diagnostic ability of retinal ganglion cell complex, retinal

8/10/2019 Diagnostic Ability of Retinal Ganglion Cell Complex, Retinal

1/7

GLAUCOMA

Diagnostic ability of retinal ganglion cell complex, retinal

nerve fiber layer, and optic nerve head measurements

by Fourier-domain optical coherence tomography

Andreas Schulze &Julia Lamparter &Norbert Pfeiffer &

Fatmire Berisha &Irene Schmidtmann &

Esther M. Hoffmann

Received: 6 August 2010 /Revised: 16 November 2010 /Accepted: 18 November 2010 /Published online: 15 January 2011# Springer-Verlag 2011

Abstract

Purpose To evaluate the diagnostic ability of Fourier-domain

optical coherence tomography (FD-OCT) measurements in

glaucoma patients, patients with ocular hypertension, and

normal subjects.

Methods Ninety-three participants with open-angle glaucoma

(OAG), 58 patients with ocular hypertension (OHT), and 60

healthy control subjects were included in the study. All study

participants underwent FD-OCT imaging. Retinal ganglion

cell complex (GCC), macular thickness, peripapillary retinal

nerve fiber layer thickness (RFNL), and optic nerve head

parameters (ONH) were measured in each participant. The

diagnostic ability was evaluated using area under the receiver

operating characteristics curves (AUROC).

Results Glaucoma patients showed a significant reduction in

GCC and macular retinal thickness compared to patients with

OHT and normal subjects. No differences in GCC were found

between the patients with OHT and normal subjects. The best

diagnostic ability in the comparison between glaucoma and

normal subjects after adjusting for age was found for cup-to-

disc ratio (AUROC=0.848), RNFL average thickness

(AUROC= 0.828), and GCC global loss volume (AUROC=

0.805). The diagnostic power of the best GCC, RNFL, and

ONH parameter did not show differences beyond random

variation (p>0.05).

Conclusions Imaging of the GCC using FD-OCT (RTVue-

100) has a comparable diagnostic ability to RNFL and

ONH measurements in distinguishing between glaucoma

patients and healthy subjects. No differences were found

between patients with OHT and normal subjects with regard

to ONH, RNFL, and GCC parameters.

Keywords Fourier-domain optical coherence tomography .

Glaucoma. Ocular hypertension . Retinal ganglion cell

complex . Diagnostic ability

Introduction

Optical coherence tomography (OCT) is a non-invasive

imaging method used to analyze the optic nerve head and

retinal layers. The ability of OCT to discriminate between

glaucomatous and normal eyes with measurements of the

optic nerve head (ONH), the retinal nerve fiber layer (RNFL),

and macular thickness (MT) has been demonstrated in various

studies [14]. Measurements of the ONH showed the highest

diagnostic accuracy for glaucoma detection (cup/disc area

ratio [2], RIM area [4]) and RNFL (inferior RNFL thickness

Presented in part at the Annual Meeting of Association for Research in

Vision and Ophthalmology, Fort Lauderdale, USA, May 2009

Financial disclosure The FD-OCT RTVue-100 was provided by the

Optovue company (Fremont, USA) at no cost.

The authors have full control of all primary data, and they agree to

allow Graefes Archive for Clinical and Experimental Ophthalmology

to review their data upon request.

A. Schulze (*) :J. Lamparter:N. Pfeiffer: F. Berisha:

E. M. HoffmannDepartment of Ophthalmology,

University Medical Center Mainz,

Langenbeckstrae 1,

55131 Mainz, Germany

e-mail: [email protected]

I. Schmidtmann

Department of Medical Biometry,

Epidemiology and Informatics (IMBEI),

University Medical Center Mainz,

Obere Zahlbacher Str. 69,

55131 Mainz, Germany

Graefes Arch Clin Exp Ophthalmol (2011) 249:10391045

DOI 10.1007/s00417-010-1585-5


2/7

[2, 5], mean RNFL thickness [4]). Segmentation discrimi-

nation and measurement of the thickness of retinal layers in

the macula region was not possible with time-domain OCT

devices. Tan et al. [6] measured the macular layers with a

complex semi-automatic segmentation algorithm for Stratus

OCT. The diagnostic power of the measurement of inner

retinal layers (nerve fiber layer, ganglion cell layer, and inner

plexiform layer, AUROC= 0.91) was comparable to peripa-pillary nerve fiber layer measurements (average RNFL

thickness, AUROC=0.94). However, these measurements

require the use of manual and complex segmentation of the

retinal layers and may, in some cases, lead to a reduced

image quality. The development of Fourier-domain OCT

devices with higher imaging speed and higher resolution

than TD-OCT devices allows for an automatic segmentation

of the retinal layers. The RTVue-100 (Optovue, Fremont,

CA, USA) represents the first FD-OCT with an automati-

cally integrated scan and analysis protocol for the measure-

ment of the retinal ganglion cell complex (GCC). The GCC

consists of the retinal nerve fiber layer, the ganglion celllayer, and the inner plexiform layer.

The aim of our study was to explore the diagnostic value

of ganglion cell complex, retinal nerve fiber layer, and optic

nerve head measurements using the FD-OCT RTVue-100 in

glaucoma patients, patients with ocular hypertension, and

normal subjects. The special focus of this investigation was

on the identification of the diagnostic ability of GCC

measurements to differentiate between glaucomatous

patients, patients with OHT, and healthy controls.

Materials and methods

Included in this observational case study were 211 eyes of 211

subjects. Ninety-three glaucoma patients, 58 ocular hyperten-

sive patients, and 60 healthy normal subjects were enrolled.

All participants underwent slit-lamp examination, indi-

rect dilated fundus examination with a 90D fundus lens,

Goldmann applanation tonometry, measurement of the

central corneal thickness (OCP, Heidelberg Engineering,

Heidelberg, Germany), visual field testing with a Humphrey

(Carl Zeiss Meditec, Jena, Germany) or Octopus (HAAG-

STREIT, Wedel, Germany) visual field analyzer, and mea-

surement of the ONH, RNFL, and GCC with Fourier-domain

OCT (RTVue-100, Optovue, Fremont, CA, USA).

All study participants had a best-corrected visual acuity of

20/60 or better, refraction error 5.0 diopters sphere and 2.0

diopters cylinder, no advanced lens opacities, no prior ocular

surgery or laser treatment, and no intraocular disease affecting

visual function or retinal structures (such as diabetic retinop-

athy or age-related macular degeneration). If both eyes of a

participant met the entry criteria, one eye was selected

randomly for this study.

Patients with primary open-angle, normal tension, and

pseudo exfoliation glaucoma with mild or moderate glaucom-

atous damage were included. Glaucoma was classified using

the enhanced visual field glaucoma staging system (GSS2)

according to Brusini [7], the GSS2 based on the three main

perimetric global indices (mean deviation, corrected pattern

standard deviation, and corrected loss variance) and plots on

an easy-to-use X-Y coordinate diagram. A further advantageof the GSS2 is that it can be used with both the Humphrey

and the Octopus visual field system. Glaucoma patients with

a maximum GSS2 index stage 2 were included in this study.

GSS2 stage 2 is defined as a mean deviation 9 dB, and/or

pattern standard deviation 8%, and/or corrected loss

variance 64 dB2 [11]. Furthermore, both visual fields had

to have a false-positive error of less than 33%, a false-

negative error of less than 33%, and a fixation loss of less

than 20% to be defined as reliable.

Ocular hypertension was defined based on the presence

of an intraocular pressure of >21 mmHg with normal optic

nerve head appearance and normal visual field.Normal subjects had to have at least one reliable normal

result on standard automated perimetry, normal disc appear-

ance based on dilated fundus examination, and intraocular

pressure


3/7

hemisphere, focal loss volume [FLV], and global loss volume

[GLV]). The FLV represents the total sum of significant GCC

loss in volume divided by the map area in percent; the GLV is

the sum of the pixels where the fractional deviation map value

is


4/7

Adjustment for gender, corneal thickness and spherical

equivalent yielded virtually the same results as adjusting

for age only.

The diagnostic power to distinguish between glaucoma

and healthy eyes of the best GCC parameter adjusted for

age (GCC global loss of volume, AUROC=0.805) was not

significantly different from the best OHN parameters (cup-

to-disc ratio, AUROC =0.848, p=0.2411; RIM volume,

AUROC=0.837, p =0.3581), and the best RNFL parameter

(RNFL average, AUROC=0.828, p=0.3647).

In the searching for an optimal model to predict

glaucoma, forward selection enabled the inclusion of cup-

to-disc ratio, RNFL average thickness, and GCC focal loss

of volume in addition to age. The area under the resulting

ROC curve was 0.878. When forward stepwise selection

was used, the resulting model included the same parame-

ters, with the exception of RNFL average thickness. The

area under the corresponding AUROC curve was 0.871.

To distinguish patients with ocular hypertension from

normal subjects, the parameters with the highest AUROC

value were found for GCC focal loss of volume (AUROC=

0.593, 95% CI 0.554-0.754), followed by RNFL thickness

in the superior hemisphere (AUROC=0.548, 95% CI

0.441-0.654) and cup-to-disc ratio (AUROC= 0.547, 95%

CI 0.439-0.655). Adjusting for gender or spherical equiv-

alent did not increase the discrimination accuracy; adjusting

Table 2 Measurement of disc parameters and peripapillary retinal nerve fiber layer in glaucoma patients, OHT patients, and normal subjects

Glaucoma mean

at mean age (SEE)

OHT mean

at mean age (SEE)

Normal mean

at mean age (SEE)

Glaucoma vs.

normal (p)

Glaucoma vs.

OHT (p)

OHT vs.

normal (p)

Disc area (mm2) 2.06 (0.04) 2.09 (0.06) 1.99 (0.04) 0.2044 0.7958 0.1969

Cup area (mm2) 1.33 (0.06) 0.84 (0.07) 0.76 (0.06)


5/7

for central corneal thickness, however, increased the

diagnostic ability. When adjusting for age and central

corneal thickness, the highest discrimination accuracy was

found for cup-to-disc ratio (AUROC= 0.693, 95% CI

0.595-0.791), RNFL thickness in the superior hemisphere

(AUROC= 0.693, 95% CI 0.595-0.791) and GCC global

loss of volume (AUROC=0.693, 95% CI 0.595-0.790).

In the search for an optimal model to predict ocular

hypertension, both forward selection and stepwise selection

lead to the inclusion of central corneal thickness in addition

Table 3 Thickness of ganglion cell complex, outer retinal complex, and full retina layer in glaucoma, or OHT patients, and normal subjects

Glaucoma mean

at mean age (SEE)

OHT mean

at mean age (SEE)

Normal mean

at mean age (SEE)

Glaucoma vs.

normal (p)

Glaucoma vs.

OHT (p)

OHT vs.

normal (p)

GCC average (mm) 86.7 (1.0) 94.6 (1.0) 94.7 (0.9)


6/7

to age. The area under the corresponding AUROC curve in

both models was 0.687.

Discussion

The comparison of glaucoma patients with normal and

ocular hypertensive patients demonstrated significant differ-ences for the ONH, RNFL, GCC parameters, and central

retinal thickness. When the retina in the ganglion cell

complex and outer retinal complex was separated, only the

GCC layer showed a significant reduction in thickness.

For the investigation of the diagnostic ability, AUROC

curves adjusted for age were used with a view to the age-

related reduction in retinal layers and the absence of age-

matched groups. The parameter with the best discriminating

ability adjusted for age was cup-to-disc ratio (AUROC=

0.848), closely followed by RIM volume (AUROC=

0.837), RIM area (AUROC= 0.834), and RNFL average

(AUROC=0.828). The best GCC parameter for glaucomadiscrimination (global loss volume of GCC, AUROC=

0.805) had a slightly lower diagnostic ability than that of

RNFL thickness and OHN parameters, although this

difference was not statistically significant.

A more marked reduction in central retinal thickness found

in glaucoma patients compared with normal subjects using the

established time-domain OCT has been reported by a number

of authors [25]. Furthermore, the significantly higher

diagnostic ability for the measurement of RNFL parameters

compared to macular thickness measurement is well docu-

mented [14].

The segmentation of retinal layers using time-domain

OCT (Stratus OCT) is limited by the lower resolution

compared to Fourier-domain OCT. An automatic segmen-

tation of retinal layers is not integrated into TD-OCT

devices. Ishikawa et al. 2005 [9] and Tan et al. 2007 [6]

developed a complex segmentation algorithm to identify

the boundaries between retinal layers for exported Stratus

OCT macular images. The best discrimination between

glaucoma patients (with or without visual field defects) and

normal subjects was found for the measurement of the

nerve fiber layer, ganglion cell layer, and inner plexiform

layer in the macular area. The combination of those three

layers with the inner retinal layer complex (now called

ganglion cell complex, GCC) had the highest repeatability

and best discrimination power compared with the measure-

ment of macular retinal thickness for glaucoma diagnosis.

A good reproducibility of ONH and RNFL measurements

with FDT-OCT RTVue-100 has been reported by different

authors [10, 11]. Tan et al. [12] demonstrated a slightly

higher diagnostic ability for GCC parameters comparing

preperimetric and perimetric glaucoma patients with normal

subjects. In the perimetric glaucoma group, the authors

found the highest diagnostic accuracy for GCC-FLV and

GCC-GLV (AUROC 0.92), and in the preperimetric glau-

coma group this was found for both GCC-GLV (AUROC

0.799) and the GCC average (AUROC 0.789). Seong et al.

[13] also demonstrated no significant differences between

AUROCs (0.945 for GCC, 0.973 for RNFL average) in

patients with normal tension glaucoma and healthy subjects.

In the present study, patients with early glaucoma damageshowed different GCC patterns as, e.g., point-shaped or

diffuse defects. This might offer an explanation for the

demonstration of GLV and FLV as the GCC parameters with

the best diagnostic accuracy.

No significant differences were observed in the RNFL,

ONH, and GCC parameters in the comparison of patients

with ocular hypertension and healthy subjects. The diag-

nostic ability (AUROCs) of the ONH, RNFL, and GCC

parameters adjusted for age and central corneal thickness

was moderate (cup-to-disc ratio, AUROC= 0.693; RNFL

thickness in the superior hemisphere, AUROC= 0.693;

GCC global loss of volume, AUROC=0.693). Results ofstudies comparing FD-OCT measurements obtained in

OHT patients and healthy subjects have not been published

to date. Using the TD-OCT (Stratus-OCT, Carl Zeiss

Meditec, Jena, Germany), Anton et al. [14] found a thinner

RIM (volume and area), larger cup/disc area ratio, and

reduced RNFL comparing 95 OHT patients with 55 normal

subjects.

Limitations of the present study were the small number

of subjects in the OHT and the control group. Due to the

fact that we used a selected study population, our results

may not be representative of German/Caucasian population.

This is a problem with most diagnostic studies. Because our

patient groups (glaucoma patients, OHT patients, and

normal subjects) did not represent age-matched groups,

we used an analysis of covariance (ANCOVA) with age as

continuous covariate to compare ONH, RNFL, and GCC

parameter values and age-adjusted AUROC curves were

used for the investigation of diagnostic ability.

In accordance with the manufactures users manual, all

measurements were taken without pupil dilation. Results

reported by other authors [15, 16] and our own findings

(poster at ARVO 2010) showed no influence of pupil

dilation on RNFL measurements. Limitations of the auto-

matic measurements without pupil dilation include con-

stricted pupils, dry eye syndrome, as well as a high rate of

blink and corneal or lens opacities.

In conclusion, measurements of GCC without pupil

dilation using the Fourier-domain OCT RTVue-100 had a

slightly lower diagnostic power than RNFL or ONH

measurements for the discrimination between glaucoma

patients and normal subjects. The differences did not,

however, reach statistical significance. Follow-up studies

on patients with ocular hypertension and early glaucoma

1044 Graefes Arch Clin Exp Ophthalmol (2011) 249:10391045


7/7

patients are required to determine the best parameter for the

diagnosis of early glaucoma and progression of glaucoma.

References

1. Anton A, Moreno-Montaes J, Blzquez F, Alvarez A, Martn B,

Molina B (2007) Usefulness of optical coherence tomography

parameters of the optic disc and the retinal nerve fiber layer todifferentiate glaucomatous, ocular hypertensive, and normal eyes.

BJ Glaucoma 16(1):18

2. Medeiros FA, Zangwill LM, Bowd C, Vessani RM, Susanna R Jr,

Weinreb RN (2005) Evaluation of retinal nerve fiber layer, optic

nerve head, and macular thickness measurements for glaucoma

detection using optical coherence tomography. Am J Ophthalmol

139(1):4455

3. Guedes V, Schuman JS, Hertzmark E, Wollstein G, Correnti A,

Mancini R, Lederer D, Voskanian S, Velazquez L, Pakter HM,

Pedut-Kloizman T, Fujimoto JG, Mattox C (2003) Optical

coherence tomography measurement of macular and nerve fiber

layer thickness in normal and glaucomatous human eyes.

Ophthalmology 110(1):177189

4. Wollstein G, Ishikawa H, Wang J, Beaton SA, Schuman JS (2005)

Comparison of three optical coherence tomography scanning areasfor detection of glaucomatous damage. Am J Ophthalmol 139

(1):3943

5. Leung CK, Chan WM, Yung WH, Ng AC, Woo J, Tsang MK, Tse

RK (2005) Comparison of macular and peripapillary measurements

for the detection of glaucoma: an optical coherence tomography

study. Ophthalmology 112(3):391400

6. Tan O, Li G, Lu AT, Varma R, Huang D, Advanced Imaging for

Glaucoma Study Group (2008) Mapping of macular substructures

with optical coherence tomography for glaucoma diagnosis.

Ophthalmology 115(6):949956

7. Brusini P, Filacorda S (2006) Enhanced Glaucoma Staging

System (GSS 2) for classifying functional damage in glaucoma.

J Glaucoma 15(1):4046

8. DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing

the Areas under Two or More Correlated Receiver Operating

Characteristic Curves: A Nonparametric Approach. Biometrics

44:837845

9. Ishikawa H, Stein DM, Wollstein G, Beaton S, Fujimoto JG,

Schuman JS (2005) Macular segmentation with optical coherence

tomography. Invest Ophthalmol Vis Sci 46(6):20122017

10. Gonzlez-Garca AO, Vizzeri G, Bowd C, Medeiros FA, Zangwill

LM, Weinreb RN (2009) Reproducibility of RTVue retinal nerve

fiber layer thickness and optic disc measurements and agreementwith Stratus optical coherence tomography measurements. Am J

Ophthalmol 1067-1074, 1074.e1

11. Menke MN, Knecht P, Sturm V, Dabov S, Funk J (2008)

Reproducibility of nerve fiber layer thickness measurements using

3D Fourier-domain OCT. Invest Ophthalmol Vis Sci 49

(12):53865391

12. Tan O, Chopra V, Lu AT, Schuman JS, Ishikawa H, Wollstein G,

Varma R, Huang D (2009) Detection of macular ganglion cell loss

in glaucoma by Fourier-domain optical coherence tomography.

Ophthalmology 116(12):23052314, e1-2

13. Seong M, Sung KR, Choi EH, Kang SY, Cho JW, Um TW, Kim YJ,

Park SB, Hong HE,Kook M (2009) Diagnostic Comparisonbetween

Macular and Peripapillary Retinal Nerve Fiber Layer Measurements

by Spectral Domain Optical Coherence Tomography in Normal-

Tension Glaucoma. Invest Ophthalmol Vis Sci 51(3):14461452

14. Anton A, Moreno-Montaes J, Blzquez F, Alvarez A, Martn B,

Molina B (2007) Usefulness of optical coherence tomography

parameters of the optic disc and the retinal nerve fiber layer to

differentiate glaucomatous, ocular hypertensive, and normal eyes.

J Glaucoma 16(1):18

15. Garas A, Vargha P, Holl G (2010) Reproducibility of retinal

nerve fiber layer and macular thickness measurement with the

RTVue-100 optical coherence tomograph. Ophthalmology 117

(4):738746

16. Savini G, Carbonelli M, Parisi V, Barboni P (2009) Effect of pupil

dilation on retinal nerve fibre layer thickness measurements and

their repeatability with Cirrus HD-OCT. Eye (Lond) 24(9):1503

1508

Graefes Arch Clin Exp Ophthalmol (2011) 249:10391045 1045

diagnostic ability of retinal ganglion cell complex, retinal

Documents