Chapter 5

Clinical Visual Electrophysiology Search

J. VERNON ODOM, MONIQUE LEYS and GEORGE W. WEINSTEIN
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GENERAL CONSIDERATIONS
ELECTRORETINOGRAM
ELECTRO-OCULOGRAM
VISUALLY EVOKED POTENTIALS
MULTIFOCAL TECHNIQUES IN ELECTROPHYSIOLOGY
CLINICAL APPLICATIONS
REFERENCES

In this chapter, we introduce the reader to some of the principles

of and major observations in clinical electrophysiology. Although
this is a brief summary that must be limited in its depth of
coverage, several other chapters in this volume point out the
utility of electrophysiologic measures in the diagnosis of particular
diseases or categories of disease1–4 or discuss their physiologic
origins.5 Additionally, several brief books6,7 and major reviews8–
10 are available for the reader who is interested in a more
extensive introduction. An excellent reference volume, which is
currently being revised, is available for the serious student of
clinical electrophysiology.11
The primary means of electrophysiologic testing are
electroretinography (electroretinogram [ERG]), electro-
oculography (electro-oculogram [EOG]), and visually evoked
potential (VEP) testing. Electroretinography, as it is classically
performed using flashes of light, provides information primarily
about the outer retinal layers (Fig. 1A and B). EOGs (and the c
wave of the ERG) reflect variations in the standing potential
across Bruch's membrane and are altered by metabolic changes
in the retinal pigment epithelium and outer retina (Fig. 1A). VEPs
are cortical responses elicited by visual stimuli. Normal cortical
responses are obtained only if the entire visual system is intact.
Disturbances anywhere within the visual system can produce
abnormal VEPs.
Fig. 1. Approximate layer
of origin of various retinal
signals recorded from the
cornea. A. On the left are
a schematic dark-
adapted flash-elicited
electroretinogram (ERG) and a schematic pattern-elicited ERG.
In the center are various retinal layers with the retinal pigment
epithelium at the top and the ganglion cell layer at the bottom.
On the right are the sources of 8-Hz flicker ERGs elicited by high-
contrast flicker. First harmonics originate in the outer retina,
whereas second harmonics have two origins: one in the outer
retina and one in the inner retina. B. On the left is a schematic
light-adapted flash-elicited ERG. In the center are various retinal
layers with the retinal pigment epithelium at the top and the
ganglion cell layer at the bottom. On the right are the sources of
the multifocal ERG. The multifocal ERG appears to include
sources from the middle to outer retinal layers. Different sources
are emphasized, depending on the precise stimulus and
recording conditions. (ERP, event-related potential; ONHC, optic
nerve head component)
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GENERAL CONSIDERATIONS
GENERAL TERMINOLOGY
As with any specialized area, clinical electrophysiology abounds
with specialized terminology. Terms that deal with general
characteristics of the stimulus or response are introduced here.
Terms specific to a particular response are introduced in that
particular section.
The stimulus for clinical visual electrophysiology is usually either
diffuse light or patterned light. The stimulus may vary in
intensity, duration, wavelength, rise time, fall time, spatial
extent, and spatial location. A diffuse light stimulus varies in time
but is uniform across a relatively large area of visual space. A
diffuse light stimulus that appears and disappears suddenly and is
of brief duration is termed a light flash or simply a flash. Diffuse,
uniform stimuli are often presented in a sphere called a cupola,
which provides Ganzfeld (full-field) stimulation. If the light
appears and disappears periodically, it is said to flicker. The
number of cycles of appearance and disappearance of light in one
second equals the temporal frequency of the flicker in cycles per
sec (cps) or Hertz (Hz).
A patterned stimulus varies not only in time but also in space. A
patterned stimulus may appear and disappear as some areas
become lighter and others become darker, or it may reverse so
that light areas become dark and dark areas become light. The
stimulator should perform these functions without any change in
mean light level or luminance, which generally requires that light
and dark areas appear equally in the pattern presented. The
temporal frequency of an appearing-disappearing pattern is equal
to the number of appearances (or disappearances) in 1 second.
However, there are two reversals in a reversal cycle. Therefore,
the number of reversal cycles in 1 second of the reversing pattern
expressed in Hz—in other words, the temporal frequency—is one-
half the number of reversals in 1 second. Because of the possible
confusion between temporal frequency and the number of
reversals, it is advisable to indicate both frequency and reversal
rate when describing the reversing stimulus. The spatial
characteristics of a patterned stimulus may be described either in
terms of the visual angle (arc tan [size/distance]) of the elements
in the pattern or in terms of their spatial frequency, which is the
number of cycles of light and dark transitions in one degree of
visual angle.
To isolate rod system from cone system function, stimuli are
presented after the patient has been in the dark for some period
of time. Responses recorded after a period of dark adaptation are
termed dark-adapted, scotopic, or rod mediated. To isolate cone
system function, patients are tested after a period in the light,
usually at a light level that suppresses rod activity. Responses
recorded after a period of light adaptation are termed light
adapted, photopic, or cone mediated.
Electrophysiologic responses elicited by visual stimuli have a
shape, or waveform, which depends on the characteristics of the
stimulus and the patient. The response can usually be
decomposed into components. If the stimulus is presented at a
slow frequency, the response is said to be transient, and peaks of
a specific polarity usually define the components. The peaks can
be characterized by their size or amplitude, their polarity positive
or negative the time to their maximum amplitude, which is
termed implicit time for the ERG and latency for the VEP. If the
stimulus frequency is fast, the peaks of the transient response
become blurred so that the response often consists of only one or
two peaks. The amplitude and implicit time or latency of these
steady state responses may be measured; for example, 30-Hz
flicker ERGs, or the response, may be Fourier analyzed and
characterized by the amplitudes and phases of the Fourier
components.
Irrespective of the response component measured, one may
establish functions relating the component to a stimulus
parameter, such as intensity, contrast, or frequency. If one varies
the stimulus parameter and measures the response, one
establishes a response function, such as an intensity response
function. However, if one uses some response criterion, such as a
criterion voltage, one determines sensitivity.12,13 If one
determines sensitivity across a range of values, one determines a
sensitivity function, such as a contrast sensitivity function.
Although functions are usually determined using a set of separate
responses, it is possible to determine response functions from a
single stimulus presentation if the parameter of interest, such as
intensity or luminance, is varied continuously (or approximately
continuously). Such continuous stimulus presentations are called
stimulus sweeps, and the responses elicited by them are termed
sweep or swept VEPs or ERGs (Fig. 2). Generally, sweep
responses are elicited by steady state stimulation as well as the
signals analyzed in the frequency domain using a lock-in amplifier
or Fourier analysis.14
Fig. 2. Sweep 30-Hz flicker
electroretinograms recorded under light-
adapted conditions. Background luminance
was 10 cd·m-2. During 16 seconds, flicker luminance increased
from 0.0314 cd·m-2 on the far left to 314 cd·m-2 at the far right.
(Redrawn from data presented in Bocquet et al.14).
A number of terms have been used to describe severely abnormal
responses, including flat, absent, extinguished, and
nonrecordable. We use the term nonrecordable as a more neutral
term. Nonrecordable indicates that under a specific set of stimuli
and recording conditions, a response was not recorded. Often,
with a change in stimulus or recording conditions, a response is
recordable.
INTERNATIONAL STANDARDS
Members of the International Society for Clinical
Electrophysiology of Vision (ISCEV) establish ophthalmic
standards for various electrophysiologic tests
(http://www.iscev.org).15–24 The accepted standards are
reconsidered and revised, if necessary, on a regular basis. These
standards are intended to assist in normalizing electrophysiologic
testing by establishing minimal standards for diagnostic test
conditions and analysis methods. Additional tests or analyses are
always permitted. Because of inevitable variations due to choice
of electrode, subjects, and other variables, the standards also
require each laboratory to establish normal values and the limits
of normal values for all tests performed in that laboratory. These
normal values and their limits should be included in clinical
reports and publications from the laboratory.
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ELECTRORETINOGRAM
The ERG is the retinal electrical potential elicited by visual
stimulation. Electroretinography dates back more than a
century.25 The amplitude of dark-adapted, flash-elicited ERGs is
usually several hundred microvolts and, therefore, does not
require complex averaging instrumentation. A schematic ERG is
presented in Figure 3. The era of clinical electroretinography
began with the introduction of the contact lens electrode in the
1950s (Fig 4).
Fig. 3. Electroretinogram (ERG) recorded
with a long-duration flash in the dark. The
schematic shows a, b, c, and d waves of the
ERG as they would be recorded with a
contact lens electrode. The light stimulus is
turned on and off as indicated by the arrows.
Fig. 4. Electrodes for clinical
electroretinography. A. Variety of
electrodes and electrode types used for
clinical electrophysiology of vision.
Contact lens, foil, fiber, or skin
electrodes may be used. Although the
electrodes vary in their properties, all
(except the skin electrodes) may
provide roughly equivalent results. The
largest variable in accounting for
differences between electrodes is often
the experience of the technician placing
the electrodes. Several countries now
require that electrodes be disposable,
making foil and fiber electrodes
favorable. B. A disposable contact lens
electrode in use. C. A homemade fiber electrode in use. D. Use
of a foil electrode.
The different waves of the ERG can be useful in detecting retinal
diseases, which may or may not affect the VEP. For example,
early stages of retinitis pigmentosa may have little or no effect on
the VEP, although the ERG may be severely altered. In
sphingolipidoses, such as Niemann-Pick disease, retinal
degeneration tends to parallel cerebral dysfunction and the ERG
may serve as a useful noninvasive diagnostic test.
FLASH ELECTRORETINOGRAMS
Retinal Physiology and the Flash Electroretinogram
Under the proper conditions, the human eye has a subjective
range of sensitivity of approximately 1010 (10 log units). The
dark-adapted flash ERG b-wave range is approximately 1 log unit
less than this. At the very lowest stimulus intensities, very near
subjective threshold, under fully dark-adapted conditions, the
ERG response consists of a slow negative deflection, termed the
scotopic threshold response (STR), which appears to reflect the
activity of amacrine cells, probably the AII type.26 As intensity
increases, the STR decreases in latency and is replaced by the b
wave about 1 log unit above subjective threshold; the a wave is
not seen until the stimulus is 2 or 3 log units brighter (Fig 5). The
c and d waves are not recorded under the ISCEV standard
conditions. Both the a and b waves increase in amplitude and
decrease in implicit time with increasing stimulus intensity.
Fig. 5. Electroretinogram (ERG) responses of
a normal subject. We present a series of
ERGs elicited by flashes of increasing
intensity in the light and in the dark. On the
left are responses obtained from the dark-
adapted eye with increasingly brighter
stimuli, measured in log units. The response
to red stimuli shows a double-humped b wave
in the light-adapted eye. An intensity
response curve is shown on the right side of
the diagram. The threshold value (T) shows
where each curve crosses the arbitrarily
chosen 50 µV level. One might also fit such functions with a
Naka-Rushton or saturation function.
When the eye is stimulated, a chain of vegetative and neural
biochemical and electrical events are activated in the retinal
neural cells, glial cells, and retinal pigment epithelium. The
electrical voltages reflecting these events are volume conducted
through the ocular media and tissues and recorded at the cornea
as the ERG. Consequently, the various waves of the ERG reflect
the algebraic summation of the activity of several processes.
Granit27 advanced an analysis of the dark-adapted flash ERG, the
main points of which are still accepted. He identified three retinal
processes, abbreviated PI, PII, and PIII. Subsequent analyses
have shown that each of the three processes can be subdivided
and localized with even greater precision. Generally, PI-related
processes derive from the choroid and retinal pigment epithelium
and are primarily reflected in the c wave. PII-related processes
reflect the activity of Müller's cells at about the level of the
bipolar cells and are primarily reflected in the b wave. PIII-related
processes primarily derive from the outer retina at about the level
of the photoreceptors and are primarily reflected in the a wave,
especially in its slope. The relationship of the a-wave slope to rod
photoreceptor currents has opened the door to the possibility of
noninvasively monitoring human rod receptor dynamics in vivo.
Perception of light in the dark-adapted and light-adapted states is
subserved by different retinal circuitry. As flash intensity
increases under light-adapted background conditions, both the a
and b wave appear at about 1 log unit above the psychophysical
increment threshold. As flash intensity increases, the a and b
waves increase roughly in parallel until the b wave reaches a
peak, after which the a wave continues to grow and the b wave
declines in amplitude and then grows again. The light-adapted
ERG is dependent on retinal cells different from those required by
the dark-adapted ERG. The dark-adapted PII is dependent only
on the on-bipolar cells, whereas the light-adapted PII is
dependent on both the on-bipolar and off-bipolar cells. The
difference in timing between activation of the on-bipolars and off-
bipolars results in a small potential difference at low flash
intensities, which appears as an a wave, accounting for the
simultaneous appearance of a and b waves in the light-adapted
ERG.28
After the photopic b wave, a negative component can frequently
be seen. This photopic negative component disappears if the
spiking activity of ganglion and amacrine cells is eliminated
pharmacologically.29,30 Consequently, in both animal models of
glaucoma31,32 and glaucoma patients,33,34 the photopic negative
component is greatly reduced or abolished.35
The cone-mediated (photopic) and rod-mediated (scotopic)
systems each contribute distinct components to both the a and b
wave. In each wave, the photopic components are seen first
because of the directness of the neuronal connections of this
system as compared with the diffuseness of the scotopic system.
These components are termed a-photopic (ap), a-scotopic (as), b-
photopic (bp), and b-scotopic (bs).

Both a and b waves originate in the outer retinal layers. The a

wave is produced primarily by the photoreceptors; the b wave is
produced by the Müller cells, largely at the level of the bipolar
cells. The ganglion cells do not contribute to the ERG because
their electrical signals are in the form of spikes that cannot be
recorded externally. The ERG has been referred to as an
amplitude-modulated (AM) signal as contrasted to the frequency-
modulated (FM) signal of the ganglion cells. A normal ERG may
be recorded in the absence of the ganglion cells or their axons
(including the optic nerve), which occurs in many eye diseases
(such as glaucoma and optic nerve injury or section).
Nutrition comes to the receptors through the choroidal
vasculature and to the inner nuclear layer (bipolar, amacrine, and
horizontal cells) from the central retinal system. A variety of
disorders may affect one, but not another of these circulations.
For example, disorders of the retinal circulation, such as central
retinal artery occlusion, tend to unmask a large negative
component as the positive (b wave) is reduced. The result has
been described as a “negative ERG,” a sign of inner retinal
ischemia. Conversely, insufficiency of the choroidal circulation,
which occurs in ophthalmic artery occlusion or degenerative
disorders such as choroideremia, halts the initial chain of events,
thereby producing reduction of both ERG a- and b-wave
amplitudes.
Because the stimulus light has a light-adapting effect on the
retina, flickering stimuli tend to isolate the photopic components
of the response, especially faster rates such as 30-Hz flicker.
Flicker ERGs are usually of small magnitude relative to single-
flash ERGs. Therefore, a flicker ERG is most informative when it is
recorded using a summing and averaging device, which can
extract relatively small signals from background interference.
Typically, under clinical test conditions, 30-Hz flicker produces a
sinusoidal response. Because the a and b waves are no longer
clearly visible, the origins of the flicker ERG are uncertain. One
line of argument suggests that the a wave, which diminishes with
light adaptation, is suppressed. Therefore, the resultant
responses consist mainly of b waves. Alternatively, Müller's cells,
which generate the b waves, are relatively less active at higher
temporal frequencies,36 so the response to 30-Hz flicker might
reflect neural activity, primarily the cone receptor potential.37 It
is also possible to separate 30-Hz flicker ERGs into linear, first
harmonic, and nonlinear, second harmonic components, which
have an apparent latency suggestive of an outer retinal (receptor
or bipolar cell) origin of the first harmonic components and an
inner retinal (amacrine or ganglion cell) origin of the second
harmonic.38 If one varies stimulation frequency, the first
harmonic has multiple maxima and minima, suggesting that at
least two sources combine to generate it and that these two
sources cancel out at around 10 Hz.38 The two mechanisms are
the on- and off-bipolar cells, which are about 180 degrees out of
phase in the region of 10 Hz.39–41 If one blocks all postreceptor
activity, there is minimal first harmonic response remaining,
which indicates that the photoreceptors do not make the major
contribution to the first harmonic in the 30-Hz region.41
Oscillatory potentials (OPs) appear as oscillations on the
ascending portion of the b wave. The sensitivity of OPs to inner
retinal diseases is consistent with suggestions that OPs derive
from inner nuclear and/or the inner plexiform layers of the retina.
However, individual oscillations may have different sources, as
the number and characteristics of the OPs change with light
adaptation and stimulus parameters.
International Standards for Clinical Electroretinography
Internationally accepted ERG standards were finally achieved in
l98915 and have been revised subsequently.16 To comply with the
international standards, a clinical laboratory must employ full-
field stimulation. ERGs may be recorded using a variety of corneal
electrodes, including contact lens, fiber, and foil electrodes.
Contact lens electrodes have been preferred in the United States.
Standard flashes must be 5 milliseconds (msec) or less in
duration at their peak and have an intensity of between 1.5 and 3
candelas per square meter per second (cd·m-2·s-1). If a
laboratory or manufacturer cannot generate a stimulus with these
characteristics, they may calibrate the stimulus relative to the
standard to generate a response of equivalent response
characteristics. The light-adapted background must be between
17 and 34 cd·m-2 depending on the luminance of the standard
flash.
Clinical ERG testing should assess the function of both cones and
rods. Rod function should be tested using at least two ERGs
recorded following a minimum of 20 minutes of dark adaptation
with a minimum of 5 seconds between flashes. A dark-adapted
ERG elicited by a low-luminance flash (2.5 log units below the
standard flash) and an ERG elicited by a standard flash are
suggested as standards for testing dark-adapted function. Dark-
adapted OPs should also be recorded. The OPs should be
measured in the dark using standard flashes and recording the
second and subsequent flashes with a 15 msec separation.
To assess cone function, one should record a light-adapted ERG
elicited by the standard flash following a minimum of 10 minutes
of light adaptation. Flicker should be presented at the standard
intensity, with the background at the same level as for the light-
adapted ERG, and the frequency should be 30 Hz. Figure 5
presents examples of normal ERGs recorded under a range of
stimulus intensities. Figure 6 presents normal ERGs recorded
using the ISCEV protocol.
Fig. 6. Electroretinograms (ERG) of a normal
subject recorded using the ISCEV protocol. A. At
the top, the light blue curve is a dark-adapted
ERG elicited by a white light of 1.72 cd·m-2·s-1
attenuated by a 2.5 log unit neutral density filter.
The subject had been dark adapted for 20 minutes. B. The
second, brown waveform is a dark-adapted ERG elicited by a
white light of 1.72 cd·m-2·s-1. C. The third, black wave shows
dark-adapted ERG oscillatory potentials elicited by a white light
with a luminance of 1.72 cd·m-2·s-1. D. The fourth, dark-blue
waveform is a light-adapted ERG elicited by l-Hz flashes of 1.72
cd·m-2·s-1 against a 22 cd·m-2 background. E. ERGs elicited by
30-Hz flickering white light of 1.72 cd·m-2·s-1 against a 22 cd·m-
2 background.

Some clinical electrophysiologists employ different stimulus

conditions or record ERGs using skin electrodes placed
underneath the eyes as their active electrodes. Although such
recordings do not conform to the standard, they can be clinically
useful. Recordings using skin electrodes may be especially useful
in children who are too old to be swaddled or sedated but remain
uncooperative with corneal electrode testing. Nonstandard
conditions are most useful if appropriate norms and normal limits
are available. Some countries, notably France, concerned about
disease transmission through contact with the cornea and tear
film require the use of disposable electrodes.
BEYOND THE STANDARD ELECTRORETINOGRAM
The ISCEV standards represent what its members regard as the
minimum needed to perform a satisfactory, clinically useful ERG
examination. Several modifications of the ERG protocol have
proven particularly useful adjuncts to the ISCEV standard ERG:
use of chromatic filters, calculation of intensity response
functions, modeling of photoreceptor current, use of long-
duration flashes, and measurement of the photopic negative
response. It is not clear which, if any, of these techniques will
gain widespread use, and in part, it depends on their careful
implementation on commercial equipment as a “standard”
protocol on that system.
Chromatic Electroretinograms
Most ERG protocols before the ISCEV standard employed
chromatic stimuli as one means of isolating rods and cones.
Consequently, most commercial clinical electrophysiology systems
provide some means by which chromatic stimuli and backgrounds
may be presented. Although the ISCEV standards eliminated this
requirement, some diseases are best studied using chromatic
stimuli. A notable example is the enhanced S cone syndrome,
which is characterized by an enhanced response to stimuli that
activate short-wavelength–sensitive cones.42–49 Additionally,
experiments investigating the photopic negative response have
frequently employed chromatic stimuli.32–34,50 Present evidence
seems to support the idea that the S cone photopic negative
response is more sensitive to glaucomatous damage than the L or
M cone photopic negative response.51
Intensity Response Functions
Sometimes referred to as Naka-Rushton or Michaelis-Menton
functions, intensity response functions have been useful in
understanding the mechanisms of a number of retinal diseases.12
The basic strategy in employing intensity response functions is to
record ERGs under a wide range of intensity levels from very dim
flashes to very bright flashes. The major question that emerges
and that has not been standardized, however, is how one fits the
intensity response functions.52–58 Few of the manufacturers of
electrophysiology equipment supply a built-in strategy for
calculating an intensity response function of the b wave.
Modeling of Photoreceptor Current
When intensity response functions for the b wave are calculated,
the a wave at higher intensities is accentuated. Using the leading
edge of the a wave, it becomes possible to calculate a response
that is largely dependent on the photoreceptors.59–70 Using
models based on the properties of the photocurrent, it has been
possible to make interesting observations in a number of
diseases.44,66,67 Implementation of the technique requires
specialized curve-fitting algorithms and a much brighter flash
than that recommended as the ISCEV standard. The widespread
clinical application of the technique depends on implementation of
the brighter flash and curve-fitting algorithms by commercial
manufacturers.
Use of Long-Duration Flashes
In his original work, Granit27 used long-duration flashes and
demonstrated an off response in the dark-adapted ERG. Several
Japanese scientists continued to use long-duration flashes.71,72
The work of Professor Miyake and colleagues73 demonstrated that
differences in photopic on and off responses could usefully
distinguish subtypes of congenital stationary night blindness,
which was further explained through subsequent work by
Sieving's group and others.74–76 Subsequently, long-duration
flashes have proven useful in understanding the mechanisms of a
number of diseases, including cancer- and melanoma-associated
retinopathies77 and juvenile X-linked retinoschisis.78,79
Measurement of the Photopic Negative Response
As noted earlier, the photopic negative response is dependent on
ganglion cell activity and is reduced in glaucoma.32–34,50
Therefore, as standard procedures are developed and established
for eliciting the response, the photopic negative response may
become a useful adjunct to standard electroretinography, and
because this response is larger and easier to record, it may
supplement, or even replace, the pattern ERG (PERG).
PATTERN ELECTRORETINOGRAMS
Although the PERG was initially thought to have the same origins
as the flash ERG, the PERG is now considered to be the sum of
local luminance and pattern responses.80–82 In the steady state
PERG, the local luminance responses have both an inner retinal
and outer retinal origin, whereas the pattern response elicited by
rapid sinusoidal modulation of sine wave gratings has only an
inner retinal origin.83 The local luminance responses appear to
represent the parallel activity of several systems whose relative
importance varies with temporal frequency.38 Consequently, the
relative importance of local luminance and pattern components of
the PERG vary as a function of a number of stimulus parameters,
including temporal frequency, contrast, and spatial frequency.
One possible source of the inner retinal local luminance
component is the so-called m wave. The m wave, originating in
the inner retina, shows a negative deflection to both the onset
and offset of light and shows spatial tuning, such that it is largest
for intermediate spot sizes.84 However, eliminating the spiking
activity of retinal ganglion cells does not substantially reduce the
m wave.85
The transient PERG waveform appears superficially like the ERG
elicited by luminance stimulation: There is an early negativity at
about 30 msec, a positivity at about 50 msec, and a later
negativity at about 95 msec. Because of this superficial similarity,
the responses were originally labeled a, b, and after potentials, as
those of the flash-elicited ERG. More recently, because the PERG
waves have different origins than those of the flash ERG,
additional nomenclatures have been proposed. We use the terms
N30, P50, and N95 to describe the waves of the PERG. Other
alternatives that have been used are p, q, and r and N1, P1, and
N2. In enucleated eyes, the PERG N95 appears to follow the
activity of the optic nerve response.86 Similarly, while leaving the
P50 relatively unaffected,87 elimination of spiking retinal neurons
eliminates not only the photopic negative response but also the
PERG N95.
N95 appears to reflect activity from the ganglion cell layer more
clearly than P50. N95 shows greater variation in amplitude with
spatial frequency (Fig. 7) and is more affected in diseases of the
optic nerve.88 P50, however, is altered in a number of diseases
that affect primarily the outer retina.88 A ratio of P50 and N95
has been suggested as useful in discriminating a number of
diseases that affect the optic nerve.88–91 Similarly, correcting VEP
latency by PERG P50 latency may improve diagnosis and
prediction of optic nerve disease.8 Examples of PERGs from a
patient with pseudotumor cerebri of the left eye, which affects
the optic nerve, are presented in (Figure 8. Holder91 recently
reviewed his approach to clinical electrophysiology, which places
the transient PERG at the center of electrophysiologic diagnosis
because of its ability to differentiate inner retinal (ganglion and
amacrine cell) from outer retinal (bipolar and photoreceptor).
Holder's review provides an excellent introduction to the range of
uses of the PERG.
Fig. 7. Relative spatial tuning of
4-Hz pattern electroretinogram
components at two light levels.
Note that N95 shows greater
relative spatial tuning than P50.
The second harmonic and the
sum of the even harmonics
show tuning similar to N95.
(Derived from data presented in
Odom et al.80)
Fig. 8. Pattern electroretinograms (PERGs) elicited by
4 Hz (eight reversals per second) from a 37-year-old
white female patient with pseudotumor cerebri of the
left eye. The upper tracing is a normal PERG from the
right eye. Note that N2 (N95) is larger than P1 (P50).
The PERG in the lower tracing, from the affected left
eye, is severely reduced. PERGs were recorded using
64 samples and an outer canthal reference.

International Standards for Pattern Electroretinography

ISCEV approved PERG standards in 2000.21The standards

emphasize the transient PERG; they discourage laboratories
without special equipment from performing Fourier transforms on
PERGs, which are an exact multiple of the stimulus cycles from
recording or using steady state PERGs. A major emphasis of the
guidelines is the care with which the signals must be recorded.
Care is important because the small size of the signals that can
be contaminated by electrical or physiologic artifacts, such as
blinks with relative ease and the use of pattern stimulation,
requires additional attention to refraction and accommodative
status of the patient.
The PERG is seldom more than 5 µV; therefore, averaging is
always necessary. Active electrodes, which do not interfere with
the optics of the eye, are recommended. Because binocular
recording is recommended, the preferred electrode locations are
the active electrode on the cornea and the reference near the
ipsilateral lateral canthus. The recommended stimulus is a
reversing black-and-white checkerboard with a stimulus field
between 10 and 16 degrees and a check size of approximately
0.8 degrees, reversing at two to six reversals per second (1 to 3
Hz) in a room with dim, indirect lighting. The stimulus contrast
should be greater than 80%, with the white areas greater than
80 cd·m-2. The amplitudes and latencies of the P50 and N95
should be measured. If one records steady state PERGs as well,
the amplitude and phase should be measured at the second
harmonic of the recommended 8-Hz stimulation rate (16
reversals per second).
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ELECTRO-OCULOGRAM
The EOG reflects metabolic changes in the retinal pigment
epithelium that depend, in part, on the neural retina. Thus, this
test supplies additional information concerning the retina and its
supporting tissues. As a test of retinal function, the EOG serves
primarily to complement the ERG. Together, these tests provide
objective information about a portion of the visual apparatus.
Often an abnormal EOG makes the diagnostician more certain of
a marginally abnormal ERG.
An example of a patient undergoing EOG testing in a cupola is
presented in Figure 9. Electro-oculography is based on the
standing potential of the eye (Fig. 10). Since the cornea is
positive with respect to the posterior aspect of the eye, the
eyeball acts as a dipole.92 Therefore, eye movements can be
recorded by electrodes arranged in pairs on the skin (usually
horizontally) (Fig. 11), so that changes in polarity can be
recorded and amplified with shifts in gaze (Fig. 12). The
amplitudes of the voltages generated by constant-amplitude eye
movements in the light and in the dark are the basic measures
obtained in the EOG.
Fig. 9. A cupola used for
Ganzfeld stimulation. Full-
field or Ganzfeld stimulation
is important to provide
uniform illumination of the
entire retina. Although a
translucent corneal contact
lens may be used, it is more common to use a cupola. A. Cupola
manufactured by LKC Technologies (Gaithersburg, MD;
http://www.lkc.com). A typical cupola has a method to control
background luminance and flash intensity (possibly wavelength).
The LKC cupola also has three light-emitting diodes (LEDs) (only
two can be seen). The central one is for fixation in
electroretinograms and flash visually evoked potentials. The two
lateral LEDs are separated by 30 degrees and are used to control
eye movements during electro-oculography. B. Adult seated with
her chin on the chin rest. Note the active electrodes are Burian-
Allen electrodes. The reference skin electrode is on the ipsilateral
earlobe and the ground electrode on the forehead. C. Child with
her chin on the chin rest. Note the active electrodes are skin
electrodes placed on the lower lid. The reference skin electrode
is near the ipsilateral outer canthus and the ground electrode on
the forehead.
Fig. 10. The standing potential of the eye. For
purposes of the electro-oculogram, the eye may be
thought of as a battery. The anterior part has a
positive polarity relative to the posterior part of the
eye. As the eye shifts in position from side to side over a 30-
degree excursion, skin electrodes record electrical changes;
these can be amplified and recorded on a computer and
displayed on an ink writer or cathode ray oscilloscope. (Adapted
from a video frame obtained from Metrovision, Pérenchies,
France: http://www.metrovision.fr.)
Fig. 11. The basis of the electro-oculogram (EOG).
Subjects are seated before a cupola as portrayed
in Figure 9. Skin electrodes are placed near the
inner and outer canthi for recording the EOG. At
regular intervals, the patient is required to move his or her eyes
back and forth through an excursion of 30 degrees. In the cupola
portrayed in Figure 9, this would be the distance between the
two outer light-emitting diodes. Typically, EOG recording is
bilateral. (Adapted from a figure provided by Metrovision,
Pérenchies, France: http://www.metrovision.fr.)
Fig. 12. A. Brief, raw tracings as
they might appear with an ink
writer or on a video monitor. B.
The processed data. The
amplitudes of these tracings are
plotted as a function of time.
The mean values are connected with a solid
green line. The minimum amplitude in the dark and the
maximum amplitude in the light are determined. The red line
represents time in the light. The red arrows indicate the
minimum and maximum values. The ratio of the light peak to the
dark trough is calculated as the light/dark or Arden ratio. (RE,
right eye; LE, left eye) (Used by permission of Metrovision,
Pérenchies, France: http://www.metrovision.fr.)
Two types of measurements may be obtained from the EOG—fast
oscillations and slow oscillations—depending on the rate at which
background light is changed (Fig. 13). In recording fast
oscillations, the light is turned on for about 1 minute, then off for
about 1 minute. The amplitude of the fast oscillations tends to
increase in the dark and decrease in the light. However, if lights
are turned off and remain off for about 40 or 50 minutes, the
standing potential will first immediately increase in amplitude,
then decrease in amplitude, reaching a minimum after about 12
minutes, and finally increase until it maintains a stable voltage at
30 to 40 minutes. When the light is turned on, a transient
decrease in the standing potential is followed by an increase to a
maximum level and a gradual return to baseline levels.
Fig. 13. Fast and slow oscillations of the
electro-oculogram. (Redrawn from data
provided by A.F. DeRouck of the State
University of Ghent, Belgium.)

The amplitude of the standing potential decreases with dark

adaptation and increases with light adaptation. It has been
suggested that the maximum amplitude achieved in light
adaptation be compared numerically with the minimum amplitude
achieved in light adaptation, which is referred to as the EOG
ratio.93 Normal ratios of 1.8 to 3.0 are found at most laboratories
(Table 1). The normal fast oscillation ratio is usually about 1.18
and varies between 1.07 and 1.38.94 When the ratio is used,
factors such as electrode placement, pupillary dilation, diurnal
changes in the standing potential, and other inconstant factors
tend to cancel each other out. Monitoring the amplitude of eye
movements independently to ensure that they are constant may
reduce further variation.95

Table 1. Ranges for Electro-Oculogram (EOG) Ratio

EOG Classification Ratio Range

0 Normal >2
1 Probably normal 1.80–2
2 Probably abnormal 1.60–1.79
3 Abnormal 1.20–1.59
4 Flat <1.20

The fast and slow oscillations reflect different metabolic processes

within the retinal pigment epithelium and choroid.96 Therefore,
they may be dissociated in disease. Characteristically, the EOG
ratio of the slow oscillations decreases in most retinal
degenerations, which typically parallels the decrease in the ERG
response (Fig. 13). In recording fast oscillations, the light is
turned on for about 1 minute, then off for about 1 minute. The
amplitude of the fast oscillations tends to increase in the dark and
decrease in the light. However, if lights are turned off and remain
off for about 40 or 50 minutes, the standing potential will first
immediately increase in amplitude, then decrease in amplitude,
reaching a minimum after about 12 minutes, and finally increase
until it maintains a stable voltage at 30 to 40 minutes. When the
light is turned on, a transient decrease in the standing potential is
followed by an increase to a maximum level and a gradual return
to baseline levels.
The amplitude of the standing potential decreases with dark
adaptation and increases with light adaptation. It has been
suggested that the maximum amplitude achieved in light
adaptation be compared numerically with the minimum amplitude
achieved in light adaptation, which is referred to as the EOG
ratio.93 Normal ratios of 1.8 to 3.0 are found at most laboratories
(Table 1. The normal fast oscillation ratio is usually about 1.18
and varies between 1.07 and 1.38.94 When the ratio is used,
factors such as electrode placement, pupillary dilation, diurnal
changes in the standing potential, and other inconstant factors
tend to cancel each other out. Monitoring the amplitude of eye
movements independently to ensure that they are constant may
reduce further variation.95
The fast and slow oscillations reflect different metabolic processes
within the retinal pigment epithelium and choroid.96 Therefore,
they may be dissociated in disease. Characteristically, the EOG
ratio of the slow oscillations decreases in most retinal
degenerations, which typically parallels the decrease in the ERG
response (Fig. 14). However, in Best's disease (vitelliform
macular degeneration), the EOG ratio is abnormal, even in
carriers, whereas the ERG and fast oscillations are normal. In
early retinitis pigmentosa, the fast oscillations and ERG may be
abnormal, whereas the EOG ratio is normal.97 In retinopathy due
to chloroquine and other antimalarial drugs, the EOG slow
oscillations may show abnormalities earlier than the ERG.
Supernormal EOGs have been noted in albinism and aniridia, in
which the common factor seems to be chronic excessive light
exposure with attendant retinal damage.98 In some systemic
diseases affecting membranes, such as cystic fibrosis, EOG fast
oscillations are abnormal even though visual function, EOG ratios,
and ERGs are normal.
Fig. 14. Electro-oculographic changes in Best's
disease. Vertical axis shows the amplitude
response in millivolts. Time is shown on the
horizontal axis in minutes. Test begins with a
five-minute preadaptation (PRE) period during
which the subject is light adapted. Then the
subject sits in darkness. Lights are turned on
after 15 minutes. The normal decrease and increase in dark and
light adaptation, respectively, are not seen, resulting in ratios
close to 1 for each eye in the subject with Best's disease. The
normal subject has an Arden ratio greater than 2.00 in each eye.
(OD, right eye; OS, left eye)
INTERNATIONAL STANDARDS FOR ELECTRO-
OCULOGRAPHY
ISCEV accepted a standard for the EOG in June 1992,18 which
has not required revision. This standard requires that the
adapting light be presented in a Ganzfeld (full-field) cupola with a
retinal illuminance of 1000 to 3000 (3 to 3.5 log) trolands, which
is equivalent to 400 to 600 cd·m-2 if the pupils are undilated or
50 to 100 cd·m-2 if the pupils are dilated. Two measures for the
slow oscillations are accepted in the standard, either the light
peak to dark trough EOG ratio or the light peak to dark baseline.
Prior to dark adaptation, patients should be preadapted to room
light levels (35 to 70 lux) for at least 15 minutes. A minimum of
15 minutes in the dark is required if one measures the light peak
to dark trough; at least 40 minutes of dark adaptation is required
if one is to measure the light peak to dark baseline. The light
peak is recorded by measuring responses in the light until there
is a clear downturn in the response, usually 12 to 15 minutes.
The measure used and the normal values and their limits should
be clearly indicated in reports and publications. In addition to the
ratio, the time to the light peak (latency or implicit time) and the
values of the dark trough or baseline should also be reported
because abnormally small dark responses may have normal EOG
ratios. Fast oscillations are not part of the standard. If fast
responses are recorded, they should be recorded for at least six
cycles. When recorded in the same session as the slow
oscillations, the fast oscillations are recorded preferably prior to
the measurement of the slow oscillations. When recorded prior to
the slow oscillations, fast responses do not appear to affect the
light/dark ratio94 (see Fig. 13).
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VISUALLY EVOKED POTENTIALS
The visually evoked potential (VEP, also referred to as the visually
evoked response or the visual event–related potential) is
produced by electrical activity in the visual cortex in response to
stimulation of the eye (Fig. 15).99–103 The response is complex,
incorporating electrical events that are related to visually initiated
reflexes and visual perception (Fig. 16). The entire visual cortex
(areas 17, 18, and 19) contributes to the VEP, but the portion of
greatest interest to ophthalmologists is the primary evoked
response, attributed to area 17. Any changes in visual stimulation
may be used to elicit a VEP (Fig. 17).
Fig. 15. Diagram of a visually evoked potential (VEP).
Signals from the scalp are amplified and processed by
a computer. The computer typically controls the
presentation and timing of the stimulus as well.

Fig. 16. Visually evoked potential (VEP) stimuli. VEPs

may be elicited by any dynamic visual stimulus. The
standard VEP stimuli are achromatic luminance flash
(on-off), pattern on-off, and pattern reversal. All
pattern changes should occur without a change in
mean luminance.
Fig. 17. Representation of cortical response
to light stimulation showing evoked
potential during initial period and rhythmic
afterdischarge in later period.

A disproportionately large cortical area represents the central

retina as compared with the peripheral retina. Therefore, the VEP
primarily reflects central visual function, especially overall visual
acuity, which makes it of particular importance in the clinical
evaluation of patients who cannot (or will not) cooperate for
subjective testing.
VEP recording begins with scalp electrodes over the occipital
cortex (Fig. 18). The tiny (5 µV) responses to flash or patterned
(e.g., checkerboard) stimuli are amplified, but may still be
“buried” in the background electrical noise that is always present.
Therefore, repeated stimuli are given and “time-locked”
responses are obtained. These responses are stored and
averaged electronically in a signal averager, and the responses
may then be recorded (Fig. 19). The VEP represents cortical
electrical activity in response to visual stimulation of the retina.
As such, the VEP encompasses the entire visual system. In
clinical settings, VEP recordings are made with scalp electrodes.
These are usually surface rather than needle electrodes,
eliminating patient acceptability as an issue in most cases.
Fig. 18. Subject with scalp electrodes
over occipital cortex and eyes closed for
nonpatterned visual stimulation.

Fig. 19. Signal averaging shows

noise and minimal responses and
smoother, averaged responses of
higher amplitude.

Back to Top
VISUALLY EVOKED POTENTIALS ELICITED BY PATTERNED
STIMULI
Patterned VEPs can be elicited by either pattern reversal (or
counterphase reversal) or pattern appearance/disappearance
(onset/offset, or on/off) using checkerboards, square wave
gratings, or sine wave gratings as pattern stimuli. Probably the
most frequently employed stimulus in clinical practice is a slow
(one to five reversals per second), square wave reversal of high-
contrast checkerboards with checks of 30 arc min or greater.
Under these conditions, the transient response waveform consists
of an early positivity at about 50 msec, a negative component at
about 70 msec, a major positive deflection at about 100 msec
followed by a second negativity at about 140 msec, and
sometimes a second positivity at about 155 msec.
The response parameters that are most frequently used clinically
are the time from stimulus onset to peak (latency) of the largest
positive component, the P100 or P2, and its amplitude. Defects of
the optic nerve, such as those encountered in a variety of optic
neuropathies, may produce prolonged latencies and/or decreased
amplitude of this component (Fig. 20).
Fig. 20. Prolonged pattern visually
evoked potential (VEP) following
optic nerve involvement. The VEPs
were elicited by 30-minute checks
reversing at 2 Hz and were recorded
with the active electrode 5 cm above
the inion referred to the right ear.
The patient, a 27-year-old white
male, had a history of optic neuritis in the right eye. The VEP
elicited from the right eye (OD) is prolonged in latency relative
to laboratory norms and the left eye (OS).
The pattern reversal evoked potential is a complicated response
that reflects the summation of several underlying processes,
depending on the exact stimulus parameters, such as check size,
reversal rate, and mean luminance. These include the summation
of local luminance and contrast responses, the summation of
pattern appearance and disappearance responses, and the
summation of movement and contrast responses. Given the
multiple processes summated in pattern reversal VEPs, there are
multiple cortical origins of pattern reversal VEPs. Responses
elicited by reversal stimulation tend to be more affected by eye
movement disorders, such as nystagmus. However, one possible
advantage of the pattern reversal VEP is that its basic waveform
remains constant as a function of age, unlike the pattern
appearance VEP.104 The major change involves a reduction in the
latency of the major positive component from about 200 msec in
early infancy to about normal adult values by 2 to 3 years of
age105.
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VISUALLY EVOKED POTENTIALS ELICITED BY LUMINANCE
CHANGE
If a luminance VEP is elicited by a luminance pulse or flash, the
typical waveform shows positive peaks at about 45, 100, and 190
msec and negative peaks at about 65 and 150 msec, followed by
what has been termed after discharge, which represents
restitution of cortical electrical activities to prestimulus conditions
(see Fig. 16).106
The initial period before about 100 msec, termed the primary
evoked response, most likely represents activity in area 17 of the
striate cortex and seems more closely related to central visual
function because the fovea and macula are disproportionately
displayed near the tip of the occipital cortex. The electrical
activity after about 100 msec, termed the secondary evoked
response, most likely represents spread of information to areas
18 and 19 as well as to other associational areas governing eye
movements, visual memory, and other poorly understood
activities.106,107
Periodic luminance stimulation (flicker) can be provided in one of
several ways: xenon flashes or lights modulated with sine or
square waves. Stimulation that is more rapid tends to collapse
the major components of the VEP into a simpler waveform. There
are three peaks in the function relating VEP amplitude to
frequency of stimulation: one at about 10 Hz, one at about 20 Hz,
and one at about 40 Hz. These three frequency regions have
different functional properties, suggesting that they represent
functionally separate neural systems.108 For example, scalp
topography of the response suggests that VEPs elicited by
stimulation of 30 Hz and higher are limited to the striate cortex
and probably reflect the same mechanisms as those that
generate the flash VEP negative-positive complex at about 40 to
70 msec. The 20-Hz peak appears to reflect the mechanisms
present in the complex at about 100 msec and the 10-Hz peak
appears to reflect the later, more diffuse activity of the transient
luminance VEP.
If patients are tested with closed eyelids at the rate of 10 Hz, the
waveform becomes a double-peaked response (Fig. 20). Most
likely, the smaller peak represents the primary evoked response
and the larger peak represents the secondary evoked response
(Fig. 21).38,39 Accordingly, a train of responses to 10-Hz
stimulation usually places the smaller peak approximately 80 to
100 msec following the preceding flash, with the larger peak
occurring between 110 and 130 msec following the preceding
flash (Fig. 22). As with all VEPs, binocular stimulation produces
larger responses if the visual system is otherwise normal. This
occurs because most cortical neurons are binocularly innervated.
Fig. 21. Visually evoked potential
recorded in response to 10-Hz
stimulation in normal right eye and in
left eye with reduced visual acuity as
a result of macular degeneration. Note
marked reduction in amplitude of
primary evoked response (smaller wave) with mild reduction in
amplitude of secondary evoked response (larger wave).
Fig. 22. Responses to 10-Hz
stimulation. A. Normal visually evoked
potential (VEP) with double-peaked
responses. B. VEP recorded in subject
with decreased visual acuity,
indicating a lack of smaller primary
evoked responses. C. Theoretic
primary evoked response. D.
Theoretic secondary evoked response.
Arrows show time at which
stimulation is delivered.

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INTERNATIONAL STANDARDS FOR VISUALLY EVOKED
POTENTIALS
The current ISCEV VEP standards and their revision, which is in
press,19recognize three types of stimuli: flash, pattern reversal,
and pattern onset/offset. All standard stimuli are transient with
two or less flashes, reversals, or appearances per second. A
standard flash, as defined in the ERG standards, should elicit the
flash VEP, although a wide-field flash is acceptable. The pattern
reversal stimulus consists of black and white checks or black and
white gratings that abruptly alternate without an overall change
in luminance. At least two pattern element sizes should be 10-
and 15-minute checks, or 1.0 and 4.0 cycles per degree gratings.
The visual field stimulated should exceed 15 degrees. The pattern
onset/offset stimulus should abruptly appear and disappear from
a diffuse background, which has the same space-averaged
luminance as the pattern. The recommended pattern/blank
screen sequence is a 200-ms pattern separated by at least 400-
ms diffuse background. The analysis time should include both
onset and offset responses. All VEPs should be recorded with
normal pupils monocularly.
Two general purposes are recognized for performing VEPs:
assessment of prechiasmal lesions and assessment of
postchiasmal lesions. For both purposes, pattern reversal is the
preferred stimulus. Flash stimuli are preferred only in the
presence of media opacities. Pattern onset/offset is mainly of
benefit if one wishes to assess acuity. To detect prechiasmal
dysfunction, it is essential that monocular stimulation be
performed. Prechiasmal defects can be detected using a single
channel with the active electrode placed over Oz; therefore, one
channel is required. However, if a postchiasmal problem is
present, it cannot be detected. Three channels are suggested as
preferable, with electrodes placed at Oz, O4, and O3 and referred
to Fz. To detect chiasmal or postchiasmal defects, recordings
must be performed over both cerebral hemispheres. The active
electrodes should be placed at locations Oz, O4, and O3 and
should be referred to a common reference at Fz. Additional active
electrodes at O1 and O2 are suggested as useful. Pattern reversal
stimulation is preferred.
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BEYOND THE STANDARD VISUALLY EVOKED POTENTIAL
As is the case of the ERG standard, the VEP standard represents
a minimum set of stimulus and response conditions that can be
clinically useful. Numerous variations on the VEP, however, can
prove to be useful in specialized clinical situations. These include,
but are not necessarily limited to, sweep VEPs, dichoptic VEPs,
and channel-specific VEPs.
Sweep Visually Evoked Potentials
Sweep VEPS are a special class of steady state VEPs in which
some stimulus parameter is changed during the course of a
recording period or sweep.109–111 Most frequently, the parameter
varied is spatial frequency or contrast. Using a standard set of
criteria, one can use this rapidly acquired information to
determine a threshold. In patients who are nonverbal or
preverbal, or whose verbal responses cannot otherwise be
trusted, these responses can be a useful means of determining
acuity or other thresholds.
Dichoptic Visually Evoked Potentials
Dichoptic VEPs are elicited when the stimuli presented to the two
eyes differ in some parameter. In the most recent past, the
stimulus parameters, which have been of greatest interest, have
been temporal frequency or phase. When one stimulates each
eye with a stimulus of different frequency (f1 and f2),
intermodulation frequencies (f1 ± f2) are generated.108,112,113
These intermodulation frequencies depend on cortical interactions
and are abnormal in many types of abnormal binocular
interactions.114–116 Similarly, phase differences in input yield
very different predictions of the type of response that will be
generated, depending on the type of binocular interaction
present.113,117,118 Dichoptic VEPs recorded in animal primate
models also indicate their utility in understanding developmental
processes of binocularity.119,120
Channel-Specific Visually Evoked Potentials
Channel-specific VEPs are VEPs elicited by stimuli that are
designed to stimulate primarily one channel or pathway. For
example, isoluminant stimuli are presumed to stimulate primarily
the parvocellular system121–123 and motion stimuli are presumed
to stimulate primarily the magnocellular system.124–129 Similarly,
patterns that appear by increasing in mean luminance and those
that appear by decreasing mean luminance appear to stimulate
the on and off pathways specifically.130,131 Although the
separation of pathways is seldom, if ever, complete, the selective
stimulation of one of several pathways permits a clearer
identification of the mechanisms of some diseases and their more
precise diagnosis.122,123,127
Back to Top
MULTIFOCAL TECHNIQUES IN ELECTROPHYSIOLOGY
For many years, clinical electrophysiologists attempted to develop
an objective map of visual function. There are many reasons for
desiring an objective map of visual function. A map of visual
function should correlate better with localized lesions than does
the standard ERG and should provide information about central
retinal function, which the standard ERG does not. A perfect
example of this usefulness of the multifocal ERG (mfERG) is
provided in Figure 23, in which a macular dystrophy is clearly
visualized on the mfERG. Lastly, ophthalmologists are familiar
with looking at visual fields and thinking of variations in function
as correlating with specific diseases.
Fig. 23. Multifocal electroretinogram
(mfERG) from a patient with
Stargardt's disease. A. Fundus. B.
Standard electroretinograms (ERGs),
which are within normal limits. C.
mfERG. First-order kernels are
presented above and second-order
kernels presented below. The left
column presents pseudocolor
representations, the middle column represents individual
tracings, and the right column presents average responses from
rings that begin in the center for the top waveform and go to the
periphery in the bottom tracing. The central ERGs are smaller in
amplitude than those in the periphery in the raw signals. This is
presented dramatically in the pseudocolor map and the raw
waveforms. Averages of concentric rings indicate that the more
central rings (two upper tracings) are smaller than the more-
peripheral rings (four lower tracings). (OPs, oscillatory
potentials)
Initial efforts to create visual function maps using
electrophysiology involved sequential stimulation of locations in
the visual field and recording the response of each location in its
turn. As one might imagine, such efforts were long and tedious
for both the patient and the electrophysiologist. Tagging different
locations in the visual field, usually by using a different frequency
for each locus, improved the ability to gain information about
several different areas of the visual field simultaneously.132
Technical limitations usually limited such efforts to two or four
visual field regions. However, Erich Sutter133–135 clearly made
true visual fields using electrophysiologic measures possible with
his introduction of the multifocal electroretinogram in the 1990s,
following almost a decade of developmental work. Once Dr. Sutter
showed the way, several groups have followed his example and
introduced their own versions of multifocal techniques. Presently,
at least four systems are available internationally: two
manufactured by Roland Consultant of Germany, one by
Metrovision of France, and one by ObjectiVision of Australia. Each
system uses a different approach. Although we present some
information about each, the clear emphasis is on the visually
evoked response imaging system (VERIS) manufactured by Dr.
Sutter's company, Electro-Diagnostic Imaging (EDI). This is not
intended as a commercial endorsement but an acknowledgment
that more is known about the operation and performance of the
VERIS than about the other systems. Readers interested in a
more detailed but still basic account of kernel analysis, are
referred to Odom, 1995,136 and those interested in a solid
introduction to the interpretation of multifocal kernels and
summary of the recent state of knowledge are referred to a
review by Donald Hood.137
GENERAL PRINCIPLES OF MULTIFOCAL SYSTEMS
At their most basic level, all multifocal systems have three basic
components: a method of tagging multiple locations in the visual
field by stimulating each location in a different manner;
extraction of the response elicited at each location, using the tag
as an identifier; and a system of displaying a field map of the
extracted responses. Current systems differ largely in their
strategy for tagging and extracting responses from different
locations. There are two basic strategies: one based on frequency
analysis and one based on time series analysis. The majority of
current research and clinical activity using multifocal systems has
been with the multifocal electroretinogram; however, the basic
strategy may be used to map any visual function—namely,
retinal, cortical, pupillary, or neuroimaging—with appropriate
adjustments for the function. Similarly, most stimuli have
involved luminance modulation; however, pattern or chromatic
modulations are possible.
PRINCIPLES OF FREQUENCY-BASED APPROACHES
In frequency-based strategies, each location to be tested is
modulated at a different temporal frequency. The recorded
response is then Fourier analyzed and each frequency of
stimulation is extracted. Although, theoretically, it should be
possible to use a wide range of frequencies, practically different
frequencies preferentially stimulate different visual subsystems;
therefore, from a pragmatic point of view, it is preferable to use a
set of stimuli that are close in temporal frequency. Roland Consult
has constructed a system that consists of a set of spaced light-
emitting diodes (LEDs) that are each modulated at a different
frequency near 30 Hz. Responses are Fourier analyzed with a
resolution of about 0.01 Hz, and the amplitudes and phases of
the first and second harmonic are calculated. Waveforms and
values can be displayed in a field map. An example of the display
and traces are shown in Figure 24. At this point, we are unaware
of published studies that have used the Roland Consult
frequency-based system. In the absence of knowledge to the
contrary, it seems reasonable to assume that the origins of these
first and second harmonic responses are the same as those for
the full-field ERG, namely, bipolar cell level for the first harmonic
and ganglion cell and amacrine cell layer for the second harmonic
(see Fig. 1).
Fig. 24. Hertz flicker
multifocal results from a
patient with Stargardt's
disease. A. Raw data. B.
Numerical results from
rings representing
distance from the fovea.
Note that as in the Stargardt's patient in Figure 23, the central
responses are nonrecordable or greatly reduced. (Used with
permission of Roland Consult, Wiesbaden, Germany:
http://www.roland-consult.de.)
PRINCIPLES OF THE TIME SERIES–BASED APPROACHES
The available time series–based systems employ pseudorandom
binary sequences. The EDI system employs an m sequence
(although modified m sequences are possible in the scientific
version of the instrument). The Roland Consult and Metrovision
systems also use m sequences, whereas the ObjectiVision uses a
subset of an m sequence termed a Kasumi sequence. The precise
algorithm varies between systems, but the general principle is
that the sequences are constructed to be independent for each
location stimulated. Responses, or kernels, are extracted for each
location by cross-correlating the response with the pseudorandom
stimuli. Most commonly, only a first- and a second-order kernel
are extracted, although in theory it is often possible to extract
even higher-order kernels and to extract “cross-kernels” that
would describe the effects of one stimulus region on another.
Kernels are calculated by cross-correlating the response with the
stimulus; therefore, they themselves are not responses in the
same sense that a standard ERG or VEP is a response. However,
they do represent and predict responses. Figure 25 provides an
illustration of what kernels represent. The first-order kernel
represents the best approximation under the stimulation
conditions of the linear response of the system. The second-order
kernel represents an estimate of the deviation from the prediction
of this linear approximation. As such, it represents the effect of
one stimulus on another.
Fig. 25. First- and second-order kernels.
A. Stimulus consisting of two impulses
with a fixed separation. Within the
context of the multifocal
electroretinogram, this might be thought
of as two frames of light at a particular
location. B. Response to a single pulse, linear prediction of the
response to two pulses with the delay illustrated in A (the
response of two single flashes added together with the
appropriate delay), and the obtained response. C. Nonlinear
behavior of the retina, that is, the difference between the linear
prediction and the obtained response. D. Second-order kernel.
The second-order kernel has three dimensions. Time from pulse
1 is on the abscissa, and time from pulse 2 is on the ordinate.
The difference between linear predictions and obtained results
(as in C) could be plotted either on the z axis (not displayed) or
as contour lines on the xy coordinates. Most multifocal systems
present the z axis representation. Off diagonals represent the
differences between predicted and obtained responses for a
specific difference in time between the two pulses. In C, The first
diagonal slice reflects the interaction of two consecutive stimuli
separated by the minimum time between stimuli. C presents this
slice for the delay illustrated in A and B viewed as a z-axis plot.
Rectifiers are physical systems with second-order amplitude–
dependent nonlinearities. (Adapted from Odom.136)
Interpretation of mfERGs and multifocal VEPs (mfVEPs) also
requires an understanding of the visual system. Although the
first-order kernel represents a best approximation of the linear
behavior of a system, the visual system is highly nonlinear.
Therefore, even a best approximation of linear behavior will
contain nonlinear contributions (Fig. 26). When we think of the
visual system, we recognize that it is highly nonlinear and that
those nonlinearities are different for the retina and the cortex. For
example, at the retinal level, one of the earliest nonlinearities is
the fact that the visual response reveals considerable attenuation
at higher luminance levels. Although there is considerable
variation with eccentricity in retinal response, this inhomogeneity
of the visual field is magnified at the cortical level because of
cortical magnification. As a result, failure to maintain fixation has
a more dramatic effect for cortical than retinal responses.
Fig. 26. Linearity and the first-order kernel of a
nonlinear system. A strong reliable first-order
kernel does not mean that the system or the
response is linear. Linear estimates of a nonlinear
process are highly dependent on the stimulus
values used, such as mean luminance or contrast. Consequently,
different experiments can yield very different estimates of the
first-order kernel. The solid line represents a logarithmic
nonlinearity such as might be imagined for the retina. The dotted
lines indicate the limits of the stimulus conditions (abscissa) and
the observed responses (ordinate). The straight lines or “linear
estimates” fitted through the two regions are very different,
reflecting the underlying nonlinearity of the function they are
estimating. Similarly, the underlying nonlinearity of the visual
system implies that first-order kernels obtained under different
conditions will differ because of the nonlinear behavior they
estimate. This limitation does not deny clinical utility of the
technique. (Adapted from Odom.136)
Knowing the stimulus is important in interpreting kernels and
understanding multifocal results (Table 2). The most common
implementation of the multifocal technique employs a video
monitor running at 75 Hz, with a space averaged mean luminance
of about 100 cd·m-2. The video frames are about 13.3 msec.
Each lighted period is only a few milliseconds in duration and
separated from the next frame by a dark remainder of the frame.
There are several consequences of this stimulus arrangement.
First, sequences that involve several lighted frames represent
several sequential flashes rather than a continuous luminance
onset period,138 which has implications for efforts to record
scotopic ERGs139 or long-duration flash ERGs.140

Table 2. Effect of Binary Control Sequence

Binary Sequence Polarity Change/Reversal

Value Light Pattern (No Pattern/Pattern) Pattern (Phase 1 or 2) Light Pattern
-1 Off No pattern (luminance) 1 Off (no change) 1 (no reversal)
+1 On Pattern 2 On (change) 2 (reversal)
+1 On Pattern 2 Off (change) 1 (reversal)
-1 Off No pattern (luminance) 1 Off (no change) 1 (no reversal)
+1 On Pattern 2 On (change) 2 (reversal)
-1 Off No pattern (luminance) 1 On (no change) 2 (no reversal)
+1 On Pattern 2 Off (change) 1 (reversal)
-1 Off No pattern (luminance) 1 Off (no change) 1 (no reversal)
+1 On Pattern 2 On (change) 2 (reversal)
-1 Off No pattern (luminance) 1 On (no change) 2 (no reversal)
-1 Off No pattern (luminance) 1 On (no change) 2 (no reversal)
+1 On Pattern 2 Off (change) 1 (reversal)

Adapted from Odom.136

Similarly, the onset of a pattern from any stimulus other than

black does not represent a response to a transition of a given
mean luminance, rather the response of a pattern following a
“flash” of a specified luminance. An imperfect means of
overcoming this limitation is to repeat the same condition in
multiple frames; one can still see the effects of the frame rate on
the resulting kernels, but they more closely approximate similar
standard conditions. Use of monitors also limits the range of
luminances that can be employed in eliciting the mfERG or
mfVEP.136 To use the pseudorandom stimulation, such as with
mfERG to record truly dark-adapted ERGs or to record the
equivalent of bright-flash ERGs, is difficult.139,141
Second, the fact that the mean luminance of the stimulus is in
the photopic range and the frequency of stimulation is quite high
suggests that the origins of the mfERG are not likely to be the
same as those of the standard ERG. A number of studies appear
to indicate that the origins of the mfERG are more like those of
photopic fast flicker; that is, the first-order kernel involves little
or no photoreceptor activity and is predominately determined by
postreceptoral cells with some ganglion cell layer involvement in
its generation, whereas the second-order kernel has some
postreceptoral level activity and considerable inner retinal
(amacrine and ganglion cell) input.142–148 To the best of our
knowledge, no studies of the origins of mfERGs have occurred
under conditions analogous to the standard ERG.
DIFFICULTIES IN PRACTICE
The uses of multifocal techniques are a trade-off between spatial
resolution, recording time, and size of the signal. The finer the
spatial resolution, the smaller the signal and the more recording
time required. Using relatively fine resolution, as recommended in
the current ISCEV guidelines (see below), one records signals
that are typically in the nanovolt range using a recording time of
at least 8 minutes per eye, divided into several much shorter
“blocks.” Therefore, careful attention to recording details is
essential. Otherwise, signals are overwhelmed by the numerous
environmental and physiologic noise sources. Similarly, stable
fixation is essential to obtain reliable mfERG recordings with
relatively fine spatial resolution. These issues of stable fixation
and small signal size may limit the utility of multifocal techniques
in those who cannot be trusted to maintain stable fixation, such
as children, patients with nystagmus, and malingerers. In
patients with small central lesions, one can usually obtain
satisfactory recordings with instructions to fixate on the center of
the screen. In a few cases, it may be advisable to reduce the
spatial resolution to decrease the recording time and the need for
precise fixation.
CURRENT ISCEV GUIDELINES FOR THE MULTIFOCAL
ELECTRORETINOGRAM

ISCEV approved guidelines for the basic mfERG in 2001.22 The

basic mfERG is that elicited by the initial procedure implemented
on the VERIS, which is the most widely known and implemented
strategy. For the basic mfERG, the retina is stimulated with a
device such as a cathode ray tube (CRT) with a 75-Hz frame rate
that generates a pattern of hexagons scaled to approximate the
distribution of cones in the retina, each of which has a 50%
chance of being illuminated every time the frame changes. The
default mfERG uses an m sequence to control the order of
light/dark transitions of the stimulus elements. The pattern
seems to flicker randomly, but each element follows a fixed,
predetermined sequence so that the space- and time-averaged
luminance of the screen over time is constant. The focal ERG
signal associated with each element is calculated by correlating
the continuous ERG signal with the on or off phases of each
stimulus element. Different stimulus patterns and flicker
sequences can be used for specialized applications. Figure 27
illustrates a typical multifocal setup.
Fig. 27. A. Typical multifocal electroretinogram
setup using the VERIS system. (Used with
permission of Interzeag Corporation, Berne,
Switzerland:

http://www.octopus.ch/products/fr3_veris_description.htm.) B.
Subject looking into one of the newer VERIS systems that
permits fixation monitoring and is therefore appropriate for use
with children as well as adults.
The overall stimulus pattern should subtend a visual angle of 20
to 30 degrees on either side of fixation. Contrast between the
lighted and darkened stimulus elements should be 90% or
greater, with a mean luminance of 50 to 100 cd·m-2. The region
of the CRT beyond the area of stimulus hexagons should have a
luminance equal to the mean luminance of the stimulus array.
Central fixation stimuli (dots or crosses) should cover as little as
possible of the central stimulus element to avoid diminishing the
response. Electrodes that contact the cornea are recommended
for mfERG recording as for the full-field ERG. The optical opening
must be clear to allow good visual acuity and refraction.
The default response of the default mfERG is the first-order
kernel, termed K1 or FOK. It is a biphasic wave with an initial
negative deflection followed by a positive peak. A second
negative deflection may occur after the peak. These three peaks
are, respectively, N1, P1, and N2. The recommendations extend
only to the most frequent default conditions and not to higher-
order kernels.
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CLINICAL APPLICATIONS
Electrophysiologic testing is most frequently used in five clinical
situations: diagnosis of retinal disease; diagnosis of optic nerve
disease; determination of organic versus functional visual loss
and identifying the locus of organic loss; determination of visual
function in nonverbal patients (mainly children); and assessing
visual system integrity behind medial opacities.
DIAGNOSIS OF RETINAL DISEASE
One of the most obvious applications of electroretinography is in
the study of hereditary and constitutional disorders of the retina.
These include partial and total color blindness (achromatopsia),
night blindness, and retinal degenerations.
In the past, electrophysiology diagnosed certain diseases, such as
retinitis pigmentosa. Because these diseases were not treatable,
electrophysiology was frequently used for diagnosis and genetic
counseling. However, as our knowledge progresses, it is becoming
increasingly clear that electrophysiology does not relate in a one-
to-one manner with genetically defined diagnoses. In the
relatively near future, many previously untreatable retinal
diseases will become treatable. Correct diagnosis will then
become crucial to the treatment. Diagnosis is likely to be
dependent on genetic testing. This will not eliminate the need for
electrophysiologic testing, however. Electrophysiology is likely to
become an important initial tool in characterizing the phenotype
of the disease so that appropriate genetic testing can be selected
to provide a definitive, treatment-related diagnosis. Not all
diseases will become treatable. Diagnosis of retinal diseases is
important even though they often are untreatable. Correct
diagnosis is essential for genetic counseling and for counseling
patients on the likely progression of their disease. When a
disorder involves primarily the rod system or primarily the cone
system, the ERG shows corresponding abnormalities that may be
important in counseling the patient (Fig. 28).
Fig. 28. ISCEV standard electroretinogram
responses in achromatopsia. The dark-
adapted responses are entirely normal. The
light-adapted response is nonrecordable.
This particular patient with achromatopsia
had no photophobia yet no residual cone
electroretinogram. Based on the response to psychophysical
tests, the patient was classified as a blue-cone monochromat.
Nearly the first dictum to emerge with the development of clinical
electroretinography was that the ERG was “extinguished” or
nonrecordable in patients with retinitis pigmentosa. With
improvements in recording techniques, however, small responses
have often been revealed. These responses are due to the cones,
which may still function even when all rod function has ceased
(Fig. 29). Retinitis pigmentosa is not the only disorder in which
the ERG is usually nonrecordable or greatly reduced in amplitude.
Other chorioretinal degenerations or inflammations, such as
choroideremia, Spielmeyer-Vogt disease, and luetic
chorioretinitis, may also result in virtually complete destruction of
the photoreceptors. This is also true in Leber's congenital
amaurosis, which is due to dysgenesis of the rods and cones.
Therefore, the nonrecordable ERG cannot be considered
pathognomonic of any of these conditions, and it is not helpful in
distinguishing between them. However, a consideration of the
presenting symptoms and fundus appearance can usually
distinguish between them.
Fig. 29. Electroretinogram
(ERG) responses in early
retinitis pigmentosa and
congenital stationary night
blindness (CSNB). Responses
in retinitis pigmentosa are
typically small or nonrecordable under all stimulus conditions. A.
Responses using ISCEV standard conditions. B. Standard ERG
responses of a patient with CSNB. The distinction between CSNB
and retinitis pigmentosa is very important in the clinical retina.
In other degenerative states of the retina, the standard ERG may
be normal; this is true in Tay-Sachs disease, in which the lesion is
located in the ganglion cells. Use of the photopic negative
response is too new to have proven useful in these cases. In
patients with paraneoplastic disease, the on response may be
significantly affected (Fig. 30).
Fig. 30. On-off response deficit in a patient with
paraneoplastic night blindness with cutaneous
malignant melanoma. The two upper tracings
present the on and off responses of a patient with metatstatic
cutaneous malignant melanoma. The on responses are greatly
reduced as compared with responses of the right eye (OD) of a
normal patient (lower tracing). (OS, left eye) (Courtesy of
Philippe Kestelyn, University of Ghent, Belgium.)
Retinal vascular disorders may have profound effects on various
ERG components. Retinal ischemia may result from many
different disease processes, such as arteriosclerosis, giant cell
arteritis, occlusion of a retinal artery or vein, and carotid artery
insufficiency. All result in a diminished b wave and a
proportionately larger a wave due to “unmasking” of the process
(PIII) responsible for the a wave (Fig. 31). Changes related to the
sensitivity of the dark-adapted ERG to light, such as latency of
the b wave or 30-Hz flicker and the intensity that generates a
half-amplitude b wave, are predictive of complications in central
retinal vein occlusion. OPs are altered in diabetic retinopathy and
may be a valuable predictor of proliferative changes.
Fig. 31. Electroretinographic responses in ischemic
vascular disease. The patient had visual loss due
to central retinal vein occulusion. Note deep a
wave and diminished b wave in the tracing for the
left eye.
Toxic states of the retina may be accompanied by ERG changes.
Siderosis produces ERG responses larger than normal in its early
stages; low-voltage responses are produced later in its course
(Fig. 32). The ERG in patients with chalcosis does not appear to
evolve through the early supernormal phase. Administration of
many drugs that may produce retinal damage, such as
chloroquine and quinine, results in a corresponding lowering of
the ERG responses (Fig. 33). ERGs have been used to assess the
extent of retinal damage in birdshot chorioretinopathy.149 In
addition, measuring the initial level of functional retinal damage,
ERGs may be used to monitor the need for and the effect of
treatment.
Fig. 32. Electroretinographic changes in
siderosis. These responses were obtained
on three different occasions from a
patient with an intraocular foreign body
containing iron. Note progressive
reduction of b-wave amplitude over a 15-
month period in both dark- and light-
adapted conditions.

Fig. 33. Electroretinographic (ERG)

changes in chloroquine retinopathy.
 Mildly subnormal ERG responses were
found in a patient with abnormal visual
fields and fundi. (WF, white females;
VF, visual field; DA, dark adapted; LA,
light adapted; T, threshold value)

Retinal detachment results in a lowered ERG response that is

usually commensurate with the area of the detached retina (Fig.
34). Some evidence exists that indicates a lowered response,
even in the presumably normal eye. However, it is not uncommon
to find that the ERG completely “recovers” following surgical
reattachment of the retina.
Fig. 34. Electroretinographic changes in
retinal detachment. Subnormal
responses were found in a patient with
approximately one-half of his retina
detached. (WM, white males; DA, dark
adapted; LA, light adapted; T, threshold
value)

Systemic diseases associated with low-voltage ERG responses

include vitamin A deficiency (in which the ERG may be restored to
normal after treatment); mucopolysaccharidosis, such as Hurler's
disease (in which the abnormal material is found in the outer
segments of the receptor); hypothyroidism (in which altered
retinal metabolism reflects that of the whole body); and the
anemias (in which the lowering of the ERG is usually, but not
always, proportionate to the hemoglobin level).
mfERGs have begun to have their impact on retinal diseases as
well. They have been used to identify subtle macular dystrophies
that are not readily detected using standard ERGs and to follow
the progression of more global retinal diseases.
OPTIC NERVE DISEASE AND GLAUCOMA
Electrophysiologic testing is used to identify a variety of optic
nerve diseases, including optic nerve compression due to tumor,
trauma, or subdural hematoma; optic neuritis, such as that
associated with multiple sclerosis; and optic atrophy, either
primary or secondary to long-standing inflammation, chronic
papilledema, or toxic causes. Compressive lesions of the optic
nerve, optic chiasm, and optic tract have distinct patterns of
abnormality (Fig. 35). Lesions of one optic nerve alter VEPs over
both hemispheres when the eye with the affected nerve is
stimulated, as compared with VEPs elicited by stimulation of the
other eye with the normal optic nerve. Lesions at the chiasm alter
VEPs recorded from both hemispheres from both eyes (although
an asymmetry may be observed). Postchiasmal lesions alter VEPs
over one hemisphere compared with the other, irrespective of the
eye stimulated.
Fig. 35. Effects of lesion
location on
electrophysiologic
responses. The numbered
rows correspond to the
lesion locations. The
columns show various
electrophysiologic tests
and the eye tested. N
indicates that test is
usually normal, and A
indicates that the test is
usually abnormal when
lesions occur in the numbered location.
In many studies, delay of the pattern reversal VEP P100
component is a useful indicator of optic nerve disease. The
pattern reversal VEP is probably most useful in attempting to
detect hidden visual loss in cases of suspected multiple
sclerosis.150 If a patient has unilateral optic neuritis, evidence of
abnormal VEPs in the normal eye indicates a subclinical lesion
suggestive of multiple sclerosis. Similarly, if symptoms of multiple
sclerosis are present in other neurologic systems with no history
of optic neuritis, the presence of an abnormal VEP strongly
suggests that a subclinical lesion of the visual pathway exists and
that the patient has multiple sclerosis.
Delayed-pattern VEPs are not specific for any optic neuropathy.
Virtually all forms of optic neuropathy (except for acute
papilledema) are associated with delays in optic nerve
conduction, yielding an abnormal pattern reversal VEP. Moreover,
delayed latencies are not specific to optic nerve disease. A variety
of retinal disorders also produce delay of pattern reversal VEPs.
Therefore, careful ophthalmoscopy should be performed to
eliminate the possibility of retinal disease causing the delay.
Additionally, flash, multifocal, and pattern electroretinography
should be considered if the VEP is abnormal to rule out the
possibility of a subclinical retinal lesion, as is sometimes observed
with multiple evanescent white dot syndrome.151,152
Retinal disease or stimulus variables do not typically prolong
latency to the same degree as optic nerve disease. However, lack
of attention to these details adds to the variability of normal and
patient values and can lead to failure to diagnose some patients
with the disease (misses) and to incorrectly diagnose some
patients as having optic nerve disease (false alarms).
Although the clinical emphasis has often been on the use of P100
latency to detect optic nerve lesions, measuring parameters in
addition to P100 latency can be useful. For example, P100
amplitude, the amplitudes and phases of steady state pattern
reversal VEPs, the amplitudes of high-frequency components of
transient VEPs, and the presence of an atypical waveform may be
helpful in improving the sensitivity. Flash VEPs are also affected in
optic nerve disease (Fig. 36).
Fig. 36. The 10-Hz flicker visually evoked
potential elicited from a patient with
unilateral compression of the optic nerve.
The intensity setting on a Grass
photostimulator was 4. (OD, affected right
eye; OS, unaffected left eye)

In most optic neuropathies, flash electroretinograms are within

the limits of normal because transsynaptic degeneration is
extremely uncommon; even individuals with transection of the
optic nerve may have normal flash ERGs many years after the
incident. However, PERGs tend to be abnormal in optic
neuropathy if optic nerve damage has been present for at least 3
to 6 months.153 Particularly the later negative component (N95)
is affected.86–88 To the best of our knowledge, attention to the
photopic negative response and the impact of optic nerve
degeneration has been limited to studies of glaucoma.32–34,51
Similarly, the optic nerve head component of the mfERG has not
been examined in cases other than glaucoma to our
knowledge.142–145
Glaucoma is a somewhat difficult disease to categorize. However,
it is clear that one of the consequences of glaucoma is ganglion
cell death, especially of large-diameter fibers that project to the
magnocellular layers of the lateral geniculate (i.e., M cells).
Consequently, VEPs elicited by stimuli, which preferentially
activate the M cells, are abnormal (e.g., rapid flicker154 or rapid
reversal of low spatial frequency patterns).155 Optic neuropathy
secondary to glaucoma of any type is also associated with
abnormal PERGs,83,87,88,156 with N95 being more reduced in
amplitude.83,87,157 Glaucoma patients also show anatomic
evidence of outer retinal damage to the rods and blue
cones.158,159 Electrophysiologic evidence is consistent with outer
retina damage because dark-adapted flash ERGs and light-
adapted flicker ERGs are abnormal (Fig. 37).57,160–162
Electrophysiologic tests currently are not included in the standard
examination for glaucoma; however, as part of a battery of tests,
electrophysiology may be useful in early glaucoma detection,
especially in patients whose visual field tests are unreliable.163
Alternatively, efforts to make mfERG142–145,164,165 or mfVEP into
viable tests of glaucoma are reasonable, as are efforts to further
refine the diagnostic utility of the photopic negative response.32–
34,51

Fig. 37. Reduced first and second harmonic

amplitudes in 12 eyes of seven patients with
glaucoma (open squares) compared with 12
normal eyes of 11 normal subjects (solid
squares). First harmonics originate in outer
retinal layers and second harmonics
originate in inner retinal layers. The stimulus
was sine wave flicker of a 28-degree field
with a 180-degree surround of equal mean
retinal illuminance of 4000 trolands
modulated at 75%. (Odom JV, Riemslag F, de
Jong L, et al: Unpublished data collected at
the Netherlands Ophthalmic Research
Institute, Amsterdam, 1989.)
ORGANIC VERSUS FUNCTIONAL VISUAL LOSS
One of the most challenging problems the ophthalmologist can
face is the differential diagnosis of organic versus functional
visual loss in the case of the patient with minimal complaints. If
the visual loss is functional, whether the patient suffers this
condition because of psychiatric problems or malingering, the
ophthalmologist is challenged to prove what is suspected during
the history taking.
The evaluation begins with careful history taking, and proceeds
through a thorough neurologic, including neuro-ophthalmologic,
evaluation. Ophthalmologic findings, such as pupillary responses
and fundus evaluation, are critical. However, once all physical
findings are determined to be normal (or cannot explain the type
and degree of visual loss manifested by the patient), the logical
next step is electrophysiologic testing.
Both the ERG and VEP provide superb means for independent
corroboration (or refutation) of a patient's symptoms. Abnormal
ERG and/or VEP responses provide documentation for an
abnormality in either the retina or the overall visual system, even
in the absence of fundus abnormalities. Conversely, normal
responses in conjunction with a fully normal examination strongly
refute a patient's claims of visual disability. It is important to
remember that a normal VEP in and of itself does not rule out a
visual abnormality either in higher brain centers166or in the
retina. Therefore, both the ERG and VEP are necessary to isolate
the location of an organic defect if there is one (see Fig. 35.
Addition of the mfERG, PERG, or photopic negative response may
be particularly helpful in making the distinction between inner
and outer retinal disease processes.
Patient cooperation is essential for accurate test results.
Uncooperative subjects who tamper with electrodes, refuse to
maintain a steady position of head and/or body, or are otherwise
noncompliant with the test procedures may leave the question
unanswered. Nevertheless, such actions tend to further support
the ophthalmologist's suspicions that the visual loss is functional
rather than organic in nature. Standard stimuli (central visual
field) and VEP recording procedures (occipital leads) are not
particularly helpful in the differentiation of organic versus
functional loss of a portion of the visual field. One must either use
stimuli limited in the visual field and/or multiple electrodes and
newer strategies of signal analysis.167
ASSESSMENT OF VISUAL FUNCTION IN NONVERBAL
ADULTS AND CHILDREN
The most frequent question for the ophthalmologist encountering
an infant or nonverbal adult or child is whether the patient can
see or recover vision. A variety of subjective tests are available to
evaluate visual function in subjects that are unable to cooperate
with visual sensory testing in the usual manner. For example,
presentation of visual stimuli will produce responses such as
blinking, head turning, cessation of random eye movements, or
optokinetic nystagmus. Teller acuity cards and similar techniques
have been adapted for clinical use to assess visual acuity in
infants and children.
However, these behavioral methods may be usefully
supplemented by electrophysiolog testing. The infant or young
child who appears blind or who has congenital nystagmus should
be tested with flash electroretinography to determine if the
disorder is in the outer retinal layers, such as in Leber's
congenital amaurosis. In disorders such as optic nerve
hypoplasia, which may be part of de Morsier's syndrome
(together with agenesis of the corpus callosum, mental
retardation, and hypopituitarism), both flash and pattern VEP
should be considered. One might imagine that the various newer
techniques discussed earlier—PERG, mfERG, and photopic
negative response—might be of interest in pediatric cases.
However, so far their use has been quite limited. PERG and
mfERG techniques require greater attention on the part of the
child. The photopic negative response has not been attempted
with children.
Flash-elicited VEPs are not useful if one is attempting to quantify
visual acuity in a child with clear media, whereas pattern VEPs
can provide such information. In assessing infant visual acuity, it
is not sufficient to employ a single pattern size. By varying
pattern element size, it is possible to assess the visual acuity of
normal and neurologically impaired children.168 The difficulty of
lengthy sessions can be partially overcome with the use of sweep
VEPs or similar strategies (Fig. 38). Because of the variability of
early neural development, absent or severely abnormal VEPs in
cases of visually delayed or neurologically impaired children are
not necessarily predictive of later visual development. Therefore,
they must be interpreted cautiously and repeated over time.
Fig. 38. Spatial frequency sweep visually
evoked potential. The gratings were
reversed at 7.5 Hz and the response at 15
Hz was recorded as grating size changed
at each 1-second interval.

Other important questions asked in pediatric ophthalmology are:

Does this child have amblyopia? Do I need to patch? Do I need to
alter patching therapy? Although several strategies related to the
relative amplitude of VEPs elicited by monocular stimulation of
the eyes have been proposed as means to examine the presence
of amblyopia and to monitor patching therapy, they have not
been widely used and have not proven themselves clinically. The
better available strategy appears to be assessing visual acuity
using sweep VEPs169or similar strategy.170
Finally, pediatric ophthalmologists may ask if a child has binocular
vision. Several strategies have been proposed as means to
examine the presence of normal binocular vision in infants and
young children, including the presence of binocular summation,
VEP components uniquely generated by binocular interaction, and
stereo VEPs. None of the techniques has been widely used.
EVALUATION OF VISUAL FUNCTION BEHIND MEDIA
OPACITIES
In most instances, the decision to operate in cases of corneal,
lenticular, or vitreal opacities can be made without recourse to
electrophysiologic testing. However, when the retina cannot be
imaged, simpler techniques, such as the potential acuity meter,
cannot be used. If the patient's history suggests a need for
further evaluation, electrophysiologic testing may be useful in
determining the functional status of the retina and later stages of
visual processing. ERGs are useful in determining general retinal
function, including whether the retina is attached. However, they
are not particularly useful in evaluating macular function. ERG
responses such as focal ERGs, mfERGs, or PERGs, which can be
useful in evaluating macular function if media are clear are less
useful with opaque media because the diffraction and absorption
of light result in reduced certainty that appropriate stimulation is
being delivered. Flash VEPs, particularly with 10-Hz stimulation,
can be helpful in determining the integrity of the visual pathways
and the normalcy of central retinal function.105,106 These
procedures compare favorably to other methods in terms of
accuracy,171,172 both in evaluating anterior105,106,173 and vitreal
opacities.174,175
Back to Top
REFERENCES
1. Carr RE, Heckenlively JR: Hereditary pigmentary degenerations
of the retina. In Tasman W, Jaeger EA (eds): Clinical
Ophthalmology. Philadelphia, Lippincott and Co, 1991
2. Cavender JC, Ai E: Hereditary macular dystrophies. In Tasman
W, Jaeger EA (eds): Clinical Ophthalmology. Philadelphia,
Lippincott and Co, 1991
3. Glaser JS, Goodwin JA: Neuro-ophthalmologic examination:
The visual sensory system. In Tasman W, Jaeger EA (eds):
Clinical Ophthalmology. Philadelphia, Lippincott and Co, 1991
4. Sanborn GE, Magargal LE: Arterial destructive disease of the
eye. In Tasman W, Jaeger EA (eds): Clinical Ophthalmology.
Philadelphia, Lippincott and Co, 1991
5. Gouras P, Charles S: Physiology of the retina. In Tasman W,
Jaeger EA (eds): Clinical Ophthalmology. Philadelphia,Lippincott
and Co, 1991
6. Carr RE, Siegel IM: Electrodiagnostic Testing of the Visual
System: A Clinical Guide. Philadelphia, FA Davis Co, 1990
7. Fishman GA, Birch DG, Holder GE, Brigell MG:
Electrodiagnostic Testing in Disorders of the Retina, Optic Nerve,
and Visual Pathway. 2nd ed. San Francisco, American Academy of
Ophthalmology, 2001
8. Brigell M, Celesia GG: Electrophysiological evaluation of the
neuro-ophthalmology patient: An algorithm for clinical use. Semin
Ophthalmol 7:65, 1991
9. Birch DG: Clinical electroretinography. Ophthalmol Clin North
Am 2:469, 1989
10. Weinstein GW, Odom JV, Cavender S: Visually evoked
potentials and electroretinography in neurologic evaluation.
Neurol Clin 9:225, 1991
11. Heckenlively JR, Arden GB (eds.): Principles and Practice of
Clinical Electrophysiology of Vision. St. Louis, Mosby–Year Book,
1991
12. Fulton AB: Intensity relations and their significance. In
Heckenlively JR, Arden GB (eds): Principles and Practice of
Clinical Electrophysiology of Vision. St. Louis, Mosby–Year Book,
1991
13. Weinstein GW, Weinberg RS, Hobson RR: Constant amplitude
electroretinography for the determination of retinal sensitivity in
normal and abnormal subjects. Am J Ophthalmol 69:836, 1970
14. Bocquet X, Charlier J, Zanlonghi X, Odom JV: A new method
for recording cone electroretinogram: The fast sweep ERG. Invest
Ophthalmol Vis Sci 30(Suppl):512, 1989
15. Marmor MF, Arden GB, Nilsson SEG, Zrenner E: Standards for
clinical electroretinography. Arch Ophthalmol l07:8l6, 1989
16. Marmor MF, Zrenner E: Standard for clinical
electroretinography (1999 update). Doc Ophthalmol 97:143,
1999
17. Marmor MF, Zrenner E: Standard for clinical electro-
oculography. Doc Ophthalmol 85:115, 1993
18. Marmor MF: Standardization notice: EOG standard
reapproved. Doc Ophthalmol 95:91, 1998
19. Harding GFA, Odom JV, Spileers W, Spekreijse H: Standard
for visual evoked potentials. Vision Res 36:3567, 1996
20. Marmor MF, Holder GE, Porciatti V, et al: Guidelines for basic
pattern electroretinography. Recommendations by the
International Society for Clinical Electrophysiology of Vision. Doc
Ophthalmol 91:291, 1996
21. Bach M, Hawlina M, Holder GE, et al: Standard for pattern
electroretinography. Doc Ophthalmol 101:11, 2000
22. Marmor MF, Hood D, Keating D, et al: Guidelines for basic
multifocal electroretinography (mfERG). Doc Ophthalmol, in press
23. Brigell M, Bach M, Barber C, et al: Guidelines for calibration of
stimulus and recording parameters used in clinical
electrophysiology of vision. Doc Ophthalmol 95:1, 1998
24. Galloway N, Arden G, Odom JV (committee members): Visual
Electrodiagnostics: A Guide To Procedures Commissioned by the
International Society for Clinical Electrophysiology of Vision
(ISCEV), to assist practitioners and administrators. Web
document http://www.iscev.org/standards
25. De Rouck AF: History of the electroretinogram. In
Heckenlively JR, Arden GB (eds): Principles and Practice of
Clinical Electrophysiology of Vision. St. Louis, Mosby–Year Book,
1991
26. Frishman L: The scotopic threshold response. In Heckenlively
JR, Arden GB (eds): Principles and Practice of Clinical
Electrophysiology of Vision. St. Louis, Mosby–Year Book, 1991
27. Granit R: The components of the retinal action potential and
their relation to the discharge in the optic nerve. J Physiol
77:207, 1933
28. Bush RA, Sieving PA: Do photoreceptors alone contribute to
the primate photopic ERG a-wave?Invest Ophthalmol Vis Sci
33:836, 1992
29. Sieving PA, Murayama K, Naarendorp F: Push-pull model of
the primate photopic electroretinogram: A role for hyperpolarizing
neurons in shaping the b-wave. Vis Neurosci 11:519, 1994
30. Sieving PA: Photopic ON- and OFF-pathway abnormalities in
retinal dystrophies. Trans Am Ophthalmol Soc 91:701, 1993
31. Frishman LJ, Steinberg RH: Origin of negative potentials in
the light-adapted ERG of cat retina. J Neurophysiol 63:1333,
1990
32. Viswanathan S, Frishman LJ, Robson JG, et al: The photopic
negative response of the macaque electroretinogram: Reduction
by experimental glaucoma. Invest Ophthalmol Vis Sci 40:1124,
1999
33. Viswanathan S, Frishman LJ, Robson JG, Walters JW: The
photopic negative response of the flash electroretinogram in
primary open angle glaucoma. Invest Ophthalmol Vis Sci 42:514,
2001
34. Colotto A, Falsini B, Salgarello T, et al: Photopic negative
response of the human ERG: Losses associated with
glaucomatous damage. Invest Ophthalmol Vis Sci 41:2205, 2000
35. Drasdo N, Aldebasi YH, Chiti Z, et al: The s-cone PHNR and
pattern ERG in primary open angle glaucoma. Invest Ophthalmol
Vis Sci 42:1266, 2001
36. Miller RF, Dowling JE: Intracellular responses of the Müller
(glial) cells of mudpuppy retina: Their relation to b-wave of the
electroretinogram. J Neurophysiol 33:323, 1970
37. Baron WS, Boynton RM, Hammon RW: Component analysis of
the foveal local electroretinogram elicited with sinusoidal flicker.
Vision Res 19:479, 1979
38. Odom JV, Reits D, Burgers N, Riemslag FCC: Flicker
electroretinograms: A systems analytic approach. Optom Vis Sci
69:106, 1992
39. Bush RA, Sieving PA: Inner retinal contributions to the
primate photopic fast flicker electroretinogram. J Opt Soc Am A
13:557, 1996
40. Kim SH, Bush RA, Sieving PA: Increased phase lag of the
fundamental harmonic component of the 30 Hz flicker ERG in
Schubert-Bornschein complete type CSNB. Vision Res 37:2471,
1997
41. Kondo M, Sieving PA: Primate photopic sine-wave flicker ERG:
Vector modeling analysis of component origins using glutamate
analogs. Invest Ophthalmol Vis Sci 42:305, 2001
42. Marmor MF, Jacobson SG, Foerster MH, et al: Diagnostic
clinical findings of a new syndrome with night blindness,
maculopathy, and enhanced S cone sensitivity. Am J Ophthalmol
110:124, 1990
43. Roman AJ, Jacobson SG: S cone-driven but not S cone-type
electroretinograms in the enhanced S cone syndrome. Exp Eye
Res 53:685, 1991
44. Hood DC, Cideciyan AV, Roman AJ, Jacobson SG: Enhanced S
cone syndrome: Evidence for an abnormally large number of S
cones. Vision Res 35:1473, 1995
45. Greenstein VC, Zaidi Q, Hood DC, et al: The enhanced S cone
syndrome: An analysis of receptoral and post-receptoral changes.
Vision Res 36:3711, 1996
46. Yamamoto S, Hayashi M, Takeuchi S: Electroretinograms and
visual evoked potentials elicited by spectral stimuli in a patient
with enhanced S-cone syndrome. Jpn J Ophthalmol 43:433, 1999
47. Marmor MF, Tan F, Sutter EE, Bearse MA Jr: Topography of
cone electrophysiology in the enhanced S cone syndrome. Invest
Ophthalmol Vis Sci 40:1866, 1999
48. Jacobson SG, Roman AJ, Roman MI, et al: Relatively
enhanced S cone function in the Goldmann-Favre syndrome. Am J
Ophthalmol 111:446, 1991
49. Kellner U, Foerster MH: Pattern of dysfunction in progressive
cone dystrophies—an extended classification. Ger J Ophthalmol
2:170, 1993
50. Colotto A, Falsini B, Salgarello T, et al: Photopic negative
response of the human ERG: Losses associated with
glaucomatous damage. Invest Ophthalmol Vis Sci 41:2205, 2000
51. Drasdo N, Aldebasi YH, Chiti Z, et al: The s-cone PHNR and
pattern ERG in primary open angle glaucoma. Invest Ophthalmol
Vis Sci 42:1266, 2001
52. Severns ML, Johnson MA: The care and fitting of Naka-
Rushton functions to electroretinographic intensity-response data.
Doc Ophthalmol 85:135, 1993
53. Gangadhar DV, Wolf BM, Tanenbaum HL: Naka-Rushton
equation parameters in electroretinogram analysis of daunomycin
effects on retinal function. Doc Ophthalmol 72:61, 1989
54. Evans LS, Peachey NS, Marchese AL: Comparison of three
methods of estimating the parameters of the Naka-Rushton
equation. Doc Ophthalmol 84:19, 1993
55. Anastasi M, Brai M, Lauricella M, Geracitano R:
Methodological aspects of the application of the Naka-Rushton
equation to clinical electroretinogram. Ophthalmic Res 25:145,
1993
56. Massof RW, Wu L, Finkelstein D, et al: Properties of
electroretinographic intensity-response functions in retinitis
pigmentosa. Doc Ophthalmol 57:279, 1984
57. Wu LZ, Massof RW, Starr SJ: Electroretinographic intensity-
response function in retinal disease. Chin Med J (Engl) 98:250,
1985
58. Sverak J, Peregrin J, Kralove H: Electroretinographic
intensity-response curves in central retinal. Arch Ophthalmol
79:526, 1968
59. Hood DC, Birch DG: A quantitative measure of the electrical
activity of human rod photoreceptors using electroretinography.
Vis Neurosci 5:379, 1990
60. Hood C, Birch DG: The A-wave of the human
electroretinogram and rod receptor function. Invest Ophthalmol
Vis Sci 31:2070, 1990
61. Breton ME, Montzka DP: Empiric limits of rod photocurrent
component underlying a-wave response in the electroretinogram.
Doc Ophthalmol 79:337, 1992
62. Breton ME, Schueller AW, Lamb TD, Pugh EN Jr: Analysis of
ERG a-wave amplification and kinetics in terms of the G-protein
cascade of phototransduction. Invest Ophthalmol Vis Sci 35:295,
1994
63. Hood DC, Birch DG: Human cone receptor activity: The
leading edge of the a-wave and models of receptor activity. Vis
Neurosci 10:857, 1993
64. Hood DC, Birch DG: Phototransduction in human cones
measured using the a-wave of the ERG. Vision Res 35:2801,
1995
65. Hood DC, Cideciyan AV, Halevy DA, Jacobson SG: Sites of
disease action in a retinal dystrophy with supernormal and
delayed rod electroretinogram b-waves. Vision Res 36:889, 1996
66. Hood DC, Birch DG: Abnormalities of the retinal cone system
in retinitis pigmentosa. Vision Res 36:1699, 1996
67. Smith NP, Lamb TD: The a-wave of the human
electroretinogram recorded with a minimally invasive technique.
Vision Res 37:2943, 1997
68. Thomas MM, Lamb TD: Light adaptation and dark adaptation
of human rod photoreceptors measured from the a-wave of the
electroretinogram. J Physiol 518:479, 1999
69. Paupoo AA, Mahroo OA, Friedburg C, Lamb TD: Human cone
photoreceptor responses measured by the electroretinogram a-
wave during and after exposure to intense illumination. J Physiol
529:469, 2000
70. Friedburg C, Thomas MM, Lamb TD: Time course of the flash
response of dark- and light-adapted human rod photoreceptors
derived from the electroretinogram. J Physiol 534:217, 2001
71. Yoshimura Y, Onoe S, Takahashi Y, et al: Electroretinogram c-
wave and slow PIII of the rabbit: Changes in peak time and
amplitude under various stimulus durations. Doc Ophthalmol
69:187, 1988
72. Nagata M, Honda Y: Studies on focal electric response of the
human retina. V. The effects of varying stimulus durations upon
the macular response [in Japanese]. Nippon Ganka Gakkai Zasshi
74:582, 1970
73. Miyake Y, Yagasaki K, Horiguchi M, Kawase Y: On- and off-
responses in photopic electroretinogram in complete and
incomplete types of congenital stationary night blindness. Jpn J
Ophthalmol. 31:81, 1987
74. Sieving PA: Photopic ON- and OFF-pathway abnormalities in
retinal dystrophies. Trans Am Ophthalmol Soc 91:701, 1993
75. Sieving PA, Murayama K, Naarendorp F: Push-pull model of
the primate photopic electroretinogram: A role for hyperpolarizing
neurons in shaping the b-wave. Vis Neurosci 11:519, 1994
76. Quigley M, Roy MS, Barsoum-Homsy M, et al: On- and off-
responses in the photopic electroretinogram in complete-type
congenital stationary night blindness. Doc Ophthalmol 92:159,
1996
77. Alexander KR, Fishman GA, Peachey NS, et al: ‘On’ response
defect in paraneoplastic night blindness with cutaneous malignant
melanoma. Invest Ophthalmol Vis Sci 33:477, 1992
78. Alexander KR, Fishman GA, Barnes CS, Grover S: On-
response deficit in the electroretinogram of the cone system in X-
linked retinoschisis. Invest Ophthalmol Vis Sci 42:453, 2001
79. Shinoda K, Ohde H, Mashima Y, et al: On- and off-responses
of the photopic electroretinograms in X-linked juvenile
retinoschisis. Am J Ophthalmol 131:489, 2001
80. Odom JV, Maida TM, Dawson WW: Pattern evoked retinal
responses (PERR) in human: Effects of spatial frequency,
luminance and defocus. Curr Eye Res 2:99, 1982
81. Odom JV, Norcia AM: Retinal and cortical potentials: Spatial
and temporal characteristics. Doc Ophthalmol Proc Ser 40:29,
1984
82. Sutter EE, Vaegan : Lateral interaction component and local
luminance nonlinearities in the human pattern reversal ERG.
Vision Res 30:659, 1990
83. Baker CL, Hess RR, Olsen BT, Zrenner E: Current source
density analysis of linear and non-linear components of the
primate electroretinogram. J Physiol 407:l55, 1988
84. Sieving PA, Steinberg RH: Contribution from proximal retina
to intraretinal pattern ERG: The M-wave. Invest Ophthalmol Vis
Sci 26:1642, 1985
85. Firshman LJ, Sieving PA, Steinberg RH: Contributions to the
electroretinogram of currents originating in proximal retina. Vis
Neurosci 1:307, 1988
86. Schuurmans RP, Berninger T: Luminance and contrast
responses recorded in man and cat. Doc Ophthalmol 59:187,
1985
87. Viswanathan S, Frishman LJ, Robson JG: The uniform field
and pattern ERG in macaques with experimental glaucoma;
removal of spiking activity. Invest Ophthalmol Vis Sci 41:2797,
2000
88. Holder GE: The significance of abnormal pattern
electroretinography in anterior visual pathway dysfunction. Br J
Ophthalmol 71:166, 1987
89. Weinstein GW, Arden GB, Hitchings RA, et al: The pattern
electroretinogram (PERG) in ocular hypertension and glaucoma.
Arch Ophthalmol 106:923, 1988
90. Odom JV, Holder GE, Feghali JG, Cavender S: Pattern
electroretinogram intrasession reliability: A two center
comparison. Clin Vision Sci 7:263, 1992
91. Holder GE: Pattern electroretinography (PERG) and an
integrated approach to visual pathway diagnosis. Prog Retin Eye
Res 20:531, 2001
92. Reeser F, Weinstein GW, Feiock KB, Oser R: Electro-
oculography as a test of retinal function: The normal and
supernormal EOG. Am J Ophthalmol 70:505, 1970
93. Arden GB, Barrada A, Kelsey JH: New clinical test of retinal
function based upon the standing potential of the eye. Br J
Ophthalmol 46:449, 1962
94. De Rouck A, Kayembe D: A clinical procedure for the
simultaneous recording of fast and slow EOG oscillations. Int
Ophthalmol 3:179, 1981
95. Riemslag FCC, Verduyn Lunel HFE, Spekreijse H: The
electrooculogram: A refinement of the method. Doc Ophthalmol
73:369, 1989
96. Steinberg RH, Linsenmeier RA, Griff ER: Three light-evoked
responses of the retinal pigment epithelium. Vision Res 23:1315,
1983
97. Weleber RG: Fast and slow oscillations of the electro-
oculogram in Best's macular dystrophy and retinitis pigmentosa.
Arch Ophthalmol 107:530, 1987
98. Weinstein GW, Ward B, Hobson RR: The super-normal EOG:
Evidence of light induced retinal damage?Doc Ophthalmol Proc
Ser 22:77, 1973
99. Regan D: Human Brain Electrophysiology: Evoked Potentials
and Evoked Magnetic Fields in Science and Medicine. New York,
Elsevier, 1989
100. Previc FH: Visual evoked potentials to luminance and
chromatic contrast in rhesus monkeys. Vision Res 26:1897, 1986
101. Schroeder CE, Tenke CE, Givre SJ, et al: Striate cortical
contribution to the surface-recorded pattern-reversal VEP in the
alert monkey. Vision Res 31:1143, 1991
102. Schroeder CE, Tenke CE, Givre SJ: Subcortical contributions
to the surface-recorded flash-VEP in the awake macaque.
Electroencephalogr Clin Neurophysiol 84:219, 1992
103. Schroeder CE, Mehta AD, Givre SJ: A spatiotemporal profile
of visual system activation revealed by current source density
analysis in the awake macaque. Cereb Cortex 8:575, 1998
104. Ossenblok P, Reits D, Spekreijse H: Analysis of striate
activity underlying the pattern onset EP of children. Vision Res
32:1829, 1992
105. Moskowitz A, Sokol S: Developmental changes in the human
visual system as reflected by the latency of the pattern reversal
VEP. Electroencephalogr Clin Neurophysiol 56:1, 1983
106. Weinstein GW: Clinical aspects of the visually evoked
potential. Trans Am Ophthalmol Soc 75:627, 1977
107. Weinstein GW: Clinical aspects of the visually evoked
potential. Ophthalmic Surg 9:56, 1979
108. Spekreijse H, Estevez O, Reits D: Visual evoked potentials
and the physiological analysis of visual processes in man. In
Desmedt JE (ed): Visual Evoked Potentials in Man: New
Developments. Oxford, Clarendon Press, 1977
109. Regan D: Speedy assessment of visual acuity in amblyopia
by the evoked potential method. Ophthalmologica 175:159, 1977
110. Norcia AM, Tyler CW: Spatial frequency sweep VEP: Visual
acuity during the first year of life. Vision Res 25:1399, 1985
111. Zemon V, Hartmann EE, Gordon J, Prunte-Glowazki A: An
electrophysiological technique for assessment of the development
of spatial vision. Optom Vis Sci 74:708, 1997
112. Regan MP, Regan D: Objective investigation of visual
function using a nondestructive zoom–FFT technique for evoked
potential analysis. Can J Neurol Sci 16:168, 1989
113. Zemon V, Pinkhasov E, Gordon J: Electrophysiological tests
of neural models: Evidence for nonlinear binocular interactions in
humans. Proc Natl Acad Sci U S A 90:2975, 1993
114. Baitch LW, Levi DM: Evidence for nonlinear binocular
interactions in human visual cortex. Vision Res 28:1139, 1988.
115. Stevens JL, Berman JL, Schmeisser ET, Baker RS: Dichoptic
luminance beat visual evoked potentials in the assessment of
binocularity in children. J Pediatr Ophthalmol Strabismus 31:368,
1994
116. France TD, Ver Hoeve JN: VECP evidence for binocular
function in infantile esotropia. J Pediatr Ophthalmol Strabismus
31:225, 1994
117. Odom JV, Chao GM: Models of binocular luminance
interaction evaluated using visually evoked potential and
psychophysical measures: A tribute to M. Russell Harter. Int J
Neurosci 80:255, 1995
118. Suter S, Suter PS, Perrier DT, et al: Differentiation of VEP
intermodulation and second harmonic components by dichoptic,
monocular, and binocular stimulation. Vis Neurosci 13:1157, 1996
119. Baitch LW, Ridder WH 3rd, Harwerth RS, Smith EL 3rd:
Binocular beat VEPs: Losses of cortical binocularity in monkeys
reared with abnormal visual experience. Invest Ophthalmol Vis
Sci 32:3096, 1991
120. Odom JV, Brown RJ, Boothe RG: Maturation of binocular
luminance interaction in normal young and adult rhesus monkeys.
Doc Ophthalmol 95:257, 1998
121. Porciatti V, Sartucci F: Normative data for onset VEPs to red-
green and blue-yellow chromatic contrast. Clin Neurophysiol
110:772, 1999
122. Porciatti V, Di Bartolo E, Nardi N, Fiorentini A: Responses to
chromatic and luminance contrast in glaucoma: a psychophysical
and electrophysiological study. Vision Res 37:1975, 1997
123. Sartucci F, Murri L, Orsini C, Porciatti V: Equiluminant red-
green and blue-yellow VEPs in multiple sclerosis. J Clin
Neurophysiol 18:583, 2001
124. Spekreijse H, Dagnelie G, Maier J, Regan D: Flicker and
movement constituents of the pattern reversal response. Vision
Res 25:1297, 1985
125. Kubova Z, Kuba M, Hubacek J, Vit F: Properties of visual
evoked potentials to onset of movement on a television screen.
Doc Ophthalmol 75:67, 1990
126. Kuba M, Kubova Z: Visual evoked potentials specific for
motion onset. Doc Ophthalmol 80:83, 1992
127. Kubova Z, Kuba M: Clinical application of motion-onset
visual evoked potentials. Doc Ophthalmol 81:209, 1992
128. Bach M, Ullrich D: Motion adaptation governs the shape of
motion-evoked cortical potentials. Vision Res 34:1541, 1994
129. Odom JV, De Smedt E, Van Malderen L, Spileers W: Visually
evoked potentials evoked by moving unidimensional noise
stimuli: Effects of contrast, spatial frequency, active electrode
location, reference electrode location, and stimulus type. Doc
Ophthalmol 95:315, 1998
130. Zemon V, Gordon J, Welch J: Asymmetries in ON and OFF
visual pathways of humans revealed using contrast-evoked
cortical potentials. Vis Neurosci 1:145, 1988
131. Harter MR: Visually evoked cortical responses to the on- and
off-set of patterned light in humans. Vision Res 11:685, 1971
132. Regan D, Milner BA: Objective perimetry by evoked potential
recording: Limitations. Electroencephalogr Clin Neurophysiol
44:393, 1978
133. Sutter RE: A practical nonstochastic approach to non-linear
time-domain analysis. In Marmarelis VZ (ed): Advanced Methods
of Physiological System Modeling. Vol 1. Los Angeles, Biomedical
Simulations Resource, 1987
134. Sutter EE: Field topography of the visual evoked response.
Invest Ophthalmol Vis Sci 29(suppl):432, 1988
135. Sutter EE, Dodsworth-Feldman B, Haegerstrom-Portnoy G:
Simultaneous multifocal ERGs in diseased retinas. Invest
Ophthalmol Vis Sci 27(suppl):300, 1986
136. Odom JV: Kernel Analysis. In Heckenlively JR, Arden GB
(eds): Principles and Practice of Clinical Electrophysiology of
Vision. St. Louis, Mosby–Year Book, 1991
137. Hood DC: Assessing retinal function with the multifocal
technique [Review]. Prog Retin Eye Res 19:607, 2000
138. Keating D, Parks S, Evans A: Technical aspects of multifocal
ERG recording. Doc Ophthalmol 100:77, 2000
139. Hood DC, Wladis EJ, Shady S, et al: Multifocal rod
electroretinograms. Invest Ophthalmol Vis Sci 39:1152, 1998
140. Kondo M, Miyake Y: Assessment of local cone on- and off-
pathway function using multifocal ERG technique. Doc
Ophthalmol 108:139, 2000
141. Ogden TE, Larkin RM, Fender DF, et al: The use of non-linear
analysis of the primate ERG to detect retinal dysfunction. Exp Eye
Res 31:381, 1980
142. Hood DC, Bearse MA Jr, Sutter EE, et al: The optic nerve
head component of the monkey's (Macaca mulatta) multifocal
electroretinogram (mERG). Vision Res 41:2029, 2001
143. Hood DC, Bearse MA Jr, Sutter EE, et al: The optic nerve
head component of the monkey's (Macaca mulatta) multifocal
electroretinogram (mERG). Vision Res 41:2029, 2001
144. Hood DC, Frishman LJ, Viswanathan S, et al: Evidence for a
ganglion cell contribution to the primate electroretinogram (ERG):
Effects of TTX on the multifocal ERG in macaque. Vis Neurosci
16:411, 1999
145. Hood DC, Greenstein V, Frishman L, et al: Identifying inner
retinal contributions to the human multifocal ERG. Vision Res
39:2285, 1999
146. Fortune B, Cull G, Wang L, et al: Factors affecting the use of
multifocal electroretinography to monitor function in primate
model of glaucoma. Doc Ophthalmol 105:151, 2002
147. Hare WA, Ton H: Effects of APB, PDA, and TTX on ERG
responses recorded using both multifocal and conventional
methods in monkey. Doc Ophthalmol 105:189, 2002
148. Viswanathan S, Frishman LJ, Robson JG: Inner-retinal
contributions to the photopic sinusoidal flicker electroretinogram
of macaques. Macaque photopic sinusoidal flicker ERG. Doc
Ophthalmol 105:223, 2002
149. Priem HA, De Rouck AF, De Laey JJ, Bird AC:
Electroretinographic studies in birdshot chorioretinopathy. Am J
Ophthalmol 106:430, 1988
150. Leys M, Candaele CM, De Rouck AF, Odom JV: The detection
of hidden visual loss in multiple sclerosis: A comparison of
pattern reversal VEPs and contrast sensitivity. Doc Ophthalmol
77:255, 1991
151. Sieving PA, Fishman GA, Jampol LM, Pugh D: Multiple
evanescent white dot syndrome. II. Electrophysiology of the
photoreceptors during retinal pigment epithelial disease. Arch
Ophthalmol 102:675, 1984
152. Leys A, Leys M, Jonckheere P, De Laey JJ: Multiple
evanescent white dot syndrome (MEWDS). Bull Soc Belge
Ophthalmol 236:97, 1990
153. Arden GB, Vaegan , Hogg CR: Clinical and experimental
evidence that the pattern electroretinogram (PERG) is generated
in more proximal retinal layers than the focal electroretinogram.
Ann NY Acad Sci 388:580, 1982
154. Schmeisser ET, Smith TJ: High frequency flicker visual
evoked potential losses in glaucoma. Ophthalmology 96:620,
1989
155. Towle VL, Moskowitz A, Sokol S, Schwartz B: The visual
evoked potential in glaucoma and ocular hypertension. Effects of
check size, field size and stimulation rate. Invest Ophthalmol Vis
Sci 24:175, 1983
156. Trick GL: Pattern reversal retinal potentials in ocular
hypertensives at high and low risk of developing glaucoma. Doc
Ophthalmol 65:79, 1987
157. Odom JV, Feghali JG, Jin JC, Weinstein GW: Visual function
deficits in glaucoma: Electroretinogram pattern and luminance
nonlinearities. Arch Ophthalmol 108: 222, 1990
158. Millecchia LL, Nork TM, Lemley HL, Schochet TL: Regional
damage to photoreceptors in human eyes with chronic glaucoma.
Invest Ophthalmol Vis Sci 33:1093, 1992
159. Nork TM: Acquired color vision loss and a possible
mechanism of ganglion cell death in glaucoma. Trans Am
Ophthalmol Soc 98:331, 2000
160. Holopigian K, Seiple W, Mayron C, et al: Electrophysiological
and psychophysical flicker sensitivity in patients with primary
open-angle glaucoma and ocular hypertension. Invest Ophthalmol
Vis Sci 31:1863, 1990
161. Velten IM, Korth M, Horn FK: The a-wave of the dark-
adapted electroretinogram: Are photoreceptors affected. Br J
Ophthalmol 85:397, 2001
162. Rosenshein JS, Cyrlin MN: Glaucoma multi-testing. Invest
Ophthalmol Vis Sci 32:811, 1991
163. Bray LC, Mitchell KW, Howe JW, Gashau A: Visual function in
glaucoma: a comparative evaluation of computerized static
perimetry and the pattern visual evoked potential. Clin Vis Sci
7:21, 1992
164. Klistorner AI, Graham SS, Martins A: Multifocal pattern
electroretinogram does not demonstrate localized field defects in
glaucoma. Doc Ophthalmol 100:155, 2000
165. Hood DC, Zhang X: Multifocal ERG and VEP responses and
visual fields: Comparing disease-related changes. Doc
Ophthalmol 100:115, 2000
166. Bodis-Wollner I, Atkin A, Raab E, Wolkstein M: Visual
association cortex and vision in man: Pattern-evoked occipital
potentials in a blind boy. Science 198:629, 1977
167. Sutter EE, Tran D: The field topography of ERG components
in man. I. The photopic luminance response. Vision Res 32:433,
1992
168. Odom JV: Amblyopia and clinical electrophysiology. In
Heckenlively JR, Arden GB (eds): Principles and Practice of
Clinical Electrophysiology of Vision. St. Louis, Mosby–Year Book,
1991
169. Gottlob I, Fendick MG, Guo S, et al: Visual acuity
measurements by swept spatial frequency visual-evoked-cortical
potentials (VECPs): Clinical application in children with various
visual disorders. J Pediatr Ophthalmol Strabismus 27:40, 1990
170. Charlier J, Bocquet X, Zanlonghi X, et al: Analyse en temps
réel des potentiels évoqués stationnaires: principes et methode.
Revue Oto Neuro Ophthalmol 8:18, 1990
171. Weinstein GW, Odom JV, Hobson RR: Visual acuity and
cataract. In Reinecke RD (ed): Ophthalmology Annual 1987.
Norwalk, CT, Appleton-Century-Crofts, 1986
172. Odom JV, Chao GM, Weinstein GW: Preoperative prediction
of postoperative visual acuity in patients with cataracts: A
quantitative review. Doc Ophthalmol 70:5, 1988
173. Odom JV, Chao GM, Hobson R, Weinstein GW: Prediction of
post cataract extraction visual acuity: 10 Hz visually evoked
potentials. Ophthalmic Surg 19:212, 1988
174. Hutton WL, Fuller DG: Factors influencing final visual results
in severely injured eyes. Am J Ophthalmol 97:715, 1984
175. Vadrevu VL, Cavender S, Odom JV: Predicting final visual
acuity in diabetic eyes with vitreous hemorrhage: 10 Hz flicker
VEPs. Doc Ophthalmol 79:371, 1992
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