1. Optic nerve and retinal nerve fiber layer analyzers
in glaucoma
David S. Greenfield, MD
There is mounting evidence that retinal nerve fiber layer Glaucoma is an optic neuropathy characterized by a typi-
(RNFL) loss precedes detectable visual field loss in early cal pattern of visual field loss and optic nerve damage
glaucomatous optic neuropathy. However, examination and resulting from retinal ganglion cell death caused by a
photography of the RNFL is a difficult technique in many number of different disorders that affect the eye. Most,
patients, particularly older individuals, and eyes with small but not all, of these disorders are associated with el-
pupils and media opacities. It is subjective, qualitative, variably evated intraocular pressure (IOP), which is the most im-
reproducible, and often unreliable. Furthermore, optic nerve portant risk factor for glaucomatous damage. Although
head and RNFL photography is time consuming, operator clinical examination of the optic nerve head has been
dependent, has limited sensitivity and specificity, and requires considered to be the most sensitive test for detecting
storage space. Imaging technologies have emerged which glaucomatous damage, evidence suggests that examina-
enable clinicians to perform accurate, objective, and tion of the retinal nerve fiber layer (RNFL) may provide
quantitative measurements of the RNFL and optic nerve head important diagnostic information [1-4]. Accurate and ob-
topography. There is good agreement between such jective methods of detecting disc and RNFL abnormali-
measurements and clinical estimates of optic nerve head ties, and their progression, would facilitate the diagnosis
structure and visual function. The reproducibility of these and monitoring of glaucomatous optic neuropathy.
instruments suggests that they have the potential to detect
structural change over time. This report will review the Clinical examination and photography of the RNFL is a
technological principles, reproducibility, sensitivity and difficult technique in many patients, particularly older
specificity, capacity to detect glaucomatous progression, individuals, those with small pupils, and subjects with
and limitations of currently available ocular imaging media opacities. It is subjective, qualitative, variably re-
technologies. Curr Opin Ophthalmol 2002, 13:68–76 © 2002 Lippincott producible, and often unreliable. In addition, optic nerve
Williams & Wilkins, Inc. head and RNFL photography is time consuming, opera-
tor dependent, has limited sensitivity and specificity,
and requires storage space. Recently, new technologies
have emerged which enable clinicians to perform accu-
The Department of Ophthalmology, The University of Miami School of Medicine, rate, reproducible, objective, and quantitative measure-
Bascom Palmer Eye Institute, Miami, Florida, USA.
ments of the retinal nerve fiber layer and optic nerve
Correspondence to David S. Greenfield, MD, Bascom Palmer Eye Institute, 7108 head topography.
Fairway Drive, Suite 340, Palm Beach Gardens, FL, 33418; e-mail:
dgreenfield@med.miami.edu
Current Opinion in Ophthalmology 2002, 13:68–76 Confocal scanning laser ophthalmoscopy (CSLO), a
technology embodied in the Heidelberg Retinal
Abbreviations
Tomograph (HRT, Heidelberg Engineering, Heidel-
CSLO confocal scanning laser ophthalmoscopy
HRT Heidelberg Retinal Tomograph
berg, Germany), enables the operator to evaluate three-
IOP intraocular pressure dimensional characteristics of optic nerve head topogra-
OCT optical coherence tomography
RNFL retinal nerve fiber layer
phy quantitatively [5-8]. Thirty-two coronal sections of
SLP scanning laser polarimetry the optic nerve head are acquired over a depth of ap-
ISSN 1040–8738 © 2002 Lippincott Williams & Wilkins, Inc.
proximately 3.5 millimeters, and a color-coded topo-
graphic map of the optic nerve head is generated.
Scanning laser polarimetry (SLP) is a technology embod-
ied in the GDx Nerve Fiber Analyzer (Laser Diagnostic
Technologies, Inc., San Diego, CA) employs a confocal
scanning laser ophthalmoscope and an integrated polar-
imeter. It evaluates the thickness of the RNFL by uti-
lizing the birefringent properties of the retinal ganglion
cell axons [9,10]. As polarized light passes through the
RNFL and is reflected back from the deeper layer, it
undergoes a phase shift. The change in polarization, re-
68

2. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 69
ferred to as retardation, is proportional to the thickness of Figure 1. Confocal scanning laser ophthalmoscopy
topographic map
the birefringent medium, and is measured to give an
index of RNFL thickness.
Optical coherence tomography (OCT, Zeiss-Humphrey
Systems, Dublin, CA) is a noninvasive, noncontact,
transpupillary imaging technology that can image retinal
structures in vivo with a resolution of 10 to 17 microns
[11,12]. Cross-sectional images of the retina are produced
using the optical backscattering of light in a fashion
analogous to B-scan ultrasonography. The anatomic lay-
ers within the retina can be differentiated and retinal
thickness can be measured [13].
This report will review practical applications and prin-
ciples underlying these posterior segment-imaging tech- A patient with moderate normal-tension glaucoma shows loss of the inferior
nologies with emphasis upon strengths and limitations of neuroretinal rim (green) and associated stereometric parameters. There is a focal
each technology. depression in the double-hump pattern of the height variation diagram
corresponding to the decreased inferotemporal quadrant height (below).
Confocal scanning laser ophthalmoscopy
Technological principles
Confocal scanning laser ophthalmoscopy employs a 670 nm “double-hump” pattern corresponding to the thicker
diode laser beam as a light source and scans the retina in retinal ganglion cell axons along the superior and inferior
x- and y- directions [14,15]. Light originating from the portions of the optic nerve head.
illuminated area passes through a diaphragm (pinhole) in
a plane optically conjugate to the retina. Planes unfo- Reproducibility
cused at the aperture are blocked by the diaphragm and Various investigators have reported high levels of repro-
do not reach the detector. Each image contains 256 x 256 ducibility using this technology [5,15,16] Brigatti et al. [7]
pixels (picture-elements); each pixel represents the reti- found that topographic variability correlated with the
nal height at that location relative to the focal plane of steepness of the corresponding region. Greater variabil-
the eye. Image acquisition and processing takes approxi- ity was found at the edge of the optic disc cup and along
mately 1.6 seconds. Thirty-two coronal sections are ob- blood vessels. Weinreb et al. [14] have determined that
tained progressing from anterior to the optic nerve head measurement reproducibility is improved from 35.5 µm
through the retrolaminar portion of the nerve head. The to 25.7 µm when a series of three examinations are ob-
axial distance between two adjacent sections is 50 to tained instead of a single image analysis. Based upon
75 m generating an axial range of 1.5 to 3.5 mm. these data, acquiring three images per eye and creation
of a mean topographic image is recommended. Finally,
A standard reference plane is established parallel to the Zangwill et al. [17] have shown that image reproducibil-
peripapillary retinal surface and is located 50 microns ity is improved with pupillary dilation, particularly in
posterior to the retinal surface along a circle concentric eyes with small pupils and cataract.
with the optic disc margin in a temporal segment be-
tween 350° and 356°. Neural rim is defined as tissue Sensitivity and specificity
within the optic disc margin and above the reference Various investigators have reported topographic differ-
plane. Optic cup is defined as tissue within the disc ences between normal, ocular hypertensive, and glauco-
margin and below the reference plane. matous eyes. It is essential to emphasize that the char-
acteristics of the study population will influence the
The optic disc margin is outlined and a color-coded discriminating power involved in differentiating glauco-
depth map is created from a mean topographic image matous from nonglaucomatous eyes. Determination of
using a software algorithm (Fig. 1). Stereometric param- sensitivity and specificity parameters is fundamentally
eters of optic nerve head topography are generated rela- linked to the severity of glaucomatous damage among
tive to the reference plane including rim area and vol- the cohort studied. For any given technology, an instru-
ume, cup area and volume, cup-disc area ratio, mean ment will appear to be more sensitive if it is used to
retinal nerve fiber layer thickness, and retinal nerve fiber separate eyes with advanced glaucoma from normal sub-
cross-sectional area. Parameters independent of the ref- jects compared with eyes with mild glaucoma.
erence plane include mean and maximum cup depth,
height variation contour, and cup-shape measure. A nor- Heidelberg Retinal Tomograph employs software with
mal retinal height variation diagram demonstrates a various statistical analyses to discriminate normal from

3. 70 Glaucoma
abnormal optic discs. These include a multivariate dis- variability and relevance in the course of the disease.
criminant analysis based upon rim volume, height varia- High instrument reproducibility is essential with known
tion contour, and cup shape measure adjusted by age limits of variability in normals and persons with disease.
[18], ranked-segment distribution curves [19,20], and re- Statistical criteria must be established for differentiating
gression analysis using a normative database of 80 normal biological change from test-retest variability. Finally,
eyes from 80 white subjects with a mean age of 57 years multicenter prospective validation must be established
[21]. The confidence interval limits derived from the with comparisons against an accepted gold standard.
later are used commercially to generate the Moorfield’s
Regression Classification Score (normal, borderline, or Confocal scanning laser ophthalmoscopy strategies for
outside normal limits). Wollstein et al. [21] reported a change detection exist including serial analyses of global
84.3% sensitivity and a 96.3% specificity for separating and regional topographic indices (eg, cup-disc ratio, cup
normal and early glaucomatous eyes by taking into ac- volume, and cup-shape measure), and color-coded
count the relation between optic disc size and the rim (red/green) significance indicators of change relative to
area or cup-to-disc area ratio. In a different study, Woll- baseline. Chauhan et al. [31••] have described a sophis-
stein et al. [22•] determined that by taking into account ticated change analysis algorithm based upon a probabi-
the optic disc size, HRT image analysis was superior in listic approach using variability estimates that employs
sensitivity (84.3%) for detection of early glaucoma com- clusters of 4 x 4 pixels to create superpixels. Three fol-
pared with expert assessment of stereoscopic optic disc low-up images are compared with a baseline image, and
photographs (70.6%). a change-probability map is created, characterized by ar-
eas with significant progression illustrated in red.
The sensitivity and specificity of various HRT param- Strengths of this algorithm include the potential ability
eters has been investigated and varies widely ranging to differentiate biological change from test-retest vari-
from 62% to 94% and 74% to 96%, respectively [18,23– ability, however it has not been validated in prospective
27]. Wide variability in discriminating power may be ex- clinical trials. Moreover, topographic measurements are
plained in part by variable sample size, definitions of dependent upon intraocular pressure and postoperative
glaucoma, and varying degrees of glaucomatous optic and diurnal changes in IOP have been reported to pro-
nerve damage. A recent study by Miglior et al. [28•] duce changes in optic disc topography thereby confound-
found fair to poor agreement (␬ statistic 0.28-0.48) be- ing detection of progression.
tween visual field examinations and HRT classifications
Two reports have described HRT detection of change.
among a population of 359 eyes (55 normal, 209 with
Chauhan et al. [31••] described significant topographic
OHT, and 95 with moderate POAG, average visual field
change in one patient with progressive glaucomatous op-
mean defect –7.6 dB) The sensitivity and specificity of
tic disc cupping. Kamal et al. [32] reported topographic
the HRT examination were, respectively, 80% and 65%,
disc changes in a cohort of thirteen ocular hyperten-
using the Mikelberg multivariate discriminant analysis
sive subjects converting to glaucoma before confirmed
[18], and 31 to 53% and 90 to 92%, using ranked-segment
visual changes. This study was limited, however, by
distribution curve analysis [19,20].
small sample size, reviewers unmasked to diagnosis,
absence of a control arm of OHT non-converters, and
Using various HRT summary data including the reflec-
inability to differentiate biological change from test-
tance image, double-hump graph, stereometric analyses,
retest variability.
and HRT classification using a multivariate discriminant
function [18] and ranked segment analysis [19,20], Limitations
Sanchez-Galeana [29•] evaluated the sensitivity and Technological limitations exist which limit the discrimi-
specificity for discriminating between 50 normal eyes nating power for disease detection. The use of a standard
and 39 eyes with early to moderate glaucoma (average reference plane and need for correct placement of the
visual field mean defect –5 dB). Masked observers were disc margin by the operator can influence many of the
used to generate an HRT classification (normal, glauco- topographic outcome variables generated. Moreover,
matous, or undetermined) and similar classifications considerable variability in optic disc morphology exists
were generated using other imaging technologies (see among normal eyes. As currently configured, software
below). Using these summary data collectively, investi- algorithms designed to classify subjects as normal or
gators reported a sensitivity and specificity for the HRT glaucomatous are based upon dedicated normative data
ranging from 64 to 75% and 68 to 80%, respectively. of approximately 100 eyes which is insufficient for popu-
lation based screening. A uniform consensus regarding
Detection of progression the most appropriate summary measures remains to
Essential elements for change detection algorithms have be established.
been previously reviewed [30]. An accepted gold stan-
dard must exist for establishing change. Surrogate mea- There is evidence that disc topography is dependent
surement parameters are necessary with little biological upon intraocular pressure [33] and cardiac pulsation [34].

4. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 71
Postoperative [35,36 ] and diurnal [37] changes in IOP Figure 2. Scanning laser polarimetry image
may produce changes in optic disc topography thereby
confounding detection of glaucomatous progression. In
addition, CSLO cannot discern vessel shift or other non-
quantitative features (eg, pallor or disc hemorrhage)
often associated with progression. Finally, as with perim-
etry, short and long-term fluctuation exists and confi-
dence intervals need to be validated to interpret mea-
surements obtained.
Scanning laser polarimetry
Technological principles
Scanning laser polarimetry (SLP) is a technology that A patient with moderate primary open-angle glaucoma shows reduced
retardation within the superior arcuate retinal nerve fiber layer bundle. Two
provides quantitative assessment of the peripapillary retardation parameters were classified as abnormal (outside 95% confidence
RNFL using a polarized diode laser light source (780 limits, illustrated in red) and four parameters were classified as borderline
nm). The parallel arrangement of neurotubules within (outside 90% confidence limits, illustrated in yellow).
the RNFL produces linear birefringence. Thus, changes
in the polarization state may be measured when light
passes through such tissue [9,10,38-40]. The change in superior/temporal), symmetry measurements between
polarization of the scanning beam (retardation) is linearly superior and inferior quadrants, and modulation param-
correlated to the thickness of the polarizing medium, and eters (an indication of the difference between the thick-
is computed to give an index of RNFL thickness. A est and thinnest parts of the RNFL) are generated. A
polarization detection unit measures the retardation of neural network number is also calculated which is
light emerging from the eye; 256 by 256 pixels (65,536) thought to reflect the likelihood of glaucoma on a scale of
are acquired in 0.7 seconds and a computer algorithm 0 to 100.
calculates retardation at each retinal position.
Reproducibility
An anterior segment compensator is incorporated within Intraoperator measurement reproducibility has been
the technology to neutralize the polarization effects of shown by Weinreb et al. [10] (mean coefficient of varia-
the cornea and crystalline lens. It consists of a fixed re- tion (CV) of 4.5%) and Chi et al. [46] (CV ranging from
tarder to adjust for the corneal retardation and assumes 3.59–10.20% for both normal and glaucomatous sub-
all individuals have a slow axis of corneal birefringence jects). Swanson et al. [47] found significant interoperator
15 degrees nasally downward and a magnitude of 60 nm variability with the NFA I, among 4 operators all of
[41,42 ]. Recent studies have demonstrated that the mag- whom only scanned each of the 11 subjects twice. The
nitude [43] and axis [44] of corneal polarization are vari- primary source of error was attributed to the variability in
able, and are strongly correlated with RNFL thickness the criterion used for establishing intensity setting. This
assessments obtained with SLP. problem was subsequently reduced in the NFA II with a
hardware modification to the light system.
At least three images are acquired using a field of view of
15 x 15 degrees and a baseline retardation map is created. Retinal nerve fiber layer thickness measurements using
Images may be obtained through an undilated pupil with the NFA II have been reported to have high levels of
a minimum diameter of 2 mm. However, uniformity in measurement reproducibility [40,48]. Hoh et al. [40] de-
pupil size is essential when longitudinally evaluating scribed excellent intraoperator reproducibility and found
RNFL measurements.[45] The probability of obtaining that variability between operators can be minimized by
a satisfactory baseline image (mean pixel SD </= 8 µm) using a single measurement ellipse acquired from the
improves from 62 to 98% if the number of scans available original baseline image. As investigators have reported
for selection is increased from three to five.[40] The high levels of measurement variability adjacent to retinal
retardation map represents a false color image with areas blood vessels [49,50], an automated blood vessel removal
of high retardation displayed in yellow and white, and algorithm has been incorporated in the third generation
areas of low retardation displayed in blue (Fig. 2). device, GDx.
The operator outlines the optic disc margin, and a ten-
pixel-wide measurement ellipse is automatically gener- Sensitivity and specificity
ated, 1.75x greater than the disc diameter. A computer As described with CSLO, there is a wide range in RNFL
algorithm automatically generates retardation mea- thickness values among normal individuals and consid-
surements throughout the peripapillary region and along erable measurement overlap between normal and glau-
the measurement ellipse. Average quadrantic measure- comatous eyes may exist. Determination of sensitivity
ments, measurement ratios (eg, superior/nasal, and specificity parameters is fundamentally linked to the

5. 72 Glaucoma
severity of glaucomatous damage among the cohort stud- tion axis has been shown to significantly increase
ied [24]. Sensitivity and specificity values will be greater the correlation between RNFL structural damage and
in studies involving eyes with advanced glaucoma than visual function, and significantly improve the discri-
in studies involving eyes with mild to moderate glau- minating power of SLP for detection of mild to moder-
coma. Tjon-Fo-Song and Lemij [38] evaluated the sen- ate glaucoma.
sitivity and specificity of the first generation device,
NFA I, for detecting glaucoma among a diverse group of Garcia-Sanchez et al. [29] evaluated the sensitivity and
200 eyes with early to advanced glaucoma (average visual specificity of the HRT, GDx, and OCT summary data for
field mean deviation –10.33 decibels) compared with a detection of early to moderate glaucoma (average visual
normal population. The sensitivity and specificity was field mean defect –5.0 dB) among three masked reviewers
reported to be 96 and 93%, respectively. Weinreb et al. (see Table 1). For the GDx, sensitivity and specificity
[51] reported a sensitivity of 74% and specificity of 92% ranged from 72 to 82% and 56 to 82%, respectively.
using a newer version of SLP with a linear discriminant
Detection of progression
function to label glaucomatous damage among a popula-
Scanning laser polarimetry strategies for change detec-
tion with early to moderate glaucoma. Garcia-Sánchez
tion exist including evaluation of change in absolute val-
et al. [52] found the sensitivity and specificity of the GDx
ues of retardation measurements, change in quadrantic
to be 78% and 86%, respectively. The most sensitive and
RNFL thickness measurements, change in double-
specific parameters in their study were ellipse modula-
hump RNFL thickness profile, and color-coded map of
tion, superior/nasal ratio, and maximum modulation.
RNFL thickness change relative to baseline. However,
as with OCT, statistical units of change probability are
In a cross-sectional study comparing OCT and SLP, Hoh
absent limiting the ability to differentiate change from
et al. [53] found that structural information generated
measurement variability, and there has been no prospec-
from both technologies was significantly correlated with
tive validation of this algorithm
visual function in glaucomatous eyes (average visual field
mean deviation –7.7 decibels). However, retardation pa- Two published reports have described SLP evidence of
rameters providing summary measures of RNFL thick- change detection in eyes with non-glaucomatous optic
ness (eg, average thickness and integral measurements) neuropathy. Colen et al. [55] described a patient with
had a weaker correlation with visual field mean defect acute nonarteritic anterior ischemic optic neuropathy
(R = 0.17 to 0.27) than with constructed retardation pa- who developed progressive loss of retardation over a
rameters (eg, modulation scores, ratio parameters, and 5-week period corresponding to a dense altitudinal visual
number; R = 0.36 to –0.51). Bowd et al. [54] recently field depression. Medeiros and Susanna [56] reported
reported that constructed SLP parameters (modulation, progressive RNFL loss over a 90-day period in a patient
ratio, number, and linear discriminant function values) with traumatic optic neuropathy.
have the greatest discriminating power. This is ex-
plained by recent evidence [44] suggesting that interin- Limitations
dividual variability in corneal birefringence has falsely Employment of a fixed corneal compensator has pro-
broadened the normative database of RNFL thick- duced considerable measurement overlap among normal
ness assessments, and reduced the sensitivity and speci- and glaucomatous eyes. Variability in corneal polariza-
ficity of this technology. Correction for corneal polariza- tion axis (CPA) [57••] and magnitude has been de-
Table 1. Comparison of scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography
GDx HRT OCT
Technological principle Birefringence SLO Interferometry
Pixels 65,000 65,000 50,000
Pupillary dilation No No Yes
Reproducibility (CV) 5%–10% [40] 5%–10% [67] 5%–10% [63]
Parameters measured Peripapillary RNFL Optic Disc Topography Peripapillary RNFL
Normative database 1200 eyes [68] 45, [19] 100 [19] or 112 [21] eyes 150 eyes*
Sensitivity [29] 72%–82% 64%–75% 76%–79%
Specificity [29] 56%–82% 68%–80% 68%–81%
Change detection algorithm Yes Yes Yes
Change probability algorithm No Yes No
Prospective validation of algorithm No No No
Evidence to detect change Yes [55, 56] Yes [31, 32] No
Limitations Fixed corneal compensator; Universal reference plane; Sampling data limited to 100
unable to differentiate topography is dependent A-scans; unable to differentiate
variability from progression upon IOP variability from
progression
SLO, scanning laser ophthalmoscopy; CV, coefficient of variation.
*Personal communication (Zeiss-Humphrey Systems, Dublin, CA).

6. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 73
scribed; there is evidence that CPA strongly effects peri- transpupillary imaging technology which can image reti-
papillary retardation measurements (Fig. 3). nal structures in vivo with a resolution of 10 to 17 microns
[11,12]. Cross-sectional images of the retina are produced
Although, there is good one-year stability of CPA mea- using the optical backscattering of light in a fashion
surements [58], long-term stability and the effect of in- analogous to B-scan ultrasonography. The anatomic lay-
traocular and refractive surgery upon such measurements ers within the retina can be differentiated and retinal
remains unknown. Furthermore, anterior and posterior thickness can be measured [13].
segment pathology may produce spurious RNFL mea-
surements [59], and caution should be used when inter- Optical coherence tomography images are obtained us-
preting images in eyes with ocular surface disease, pre- ing a transpupillary delivery of low coherence near-
vious keratorefractive surgery, media opacification, and infrared light (850nm) from a super-luminescent diode
extensive peripapillary atrophy. laser [11–13,60]. Backscatter from the retina is captured
using the same delivery optics and resolved using a fiber-
Although a change analysis algorithm exists, statistical
optic interferometer set in a standard Michelson con-
units of probability are absent. Thus, biological change
figuration. Modulating the reference arm allows longitu-
cannot be differentiated from measurement variability.
dinal information to be extracted to the resolution as
Finally, prospective studies are necessary to validate
defined by the low coherence super-luminescent diode.
change analysis strategies.
Cross-sectional OCT images of the retina are con-
Optical coherence tomography structed from the backscattering information provided
Technological principles by 100 individual longitudinal A-scans. A digitized,
Optical coherence tomography (OCT, Zeiss-Humphrey composite image of the 100 A-scans is produced on a
Systems, Inc., Dublin, CA) is a noninvasive, noncontact, monitor with a false color scale representing the degree
of light backscattering from tissues at different depths
Figure 3. Peripapillary retinal nerve fiber layer retardation map within the retina.
and thickness plot
A minimum pupillary diameter of 5 mm is required to
obtain satisfactory OCT image quality. Images may be
acquired using either a linear or circular scanning beam.
Scanning acquisition time is approximately one second.
A circular scan of the RNFL is generally performed with
a diameter of 3.4 mm (Fig. 4) to avoid areas of peri-
papillary atrophy. Circular scans of this diameter contain
100 axial scans spaced 110 microns apart. This scan is
then converted into a radial image by an automated
“smoothing” technique. A computer algorithm identifies
and demarcates the signal corresponding to the RNFL,
and mean quadrantic and individual clock hours of
RNFL thickness measurements are calculated.
Reproducibility
Schuman et al. [61] evaluated the reproducibility of reti-
nal and RNFL thickness measurements using circular
scans around the optic nerve head in normal and glau-
comatous eyes. Scan diameters of 2.9, 3.4, and 4.5 mm
were evaluated and internal fixation was compared with
external fixation. Measurement SDs were approximately
10 to 20 µm for overall RNFL thickness, and 5 to 9 µm
for retinal thickness. The authors found a circle diameter
of 3.4 mm to be superior; internal fixation was signifi-
Peripapillary retinal nerve fiber layer (RNFL) retardation map (A) and
cantly less variable than external fixation. Baumann et al.
corresponding RNFL thickness plot (B) in the right eyes of six normal individuals [62] found that the mean coefficient of varation of retinal
with different corneal polarization axis values (18°, 27°, 37°, 52°, 59°, 76° nasally thickness measurements at locations outside of 500 µm
downward from top left to bottom right). Upper and lower margins in (B)
represent 95% confidence intervals. Note that peripapillary retardation and
from fixation in normal eyes was 10%. The authors used
measured RNFL thickness increase with increasing corneal polarization axis. an OCT prototype characterized by a 2.5 second scan
(Reprinted with permission: Greenfield DS, Knighton RW: Stability of corneal acquisition time. Recently, Blumenthal et al. [63] evalu-
polarization axis measurements for scanning laser polarimetry. Ophthalmology
2001, 108:1065–1069. Figure 3).
ated the CV for mean RNFL thickness in normal and
glaucomatous eyes (6.9% and 11.8% respectively) using a

7. 74 Glaucoma
Figure 4. Optical coherence tomography image of a normal receiver operator characteristic (ROC) curve was found
eye obtained using a 3.4 mm peripapillary measurement scan
for OCT inferior quadrant thickness, followed by the
FDT number of total deviation plot points </= 5%, SLP
linear discriminant function, and SWAP pattern SD.
Zangwill et al. [66• ] compared the ability of OCT, HRT,
and GDx to discriminate between normal eyes and eyes
with early to moderate glaucomatous visual field loss. No
significant differences were found between area under
the ROC curve and the best parameter from each instru-
ment: OCT inferior RNFL thickness, HRT mean height
contour in the inferior nasal position, and GDx linear
discriminant function).
Garcia-Sanchez et al. [29] evaluated the sensitivity and
specificity of the HRT, GDx, and OCT summary
The anterior and posterior limits of the retinal nerve fiber layer (RNFL) are
demarcated using a computer algorithm (arrows) and clock hour and quadrantic
data for detection of early to moderate glaucoma (aver-
RNFL thickness measurements are obtained. age visual field mean defect –5.0 dB) among three
masked reviewers (see Table 1). For the OCT, sensi-
tivity and specificity ranged from 76 to 79% and 68 to
commercially available device capable of performing 81%, respectively.
scan acquisition times in one second.
Detection of progression
Published series of peripapillary retinal nerve fiber layer Change analysis software has only recently been intro-
measurement using optical coherence tomography have duced; therefore no reports have described longitudinal
sampled 100 evenly-distributed points on a 360 degree change in patients with disease progression. As presently
peripapillary circular scan. Ozden et al. [64] evaluated configured, this algorithm generates a serial analysis of
whether a four-fold increase in sampling density im- RNFL thickness measurements among two OCT im-
proves the reproducibility of OCT measurement. ages, however statistical units of change probability are
Twenty-two eyes of 22 patients (normal subjects, 3 eyes; not provided. Thus, true biological change cannot be
ocular hypertension, 2 eyes; glaucoma, 17 eyes) were differentiated from test-retest variability.
evaluated. Optical coherence tomography scanning con-
sisted of three superior and inferior quadrantic scans Limitations
(100 sampling points/ quadrant) and three circular scans Currently, no statistical units of change probability are
(25 points/quadrant). Retinal nerve fiber layer thickness absent from the change analysis software, therefore one
measurements and CV were calculated for the superior cannot differentiate biological change from measure-
and inferior quadrants for each sampling density tech- ment variability by performing serial analysis of abso-
nique. Normal eyes showed no difference between the lute RNFL thickness values. Pupillary dilation is re-
25 point/quadrant and 100 point/quadrant scans, respec- quired to obtain acceptable peripapillary measurement
tively. Among glaucomatous eyes, however, the CV in scans. Finally, sampling is limited to 25 A-scans per
25-point/quadrant scans (25.9%) was significantly higher quadrant, which may limit the ability to detect localized
than that in 100-point/quadrant scans (11.9%, p = 0.01). change [64].
Sensitivity and specificity Conclusions
Cross-sectional studies have compared OCT with CSLO Recent advances in ocular imaging technology provide a
[65] and SLP [53] in normal, ocular hypertensive, and means to obtain accurate, objective, quantitative, and
glaucomatous eyes. OCT was capable of differentiating reproducible structural measurements of optic disc to-
glaucomatous from non-glaucomatous eyes, and RNFL pography and RNFL thickness. Current imaging sys-
thickness measurements using OCT correlated with re- tems can differentiate between normal eyes and eyes
tardation measurements using SLP and topographic with mild to moderate glaucomatous optic neuropathy.
measurements using CSLO. Although conflicting data exists, sensitivity and specific-
ity values approximate 70 to 80% depending upon
Bowd et al. [54] compared the discriminating powers of sample size, definition of glaucoma, and severity of glau-
SLP, OCT, short-wavelength automated perimetry comatous damage. Any one technology will have limited
(SWAP), frequency-doubling technology perimetry usefulness as a single test to diagnose glaucoma and at
(FDT) for detection of early glaucoma (average visual the present juncture should not be used as an indepen-
field mean defect –4.0 dB). The largest area under the dent diagnostic screening test. However, these instru-

8. Optic nerve and retinal nerve fiber layer analyzers in glaucoma Greenfield 75
ments have considerable potential for use as adjunctive References and recommended reading
measures of glaucomatous damage along with careful Papers of particular interest, published within the annual period of review,
clinical and perimetric examination. have been highlighted as:
• Of special interest
•• Of outstanding interest
There is no uniform agreement regarding the most ap-
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Currently available imaging technologies hold consider- 9 Dreher AW, Reiter K, Weinreb RN: Spatially resolved birefringence of the
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This study found the Heidelberg Retinal Tomograph to be superior to clinical evalu-
Acknowledgments ation of optic disc stereophotographs but was limited by the use of disparate ob-
servers with limited levels of agreement.
Supported in part by the New York Community Trust, New York, New York; The
Kessel Foundation, Bergenfield, New Jersey; The Boyer Foundation, Melbourne, 23 Iester M, Mikelberg FS, Drance SM: The effect of optic disc size on diagnostic
FL; and NIH Grant R01-EY08684, Bethesda, Maryland. The author has no propri- precision with the Heidelberg retina tomograph. Ophthalmology 1997,
etary interest in any of the products or techniques described in this manuscript. 104:545–548.

9. 76 Glaucoma
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•
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•
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•• serial topographic changes in the optic disc and peripapillary retina using
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57 Greenfield DS, Huang X-R, Knighton RW: Effect of corneal polarization axis
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1999, 83:290–294. determinations using the GDx nerve fiber analyzer and outlines the optical limita-
tions of using a fixed corneal compensator to neutralize anterior segment polariza-
33 Lusky M, Morsman D, Weinreb RN: Effects of intraocular pressure on optic tion. A novel method for estimating corneal birefringence is described using macu-
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37 Lee BL, Zangwill L, Weinreb RN: Change in optic disc topography associated fiber layer thickness measurements using optical coherence tomography.
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38 Tjon-Fo-Sang MJ, Lemij HG: The sensitivity and specificity of nerve fiber layer 62 Baumann M, Gentile RC, Liebmann JM, et al.: Reproducibility of retinal thick-
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64 Ozden RG, Ishikawa HI, Liebmann JM, et al.: Increasing sampling density
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65 Mistlberger A, Liebmann JM, Greenfield DS, et al.: Heidelberg retina tomog-
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This report provides a comparison of the ability of OCT, GDx, and HRT to discrimi-
43 Knighton RW, Huang W-R, Greenfield DS: Linear birefringence measured in nate between healthy eyes and eyes with mild to moderate glaucoma and found no
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43:82–86. tor characteristic curves.
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ization axis improves the discriminating power of scanning laser polarimetry. surements of the optic nerve head with laser tomographic scanning. Ophthal-
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45 Hoh ST, Greenfield DS, Liebmann JM, et al.: Effect of pupillary dilation on 68 Choplin NT, Lundy DC, Dreher AW: Differentiating patients with glaucoma
retinal nerve fiber layer thickness measurement using scanning laser polarim- from glaucoma suspects and normal subjects by nerve fiber layer assessment
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