The 'two global flash' mfERG in high and normal tension primary open-angle glaucoma.

Abstract

To analyse the sensitivity of the '2 global flash' multifocal electroretinogram (mfERG) to detect glaucomatous dysfunction in normal tension (NTG) and high tension primary open angle glaucoma (POAG) patients.
MfERGs were recorded from 20 NTG and 20 POAG patients and compared to those of 20 controls. The mfERG array consisted of 103 hexagons. Each m-sequence step started with a focal flash that could be either dark or light (m-sequence: 2--13, L(max): 200 cd/m(2), L(min): 1 cd/m(2)), followed by two global flashes (L(max): 200 cd/m(2)) at an interval of approximately 26 ms. Focal scalar products (SP) were calculated using focal templates derived from the control recordings (VERIS 4.8). We analyzed 5 response averages (central 7.5 degrees and 4 adjoining quadrants) of the response to the focal flash, the direct component at 10-40 ms (DC) and the following two components induced by the effects of the preceding focal flash on the response to the global flashes at 40-70 ms (IC-1) and at 70-100 ms (IC-2).
Both NTG and POAG patients differed from controls in the IC-1 response to the superior quadrants, and POAG patients also differed from controls in the centre. The most sensitive parameter was the IC-1 of the superior temporal quadrant with an area under the ROC curve of 0.82 for POAG and 0.79 for NTG. The DC and the IC-2 did not differ significantly between the groups. When all five response averages of the IC-1 were taken into consideration 90% of the NTG patients and 85% of the POAG patients were correctly classified as abnormal while 80% of the control subjects were correctly classified as normal.
This stimulus sequence holds promise for the diagnosis of early functional changes in POAG. A new finding is that both NTG, as well as POAG can be differentiated from control subjects.

Full text

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ORIGINAL PAPER
The ‘two global flash’ mfERG in high and normal tension
primary open-angle glaucoma
Anja M. Palmowski-Wolfe Æ Æ
Margarita G. Todorova Æ Æ Selim Orguel Æ Æ
Josef Flammer Æ Æ Mitchell Brigell
Received: 20 July 2006/Accepted: 19 October 2006/Published online: 8 December 2006
? Springer Science+Business Media B.V. 2006
Abstract
Purpose
flash’ multifocal electroretinogram (mfERG) to
detectglaucomatousdysfunctioninnormaltension
(NTG) and high tension primary open angle
glaucoma (POAG) patients.
Methods
MfERGs were recorded from 20 NTG
and 20 POAG patients and compared to those of
20 controls. The mfERG array consisted of 103
hexagons. Each m-sequence step started with a
focal flash that could be either dark or light
(m-sequence: 2^13, Lmax: 200 cd/m2, Lmin: 1 cd/m2),
followedbytwoglobalflashes(Lmax:200 cd/m2)at
an interval of ~26 ms. Focal scalar products (SP)
werecalculatedusingfocaltemplatesderivedfrom
thecontrolrecordings(VERIS4.8).Weanalyzed5
response averages (central 7.5 degrees and 4
adjoining quadrants) of the response to the focal
flash, the direct component at 10–40 ms (DC) and
the following two components induced by the
effects of the preceding focal flash on the response
Toanalysethesensitivityofthe‘2global
to the global flashes at 40–70 ms (IC-1) and at 70–
100 ms (IC-2).
Results
Both NTG and POAG patients differed
from controls in the IC-1 response to the superior
quadrants, and POAG patients also differed from
controls in the centre. The most sensitive param-
eterwastheIC-1ofthesuperiortemporalquadrant
with an area under the ROC curve of 0.82 for
POAGand0.79forNTG.TheDCandtheIC-2did
not differ significantly between the groups. When
all five response averages of the IC-1 were taken
into consideration 90% of the NTG patients and
85% of the POAG patients were correctly classi-
fied as abnormal while 80% of the control subjects
were correctly classified as normal.
Conclusions
This stimulus sequence holds prom-
ise for the diagnosis of early functional changes in
POAG. A new finding is that both NTG, as well as
POAGcanbedifferentiatedfromcontrolsubjects.
Keywords
POAG ? Normal tension glaucoma
mfERG ? Global flash ? Glaucoma ?
Introduction
Open angle glaucoma, a leading cause of blind-
ness worldwide [1], affects at least 1.7% of the
population over 40 years of age in industrial
countries [2]. In POAG an increasing loss of
ganglion cell fibers results in a progressive optic
A. M. Palmowski-Wolfe (&) ? M.G. Todorova ?
S. Orguel ? J. Flammer
Department of Ophthalmology, University Eye
Hospital, Mittlere Strasse 91, 4012 Basel, Switzerland
e-mail: palmowskia@uhbs.ch
M. Brigell
Pfizer Global Research & Development, Ann Arbor,
MI 48105, USA
123
Doc Ophthalmol (2007) 114:9–19
DOI 10.1007/s10633-006-9033-x

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atrophy with an increased cup/disc ratio and an
irreversible visual field loss [3]. In an attempt to
detectearlyglaucomatous
mfERG has been studied as a possible diagnostic
tool for the past decade. In experimental glau-
coma, nerve fiber cell damage induced in the
primate results in a marked reduction of ampli-
tude in the mfERG [4–6].
In humans, initial studies that describe changes
in the mfERG secondary to glaucoma show only
a small reduction in amplitude and an increase in
latencies [7–10] in POAG patients when com-
pared to a control group. However, changes in
stimulation parameters have lead to an increased
sensitivity of the mfERG to detect glaucomatous
dysfunction. These changes have primarily fo-
cused on enhancing nonlinear contributions to the
mfERG, in particular a response component, the
optic nerve head component (ONHC), whose
propagation time correlates well with the length
of the ganglion nerve fibers and thus seems
dependent on the nerve fiber layer [11–16]. In
theprimate,thenaso-temporal
thought to be caused by this component is
diminished following intravitreal administration
of Tetrodotoxin, which blocks amacrine and
ganglion cells [16]. The ONHC appears to be
diminished in glaucoma [15, 17]. Bearse et al.
have shown that the ONHC asymptotes in
amplitude at a contrast of about 60% whereas
the retinal component (RC) shows a linear
relationship with contrast [18]. Thus low contrast
recordings were thought to be more sensitive to
retinal dysfunction in patients with open angle
glaucoma (OAG) as reducing the stimulus con-
trast to 50% would enhance the relative contri-
bution of the inner retina. While this was the case,
sensitivity did not increase enough to detect
individual patients as having POAG [7, 19, 20].
With an increase in the stimulus base interval,
a small induced response component resulting
from the response to the following stimulus in the
m-sequence cycle becomes apparent. At a stim-
ulus base interval of ~54 ms there is no overlap
between the induced component and the m
sequence response. Under these conditions, oscil-
latory potentials become apparent in the induced
component [21] and the sensitivity to detect NTG
increases to about 85% [22].
dysfunction, the
asymmetry
Adaptive mechanisms can be enhanced by
interposing bright global flashes into the stimula-
tion sequence, as suggested by Sutter et al. [23].
When global flashes are introduced into the
stimulus sequence, the mfERG sensitivity to
detect retinal dysfunction in glaucoma increases
to 50% with the use of 3 global flashes [24] and to
about75%withaspecificityof83%with theuseof
asingle global flash [25]. Also, inthe areaof alaser
induced focal ganglion cell fiber layer defect in the
primate, a mfERG with one global flash showed
fewer and smaller high frequency oscillations,
especially in the response to the global flash but
also to the focal flash [26]. These changes affected
high frequency components as well as low fre-
quency components where P2 and N2 were
reducedinamplitudeandincreasedinlatency[26].
In the present study we examine the sensitivity
of a mfERG stimulus with two global flashes to
detect glaucomatous dysfunction in NTG and
POAG patients.
Methods
Subjects
MfERG recordings were obtained from 20
patients with NTG, 20 patients with POAG and
compared to a control group of 20 normal
subjects. The tenets of the Declaration of Hel-
sinki were adhered to. The study was approved by
the institutional review board of the University of
Basel. Informed consent was obtained from
patients and subjects after explanation of the
nature and possible consequences of the study.
Inclusion criteria for glaucoma patients were a
cup disc ratio of at least 0.5 as measured with the
HRT (Heidelberg Retina Tomograph, Heidel-
berg Engineering, Heidelberg, Germany), local-
ized thinning of the neuro-retinal rim of the optic
disc, and the presence of a glaucomatous visual
field defect. For POAG patients the highest
measured IOP was >21 mmHG, while for the
NTG patients this had to be less than 22 mmHg.
Exclusion criteria were the presence of other
ocular or systemic diseases, such as diabetes
mellitus or hypertension as well as refractive
errors exceeding 6 diopters of hyperopia or
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myopia. The right eye of each subject was
included unless it did not fulfill the inclusion
criteria or met any of the exclusion criteria. In this
case, the left eye was included, if it fulfilled the
eligibility criteria.
MfERG recording
For mfERG recording, patients were adapted to
ambient room light for 30 minutes. Prior to
recording, the pupil was
(Tropicamide 0.5%, Phenylephrin 1%) and the
cornea was anesthesized (Proxymetacain Hydro-
chlorid). Electrical responses were recorded
monoculary via a bipolar Burian-Allan contact
lens electrode (Hansen Ophthalmic Develop-
ment Labs, Iowa City, IA), that was wetted with
a drop of synthetic carbomer (Thilo-Tears SER).
The other eye was occluded during the record-
ing. The ground electrode was placed on the
forehead. Subjects were refracted for best visual
acuity at 40 cm. The distance between the
subject and the screen was adjusted to compen-
sate for changes in stimulus size induced by the
refractive lens.
During recording, the central 50 degrees of the
retina were stimulated with a Veris scientific 4.8
(Visual Evoked response Imaging System, VE-
RIS EDI, San Mateo, California). The stimulus
array consisted of 103 hexagons displayed on a
monochrome monitor. The stimulus hexagons
were scaled with eccentricity in order to take
into account the retinal cone distribution and thus
to achieve approximately equal focal response
signals in the controls [27].
Figure 1 depicts the stimulus sequence used:
Hexagons flickered between black and white
according to an m-sequence of 2^13 (frame rate:
75 Hz). Each m-sequence step started with a focal
flash that could be either light or dark (Lmax:
200 cd/m2, Lmin: £1 cd/m2), (M), followed by two
global flashes (F, Lmax: 200 cd/m2). A dark frame
(B, Lmax: £1 cd/m2) separated each flash in the
sequence. Thus one stimulus base interval con-
sisted of the following sequence: MBFBFB, with
a stimulus base interval of ~80 ms and a contrast
of 99%. The background was set at 50 cd/m2.
Retinal signals were amplified (100 000) and
bandpass filtered at 10–300 Hz. The total record-
maximally dilated
ing time of 10 min 55 sec duration was divided
into 32 segments. Segments with contaminated
signals were discarded and re-recorded. The
artifact rejection technique, incorporated in the
software, was applied twice [27]. Spatial filtering
was not used.
Response analysis
The mfERG first order response component is
calculated by adding the focal mean response to a
stimulus base interval starting with a light m-
sequence stimulus and subtracting those starting
with a dark m-sequence stimulus (Fig. 1). There-
fore a response to global flashes (full-screen
flashes) will only occur if they are influenced
differently by the response to the preceding focal
flash, which is the only stimulus frame that is not
constant in the individual stimulus base intervals.
Thus the presence of a response to a global flash
demonstrates the presence of retinal adaptation
which may be presumed to be of inner retinal
origin. In addition, it has been suggested to
Fig. 1 Figure 1 depicts the stimulus sequence of the
mfERG (top) and an example of the resulting retinal
responseelicited(below).Eachstimulusstartedwithafocal
flash that could be either light or dark (Lmax: 200 cd/m2,
Lmin: 1 cd/m2), followed by two global flashes (F, Lmax:
200 cd/m2) at an interval of ~26 ms. A dark frame
(B, Lmax: £1 cd/m2) separated each step in the stimulus
sequence. The three epochs analyzed are highlighted: the
response to the focal flash at 10–40 ms (direct component,
DC) and the following two components induced by the
global flashes at 40–70 ms (IC-1) and at 70–100 ms (IC-2)
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represent influences of lateral interactions. [23,
24, 28–30]
Figure 1 shows the three epochs of the first
order response component that were analyzed:
the response to the focal stimulus, found at
10–40 ms (direct component, DC) and the fol-
lowing two components induced by the effects of
the focal stimulus on the following global flashes
at 40–70 ms (induced component 1, IC-1) and at
70–100 ms (induced component 2, IC-2). The
focal scalar product (SP), that is the cross product
of the focal waveform and its template, was
analyzed for each location and for each of the
three epoch lengths (DC, IC-1, IC-2). The corre-
sponding focal templates were derived from the
20 control recordings for each of the three epoch
lengths (DC, IC-1, IC-2).
Figure 2 shows the areas over which the focal
SP were averaged to form these response aver-
ages for the central 7.5 degrees (C) and the four
adjoining quadrants (field view): ST: superior
temporal; SN: superior nasal, IN: inferior nasal
and IT: inferior temporal. For analysis of the five
group averages, a repeat measure ANOVA was
performed, taking into account the effects of
location and age.
Results
Neither age nor visual acuity differed between the
three groups studied. Mean age was 53.9 (SD
13.1) years in the control group, 56.6 (SD 8.1)
years in the NTG group and 61.0 (SD 10.7) years
in the POAG group (ANOVA P = 0.126). Snel-
len visual acuity was ‡0.8 in all participants. At
the time of the study, IOP was under 21 mmHG
in all patients. Mean IOP was 11.7 (SD 2) mmHg
in the control group, 13.5 (SD 1.8) mmHg in the
NTG group and 14.4 (SD 3.5) mmHg in the
POAG group. Mean cup-disc-ratio was 0.33 (SD
0.06) in the control group, 0.65 (SD 0.11) in the
NTG group and 0.61 (SD 0.14) in the POAG
group. Mean MD was 5.25 (SD 3.4) dB in the
NTG group and 5.94 (SD 3.05) dB in the POAG
group. The control group differed from the NTG
and POAG groups in IOP and cup-disc-ratio, but
the NTG and the POAG groups did not differ
significantly in IOP, cup-disc-ratio or MD.
Figure 3 shows a trace array from the right eye
of a control subject over the entire epoch
analyzed, 10–100 ms. The responses show a large
naso-temporal asymmetry. When small nasal and
small temporal response averages were analyzed
(Fig. 4), it became apparent that the naso-tem-
poral asymmetry observed was mainly due to a
larger amplitude in the response average from the
nasal field, in particular of the DC, but also of the
IC-1 response. This naso-temporal asymmetry
was seen in the control subjects and also persisted
in the NTG and POAG patients. When all three
response components were analyzed, considering
the effect of location and age, no significant
differences were found between the groups in
Fig. 2 Figure 2 shows the areas over which the focal SP
were averaged to form response averages for the central 7
degrees (C) and the four adjoining quadrants: ST: superior
temporal; SN: superior nasal, IN: inferior nasal and IT:
inferior temporal
Fig. 3 Figure 3 shows a trace array of the right eye of a
control over the entire epoch analyzed, 10–100 ms. The
responses show a large naso-temporal asymmetry
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either amplitude or latency. When we attempted
to average larger areas, the naso-temporal asym-
metry resulted in a smearing out of peaks and
troughs, preventing reliable peak to trough mea-
surements. We therefore calculated focal scalar
products for each epoch length analyzed as
described in the method section. These focal
scalar products were then averaged to form five
response averages (Fig. 2).
Figure 5 shows the mean of each response
average for the DC (a), the IC-1 (b) and the IC-2
(c). The error bars depict the standard error of
the mean. Neither the DC (Fig. 5a), nor the
response to the second global flash, the IC-2
(Fig. 5c),
differedsignificantly
groups. This held true for all response averages
examined.
The IC-1 (Fig. 5b), the response induced by the
first global flash, differed significantly between
the subject groups (P = 0.003). There was also a
significant difference in the location effect be-
tween groups P = 0.003. Surprisingly, this differ-
ence did not seem related to a naso-temporal
asymmetry, but occurred in the superior and
central fields (Table 1). In the superior fields
both, the NTG and the POAG patients were
significantly lower in amplitude than the control
subjects (P < 0.02, multivariate ANOVA, Sidak).
In the central response average, only POAG
patients had significantly smaller IC-1 amplitudes
betweenthe
than the control patients (P = 0.003). In the
inferior quadrants POAG and NTG patients did
not differ from the control group. There was no
significant difference between POAG and NTG
patients.
Figure 6 shows the distribution of the mean
defect for each of the visual field quadrants (G2
program, Octopus 101, Haag-Streit AG). While
on average the MD was higher in the superior
fields, it did not differ significantly between
quadrants. Also, the MD of the four quadrants
did not correlate significantly with the age
adjusted log-mfERG response of IC-1.
The area under the receiver operating char-
acteristics (ROC) curve is a measure of the
ability of a parameter to differentiate between
patients and controls. Table 2 shows the area
under the ROC curve for the IC-1 for each of the
group averages examined. Figure 7 depicts ROC
curves for the IC-1 of the superior temporal
quadrant where POAG patients differed most
from the controls. Here, for NTG patients, the
area under the ROC curve was 0.79 and for
POAG it was 0.82, which is significantly better
than chance (P £ 0.02). With a cutoff value of
2.5 nV/deg2, 80% of the NTG patients and 75%
of the POAG patients were correctly classified as
abnormal while 80% of the control subjects were
correctly classified as normal. Table 2b contains
the information on sensitivity and specificity for
Fig. 4 Figure 4 (top left) shows the responses that were
averaged to form a small nasal and a small temporal
response average (field view). The plots to the right show
the mean peak (P) to trough (N) amplitudes for the three
response components (M, IC-1 and IC-2) shown in Fig. 1.
The error bar depicts ±1 SEM. For each group, the left
column depicts the temporal response average, the right
column depicts the nasal response average
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all the response averages analyzed. Individual
subjects’ or patients’ responses may be affected
differently in the various response averages
analyzed. When all five response averages of
the IC-1 were taken into consideration, and using
the cutoff values depicted in Table 2 b, 90% of
the NTG patients and 85% of the POAG
patients were correctly classified as abnormal
while 80% of the control subjects were correctly
classified as normal.
Fig. 5 depicts the mean of each response average (groups are shown in Fig. 3) for the DC (a), the IC-1 (b) and the IC-2 (c).
The error bars depict ± 1standard error of the mean
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Discussion
In this study, significant changes were observed in
the IC-1, where both NTG and POAG patients
differed from controls in the response averages of
the superior quadrants, and POAG patients also
differed from controls in the centre. The most
sensitive parameter was the IC-1 of the superior
temporal quadrant where 80% of the NTG
patients and 75% of the POAG patients were
correctly classified as abnormal while 80% of the
Fig. 5 continued
Table 1 For the IC-1 and for each response average,
Table 1 lists how the three groups: NTG, POAG and
Control, compared to one another. Significant differences
are highlighted in bold (multivariate ANOVA, Sidak)
QuadrantsGroups
P-value
superior-temporalcontrols-NTG
Controls-POAG
NTG-POAG
controls-NTG
controls-POAG
NTG-POAG
controls-NTG
controls-POAG
NTG-POAG
controls-NTG
controls-POAG
NTG-POAG
controls-NTG
controls-POAG
NTG-POAG
0.001
0.000
0.992
0.016
0.000
0.302
0.661
0.052
0.382
1.000
0.417
0.426
0.443
0.003
0.103
superior-nasal
inferior-nasal
inferior-temporal
centre
Fig. 6 shows the distribution of the mean defect for each
of the visual field quadrants. The error bars depict ±1
standard error of the mean. While on average the MD was
higher in the superior fields, it did not differ significantly
between quadrants
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control subjects were correctly classified as nor-
mal when a cutoff value of 2.5 nV/deg2was used.
The DC and the IC-2 did not differ significantly
between the groups. These results compare well
to a study by Fortune et al. [25] who also found
the induced component to be most sensitive when
a one flash mfERG was applied, allowing glau-
coma subjects to be identified with a sensitivity of
75% when a cutoff value of 2.75 nV/deg2was
used.
In a mfERG with one global flash, Chu et al.
[28] also showed an overlap of the DC but
separated IC between glaucoma patients and a
control group when, as in the present study, focal
flashes of high luminance difference were used.
Recording the response to various luminance
differences between the DC and the IC (which
remained at a stable luminance) of a one flash
mfERG they were able to calculate an adaptive
index that reflects the tendency of the DC to
saturate at higher luminance differences and that
also reflects nonlinear contributions to the DC.
This saturation was less obvious in glaucoma,
possibly due to reduced amplitudes at mid lumi-
nance difference levels. This adaptive index of the
DC had a very high sensitivity of 93% with a
specificity of 95%. This is higher, than the
sensitivity found in the present study where,
when all five response averages of the IC-1 were
taken into consideration, 90% of the NTG
patients and 85% of the POAG patients were
correctly classified as abnormal while 80% of the
Table 2 The ability of the IC-1to differentiate beween
NTG, POAG and Control is shown for each response
average. (a) depicts information on the area under the
ROC curve with the corresponding P value when POAG
and NTG are compared to the control group. (b) informs
about sensitivity and specificity for the different response
averages using given cutoff values
STSNIN ITCentral
(a)
POAGArea
P-value
Area
P-value
0.81
0.00
0.79
0.00
0.81
0.00
0.75
0.01
0.70
0.03
0.58
0.36
0.65
0.09
0.50
0.97
0.78
0.00
0.61
0.21
NTG
(b)
Cutoff value in nV/deg2
% classified abnormal
2.50
75
80
80
2.40
75
75
85
2.30
65
45
80
1.40
30
25
80
3.40
55
15
85
POAG
NTG
control % Classified normal
Fig. 7 Figure 7 depicts the receiver operating character-
istics (ROC) curves for the IC-1 of the superior temporal
quadrant for NTG patients (left) and POAG patients
(right). If the values were aligned on the diagonal, this
ability would be equal to chance. For a sensitivity and
specificity of 100%, the ROC curve would follow the
leftmost and the topmost margin of the graph. Thus, the
area under the ROC curve is a measure of the ability of
this parameter to differentiate between patients and
controls. For NTG patients, the area under the ROC
curve was 0.79 and for HTG it was 0.82, which is
significantly better than chance (P £ 0.02)
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control subjects were correctly classified as nor-
mal. A longer follow period would be necessary
to evaluate, what percentage of the 20% control
subjects classified as abnormal will develop glau-
coma. Thus at present, it is to early to tell,
whether there is a 20% false alarm rate or
whether the mfERG may be more sensitive to
detect glaucomatous damage than either visual
field defects or an increased cup-disc ratio,
parameters which are currently required for the
diagnosis of glaucoma.
The higher sensitivity and specificity found by
Chu et al may also reflect more progressed
glaucoma in their patients (mean MD: 7.79 (SD
5.76) [28], than in the present study where mean
MD was 5.25 (SD 3.4) dB in the NTG group and
5.94 (SD 3.05) dB in the POAG group. A
disadvantage of the adaptive index suggested by
Chu et al. [28] is that it requires multiple mfERG
recordings. In order to obtain this adaptive index
patients underwent 4 mfERG recordings, each
lasting 8 min [28] which is difficult to achieve in a
clinical setting. This compares to one 10 min
recording in the present study. From Fig. 4 in
their paper [28] it seems that a small reduction in
luminance difference of the focal flash to 1.42
cd*s/m2results in a clearer separation between
both the DC and the IC of the one flash mfERG.
This would be a promising approach in order to
try and further increase sensitivity and specificity,
using only a single recording eg. with the 2 flash
mfERG.
In the present study, meaningful peak to
peak measures were not feasible, as very small
amplitudes with broad peaks were seen in quite
a few mfERGs recorded. Therefore we chose
the scalar product measure in order to objec-
tively analyze each mfERG. The relevant find-
ings of the present study are based on the scalar
product measure, which reflects changes in
amplitude as well as in latency. Fortune et al
reported an amplitude reduction of the induced
component in the one flash mfERG [25]. Thus,
from this and from our observation of very
small amplitudes, it is reasonable that our
results also reflect reduced amplitudes. On the
other hand, it seems likely, that latencies would
also be affected to some extend, as they have
previously been found to be slightly increased in
the linear and nonlinear [9, 10] components of
the mfERG without a global flash in glaucoma
patients
In the no global flash-mfERG response of
POAG patients small but robust changes have
been reported [7–10]. Even though Fig. 5a shows
a tendency for a reduced DC response in POAG,
changes observed in the DC of the 2 flash mfERG
did not approach significance level in either the
NTG or POAG patients. The DC of the flash
mfERG reflects different adaptive mechanisms
across the retina that are not present in the
conventional high contrast noflash mfERG [28].
This may be a result of the interdependence
between the focal flash and the global flashes, in
particular the dependence of the DC on the
global flash (see following discussion).
Studies using one global flash in the mfERG
stimulus sequence suggest that the luminance
parameters used in our study (200 cd/m2) appear
to be among the stimulus settings that produce the
largest IC- responses as well as good DC-
responses. Shimada et al studied the one global
flash mfERG response to various luminance con-
ditions, ranging between 12.75 cd/m2and 800 cd/
m2. The luminance conditions were independently
changedfortheglobalflashandthefocalflash[31].
With increasing luminance intensity of the global
flash, the inter-individual variability was reduced.
At the same time, the DC became sequentially
smaller and its implicit time shorter. The IC-
response was largest at a global flash intensity
between100–200 cd/m2.Forverydimfocalflashes,
the mfERG DC- and IC- response were below
noise level. With increasing luminance of the focal
flashesupto200 cd/m2,theIC-responseincreased,
thereafter the amplitudes and latencies of the IC
decreased [31]. Increasing the luminance and
contrast conditions of the focal flash in a mfERG
stimulation with one global flash in the stimulus
sequenceshowedanincreasingreductionintheIC-
response amplitude of glaucoma patients when
compared to a control group. In contrast, the
response to the focal flash, the DC, differed most
between glaucoma and control subjects at a mid
luminance difference [28].
It is interesting to note that in the one global
flash mfERG, not only do adaptive effects of
the focal m-sequence stimulus influence the
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IC- response, but the global flashes also influence
the response to the focal flash [31]. This also holds
true for stimuli with 3 global flashes, where the
response to the focal flash is greatly altered [24].
These nonlinear contributions, have been re-
ported to be much larger in the IC than in the
DC. Of the nonlinear contributions to the
mfERG, theopticnerve
(ONHC) which has been attributed to the nerve
fiber layer [11–16] is reflected in a large naso-
temporal asymmetry of the mfERG response that
may be diminished in glaucoma [15, 17]. Indeed,
the IC has been shown to contain a large naso-
temporal asymmetry, while this is only slightly
present in the focal flash response [24, 25, 29–31].
These adaptive mechanisms are generally attrib-
uted to the inner retina [24, 25, 29, 30], suggesting
that a global flash paradigm lends itself to the
diagnosis of glaucoma.
In the present study however, even though the
trace arrays of the stimulus show a marked naso-
temporal asymmetry, this did not differ between
the groups. The differences observed were con-
centrated on the upper hemifield. Nonetheless,
we did not find a significant difference in the
distribution of the mean defect of the different
quadrants of the visual fields in either NTG or
POAG patients that might explain this finding.
This is in agreement with previous studies that did
not find mfERG changes co-localized to visual
field defects, either for the no global flash mfERG
[19, 22] or for the pattern mfERG [32].
In conclusion, our results support previous
findings, that interposing bright global flashes into
the stimulation sequence, increases the sensitivity
of the mfERG to detect retinal dysfunction in
glaucoma [24, 25, 28]. While the second induced
component of a 3 global flash mfERG had a 50%
sensitivity to detect glaucomatous damage [24],
this was increased to 75% with use of a single
globalflashmfERG
curve:0.88) [25]. The 2 global flash stimulus
applied here, showed a comparable ability to
differentiate POAG patientsfrom control subjects
when the first induced component in the superior
temporal quadrant was analysed (Area under
ROC curve: NTG: 0.79; POAG: 0.82). When all
five response averages of the IC-1 were taken into
consideration, 90% of the NTG patients and 85%
headcomponent
(Areaunder ROC
of the POAG patients were correctly classified as
abnormal while 80% of the control subjects were
correctly classified as normal. Thus, a further, new
finding of this study is, that this IC-1 had a similar
ability to separate POAG, as well as NTG patients
from the control group.
Acknowledgements
statistical advice and Pfizer for grant support (APW,MT).
We thankAndyScho ¨tzaufor
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