70 is borderline, and ≥ 71 is indicative of glaucoma.

Results

The experimental group, comprising 19 subjects, was aged 64.09 ± 9.44 years (range, 44-77 years) and had Humphrey visual field analyzer mean deviation (MD) of -1.48

± 1.60 dB. The mean age of the normal control group was 59.25 ± 10.52 years, which was somewhat younger than the experimental group (p = 0.089; two-tailed t test).

Heidelberg Retina Tomograph

At 95% specificity, HRT MRA detected 14 of 19 cases, yielding a sensitivity of 74% (95% confidence interval (CI): 51-88%). HRT results are shown in Figure 1, which also displays the relationship to the 99.9% CI.

Fig. 1. Results of HRT Moorfields’ regression analysis with respect to 95% and 99.9% confidence limits of normality. CL: confidence limit.

GDx

The distribution of the GDx ‘number’ for the control group was positively skewed with a mean value of 20.18, compared to 36.16 for the glaucoma patients. Log10 transformation of the ‘number’ gave normally distributed values (Shapiro-Wilks’ test for normality, p > 0.1). These results are illustrated in Figure 2 and show a large degree of overlap between the two groups. For the controls, the mean of log10 the ‘number’ was 1.22 ± 0.26 with a 95% confidence limit of 1.73. Three subjects with perimetric defects had values outside this threshold; therefore, at 95% specificity, the sensitivity was 16% (95% CI: 6-38%). The receiver-operating characteristic curve for the ‘number’ is shown in Figure 3.

dence limit of HRT MRA and the ‘borderline’ category of the ‘number’. However, using these diagnostic thresholds, HRT and GDx still failed to detect four patients (26%) with confirmed visual field loss.

Discussion

This research reviewed the ability of HRT and GDx to detect early glaucoma. The premise was to utilize parameters and indices that are incorporated within the instrument software, without needing supplementary data analysis, in order to simulate the probable use of the equipment in routine practice.

It has been difficult to make comparisons between these instruments from the results of previous studies, due to the use of varying cut-off criteria and sample populations. Therefore, this study used the 95% confidence limit of normality as the cut-off value in order to allow better comparison between the different technologies.

The experimental group comprised patients with very early perimetric defects (average mean deviation -1.48 ± 1.60 dB), which represents a far earlier stage of glaucoma than in many other studies.6-10 This population of patients presented the instruments with a diagnostic challenge, but both the techniques have the theoretical ability to succeed in this role and, indeed, HRT has already been shown to be able to diagnose pre-perimetric glaucoma.18

The study used three different systems to define the limit of normal values. HRT analysis was based on the MRA, which used a group of 80 controls,13 while the GDx ‘number’ was examined with respect to a group of 44 control subjects. The latter, together with the GDx internal normative database, were used as a basis for comparison of the other three GDx parameters.

The MRA has excellent discriminatory ability,13 and compares favorably with other algorithms.19,20 When presented with an experimental group of patients with very early visual field loss, it yielded a sensitivity of 74% (95% CI: 51-88%). Research on a group of patients with more advanced disease (-5.14 ± 5.46 dB),21 which employed a previously described HRT linear discriminant function,22 gave a sensitivity of 51% at 96% specificity. The lower level of sensitivity in that study compared to that found using MRA may be a manifestation of the superiority of the latter, especially on account of the lesser degree of perimetric loss. A contributory factor may be its consideration of disc size.

Determining diagnostic accuracy for GDx was not as straightforward as for HRT, due to the nature of the GDx output. Using the 95% CI derived from a group of 44 normals, the sensitivity of the ‘number’ was 16% (95% CI: 6-38%). Analysis of the discrete categories produced by recommended interpretation of the ‘number’ gave a sensitivity of 16% (95% CI: 6-38%) at approximately 95% specificity (95% CI: 88100%), when a result of ‘glaucoma’ was used as the diagnostic threshold. The alternate criterion of ‘borderline’ resulted in sensitivity and specificity values of 47% (95% CI: 27-68%) and 84% (95% CI: 71-92%), respectively.

A similar study found the ‘number’ to have 24% sensitivity at 96% specificity.21 The authors used the raw values of the ‘number’ rather than log10 values, but this factor does not appear to account for the difference, as when the data set from this study was analyzed the same way, the sensitivity was unchanged at 53%. This finding

is surprising in light of the different stages of field loss between the two studies (-1.48 dB versus -5.14 dB).

This study found a large disparity in the sensitivity estimates of the GDx parameters AT, EM, and TPA, depending on the definition used to determine the limits of normality. When the 95% confidence limit of the GDx internal database was used, the three parameters each had sensitivities of 11%, whereas when the 95% confidence limit from the group of 44 normal controls was used, far higher sensitivity values were found of 53% (AT and TPA) and 58% (EM). These findings indicate how sensitive diagnostic measures of performance are to the characteristics of the normal database.

A feature of polarimetry, which has recently been highlighted, is the effect of corneal polarization on retardation values:23-25 it has been shown that interand intrasubject differences in corneal polarization are not adequately dealt with by the GDx, which assumes a standardized value. Systems have been proposed by Garway-Heath et al.23 where retardation values from the perifovea or temporal aspect of the peripapillary retina are used as a basis for correcting retardation values. Garway-Heath et al. also propose that GDx parameters that express ratios (rather than absolute measurements) are relatively immune to anomalous corneal polarization, and that this is the reason for their reported superior diagnostic accuracy.

HRT consistently detected more cases of glaucoma than GDx. However, HRT still failed to identify 26% of patients with confirmed visual field loss. Similar research with MRA found a level of 16% for patients with slightly more advanced perimetric loss (-3.6 dB).13 These findings are likely to be due to the wide range of normal disc appearances within the population, resulting in some cases with early loss appearing to be within normal limits.

Capturing cases with confirmed development of visual field loss is difficult and, therefore, this study is based upon the results of a relatively small sample (19 eyes from 19 patients), with corresponding wide confidence limits for sensitivity and specificity estimates (on average, approximately 20% either side of the estimated value). Similarly, the low number of normals (n = 44) may have caused inaccuracies in the derivation of the 95% confidence limit of normality. This study has used a variety of methods for analyzing GDx data, which could be used to indicate fruitful areas for further research.

Conclusions

MRA of HRT data shows significant promise for the detection of early glaucoma. Of the GDx parameters reviewed, the ‘number’ provided the best discriminator between glaucoma patients and controls. When the cut-off criteria were set to yield 95% specificity, the sensitivity of HRT for detecting very early glaucoma was 74%, while that for GDx was 16%.

Five (26%) patients with early visual field loss were not identified by either instrument. Therefore, although HRT and GDx can provide useful data to aid in clinical management decisions, when used in isolation, they will fail to detect early glaucoma in a significant number of cases.

Acknowledgment and declaration

Research sponsored by the NHS R&D, Grant Number 95/18/04. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Department of Health.

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