Comparison of functional and morphological diagnostics in glaucoma patients and healthy subjects

Original Paper Ophthalmic Res 2013;49:192–198 DOI: 10.1159/000345074

Received: June 13, 2012 Accepted after revision: October 10, 2012 Published online: January 10, 2013

Comparison of Functional and Morphological Diagnostics in Glaucoma Patients and Healthy Subjects M.K.J. Klamann a A. Grünert b A.-K.B. Maier a J. Gonnermann a A.M. Joussen a K.K. Huber b a Department of Ophthalmology, University Medicine Charité Berlin, Berlin, and b Department of Ophthalmology, Heinrich Heine University, Duesseldorf, Germany

Key Words Blue-on-yellow perimetry ⴢ Glaucoma ⴢ Heidelberg Retina Tomograph III ⴢ Imaging ⴢ Microperimetry ⴢ Optical coherence tomography ⴢ Retinal nerve fibre layer thickness ⴢ Visual field testing

Abstract Purpose: To evaluate the diagnostic value of microperimetry (MP), blue-on-yellow perimetry (B/YP), confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph, HRT, III) and optical coherence tomography (OCT) in discriminating eyes with early glaucoma from healthy subjects. Material and Methods: Prospective examination of 22 eyes of subjects with early primary open-angle glaucoma and 24 eyes of healthy control subjects. After a complete ophthalmological examination, B/YP, MP, OCT and HRT III were determined.

Morphological and functional parameters were analysed.

Results: Mean sensitivity threshold values obtained with B/YP and MP did not show significant differences between glaucoma patients and the control group (p = 0.321 and p = 0.281). Retinal nerve fibre layer (RNFL) thickness was significantly decreased in patients with glaucoma with both HRT III and OCT (p = 0.018 and p ! 0.001). Conclusions: While B/YP and MP had no ability to discriminate between subjects with early glaucoma and healthy subjects, RNFL thickness

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measured with HRT III and OCT showed a significant difference. In early primary open-angle glaucoma, morphological changes like RNFL thickness seem to occur prior to functional defects in the visual field.

Copyright © 2013 S. Karger AG, Basel

Introduction

Glaucoma is a progressive optic neuropathy in which there is loss of retinal ganglion cells and corresponding nerve fibre layer loss resulting in visual field defects.

Because injury due to glaucoma is largely irreversible, early detection and prevention of glaucomatous damage is crucial. It has been demonstrated that structural damage to the optic nerve head and retinal nerve fibre layer (RNFL) can occur well before any detectable functional visual loss [1, 2]. Other authors have shown that the opposite may also be true: in some cases, functional loss can be detected before structural loss [3, 4–6].

RNFL and optic nerve head evaluations are essential in primary open-angle glaucoma diagnosis. Classic diagnostic techniques, such as funduscopy or optic nerve head and RNFL photography, constitute a qualitative analysis of these structures with high subjectivity and variability [7, 8].

Matthias K.J. Klamann, MD Department of Ophthalmology University Medicine Charité Berlin Augustenburger Platz 1, DE–13353 Berlin (Germany) E-Mail matthias.klamann @ charite.de

Over the past decade, imaging of the optic nerve head and RNFL has gained widespread use for the diagnosis and follow-up of patients with glaucoma and those at risk for glaucoma. Optical coherence tomography (OCT) is a high-resolution, cross-sectional imaging technique that allows in vivo measurement of tissue thickness [9–11].

Previous reports have shown that OCT has a high sensitivity and specificity for diagnosing glaucoma, and has a good correlation with visual field findings detected with static automated perimetry (SAP) [10–13]. The Heidelberg Retina Tomograph III (HRT III) is a confocal scanning laser ophthalmoscope that acquires 3-dimensional topographic images of the optic nerve head and the parapapillary RNFL with a high degree of discrimination between healthy and glaucomatous eyes [14–19]. SAP is widely used for the diagnosis and follow-up for a patient with glaucoma. SAP can remain within normal limits until there is 25–50% loss of retinal ganglion cells [20].

Microperimetry (MP) is a procedure in which retinal sensitivity is assessed while the fundus of the eye is directly examined, and it enables an exact correlation between macular pathology and corresponding functional defects. Early loss of retinal sensitivity can be detected with MP where a standard visual field examination is normal [21, 22]. Blue-on-yellow perimetry (B/YP) is a type of visual field examination technique, which is a combined method of visual field test and colour vision test. Previous studies have shown that the B/YP is a highsensitivity method for detecting early visual field defects and predicting the development of visual field loss in glaucoma [23–26].

The purpose of the present study is to investigate the correlation between the functional diagnostics MP and B/YP and the morphological diagnostics HRT III and OCT in early primary open-angle glaucoma. Furthermore, the diagnostic ability of MP, B/YP, HRT III and OCT in discriminating glaucoma from normal eyes was evaluated.

Materials and Methods Twenty-two eyes of subjects with very early primary open-angle glaucoma on both eyes and 24 eyes of normal control subjects with no pathological change on either eye were enrolled into this prospective study. One randomly selected eye of all subjects was analysed. Each study participant underwent a complete ophthalmological examination, including a medical history review, bestcorrected visual acuity measurement, slit-lamp biomicroscopy, intra-ocular pressure (IOP) measurement using Goldmann applanation tonometry, gonioscopy, dilated fundus examination, stereoscopic photographs of the optic disc and a baseline bilateral

Functional and Morphological Diagnostics in Glaucoma Patients

SAP threshold visual field testing using the 24-2 Swedish interactive threshold algorithm (Octopus, Haag-Streit).

Normal eyes had IOPs of !18 mm Hg, with no history of increased IOP, normal optic disc, based on masked analysis of stereophotographs with intact rims, no haemorrhages, notches, excavation, localized pallor or nerve fibre defects and normal visual fields. A normal visual field was defined as a mean deviation and pattern standard deviation within 95% confidence limits and a glaucoma hemifield test result within normal limits. Family history of glaucoma was an exclusion criterion.

Primary open-angle glaucoma was diagnosed as elevated IOP (121 mm Hg by Goldmann applanation tonometry), glaucomatous cupping on funduscopic examination and open angle in gonioscopy. The optic disc was examined using the diagnostic criteria described by Jonas [27] depending on the degree of glaucomatous cupping, ranging from 0 to V. Cupping was evaluated by one examiner only. Gonioscopy was examined using the Shaffer classification. Eyes classified as glaucomatous had 2 consecutive (repeatable) normal visual field test results (pattern standard deviation inside the 95% confidence limits and/or glaucoma hemifield test result inside normal limits). In these very early stages of glaucoma, no characteristic glaucomatous visual field defects like arcuate, Bjerrum, Seidel, paracentral scotoma or nasal step were detected.

To be included, subjects had to have a best-corrected visual acuity 1 0.3 dec., refractive error within 85.0 dpt sph. and 83.0 dpt cyl., open angles on gonioscopy, clear ocular media [nuclear opalescence, nuclear colour and cortical changes up to grade 3 (NO1–3, NC1–3, C1–3) on the Lens Opacities Classification System III]. Subjects were excluded if they had a history or evidence of intra-ocular surgery or laser, retinal macular pathology, abnormal discs such as tilted discs and unwillingness or inability to participate in the study.

Nerve Fibre Layer Assessment Stratus OCT (Carl Zeiss Meditec, Stratus) was used to measure the thickness of the peripapillary RNFL. Fast RNFL thickness scan protocols using circumpapillary scans with a present diameter of 3.40 mm centred around the optic nerve head were used.

Fast RNFL thickness scan protocols consisted of 3 scans each of 256 measuring points continuously captured in 1.8 s. Only goodquality OCT data as judged by the appearance of the RNFL pictures were used for further analysis. Images with artefacts, missing parts or showing seemingly distorted anatomy were excluded.

The signal strength in every scan was determined to be better than 7.5.

Confocal scanning laser ophthalmoscopy was performed by using HRT III. The HRT III uses a 670-nm diode laser as a light source. Sixty-four confocal images, each with 384 ! 384 pixels, were converted to a single topographic image. Only mean topographic images of good quality (standard deviation ^50 ␮m) were included. Although the HRT III has the same scanning specifications as the HRT II, the HRT III uses an expanded normative database with ethnic specific data. An experienced operator masked to the diagnosis and clinical assessment assessed the disc margin on all eyes examined.

Visual Field Assessments The yellow background luminance in B/YP 30-2 (Octopus, Haag-Streit) was 89 cd/m2. A Goldmann size V blue stimulus was

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Table 1. Descriptive statistics of age, IOP and gender

Age, years IOP, mm Hg Gender, n Female Male

Normal (n = 24)

Glaucoma (n = 22) p

59.0889.250 13.4283.256

62.45813.179 13.7383.971

15 9

9 13

0.326 0.754 0.148

Table 2. Mean sensitivity for B/YP and MP in normal subjects and glaucoma patients

B/YP, dB MS ST SN IT IN MP, dB MS ST SN IT IN

Normal (n = 24)

Glaucoma (n = 22) p

19.6583.63 19.0583.98 18.8684.17 19.7584.09 20.3383.61

18.1786.47 17.9086.43 17.2187.44 19.3885.94 18.3586.64

0.321 0.525 0.603 0.886 0.212

19.1681.14 19.2780.90 19.3281.09 19.0381.20 19.0281.49

18.0182.89 17.5884.60 17.6284.22 18.3781.94 18.4881.98

0.281 0.511 0.325 0.437 0.445

MS = Overall mean sensitivity threshold; ST = mean sensitivity superior temporal quadrant; SN = mean sensitivity superior nasal quadrant; IT = mean sensitivity inferior temporal quadrant; IN = mean sensitivity inferior nasal quadrant.

Table 3. Mean defect for B/YP and MP in normal subjects and glaucoma patients

B/YP, dB MD ST SN IT IN MP, dB MD ST SN IT IN

Normal (n = 24)

Glaucoma (n = 22) p

1.9982.80 1.6883.18 2.2183.36 2.2482.77 1.9982.85

3.0385.15 2.2585.28 3.4186.24 3.4186.26 4.4286.52

0.321 0.736 0.785 0.662 0.164

0.2981.07 0.6180.91 0.5681.09 0.2581.21 0.0481.46

1.1982.15 2.3984.61 2.2384.23 0.7481.88 0.5681.90

0.121 0.286 0.215 0.228 0.369

Statistics Statistical methods included the Pearson correlation coefficient to examine the predictive value of variables in the separation of glaucoma from suspect or normal. Normally distributed variables were compared with the independent-sample t test. Numerical variables that were not normally distributed were compared with the Mann-Whitney U test. The ␹2 test was used to compare the gender difference between the preperimetric glaucoma group and the control group. Receiver-operating characteristic (ROC) curves were drawn for a variety of variables, and the area under the curve (AUC) was used as a statistic in nonparametric analysis to estimate the value of each method in identifying glaucoma eyes. The ROC curve represents a sensitivity/ specificity pair: 1.0 represents a perfect discrimination (100% sensitivity and 100% specificity) having an ROC curve passing through the upper left corner, whereas 0.5 means that there is no difference between the 2 distributions. All tests were two-tailed, and a 5% significance level was maintained throughout. The procedures of the analysis program PAWS (v 18.0, Version for Mac) were used. At all times, p values lower than 0.05 were considered to be significant.

Results

MD = Overall mean defect threshold; ST = mean defect superior temporal quadrant; SN = mean defect superior nasal quadrant; IT = mean defect inferior temporal quadrant; IN = mean defect inferior nasal quadrant.

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used for the stimulus target, and the target duration time was 200 ms with an interval time of 600 ms. A reliable visual field was defined as having a false-positive error less than 33%, a false-negative error less than 33% and a fixation loss less than 20%.

Furthermore the manually adapted MP Humphrey 20-2 pattern test (Micro Perimeter MP-1; Nidek Technologies, Italy) was performed on all subjects. In the MP Humphrey 20-2 pattern, a Goldmann III stimulus was used. The stimuli were projected onto a white background with a background illumination of 1.27 cd/m2 and a 100-ms presenting time stimulus.

Every subject was examined following a standardized action: B/YP was carried out first. During a break of 1 h, the participants were allowed to relax. Afterwards, MP was tested. Subsequently, first OCT, then Heidelberg retina tomography were conducted.

In 5 participants, OCT had to be repeated due to early head movements. After repetition, all subjects could be included in the study.

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Materials The descriptive statistics are found in table 1.

Functional Assessment Regarding functional diagnostics, the mean sensitivity threshold values in B/YP and MP did not show any significant difference between glaucoma patients and the control group (p = 0.321 and p = 0.281). The mean sensitivity threshold values obtained with B/YP and MP between glaucoma patients and control subjects did not differ significantly in any quadrant (superior temporal quadrant, superior nasal quadrant, inferior temporal quadrant, inferior nasal quadrant, table 2).

Klamann /Grünert /Maier /Gonnermann / Joussen /Huber

0.5

28 29 30

20

RNFL thickness

0.4

4

Table 4. Correlation mean sensitivity threshold between B/YP and MP in quadrants

Quadrant

Pearson correlation r

Mean sensitivity Superior temporal Superior nasal Inferior temporal Inferior nasal

0.606 0.567 0.606 0.363 0.469

p (2-tailed) <0.001 <0.001 <0.001 <0.001 0.001

0.3

0.2

Table 5. Correlation mean defect threshold between B/YP and MP in quadrants HRT OCT

0.1 Glaucoma

Control

Fig. 1. Box plot: range of RNFL thickness measured by HRT III

and OCT in the glaucoma and control groups.

Furthermore, the mean defect threshold values in B/ YP and MP did not show any significant change between glaucoma patients and the control group (p = 0.321 and p = 0.121). Similarly, the difference in mean defect threshold values obtained with B/YP and MP between glaucoma patients and control subjects was not significant in any quadrant (superior temporal quadrant, superior nasal quadrant, inferior temporal quadrant, inferior nasal quadrant, table 3).

The correlation between mean sensitivity thresholds measured by B/YP and MP was significant (r = 0.606, p ! 0.001). This correlation was evident in all quadrants (table 4).

Further, a negative correlation between mean defect thresholds measured by B/YP and MP was significant (r = –0.433, p = 0.003). This correlation was significant only in both superior quadrants (table 5).

Morphological Assessment Regarding morphological diagnostics, RNFL thickness was found to be significantly decreased in patients with glaucoma with both HRT III and OCT (p = 0.018 and p ! 0.001, fig. 1). The correlation between RNFL thickness measured with HRT III and OCT was significant (r = 0.488, p = 0.001).

Functional and Morphological Diagnostics in Glaucoma Patients

Quadrant Mean defect Superior temporal Superior nasal Inferior temporal Inferior nasal

Pearson correlation r –0.433 –0.545 –0.609 –0.169 –0.280

p (2-tailed) 0.003 <0.001 <0.001 0.261 0.059

Comparison between Functional and Morphological Assessments Comparing morphological and functional diagnostics, neither a good correlation between HRT III RNFL thickness and B/YP mean sensitivity threshold nor a good correlation between RNFL thickness measured with HRT III and B/YP mean defect threshold were found (r = 0.103, p = 0.497 and r = –0.067, p = 0.658).

Regarding RNFL thickness measured with HRT III and mean sensitivity threshold measured with MP, a significant correlation was evident (r = 0.300, p = 0.043).

This correlation existed over both superior quadrants (superior temporal r = 0.304, p = 0.040 and superior nasal r = 0.349, p = 0.017). Comparing HRT III RNFL thickness and mean defect measured with MP, no correlation was present (r = 0.256, p = 0.861).

Regarding OCT RNFL thickness, neither a good correlation was found in comparing it with B/YP mean sensitivity threshold, nor was a good correlation with B/YP mean defect threshold evident (r = 0.089, p = 0.555 and r = –0.053, p = 0.725).

Nevertheless, a significant correlation between RNFL thickness measured with OCT and MP mean sensitivity threshold was determined (r = 0.307, p = 0.038). This was evident only in the inferior temporal quadrant (r = 0.318, Ophthalmic Res 2013;49:192–198

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1.0

0.8

0.8

0.6

0.6

Sensitivity

Sensitivity

1.0

0.4 Source of the curve B/YP MS B/YP MD MP MD MP MS

0.2

0

Source of the curve HRT OCT

0.2

0 0

0.2

0.4 0.6 1 – specificity

0.8

1.0

Fig. 2. ROC curve obtained for the mean sensitivity (MS) thresh-

old measured by B/YP and MP and for the mean defect (MD) threshold measured by B/YP and MP.

p = 0.031). Likewise a significant correlation was found between MP mean defect threshold and RNFL thickness measured with OCT (r = 0.329, p = 0.261; inferior temporal quadrant r = 0.329, p = 0.026).

The ROC curves obtained for B/YP, MP, OCT and HRT III are displayed in figures 2 and 3. The AUC was found to be 0.703 with HRT III and 0.886 with OCT. In addition, the AUC was 0.586 with mean sensitivity threshold measured with B/YP, 0.415 with mean defect threshold with B/YP, 0.594 with mean sensitivity threshold with MP and 0.632 with mean defect threshold with MP. No significant difference was found.

Discussion

In this study, eyes of healthy subjects and preperimetric glaucomatous patients were compared regarding RNFL thickness measured by HRT III and OCT as well as visual field testing as assessed by B/YP and MP. The aim of this present study was to find a sensitive method of predicting early glaucoma. In summary, we showed that in preperimetric glaucoma morphological changes of RNFL thickness may appear earlier than functional changes in visual field testing.

The results of the present study are based on the assumption that the clinical classification of glaucomatous 196

0.4

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0

0.2

0.4 0.6 1 – specificity

0.8

1.0

Fig. 3. ROC obtained for RNFL thickness measured by HRT III and OCT.

eyes is evaluated by one examiner only. Since a disagreement between different examiners can occur, the findings of the present study need to be considered carefully in relation to daily clinical routine.

In this study neither MP nor B/YP showed a significant difference between healthy and glaucoma subjects.

Neither showed a significant difference in mean sensitivity and mean defect over any quadrant. However, a significant correlation in mean sensitivity and mean defect between B/YP and MP was found. According to this correlation, mean sensitivity was evident over all quadrants and mean defect was apparent over both superior quadrants.

In previous studies, Sanchez-Galeana et al. [28] found that RNFL thickness measured with OCT was topographically correlated with glaucomatous visual field defects measured with B/YP. Zhong et al. [29] reported only a mild correlation between B/YP and OCT for preperimetric glaucoma. Our results showed neither a correlation between B/YP mean sensitivity and OCT, nor between B/YP mean defect and OCT. Furthermore we did not find a correlation between RNFL thickness measured with HRT III and B/YP mean defect and B/YP mean sensitivity. This may be due to a lower sensitivity of B/YP for this very early stage of glaucoma in our study. A further point may be the fact that cataracts predominantly cause a general reduction in B/YP [30]. In our study only phakic Klamann /Grünert /Maier /Gonnermann / Joussen /Huber

eyes were included. So beginning lens opacification should be considered. As age is a significant risk factor in primary open-angle glaucoma [31], and cataract is more common in an older population, cataract and glaucoma are likely to coexist. The reliability of B/YP in detecting early glaucoma in these patients should be reconsidered.

Summarizing, conducting B/YP did not show any advantage in predicting preperimetric glaucoma versus morphological imaging techniques. Even MP did not show any advantage in predicting preperimetric glaucoma versus HRT III and OCT, but a good correlation with RNFL thickness was found. We showed that if using visual field tests in early stage glaucoma, MP is predominant to B/YP. This appears even more in phakic eyes with beginning lens opacification.

Even compared to SAP, MP is supposed to allow earlier detection of a reduction in retinal sensitivity [32]. So the role of MP in detecting glaucoma may be reconsidered.

Several authors determined the RNFL average and inferior thicknesses as the best parameters for discriminating between healthy and glaucomatous subjects [33, 34].

Glaucomatous changes have been said to affect the inferior optic nerve pole in the earliest stages [35]. Pueyo et al. [36] reported that the RNFL average thickness is the best OCT parameter for discriminating between healthy and glaucomatous subjects, with sensitivity at 66% and specificity fixed at 90%. Badala et al. [37] found that Stratus OCT was more sensitive for detecting glaucoma at high specificity than was HRT III. As in our study the AUC was found to be 0.703 with HRT III and 0.886 with OCT with a good ability in discriminating between normal and glaucomatous subjects.

In contrast to the assumption that structural loss precedes functional loss, former studies have shown that in some cases functional loss can be detected before structural loss [4, 5]. In contrast, Harwerth et al. [3] noted that beneath preperimetric glaucoma instances of visual field defects preceding RNFL thinning can occur. Crabb et al.

[6] found that the explanation for the general disagreement between any two measures of glaucomatous damage may be a measurement error. Nevertheless, similarly to Zeimer et al. [38], we observed a reduction in retinal thickness at the posterior pole in patients with glaucoma.

The reduction of RNFL thickness in patients with early stages of glaucoma was significant with both OCT and HRT III. We also found a good correlation between OCT and HRT III in measuring RNFL thickness. While comparing RNFL thickness with visual field reduction, our study suggests that morphological defects seem to occur earlier than visual field defects in patients with early primary open-angle glaucoma. In this very early stage of glaucoma, neither B/YP nor MP were able to discriminate between glaucomatous eyes and healthy subjects. Hence, performing a visual field test may be not sufficient to detect early damage in glaucomatous eyes. In screening of early glaucoma, an additional examination of the RNFL may be recommended.

Disclosure Statement No competing interest to declare.

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