Electrophysiologic Testing Email

in Disorders of the Retina, Optic Nerve,
and Visual Pathway

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Ophthalmology
trophysiologic
Monograph
listing
2, Elec-
in Disor4ers of
the Retina, Optic Nerve, and Visual

~IFELONG
Pathway, Second Edition, Is one
EDUCATION
FORTHE
OPHTirALMOLOGIST~ component
of the Lifelong
Education for the Ophthalmologist
framework,
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continuing
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clinical
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assists members
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Copyright @ 2001 Gerald Allen Fishman,

U sed by permission.
Copyright @ 1990 American
All rights reserved.
Academy
MD
of Ophthalmology
,ibrary of Congress Cataloging-in-Publication
Data
Electrophysiologic testing in disorders of the retina, optic nerve, and visual pathway I
Gerald Allen Fishman ...[et al.].-2nd ed.
p. ; cm. -(Ophthalmology
monographs; 2)
Includes bibliographical references and index.
ISBN 1-56055-198-4
1. Electroretinography. 2. Electrooculography. 3. Visual evoked response. I. Fishman,
Gerald Allen, 1943- II. Series.
[DNLM:
1. Retinal Diseases-diagnosis.
2. Electrooculography. 3. Electroretinography.
4. Evoked Potentials, Visual. 5. Optic Nerve Diseases-diagnosis.
WW 270 E38 2001]
RE79.E4 F57 2001
617.7'307547-dc21
00-056208
)5 04
Printed
03
02
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in Singapore
3 2
Contents
Preface
Xttt
Acknowledgments
Chapter 1
XV!
THE ELECTRORETINOGRAM
Gerald Allen Fishman, MD

1-1
Components and Origins of the ERG 2

1-1-1
1-1-2
1-1-3
1-1-4
a-, b-, and c-Wavesand Off-Responses2

Scotopicand PhotopicThresholdResponses 6
EarlyReceptorPotential 7
OscillatoryPotentials 8
1-2
Measurement of the ERGComponents 10
1-3
Recording Procedure 11
1-4
Recording Electrodes 12
1-4-1
1-4-2
1-4-3
1-4-4
1-4-5
1-4-6
1-4-7
1-5
The ERG Under Light- and Dark-Adapted Conditions 14

1-5-1
1-5-2
1-5-3
1-5-4
1-6
Burian-AllenElectrode 12
Dawson-Trick-Litzkow
Electrode 12
ERG-JetElectrode 13
Mylar Electrode 13
Skin Electrode 13
Cotton-WickElectrode 13
Hawlina-KonecElectrode 14
With a Constant-lntensityStimulus 17
With Variable-lntensityStimuli 18
With Different-Wavelength
Stimuli 20
With Variable-Frequency
Stimuli 21
Other Factors Affecting the ERG 23

1-6-1 Durationof Stimulus 23
1-6-2 Size of RetinalArea Illuminated 24
1-6-3 Interval BetweenStimuli 24
1-6-4 Size of Pupil 25
1-6-5 Circulationand Drugs 25
1-6-6 Developmentof Retina 25
1-6-7 Clarityof OcularMedia 27
1-6-8 Age, Sex, and RefractiveError 27
1-6-9 Anesthesia 27
1-6-10 DiurnalFluctuations 28
1-7
The ERG in Retinal Disorders 28
vi
Contents
1-8
Diffuse Photoreceptor Dystrophies 29

1-8-1 Rod-{;oneDystrophies 30
1-8-1-1 Retinitis Pigmentosa 30
1-8-1-2Allied Disorders 35
1-8-2 Cone-RodDystrophies 39
1-9
Stationary Cone Dysfunction Disorders 43

1-9-1 CongenitalAchromatopsia 43
1-9-2 CongenitalRed-GreenColor Deficiency 44
1-10 Stationary Night-Blinding Disorders 45

1-10-1 CongenitalStationaryNight Blindness 45
1-10-2 OguchiDisease 50
1-10-3 FundusAlbipunctatus 50
1-10-4 FleckRetinaof Kandori 53
1-11 Hereditary Macular Dystrophies 54
1-11-1 StargardtMacularDystrophy 54
1-11-2 Best MacularDystrophy 56
1-11-3 Pattern Dystrophies 58
1-11-4 North CarolinaMacularDystrophy 59
1-11-5 ProgressiveBifocalChorioretinalAtrophy 59
1-11-6 Cone Dystrophies 60
1-11-7 SheenRetinalDystrophies 64
1-12 Chorioretinal Dystrophies 65
1-12-1 ChoroidalAtrophy 65
1-12-2 GyrateAtrophy 65
1-12-3 Choroideremia66
1-13 Angioid Streaks 69
1-14 Hereditary Vitreoretinal Disorders 69
1-14-1 X-IinkedJuvenileRetinoschisis 69
1-14-2 Goldmann-Favre
Syndrome 72
1-14-3 WagnerDisease 72
1-14-4 Stickler Syndrome 73
1-14-5 AutosomalDominantNeovascularInflammatoryVitreoretinopathy73
1-14-6 AutosomalDominantVitreoretinochoroidopathy73
1-14-7 FamilialExudativeVitreoretinopathy74
1-15 Inflammatory Conditions 75
1-15-1 Birdshot Retinochoroidopathy76
1-15-2 Multiple EvanescentWhite-DotSyndrome 78
1-15-3 AcuteZonal OccultOuterRetinopathy82
1-15-4 Pseudo-Presumed
OcularHistoplasmosisSyndrome 83
1-15-5 BehgetDisease 83
1-16 Circulatory Deficiencies 84
1-16-1 Sickle Cell Retinopathy84
1-16-2 TakayasuDisease 84
1-16-3 CarotidArtery Occlusion 84
Contents
1-16-4 Centraland BranchArtery and VeinOcclusions 85

1-16-5 Hypertensionand Arteriosclerosis 88
1-17 Toxic Conditions 88
1-17-1 Chloroquineand Hydroxychloroquine88
1-17-2 Chlorpromazine90
1-17-3 Thioridazine91
1-17-4 Indomethacin93
1-17-5 Quinine 93
1-17-6 Methanol 95
1-17-7 Gentamicin 95
1-17-8 Ethyl-m-Aminobenzoic
Acid Methanesuifonate97
1-17-9 Cisplatin 97
1-17-10 Glycine 97
1-17-11 Canthaxanthin97
1-17-12 Vigabatrin 98
1-17-13 Deferoxamine98
1-17-14 Sildenafil 99
1-18 Vitamin A Deficiency and Retinoids 99
1-19 Optic Nerve and Ganglion Cell Disease 100
1-20 Opaque Lens or Vitreous 102
1-21 Diabetic Retinopathy 102
1-22 Miscellaneous Conditions 104
1-22-1 Retinal Detachment 104
1-22-2 Siliconeoil and SulfurhexafluorideGas 104
1-22-3 Thyroidand Other MetabolicDysfunctions 105
1-22-4 ParkinsonDisease 106
1-22-5 MyotonicDystrophy 106
1-22-6 Duchenneand BeckerMuscularDystrophies 106
1-22-7 Kearns-SayreSyndrome 107
1-22-8 NeuronalCeroidLipofuscinoses 110
1-22-9 RetinalDegenerationWith SpinocerebellarAtaxia 112
1-22-10 Tay-SachsDisease 114
1-22-11 Creutzfeldt-Jakob
Disease 114
1-22-12 IntraocularForeignBodies 115
1-22-13 Myopia 116
1-22-14 Albinism 117
1-22-15 TaurineDeficiency 117
1-22-16 Bietti CrystallineDystrophy 117
1-22-17 Cancer-Associated
Retinopathy 118
1-22-18 EnhancedS-ConeSyndrome 120
1-22-19 PigmentedParavenousRetinochoroidalAtrophy 120
1-23 Summary 124
References 124
Suggested Readings 152
vii
Contents
4-3-2 Optic Nerve Disease 214

4-3-2-1 Optic Nerve Demyelination216
4-3-2-2 Optic NerveCompression 219
4-3-2-3 Optic Atrophy 219
4-3-2-4 MiscellaneousOptic Nerve Dysfunction 221
4-3-3 Glaucoma 221
4-3-4 VEPAbnormalitiesand the PERG226
4-3-5 NonorganicVisual Loss 226
4-4
Summary 227
References 227
Chapter 5
THE VISUAL EVOKED POTENTIAL

Mitchell G. Brigell, PhD
5-1
Origins of the VEP 239
5-2
VEP Stimulus Parameters 240
5-3
VEP Response Parameters 242
5-4
Clinical Use of the VEP in Adults 245

5-4-1 Media Opacities 245
5-4-2 RetinalDiseases 246
5-4-2-1CentralSerous Retinopathy 246
5-4-2-2 MacularDisease 246
5-4-2-3Glaucoma 246
5-4-3 DemyelinativeOptic Neuropathies 246
5-4-3-1Optic Neuritis 246
5-4-3-2 Multiple Sclerosis 247
5-4-3-3 Leukodystrophies248
5-4-3-4 NutritionalAmblyopia 248
5-4-4 CompressiveOptic Neuropathies 249
5-4-4-1 DysthyroidOptic Neuropathy250
5-4-4-2 IdiopathicIntracranialHypertension 250
5-4-5 AnteriorIschemicOptic Neuropathies 250
5-4-6 TraumaticOptic Neuropathies 251
5-4-7 ToxicOptic Neuropathies 251
5-4-7-1 Ethambutol 251
5-4-7-2Cisplatin 251
5-4-7-3 Deferoxamine252
5-4-8 InflammatoryOptic Neuropathies 252
5-4-9 HereditaryOptic Neuropathies 252
5-4-9-1AutosomalDominantOpticAtrophy 252
5-4-9-2 LeberHereditaryOptic Neuropathy252
5-4-9-3 MitochondrialMyopathies 253
5-4-10 OperatingRoomMonitoring 253
237
Contents
xi
5-4-11 Neurodegenerative
Diseases 254
5-4-11-1AlzheimerDiseaseand Other Dementias 254
5-4-11-2SpinocerebellarDegeneration254
5-4-12 FunctionalDisorders 254
5-4-13 Disordersof the OpticChiasm,Optic Radiations,and Visual Cortex 256
5-4-13-1The HemifieldVEPand ParadoxicalLateralization 256
5-4-13-2ChiasmalCompression 257
5-4-13-3Albinism 257
5-4-13-4Dysfunctionof the Optic Radiationsand Visual Cortex 257
5-4-13-5Migraine 257
5-4-13-6DevelopmentalDyslexia 258
5-4-13-7Cortical Blindness 258
5-5
Clinical Use of the VEP in Children 258

5-5-1
5-5-2
5-5-3
5-5-4
5-5-5
5-5-6
5-5-7
5-6
Practical Guidelines 264

5-6-1
5-6-2
5-6-3
5-6-4
5-7
Estimationof VisualAcuityin Infants 259

ChildhoodAmblyopiaand BinocularFunction 260
OculomotorDisorders 262
DelayedVisual Maturation 262
Optic Nerve Hypoplasia 262
Optic NerveGliomas 262
PrognosticValueof the VEPin NeurologicDiseases 263
Instrumentation 264
Patient Preparation 264
Adult Protocol 264
PediatricProtocol 266
Summary 267
References 268
CME Credit
281
Answer Sheet
282
Self-Study Examination
283
Index
291
GeraldAllen Fishman,MD
The full-field
(ganzfeld)
light-evoked
elec-
troretinogram (ERG) is the record of a diffuse electrical response generated by neural

and nonneuronal cells in the retina. The response occurs as the result of light-induced
changes in the transretinal movements of
adapted, rod-dominated
cat retina, demonstrated that the ERG consisted of three
processes, appropriately
called PI, PII, and
PIll. The Roman numerals designated tht
order in which a gradual increase in ether
narcosis suppressed the various ERG com-
ions, principally sodium and potassium, in

the extracellular space. This retinal potential can be recorded in all vertebrates and in
ponents in the cat. The PI, PII, and PIll

processes of Granit correspond to the c-, b-,
and a-waves, respectively, by which the
many invertebrates.
It was first identified
in
recordings from a frog eye in 1865 by the
Swedish physiologist Alarik Frithiof Holm-
components
gren, who initially misinterpreted

the waveform as arising from action potentials in the
optic nerve. Although James Oewarl of
Scotland recorded this potential in humans
as early as 1877, electroretinography
did not
find widespread
clinical
application
until
1941, when the American psychologist Lorrin RiggsZ introduced a contact-Iens electrode for human use. In 1945, Gosta Karpe3
reported the results of a study on 64 normal
and 87 abnormal human eyes, providing the
initial groundwork
for clinical investigation.
The ERG represents the combined electrical activity of different cells in the retina.
In 1908, Einthoven and Jolly4 reported on
three components
of the ERG. An initial
tionally
of the ERG are now conven-
named.
Subsequently, the PIll component was

found to consist of two separate components, or phases, that arise from two different classes of retinal cells (Figure 1-1 ). The
initial
phase (termed
the receptor potential or
fast PIll), the leading edge of which substantially forms the a-wave, reflects the activity of photoreceptor
cells and arises from
light-evoked
closure of sodium channels
along the plasma membrane of receptor-cell
outer segments (Figure l-IA). The second,
more slowly developing phase ( termed the
slow PIll) has its origin from a hyperpolarization in the distal end of Muller cells.
This response of the Muller cells is thought
to be stimulated by a light-induced
decrease in extracellular
potassium
in the
negative deflection was designated by the

letter "a"; a subsequent positive compo-
vicinity of photoreceptor-cell
inner segments developing as a consequence of pho-
nent, normally greater in amplitude, was

termed "b"; and a final, prolonged positive
toreceptor-cell
component
was referred
Ragnar Granit,5 working
activity
(Figure
1-1 B ).
to as "c." In 1933,
with the dark1
The Electroretinogram
Pigmentepithelialpotential
b
c
Time
a
-#
Slow Pill potential
50
200
150
100
Time
Light
(ms)
Figure 1-1 (A) ERG a- and b-wave response to lO-ms

flash in dark-adapted
human eye. Also illustrated
is
COMPONENTSAND ORIGINS OF THE ERG
dashed-curve fit of receptor model, which provides

estimate of receptoral contribution
to ERG. Note that
peak a-wave amplitude does not represent peak recep-
1.1.1 a., b-, and c-Waves and Off-Responses
tor response, because rod a-wave of human ERG to

moderately intense flashes is partly postreceptoral
in
origin. (B) ERG a-, b-, and c-wave response to 4-s

stimulus in cat eye, as well as slow PIlI
pigment epithelial potentials,
and retinal
whose origins are Muller
The site of origin of the ERG components

has been a subject of investigation
for more
than half a century. Various approaches for
investigation have compared the results from
cells and retinal pigment epithelium, respectively.

Pat1 A modified with permission of Kluwer Academic Publishersfrom l{ood DC, Birch DG: Assessingabnormal rod
photoreceptor activity with the a-wave of the electroretinogram: applications and methods.Doc Ophthalmol1997 ;
92:253-267. Pat1 B modified with permission of Elsevier
Sciencefrom Ripps H, Witkovsky P: Neuron-glia interaction
in the brain and retina. In: OsborneNN, Chader GJ, eds:
Progress in Retinal Research. Elmsford, NY:. Pergamon
Press; 1985;4:181-219. Copyright 1985, Pergamon Press
PLC.
1. The predominantly
..
vanous species
cone or rod retinas of
2. Chemical destruction, with toxins known

from histologic data to destroy specific retinal cells6
3. Microelectrode
investigations
of individ-
ual cell layers

4. Observations of the ERG components'
variation with various stimulus intensities
and adaptation
levels
In vertebrate retinas, the absorption of

light by visual pigment in photoreceptor
1-1 Components
outer segments initiates a sequence of molecular events localized to these segments

that generates a wave of hyperpolarization
of the photoreceptors. In rod photoreceptors, the photo-activated
visual pigment
rhodopsin activates a protein, called transducin (or G-protein), which in turn activates
the enzyme cyclic guanosine
monophos-
phate phosphodiesterase (cGMP PDE), ultimately resulting in a reduction in photoreceptor-cell cGMP levels. This reduction in
cGMP levels causes the closure of sodium
ion channels in the outer-segment
membrane, which are normally permeable to
these ions in darkness. A hyperpolarization
(negative change in intracellular electrical
potential) results from the light-induced
decrease of the inward-directed
sodium
current across the plasma membrane of
photoreceptor outer segments (more precisely, a decrease in sodium conductance
of the plasma membrane). The electrical
change thus generated can be measured as
the corneal negative a-wave of the ERG.
There is a suitable amount of evidence
from different sources that the scotopic
(dark-adapted) ERG a-wave reflects essentially solely rod photoreceptor-cell
activity.
By investigating the monkey photopic
ERG during the intravitreal administration
of glutamate analogs, Bush and Sieving7
were able to demonstrate a proximal retinal
component in the primate photopic (lightadapted) ERG a-wave. They concluded
that at the flash intensities commonly used
to elicit the ERG a-wave in clinical diagnostic testing, this component is likely to
contain a significant contribution
from retinal activity postsynaptic to cone photOreceptor cells.
The light-induced
hyperpolarization
of
photoreceptor cells diminishes the release
of a neurotransmitter
at their synaptic ter-
and Origins
of the ERG
minals. This modulation of neurotransmitter release in turn causes a depolarization

or
hyperpolarization
of the postsynaptic bipolar and horizontal cells. Mainly as a consequence of bipolar-cell depolarization,
an increase in extracellular potassium, primarily
in the postreceptoral outer plexiform layer,
causes a depolarization
of Muller (glial)
cells.8 The resulting transretinal current
flowing along the length of the radially oriented Muller cells appears to contribute
substantially to the corneal positive b-wave
of the clinical ERG.9-11 A more proximal increase in extracellular potassium that occu'1s
at the level of the inner plexiform layer following light stimulation
appears to derive
from depolarization
of amacrine, bipolar,
and ganglion cells.12 The more distal increase in extracellular potassium in the
outer plexiform layer contributes appreciably more to the extracellular current, and
thus to the b-wave, than does the proximal
potassium increase.13
A decrease in extracellular
around photoreceptor-cell
potassium
outer segments
following light absorption also alters a

standing electrical potential that exists between the apical and basal surfaces of retinal pigment epithelial (RPE) cells. A flash
of light induces a transient hyperpolarization at the apical surface of RPE cells and a
hyperpolarization
of Muller cells, which
combine to form a monophasic, corneal positive deflection that follows the b-wave, referred to as the (-wave. Thus, the c-wave
represents the algebraic summation of a
corneal positive component, resulting from
a change in the transepithelial
potential induced by hyperpolarization
at the apical
membrane of the RPE cells, and the
corneal negative
hyperpolarization
component generated by
at the distal portion of
the Muller cells, the slow PIll (see Figure

1-lB).14 Diffuse degeneration or a malfunction of RPE cells reduces the c-wave amplitude of the ERG. Similarly, diffuse photoreceptor-cell degeneration causes a reduction
in ERG c-wave amplitude. Ample evidence
exists that the c-wave, although reflecting
alteration of electrical activity at the level of
RPE cells, depends on rod receptor-cell activity. The c-wave has rod spectral sensitivity, is lost when the retina is light-adapted,
and is absent in cone-dominant
retinas.15
However, Tomita et al16 reported a conespecific c-wave found in cone-dominant
retinas.
The c-wave, which in humans is recorded with a fully dilated pupil in a darkadapted eye, generally peaks within 2 to
10 s following the onset ofa flash stimulus,
depending on flash intensity and duration.
Both the c-wave amplitude and the time
from stimulus to response peak increase
with stimulus intensity or stimulus duration. Because the response develops over
several seconds, it is subject to interference from electrode drift, eye movements,
and blinks. Special recording electrodes,
DC amplification
(rather than AC amplification, which is used for standard ERG
recordings), and both high-luminance
and
extended-duration
light stimuli are necessary for an optimal recording of the ERG
c-wave.17 These procedural constraints, in
addition to the wide physiologic variability
in c-wave amplitude and waveform (some
normal individuals appear to lack a recordable c-wave entirely), have limited the clinical application of c-wave measurements.
A study by Sieving et al18 on monkey

retina led them to conclude that the photopic ERG b-wave results from opposing
field potentials generated by depolarizing
and hyperpolarizing
bipolar and horizontal
cells. A "push-pull
model" was proposed
whereby depolarizing bipolar-cell activity
makes an essential contribution
to the
b-wave amplitude, which is appreciably
modified in amplitude and shape by electrical activity generated from hyperpolarizing
bipolar/horizontal
cells. The depolarizing
and hyperpolarizing
bipolar cells could participate in generating the photopic ERG
b-waveform by modulating the extracellular
potassium that reaches the Muller cells.
The b-wave voltage would then be generated from depolarizing Muller cells as a
result of the changes in extracellular
potassium.
Subsequent investigationsl9-22 have
led to the conclusion that the total darkadapted ERG in response to a brief flash
stimulus can be considered as the sum of
photoreceptorand bipolar-cell components, although some contribution
from
Muller cells is not precluded. The initial
negative portion (rod a-wave) of the darkadapted response to relatively intense stimuli, including the return to baseline, can
be considered as the sum of a negativedirected contribution
from the photoreceptors and a somewhat delayed, but ultimately larger positive-directed
contribution
(rod b-wave) from the rod on-bipolar cells.2
The initial 15 ms of the a-wave seems to
approximately
represent the photoreceptor
responses (see Figure l-lA).21 Rod receptors synapse selectively onto on-bipolar
cells, which depolarize in response to light,
but, unlike cone receptor cells, rods make
no direct contact onto off-bipolar cells.
There are also negative inner-retinal
com-
...
I-I
ponents that likely contribute to the darkadapted a-wave at high stimulus intensities,
including a probable contribution
from
amacrine cells.2 In the cat, at maximal
stimulus intensities, this can amount to
about one third of the overall dark-adapted
a-wave amplitude.2
Not readily recognized is how appreciably an off-response can contribute to the
photopic b-wave amplitude. The traditionally very brief strobe-flash stimuli used for
ERG recordings preclude isolation of that
portion of the off-response that is part of
the photopic b-wave amplitude. However,
with more prolonged flashes, it can be
made apparent that a substantial portion of
the photopic b-wave is actually an off-response component,
d-wave (Figure
1-2). As
indicated, hyperpolarizing
bipolar cells,12
probably in addition to other cells such as
the photoreceptors,23 likely generate the
Components
Sieving.24 A small positive wave at the end

of the descending portion of the ERG
b-wave response to a high-Iuminance
flash
is also an off-response component, which
has been designated as the "i-wave" to suggest that the character of the wave is the result of interference
between on- and offresponse components.2.1
...
Electrical events within ganglion cells or
optic nerve fibers do not contribute to the
flash-elicited
a- or b-waves of the ERG.
Thus, disorders such as glaucoma and various types of optic atrophy, which selectively
cells and/or optic nerve
axons, do not ordinarily reduce ERG a- or

b-wave amplitudes. Although isolated reports on both animals and humans show
that ERG amplitudes increase following
Figure 1.2 With longer-
duration flashes, pho-
~/{'
~--
25ms
V-r--~
20ms
-~--~
15msi I
-0
-C
"'
"'
i:i:
10ms
5ms
0
20
40
of the ERG
likely generate the "true" (on-response)

photopic b-wave by increasing the concentration of extracellular potassium. Photopic
on- and off-pathway abnormalities
in various retinal dystrophies were described by
affect ganglion
off-response component of the b-wave amplitude, while depolarizing bipolar cells
and Origins
60
80
Time
100
(ms)
120
140
topic b-wave can be

demonstrated to contain substantialoffresponse ( d-wave);
i-wave is also offresponse component.
COU11esy
Neal S. Peachey,
PhD.
TheElectroretinogram
section of the intracranial portion of the

optic nerve,26,27 this has not been a consistent finding.28 Because the ERG b-wave
necessarily depends on electrochemical
events that generate the ERG a-wave, any
retinal disorder that prevents generation of
a normal a-wave will also affect the development of a normal b-wave, Examples include retinitis pigmentosa, retinal detachment, and ophthalmic artery occlusion. The
converse, however, is not true. Disorders
that result in a diffuse degeneration or dysfunction of cells in the inner nuclear layer
(Muller or bipolar cells) can selectively decrease the ERG b-wave amplitude without
diminishing
the ERG a-wave. A notable example is central retinal artery occlusion,
where the choroidal circulation maintains
blood flow to the photoreceptor
cells and
sustains the biochemical events that generate the a-wave.
To reduce a- and/or b-wave amplitudes,
a disorder must affect a large area of retinal
tissue. Th us, focal lesions of the fovea ( defined as a region the approximate size of
the optic disc, 1.5 mm in diameter, centered at the foveola) do not affect the a- and
b-wave amplitudes elicited bya full-field
flash stimulus. The work of Armington et
al29 suggests that a loss of one half the photoreceptors across the entire retina may result in approximately
a 50% reduction in
ERG amplitude. Fran~ois and de Rouck30
observed that a macular lesion, up to a size
of 3 disc diameters, produced by photOCOagulation did not modify ERG amplitudes.
This finding was in accord with the investigations by Schuurmans et al,31 who demonstrated in rabbits that photocoagulation
of a
20 retinal area of the posterior pole did not
decrease the ERG amplitude. Between 20
and 60 of photocoagulation
caused decreases in ERG amplitude that were proportionally related to the destroyed area.
Thus, normal full-field
ERG recordings
may be obtained in patients with marked
impairment
in central vision resulting from
disorders that affect the visual system at or
central to the retinal ganglion cells or from
photoreceptor-cell
degeneration limited to
the fovea. Conversely, markedly reduced or
even nondetectable
ERG amplitudes can
be found in the presence of 20/20 acuity, as
seen in some cases of retinitis pigmentosa.
1-1-2 Scotopic and Photopic
Threshold Responses
The scotopic threshold response (STR) is a
small, negative-directed
ERG response that
can be recorded after a prolonged period of
dark adaptation with the use of very dim
light stimuli.32.33 This response is observed
with light stimuli too dim to elicit cone
pathway signals or a rod ERG b-wave. The
STR appears to originate from electrical activity in retinal amacrine cells, which release potassium upon light stimulation and
cause depolarization
of Muller cells.34 In
patients with juvenile X-Iinked retinoschisis, a disease in which pathologic changes in
Muller cells have been observed,35 the STR
is absent.36 This observation implies Muller
cell, as well as amacrine cell, involvement
in the origin of the STR. Although the clinical diagnostic value of the STR has yet to
be fully defined, it is said to be absent in
some forms of congenital stationary night
blindness and is diminished in glaucoma.34
A somewhat similar, delayed corneal negative response, elicited from cones under
photopic conditions, has been termed the
photopic negative response (PhNR).37 The amplitude of this response was found to be reduced in a macaque model of experimental
1-1 Components
and Origins
of the ERG
glaucoma.37 Ganglion cells or their axons,

and possibly amacrine cells, are involved in
generating the response. This tlash-evoked
electrical signal is similar to the photopic
threshold response (PTR) described by
Spileers et al.38
1.1.3 Early Receptor Potential
The early receptor
rapid, transient
potential
waveform
(ERP)
recorded
is a
almost
immediately
after a light-flash stimulus,
particularly after one of high intensity in a
dark-adapted eye. The response, which is
complete within 1.5 ms, originates from the
bleaching of photopigments
at the level of
the photoreceptor
outer segments. This potential, first described by Brown and Murakami39 in 1964, was found by Pak and
Cone40 to consist of two components, designated R1 and Rz. The initial, corneal positive portion (R1) has a peak time of approximately 100 microseconds (Jls) and appears
to be primarily a cone response. The second, corneal negative component (Rz) has a
peak time of approximately
900 JlS and consists of contributions
from both rods and
cones. This corneal negative component
is essentially complete by the time the
a-wave begins (Figure 1-3). Both positive
and negative components of the ERP resist
anoxia. The initial, positive phase can still
be observed in the frozen eye, while the
second, negative phase disappears on cooling. This potential appears to reflect molecular events within photoreceptor
visual
pigments and corresponds to their photochemical kinetics. The corneal positive
component, R1, has been associated with
the conversion of lumirhodopsin
to metarhodopsin I during the bleaching of visual
pigment, while the corneal negative component, Rz, is generated by the conversion
of metarhodopsin
I to metarhodopsin
II.
-#
a.wave
descendinglimb
Figure 1.3 Note positive (+) Rl and negative (-) Rz

portions
of ERR ERP occurs immediately after high-
luminance stimulus. Its negative portion

a-wave of ERG.
blends with
The ERP is thought to originate as the

result of charge displacements
that occur
within photoreceptor
outer segments dur-
quently termed these wavelets oscillatory

potentials (OPs). These potentials are high-
ing the photochemical

reactions described
above. Its recovery rate has been correlated
with the regeneration rates of these visual
frequency, low-amplitude
components of
the ERG, with a frequency of about 100 to
160 Hz, to which both rod and cone sys-
pigments.
tems can contribute.46,47 By comparison, the

a- and b-waves are dominated by frequency
The human ERP is probably
generated predominantly
by the cones. By
evaluation of cone-deficient
subjects, the
rod contribution
to the ERP has been estimated to be between 20% and 49%.41.42
This response in humans is technically considerably more difficult to record than the
ERG, and it is therefore not seen in routine
ERG recordings. It requires the use of a
high-intensity
flash stimulus, the delivery
of the stimulus to the eye preferably in
Maxwellian
view (requiring the use of a
condensing lens and careful optical focusing), and isolation of the recording electrode from the flash stimulus to avoid a
photovoltaic
artifact that would
recording of the ERP response.
ment of the ERP can be useful
of human retinal disorders that
obviate
Measurein the study
cause pho-
toreceptor-cell
degeneration because it reflects a direct measure of visual photopigment activity. Its amplitude is proportional
to the quantity of bleached pigment molecules. A review of the ERP and its measurement in various human retinal disorders
can be found in Muller and Topke.43
1.1.4 Oscillatory Potentials
In 1954, Cobb and Morton44 first reported
the presence of a series of oscillatory
wavelets superimposed on the ascending
limb of the ERG b-wave after stimulation
by an intense light flash. Yonernura45 subse-
components of about 25 Hz.46

The cellular origin of OPs in the retina
is somewhat uncertain, although it is likely
they are generated by cellular elements
other than those that generate the a- and
b-waves. Current information
supports the
conclusion that cells of the inner retina,
supplied by the retinal circulation, such as
the amacrine or possibly interplexiform
cells, are the generators of these potentials.
lntravitreal
injection of glycine, which produces morphologic changes in amacrine
cells,48 results in a loss of OPs. Drugs that
serve as antagonists to the inhibitory
neurotransmitters gamma-aminobutyric
acid
(GABA), glycine, and dopamine can selectively reduce OPS.49,50
Reduction in amplitude of OPs becomes
apparent in the presence of retinal ischemia, such as that seen in patients with diabetic retinopathy, central retinal vein occlusion, and sickle cell retinopathy. Reduction
in or amplitudes has also been reported in
patients with X-Iinked juvenile retinoschisiS,51in some patients with congenital stationary night blindness,52 and in patients
with Beh<;et disease.53
Technically, OP responses are recorded
with procedures similar to those used for
standard a- and b-wave amplitudes. However, for optimal isolation, the high-pass
filter setting on the amplifier should be set
at about 100 Hz rather than about 1 Hz,
which is frequently used when recording
the lower-freQuencv
a- and b-waves. Fur-
1-1 Components
and Origins
Blue-lightstimulus
of the ERG
White-Iightstimulus
0:
O
in
>
'6
0:
O
ij)
>
~
0
C)
"'
"'
L{)
N
Rod OPs
Cone OPs
2
0=
O
u;
.>
'6
>
"LO
"'
c
o
v;
>
'6
'f..
""
N
20
40
60
80
100
Time (ms)
ther, a "conditioning"
flash should be presented to a dark-adapted eye approximately
15 to 30 s prior to averaging a subsequent
set of three or four responses to additional
flashes presented at about 15-s intervals.
Responses obtained under these stimulus
conditions are from the cone system (the
conditioning
flash having adapted the rod
system so that it does not contribute to the
subsequent flash-elicited
OPS).47 OPs from
the rod system can be obtained with lowintensity blue light (Figure 1-4).
Although OPs are generated by cells
of the inner retina, they will be reduced
in amplitude by disorders that affect outer,
more distal retinal cells, because the distal
cells provide electrical signals that comprise the input to the more proximal cells
that generate the OPs. Thus, diseases that
seem to affect primarily the outer retina,
such as cone dystrophy or retinitis pigmentosa, reduce OPs as well as a- and b-wave
amplitudes.
...
20
40
Time
60
80
100
(ms)
Figure 1-4 ( A) Single-flash and (8) OP responses to

blue- and white-Iight stimuli
in dark-adapted
eye.
OPs to blue stimulus are from rod system, while

those to white stimulus are from cone system.
CourtesyNeal S. Pealhey,PhD.
10
Figure 1-5 Methods of measuring ERG (A) waveform

amplitudes and (B) time relationships. Most examiners measure b-wave amplitude from trough of a-wave
MEASUREMENT OF THE ERG COMPONENTS
to peak of b-wave. Latency of response refers to time

from stimulus onset to beginning of a-wave, while implicit time ( b-wave response illustrated)
from stimulus onset to peak of b-wave.
is measured
An evaluation of ERG components includes the measurement of both amplitude and timing characteristics. Latency
( the time from the onset of the stimulus
until the beginning of ~he response), implicit time (the time from the onset of the
light stimulus until the peak amplitude response), and amplitude are all depicted in
Figure 1-5. Note that the a-wave peak amplitude is measured from the baseline to
the trough of the a-wave, while the b-wave
is traditionally
measured from the trough of
the a-wave to the peak of the b-wave. If
only the a- and b-waves are included, the
duration of the ERG response is less than
0.25 s. Table 1-1lists the author's normal
ranges of a- and b-wave amplitudes and implicit times to single-tlash stimuli under
scotopic and photopic conditions. These
values will vary with the intensity of the
light stimulus, the state of retinal adaptation, and several other variables
in Sections 1-5 and 1-6).
(described
1-3
Recording
Procedure
11
TABLE
1-1
Range of ERG Values Obtained on 100 Normal Control Subjects
From Authors Electrophysiology Laboratory
Maximal
Dark-Adapted
(Scotopic)
(Photopic)
a-waveamplitude
a-waveimplicit time
b-waveamplitude
b-waveimplicit time
70-137 ~V
273-684
12-15 ms
132-320
~V
Rod-lsolated
(Scotopic)
Light-Adapted
32.Hz Flicker
273-684 ~V
74-137IJV
56-70 ms
22-32 ms
~V
12-15 ms
489-908
31-38 ms
~V
33-54 ms
-#
The ERG amplitude responses from the

right and left eyes of normal subjects under
controlled standard conditions using a fullfield stimulus are usually within 10% of
each other, with a maximal difference of approximately 20% to 24%. The 24% represents the maximal difference caused by
shifts in the position of a contact lens even
under controlled conditions. Thus, a difference in amplitude between the two eyes is
probably pathologic if it is distinguishable
by between 20% and 24% and likely to be
pathologic if it exceeds 24%. Some investigators indicate that a reduction in ERG amplitude during serial followup examinations
is significant, at the 99% confidence limit,
if a decline greater than 31% occurs to a
single-flash white stimulus or greater than
44% to a 30-Hz flicker stimulus.54
Because actual ERG amplitudes, as measured in microvolts, do not follow a normal
gaussian distribution,
nonparametric
methods are likely most suitable for obtaining a
range of normal results for clinical testing.55
Converting
ERG amplitudes into log values
better simulates a normal distribution
of
amplitude data.55
RECORDINGPROCEDURE
The most basic aspect of obtaining an ERG
is an adequate light stimulus that allows
variation in stimulus intensity over a range
suitable for clinical electroretinography.
The specific stimulus is probably less important for clinical use than is the ability to
calibrate the stimulus and maintain it at a
constant luminance. Many examiners use a
Grass xenon-arc photostimulator,
with a
flash duration of 10 ].1s.
A contact-Iens electrode with a lid speculum is most often used to record retinal
responses to the light stimulus. A topical
anesthetic is administered
to the eye to reduce any difficulty
and discomfort associated with lens insertion. A ground electrode
is generally placed on the patient's earlobe
with electrode paste. A reference, or "inactive," electrode is placed centrally on the
patient's forehead slightly above the supraorbital rims or on the mastoid region or earlobe. The reference electrode serves as the
12
more negative pole, having been placed

closer to the electrically negative posterior
pole of the eye. (In the Burian-Allen
bipolar electrode, discussed in Section 1-4-1, a
silver reference electrode is incorporated
within the lid speculum, obviating the need
for a separate reference electrode.)
The corneal contact lens (active electrode ), ground electrode, and reference
electrode all connect with a junctional box,
from which the signals are delivered to additional recording components for amplification and, finally, display. Most often, display and amplification
systems are contained within a single unit. A differential
amplifier is used to detect and amplify the
difference in voltage between the active
corneal electrode and the inactive reference
electrode that develops following light
stimulation of the retina.
RECORDINGELECTRODES
Important features of ERG recording
trodes include
elec-
1. Quality components with low intrinsic

noise levels, which facilitate stability of responses
2. Patient tolerance, with limited
of the corneal surface
3. Availability
irritation
at a reasonable cost
1-4-1 Burian-Allen Electrode

The Burian-Allen
electrode
has lens sizes
suitable for adults to premature infants.56

These lenses have the advantage of a lid
speculum, which promotes a more consistent input of light entering the pupil by
controlling,
or at least limiting, the effects
of blinking and lid closure during photic
stimulation.
Images viewed through the
central portion of the lens, made of polymethylmethacrylate
(PMMA), show variable degrees of blur. Thus, the lens is not
optimal for use when stimulus image clarity
is vital, for example, when recording the
pattern ERG.
The recording electrode consists of an
annular ring of stainless steel surrounding
the central PMMA contact-Iens core. In the
bipolar version of the Burian-Allen
lens, a
conductive coating of silver granules suspended in polymerized
plastic is painted on
the outer surface of the lid speculum. This
conductive coating serves as a reference
electrode, obviating the need for an additional separate silver-silver
chloride wire, as
is necessary with the unipolar model.57 It is
noteworthy that the ERG amplitudes obtained with a bipolar electrode will be predictably smaller than those obtained with
a monopolar electrode.
1-4-2 Dawson-Trick-Litzkow Electrode
The Dawson-l'rick-Litzkow
(DTL) electrode consists of a low-mass conductive
Mylar thread whose individual fibers (approximately
50 pm in diameter) are impregnated with metallic silver. The conductive
thread virtually floats on the corneal film
surface.58
When compared to the Burian-Allen
electrode, the amplitudes of the ERG responses recorded with the DTL electrode
are, on average, reduced 10% to 13%. However, the variance in signal amplitude with
the DTL electrode was found to be less
than with the Burian-Allen
electrode. In addition, the noise characteristics of the DTL
electrode were favorable, as was its tolerance for extended recording periods.59
..
1-4
Major advantages of the DTL electrode

include its low cost, patient acceptance, and
stimulus image clarity. However, eyelid
blinks following flashes can cause movement artifacts, which will sometimes obscure ERG components. Proper placement
of the DTL electrode thread deep and
loose within the lower-Iid conjunctival
sac
can minimize electrode displacement from
eye blinks or eye movements and thus
allow highly reproducible
retinal potentials
to be recorded.6 While facilitating greater
reproducibility,
positioning the electrode
deep within the conjunctival
sac, as opposed to having it ride on the lower-Iid margin, results in the measurement of appreciably lower ERG amplitudes.61
143 ERG-Jet Electrode
The ERG-jet electrode lens is made of a
plastic material that is gold-plated at the
peripheral circumference
of its concave sur
face.62 Its advantages include sterility (the
lens is packaged and can be discarded after
each use), simplicity in design, and ease of
insertion, which has potential benefit for
sensitive eyes. Movement of the lens during recordings and absence of a lid speculum could contribute to variability of
recordings in individual
instances.
1-4-4 Mylar Electrode
Aluminized
or gold-coated Mylar has also
been used for recording ERG potentials.63.64
The gold-foil electrode is preferable to the
aluminum Mylar because it provides a more
stable baseline and is less likely to dislodge
or flake.65 The gold-foil electrode, which
fits over the lower eyelid, when correctly
positioned, is less sensitive to eye movement than is the DTL electrode, yet more
sensitive to such movement than are con-
Recording
Electrodes
13
tact-Iens-style
recording electrodes. Both of
these electrodes are probably unsuitable for
DC amplification
measurements because of
rather large low-frequency
drift. Borda et
al65 reported a 34% to 44% reduction in amplitude with a gold-coated Mylar electrode
than with a contact-lens electrode.
145 Skin Electrode
For specific purposes-for
instance, recording ERGs from infants and young childrenthe corneal electrode can be replaced by an
electrode placed on the skin over the infra,.
orbital ridge near the lower eyelid. Recorded
amplitudes are 10 to 100 times smaller than
those obtained using a corneal electrode.66.67
Coupland and Janaky68 observed that the
ERG amplitudes recorded with skin electrodes ranged from between 43% and 73%
of those obtained with DTL electrodes.
Both the lower amplitudes and the variability in responses with the use of skin electrodes preclude their use for purposes other
than screening. Whenever possible, it is
preferable to select a smaller recording
electrode with a lid speculum, such as an
infant Burian-Allen
electrode, which can be
used successfully in children and infants.
146 Cotton-Wick Electrode
Sieving et al69 introduced an electrode consisting of a Burian-Allen
electrode shell fitted with a cotton wick. This electrode, as
well as earlier variants of a cotton-wick
configuration, is of value in recording ERG am.
plitudes to a high-luminance
flash and for
recording the ERP, because the lens is free
of a photovoltaic
artifact, which can occur
when intense light illuminates
the metal
present in other recording electrodes.
14 TheElectroretinogram
147
Hawlina-Konec Electrode
The Hawlina-Konec
(HK) loop electrode is
a noncorneal electrode, consisting of a thin
metal wire (silver, gold, or platinum) that is
molded to fit into the lower conjunctival
sac. The wire is Teflon-insulated,
except
in its central region, where three windows,
3 mm in length, are formed on one side.
Electrical
contact is made with the scleral
conjunctiva through these small uninsulated portions. The HK electrode may be

used without topical anesthetic, although
this may not be advisable in sensitive patients or certain young children. Pattern
ERG recordings with this electrode are in
the same amplitude range as observed with
the gold-foil electrode, while flash ERG
amplitudes
recordable
are about two thirds those

with corneal electrodes.
THE ERG UNDER LIGHTAND DARK-ADAPTEDCONDITIONS

The recording of the photopic (cone) ERG
potential can be done before or after dark
adaptation, with the patient light-adapted
to a background light intensity of at least
5 to 10 foot-lamberts,
or 17 to 34 cd.m-2
(candela per meter squared), which facilitates the recording of a response exclusively from the cone systein.70 Regardless
of which sequence is adopted, the response
obtained to a high-Iuminance
stimulus
(Figure 1-6) is relatively small in amplitude,
with a short implicit time and a brief duration. The amplitude of the cone b-wave
grows with stimulus intensity and tends to
approach a maximal limiting value at the
highest intensities. The cone b-wave implicit time increases slightly with increasing
stimulus luminance.71
If single-flash or 30-Hz flicker cone responses are obtained after a period of dark
adaptation, it is vital to wait approximately
10 to 12 min for light adaptation before obtaining final photopic amplitudes, because
there is a progressive increase in ERG amplitude, the extent of which depends on
the level of the background adapting light
and the stimulus intensity.71-78 More intense backgrounds and stimuli will be associated with greater increases in cone ERG
amplitudes during the period of light adaptation. With certain stimulus and background intensities, amplitudes can approximately double (Figure 1-7). A progressive
decrease in cone b-wave implicit time may
also be noted during the course of light
adaptation.76 In normal individuals,
a rodcone interaction appears to influence the
light-adapted
cone b-wave implicit time.
Light adaptation of the rods shortens the
implicit time of the cone b-wave.79
Figure 1-6 also shows scotopic responses
elicited with a white-Iight
stimulus of high
luminance after 30 min of dark adaptation.
Note the increase in ERG amplitude and
implicit time as compared to the lightadapted recording. This response, although
evoked under dark-adapted conditions, has
both rod and cone components. However,
the rod component is dominant and is the
major contributor to both the increased amplitude and the increased implicit time.
This is understandable
because the rod
population is appreciably greater than that
of the cones (about 17 rods to 1 cone) and
the rod cells are intrinsically
more sensitive
to light. An isolated rod response can be
evoked by a low-intensity
short-wavelength
(blue) stimulus (see Figure 1-6).
1-5 The ERG Under Light- and Dark-Adapted
NormalERG
Photopicwhite
5-minscotopicwhite
15-minscotopicwhite
30-minscotopicwhite
30-minscotopicblue
14blue flicker 10 Hz
18redflicker 30 Hl
Conditions
15
Figure1-6Normal ERG
responsesunder photopic and scotopicconditions. Coneresponses
are generally isolated
under proper photopic
conditions and with either single-/lash or 30Hz flicker stimulus,
while rod function can
be isolated with useof
low-Iuminance, shot1wavelength(blue) stimulus as either single...
flash or flicker at 10
Hz. High-Iuminance
white-Iightflash under
dark-adapted conditions measurescombined
rod and coneresponse,
which, in normal subject,
is predominantly from
rod system.lirms 14
and 18refer to stimulus
intensity. In thisfigure,
as well as in subsequent
figures, time calibration
of 20 ms refersonly to
single-/lash recordings.
Vet1icalline indicates
stimulus onset.
16
c:
O
in
>
'6
~
a
.
"'
"0
E
":9-
"05.
t~c
160
Figure 1-7 (A) Light-adapted
single1lash white and
(B) -,O-Hz white flicker cone responses at 1 and 20

min of light adaptation
proximately
subsequent to period of ap-
30 min of dark adaptation.
portance of allowingfor
Note im-
suitable period of light adap
tation to properly determine maximal
cone amplitu&
responses. Also note changes in implicit
time during
light adaptation.
CourtesyNeal S. Peachey,PhD.
Rods and cones contribute independently to the scotopic ERG amplitude. That
is, the rod contribution
to the scotopic
b-wave is the same whether the cone contribution is present or absent. As will be
emphasized in later sections, excluding the
influence of retinal or choroidal disease,
those recording conditions that determine
the relative cone and rod contributions
to
the ERG response include the intensity,
wavelength, and frequency of the light
stimulus, in addition to the state of retinal
adaptation. Therefore, a comprehensive
evaluation of retinal function includes obtaining ERG responses under testing condi
tions that include
3,
Evaluation of the ERG with a constant

stimulus intensity during dark adaptation
Evaluation of the dark-adapted retina
with various stimulus intensities
The ERG response to stimuli of different
4,
wavelengths
The ERG response to different
1,
2,
frequencies
stimulus
The ERG response with the retina lightadapted is also part of the evaluation.
Conditions
17
100,.V L
20 ms
1-5-1
Figure
1-8 is a schematic
-' --::::" -:~ representation
J
of
bl
the ERG
during
dark
adaptation
use of a high-Iuminance
the b-wave
includes
bl and bz. Note

amplitude
topic
response
light
with
is likely
to a receptor
segments.
both
cells
progressively
more
exposure.
The
bz, occurs
ceptor
ERG
changes
a biphasic
flash,
a-wave
as well
limb
dark
an OP divides
components.80
progressively
tion
their
that
in amplitude
the implicit
The
a light-adapted
to a dark-
note
with
the high-Iuminance
the presence
sensitivity.
a-wave
that
its a1 and az
amplitude
during
cells
during
It is likely
into
dark
gradually
82
of
of OPs on
of the b-wave
increases
as photoreceptor
time
as the
Also
adaptation.
25 min
of
in rod-re-
also increases
the a-wave
to
light
development
as the appearance
the ascending
progressive
relates
of previous
increase
Note
from
15min
and become
of the increase
response.
of
as the
bz develops
a- and b-waves
adapted
stimu-
sensitive.
major
because
10min
elicited
flash
dark-adapt
as the entire
response.
of both
when
in amplitude
and intensity
of b1, as well
and/or
rod component
rate at which
the duration
the rod
b1 (a com-
or high-intensity
photoreceptor
-#
to a "neu-
the outer
and rod response
increase
6min
growth
conditions
Subsequently,
the b-wave)
in
of the adapting
photopic
Ius) and bz (a presumed
The
initial
related
within
cone
at
pho-
of primarily
adaptation
by a moderate
1 min
less than
The
adaptation
under
increase
seen under
to the removal
used
bined
that
adaptation.
network
the
subcomponents,
it occurs
of dark
with
Traditionally,
the immediate
of b1 amplitude
ral"
two
of b1 from
conditions;
1 min
flash.
also
adaptarecover
Figure 1-8 ERG responses during dark adaptation

with use of high-Iuminance stimulus. Increases in both
a- and b-wave amplitudes with progressive dark
adaptation
are apparent; bl wave has both rod- and
cone-system components, while b2 wave is likely exclusively rod-system component. OPs are also more apparent with progressive dark adaptation.
18
kxaminers need to be aware of an artifact

that may be present, particularly with the
use of a bipolar recording electrode, in the
clinical ERG of some patients. This artifact
occurs with a latency that is fast enough to
interfere with the scotopic b-wave of the
ERG. Because most of the artifact is probably due to a reflex contraction of the orbicularis muscle, it has been termed the photomyoclonic reflex. 81This artifact is less likely
to be apparent
with bipolar
with the use of unipolar
than
lenses.
1-5-2 With Variable-lntensity Stimuli

Figure 1-9 shows dark-adapted ERG responses to flash stimuli of minimal, moderate, and high luminance. Generally, the amplitudes of both a- and b-waves increase
and the implicit times decrease as a func-
Figure 1-9 ERG responses in dark-adapted
eye with
stimuli of different white-Iight intensities. Note shot1er

implicit
times and larger amplitudes as stimulus in-
tensity is increased. OPs are most apparent with highintensity stimulus.
tion of stimulus luminance; in both cases,

the curves approach a plateau at high stimulus intensities. It is noteworthy that, as already indicated, the b-wave implicit time
appears to increase with stimulus intensity
under light-adapted
conditions. As a reference, a standard flash stimulus strength has
been defined as one that produces at least
1.5 to 3.0 cds.m-2 (candela-second per
meter squared) at the surface of a full-field
bowl (3.43 cds.m-2 = 1 foot-lambert).7o
Figure
1-10 shows a series of ERG re-
sponses to flashes of increasing intensity.

The lowest-intensity
flashes elicit an exclusively rod response, while high- and
medium-intensity
stimuli evoke responses
that, as already noted, are rod-dominant,
but contain both rod and cone components.
Note the absence of the a-wave at the
lower stimulus intensities. Because there is
a large magnification
of electrical activity as
signals are transmitted from photoreceptor
cells to inner retinal neurons, the b-wave
1-5 The ERG
Under Light-
and Dark-Adapted
-0.5
appears to be at least 1 log unit more sensi-
250 "V L
tive than the a-wave. Thus, b-wave amplitudes can be measured at low stimulus intensities, where a-wave responses are not
yet apparent.
ERG investigations
of patients with retinal disorders now more frequently
include
studies of scotopic b-wave responses to a
range of full-field
stimulus
obtain a stimulus/response
intensities to
(S/R), or Naka-
Rushton-type,
function. The normal S/R
function (Figure 1-11) exhibits an increasing amplitude over a stimulus range of
about 2 log units. The S/R relationship can
be summarized
R/Rmax
= 1"/(1"
by the equation
20ms
-1.0
:J
N
E
0;
"8
"iI
9
0)
-1.5
"E
.2
-5j
(0
Lr:
-2.0
u
~
(0
~
+ a")
where R is the b-wave amplitude produced

by a flash of intensity I (typically, in footlamberts per second or cds.m-2) and <1(sigma) is the value of the flash intensity that
produces one half the maximal response
Rmax.The <1value is an index of retinal sensitivity, whereas the exponent n, which has
a value of about 1 for the normal retina,
refers to the slope of the SIR function.
SIR determinations
can provide information that has implications
for the nature of
various retinal degenerative disorders. F or
example, a total loss of retinal receptor cells
in isolated retinal regions would probably
reduce Rmax, but not appreciably affect the
value of <1or n. In contrast, Massof et al82
proposed that a notable reduction in the
overall concentration
of rhodopsin, as might
occur if the outer segments of the photoreceptor cells were shortened as the result of
a disease process, would not appreciably affect Rmax, but would decrease the retinal
sensitivity, that is, the value of <1.The term
log K is also used when referring to retinal
sensitivity.
19
Conditions
-2.5
-3.0
Figure 1.10 Series of ERG responses to white-Iight
stimuli of increasing luminance. Lowest-luminance
flashes elicit exclusively rod response, while higherand medium-Iuminance
stimuli evoke responses that
represent combined rod and cone activity. Note absence of a-wave at lowest stimulus intensities.
CourtesyNeal S. Peachey,PhD.
20
600
Figure 1-11 Flash stimuIus versus amplitude

sponse function
re
curve
-Rmax
500
with equation used to

determine curve fit.
400
~
"'
-0
300
""E
<
.'/,Rmax"
200
R
Rmax
I" + a"
Lo,g(J
100
0
-4.0
.3.5
-3.0
-2.5
-2.0
1.0
-0:
Flash luminance (Iog cds.m-2)
1-5-3 With Different-Wavelength Stimuli

As already noted, a low-intensity
blue stimulus can elicit an ERG response that is exclusively from the rod system. Figures 1-6
and 1-12 illustrate this response in a fully
dark-adapted eye. The low-intensity
stimulus precludes stimulation of significant cone
activity, while the use of a broad-band filter
that transmits light in the short-wavelength
(blue) region of the spectrum (less than
460 nm) maximizes stimulation of the rods.
Alternatively,
a rod response can be elicited
by using a dim white flash that is 2.5 log
units below the recommended
standard
white flash of 1.5 to 3.0 cds.m-2.7o A longwavelength
(orange-red)
light (about 600
nm) elicits a characteristic biphasic positive

response (see Figure 1-12). The early portion of the response, referred to in the literature as the x-wave,83 is ascribed to cone activity. This peak is missing in protanopes
and protanomals84 (red defectives) and
achromats (those totally color-blind, also
called monochromats). The late peak ascribed to rod activity is absent or markedly
reduced in, among others, patients with
congenital stationary night blindness.
Blue and orange-red or red stimuli can
be "scotopically
balanced" to produce
equal amplitudes from the dark-adapted
eye. By digital subtraction of the matched
responses, the rod contribution
can be eliminated, thereby facilitating the determination of dark-adapted cone function.71 In
addition to a single-flash stimulus, intermittent chromatic stimuli can be used to elicit
10-Hz blue or 30-Hz red flicker responses
to obtain isolated responses from the rod
or cone systems, respectively
1-12).
(see Figure
Conditions
21
FIgure1-12ERG responsesto either singleflash or flicker chromatic stimuli. Lowluminance blue stimuli
measureisolated rod
function, while 30-Hz
red or orange-redflicker
stimuli determinecone
function. Both cone
(x-wave) and rod
(b-wave) function
can bedetermined
with useof single-flf1sh
30-mindark-adaptedblue
(rodresponse)
30-mindark-adaptedred
(coneand rod response)
long-wavelength(red)
stimulus after dark
adaptation. Time-base
settingsfor 10-Hz and
30-Hz stimuli were
61.4 and 20.4 ms/di-
'4 blueflicker 10 Hz
(rodresponse)
vision, respectively.
18red flicker 30 Hz
(coneresponse)
1.54 With Variable-Frequency Stimuli

As the frequency
light of moderate
of retinal
intensity
stimulation
with
increases from
1 to 70 flashes per second, the various types

of retinal receptors become incapable of responding. The stimulus frequency at which
separate responses can no longer be recorded
is the flicker-fusion
frequency (Figure 1-13).
Up to approximately
20 flashes per second,
the rods can respond with a separate response for each flash. On the other hand,
the cones can generate separate responses
to flash stimulus rates as high as 70 flashes
per second.
The flicker-evoked
responses indicated
in Figures 1-12 and 1-13 represent electri-
cal activity from both photoreceptor

cells,
which generate the a-wave, and more proximal retinal cells, which generate the bwave. The greater the luminance of the
stimulus, the higher will be the flickerfusion frequency. Measurement
of both
flicker-fusion
frequency and the amplitudes
seen at faster stimulus frequencies is of
value in the diagnosis of diseases with predominantly cone pathology. These responses are of more optimal quality, and
better tolerated by the patient, if obtained
in the presence of a background light
equivalent to that used for obtaining singleflash cone responses.
22
~
o
in
0>
~
0
~
"'
"0
~
0E
<
Time (16 msldivision)
Figure 1-13 With intensity held constant, light flashes

of increasingfrequency
record responses that progres-
sively decrease as stimulus frequency is increased.

Frequency is reached when individual
responses are
no longer recordable (flicker-fusion frequency). Individual responses can be elicited in normal subjects
with frequencies as high as 50 to 70 Hz.
Using glutamate analogs to obtain a relatively selective blockade of either on- or

off-bipolar cells of the monkey retina, Bush
and Sieving85 found a major contribution
from postsynaptic or second-order neuron
elements (essentially, bipolar cells) to the
photopic fast-flicker
ERG response. These
are the same cells that are exclusively or
partly responsible for the b-wave and the
d-wave of the photopic single-flash ERG.
In 1989, a basic protocol describing standardized procedures for recording ERG
waveforms under different stimulus conditions became available.86 This document
was subsequently
updated and republished
in 19957 and again in 1999.87 Standards for
the recording of five commonly obtained
responses were descri bed. F our of the five
recommended
responses are depicted in
Figure 1-14.
1. A response evoked from the rods in an
eye dark-adapted for at least 20 min
2. A "maximal"
response, normally
pro-
duced by a combination
of the cone and rod
systems, in a dark-adapted eye
3. Oscillatory
potentials
1-6 Other F actors Affecting
4. A single-flash response from the cone

system in a light-adapted
eye
5. Responses obtained from the cone system, preferably in a light-adapted
eye, to a
rapidly
23
the ERG
repeated
(flicker)
Figure 1-14 F our of five responses recommended as

standard test conditions by International
for Clinical Electrophysiology
(A) Light-adapted
Society
of Vision (ISCEV).
condition. (B) Dark-adapted
condition.
stimulus
The report also includes sections on

basic technology, clinical protocol, pediatric
ERG recording, and specific responses.
This document provides useful information
that will assist those who record ERG responses to do so in a more standardized
fashion so that recording protocols between
different laboratories will have a greater
degree of commonality.
This, in turn, will
facilitate a more productive comparison
of patient data between different testing
sites.
OTHER FACTORSAFFECTINGTHE ERG

1-6-1 Duration of Stimulus
For short-duration
flashes, a reciprocal
rela-
tionship exists between stimulus duration

and intensity such that if the intensity is
held constant, longer stimulus durations
24
will result in larger ERG amplitudes up to a

certain duration limit. In the human eye,
some investigators found that responses to
stimuli longer than 20 ms are all identical in
amplitude.88 Johnson and Bartlett89 determined a longer duration limit of 100 ms in
the dark-adapted eye. An increase in stimulus duration beyond this level resulted only
in an increased duration of the response,
but not in a greater amplitude. Whether
stimuli of 20 or lOO ms are used, an appropriate interval between light flashes of
these durations must be maintained to preserve dark-adapted conditions and the consequent reproducibility
of amplitudes. For
standard recordings, a maximum duration
of S ms has been recommended}O
As indicated in the discussion of offresponses, if longer-duration
stimuli are
used under photopic conditions, a major
contribution
to the b-wave can be demonstrated to consist of an off-response (d-wave).
Longer-duration
stimuli separate the offresponse from the b-wave, revealing its appreciable contribution
to the b-wave response that is obtained with the more typical short-duration
flashes (see Figure
1-2).
1-6-2 Size of Retinal Area Illuminated

The full-field
flash-evoked
ERG results
from a diffuse and basically homogeneous

retinal response. The surface of the retina
and ocular media scatters the stimulus so
that the entire retina is affected. Thus, a
light focused on the optic disc can produce
a sizable ERG due entirely to internal scatter. With direct-flash methods, in which the
light stimulus is not reflected from within a
diffusing sphere, the stimulus will illuminate various retinal areas in a nonhomoge-
neous manner. Thus, the total response is

the summation of multiple small ERGs of
different amplitudes and implicit times.
The overall amplitude will be reduced and
the implicit time slightly prolonged. A fullfield stimulus is obtained when light is
evenly diffused from within a sphere and
consequently
illuminates all retinal areas
homogeneously.
By this method, multiple
ERG responses from the retina that are relatively similar in both amplitude and time
course are summated.90-92 These summated
regional responses differ somewhat because
of the lack of retinal spatial isotropism and
restrictions on homogeneous retinal illumination imposed by the pupillary aperture.90
Nevertheless,
a full-field
stimulus has been
strongly recommended.7
Full-field
dome
stimulators are preferable to ocular diffusers, such as lOO-diopter or opalescent contact lenses, because measurement of the
extent and intensity of retinal illumination
is difficult with the latter.7o
1-6-3 Interval Between Stimuli
The importance of the interval between
successive stimuli, particularly those of
high intensity or long duration, was mentioned in Section 1-6-1. In the dark-adapted
eye, it is important to keep successive stimuli far enough apart to prevent excessive
light adaptation, which will tend to decrease both the amplitude and the implicit
time of the response. The precise interval
will vary, depending on the duration and
luminance of the stimulus. When a darkadapted rod-isolated response is measured,
a minimum interval of 2 s between flashes
is recommended,
while an interval of at
least 10 s between stimuli is desirable when
measuring the dark-adapted maximal combined rod and cone response.70 In the lightadapted eye, an interflash interval of at
1-6 Other F actors Aftecting
least 500 illS (0.5 s) should be sufficient to

avoid attenuation of successive responses.70
1.6-4 Size of Pupil
Retinal illumination
is proportional to pupil
area. ERG recordings are optimally obtained
when the pupils are fully dilated. In the
dark-adapted eye with use of a high-Iuminance, brief flash stimulus, pupil size is of
only moderate concern except in the presence of significant miosis, as in glaucoma
patients receiving miotics. In these patients,
a reduction in amplitude might be anticipated as less light reaches the retina. However, in the light-adapted
eye, particularly
with the use of a flicker stimulus, proper
pupil dilation
is required.
1.6.5 Circulation and Drugs

Henkes,93 among others, has shown that
agents modifying systemic blood pressure
and blood flow can affect the ERG amplitude. Vasodilators, including papaverine,
acetylcholine chloride, and tolazoline
(Priscoline), have produced an increase in
b-wave amplitude. Hyperventilation
can
also cause an increase in ERG amplitude.
1-6-6 Development of Retina
With intense stimuli,
both photopic
and
scotopic ERG components can be recorded

within 14 hours of birth, although reports
vary from different laboratories as to when
recordable responses can first be obtained.
From their study of both term and preterm
infants, Mactier et al94 observed that an
ERG was recordable as soon as 7 hours
after birth and as early as 30 weeks after
conception. Horsten and Winkelman95 reported that an ERG can be recorded from
all normal infants within a few hours of
birth and even from premature infants well
the ERG
25
before term. Implicit times, however, are

prolonged as compared to adult values.
The photopic component, according to
these authors, achieves adult values at approximately
2 months of age, while the
maximum b-wave amplitude obtainable
under dark-adapted conditions gradually
increases, reaching adult levels at approximately 1 year, a finding also noted by others.96,97Amplitude
and implicit-time
responses change rapidly during the first
4 months and more slowly thereafter98,99
(Figure 1-15). At 2 to 3 months of age, the...
mean maximum dark-adapted b-wave amplitude is about half that of adults.97,loo
Oark-adapted
~RG sensitivity, defined as
the flash intensity that produces half the
maximum ERG b-wave amplitude, becomes equivalent to that of adults at age
5 to 6 months.loo,lol Flicker-fusion
findings
resemble adult values at 2 to 3 months of
age, while implicit times reach adult values
at about 1 year of age. Normative data from
full-field
ERG measurements on healthy
preterm infants at 36 and 57 weeks postconception are available in a report by Birch
et al.loz
Mets et allo3 demonstrated that there
were no differences between premature infants with, and those without, mild degrees
of retinopathy of prematurity
(ROP) in the
values for maximal scotopic ERG amplitudes or sensitivity. Although Fulton and
Hansenl04 also noted that rod b-wave amplitudes were within the 95% "prediction"
interval for normal infants or children with
mild ROP, they observed a reduction in bwave sensitivity (log K), as well as an attenuation of the OPs. Rod photoreceptor
responses, as determined
by measurement of
the a-wave amplitude and sensitivity, were
26
Figure 1-15 Rapid development of ERG responses

occurs within first
4 months after birth.
CourtesyDavid G. Birch, PhD.
also low. In an earlier study, Fran~ois and de

RoucklOS reported ERG findings on 98 patients with various cicatricial stages of ROP.
In moderately advanced stages, the most
frequently observed ERG change was a reduction of both a- and b-wave amplitudes,
with the b-wave more affected than the awave. In the most advanced stages, when
the retina was detached, it was not surprising that the ERG was nondetectable.
Different results from various laboratories investigating ERG development
in infants
might be anticipated, not only because of
different experimental
conditions, but also
as a consequence of wide individual variability in postnatal evolution of the ERG.
1-6 Other F actors Affecting
1.6.7 Clarity of Ocular Media

Opacification
of the lens, particularly associated with yellowing of the nucleus with
age, can reduce the ERG a- and b-wave
amplitudes and prolong implicit times as
the consequence of its filter effect, which
reduces the amount of light reaching the
retinal photoreceptors.
Similar reduction
in amplitude and prolongation
of implicit
times can be seen with hemorrhage in the
vitreous. Less extensive opacities within
the lens cortex can scatter or diffuse light
to a degree for which ERG amplitudes and
implicit
times will not be adversely affected.
1.6.8 Age, Sex, and Refractive Error

Both age and refractive errors are associated
with a measurable decrement in the ERG
amplitude. PetersonlO6 noted a linear reduction with age of the b-waveamplitude,
apparently the same for both sexes, from
about age 10. An exception was noted in
women 40 to 49 years of age, in whom a
significant increase occurred, possibly related to hormonal factors. In all age groups,
women had a statistically significant higher
value of the b-wave amplitude-a
finding
also noted, at least in some age groups, by
Vainio-Mattila,lo7
Zeidler,lo8 and Birch and
Anderson.99 However, Iijima55 found no
significant
or implicit
gender differences in amplitude

time of the photopic and sco-
topic responses in a study of 72 men and

42 women. The slightly smaller ERG amplitudes found in men, as compared to
women, by most observers may be due to a
greater axial length of the eye in men. Even
early ERG investigations
by Karpe et allo9
disclosed a reduction in ERG amplitude
with age and higher amplitudes in women,
particularly in patients above age So. A similar age-related reduction in ERG ampli-
the ERG
tilde, for at least some components
27
of the
response, was noted by Zeidler,lo8 Martin

and Heckenlively,ll
Weleber,111 and lijima.55 No age-related changes in photopic
or scotopic implicit times were reported by
Weleber,lll
while lijima55 noted a prolongation of the b-wave implicit time with age
that was most apparent under scotopic
conditions.
In a report by Lehnert and Wonsche,112
a significant reduction in b-wave amplitude
did not occur until the third decade. Birch
and Anderson99 noted a 50% decline in
...
rod and cone responses by ages 69 and 70,
respectively, compared to amplitudes obtained in young adults (ages 15 to 24 years).
Implicit times of the b-wave increased
with age for all responses. In high myopes
(6 diopters or greater), a reduction in the
b-wave amplitude can be observed.l06.113
The responses are usually minimally
to
moderately subnormal, but may occasionally be markedly subnormal. Apparently, an
increase in axial length, independent
of any
associated chorioretinal
important
contributing
degeneration,
is an
factor.113
1.6.9 Anesthesia
Anesthesia may
tude to variable
on the nature of
ries report up to
affect the b-wave amplidegrees, depending in part

the drug. Some laboratoa 50% reduction in sco-
topic b-wave amplitude with certain drugs.

The photopic responses and scotopic a-wave
amplitudes are generally either minimally
affected or not altered. ERG changes also
occur in patients during inhalation of nitrous oxide. Under light narcosis, an increase in the b-wave amplitude is noted,
while deep narcosis induces a decrease in
28
the b-wave potential. Presumably, with

most general anesthetics, the ERG amplitude depends on the level of narcosis. In
the serum. Thus, serial ERG recordings on

patients to monitor evidence of progression
or improvement
are best performed at ap-
young children
proximately
sedated with a barbiturate
the same time of day.
such as thiopental (Pentothal), appreciable

reductions in ERG amplitudes have been
seen, whereas ketamine seems not to have
a notable effect on amplitudes.
Padmos and van Norrenl14,115 observed
THE ERG IN RETINAL DISORDERS

a
prolonged cone dark adaptation, measured

by ERG, with the use of halothane anesthesia; this effect was attributed to a delay
in cone pigment regeneration. A similar
prolongation in cone dark adaptation was
seen with the use of other volatile anesthetics, such as methoxyflurane,
chloroform, and diethylether.116 These authors
showed that rod as well as cone dark adaptation was prolonged with the use of halothane anesthesia.117
1-6-10 Diurnal Fluctuations
A diurnal variation of the rod ERG amplitude has been noted with an approximately
13% reduction in b-wave amplitude occurring 1.5 hours after the onset of daylight,
which corresponds to the time of maximal
rod outer-segment
disc shedding.118 Nozaki
et al119studied the circadian rhythm of the
maximal dark-adapted ERG a- and b-wave
amplitudes in 14 normal subjects at 6-hour
intervals over a 24-hour period beginning at
6:00 am. In their 14 subjects, the a-wave
amplitude showed no circadian rhythm. In
8 of the 14 subjects, the b-wave amplitude
showed a circadian rhythm and was lowest
at 6:00 am and highest at noon. This
rhythm showed a good correlation with the
circadian rhythm of dopamine 13-hydroxylase, but not with corticosteroid
levels in
Various retinal and choroidal diseases or

disorders can affect the ERG. Figure 1-16
illustrates the patterns of abnormal ERG
responses in photopic and scotopic conditions. The terms negative-negative and negative-positive were used by Henkes120 for relatively lower luminance recordings. Both
are characterized by a more prominent awave amplitude compared to the b-wave.
In the negative-negative
response, the bwave amplitude is decreased; in the negative-positive
response, the b-wave amplitude remains normal while the a-wave
amplitude is increased. It is likely that the
negative-positive
response can occur as a
variant of normal, although Henkes described its occurrence in some patients
with central retinal vein occlusion.
Van Lith121 argued effectively that qualitative descriptions or labels of ERG waveforms as "subnormal"
or "absent" are less
desirable than quantitative
determinations,
which document a percentage reduction in
ERG amplitude. Van Lith suggested expressing amplitude reduction as a percentage of the mode and lower limit. The mode
is used instead of the mean because in most
laboratories there is an asymmetric frequency distribution
of normal ERG amplitude values. Nevertheless, van Lith determined the lower limit by obtaining a standard deviation value of 2 in reference to the
mode. Reductions in ERG amplitudes were
then expressed as a percentage of the mode
1-8
and the lower limit. In instances of uniocular disease involvement,

van Lith recommended using the uninvolved
eye as a control when its amplitude is greater than the
mode.
An alternative recommendation
is to list
the median value and the actual values on
either side of the median that bracket 95%
of the normal responses.ss Regardless of
whether the mode, median, or lower limit
(however determined}
is used, the fundamental issue is that describing an ERG result solely as "subnormal"
is inexact and in
need of quantitative
documentation.
With reference to "absent" ERG recordings, it is advocated that a mean background
or noise level be determined
so that terms
such as "nondetectable,"
"nonrecordable,"
and "extinguished"
can be stated in a more
precise, quantitative
manner. Thus, the
term "nondetectable"
should be expressed
with reference to a specific background
level under a specific set of stimulus and
recording conditions. Of necessity, this
monograph uses such nonquantitative
terms as "subnormal"
and "nondetectable"
because reports on various retinal diseases
in the literature, which are discussed below,
rarely provide
these terms.
quantitative
definitions
of
Diffuse
Photoreceptor
29
Dystrophies
Figure 1.16 Patterns of normal and abnormal
ERG
c#
responses under photopic and scotopic conditions.
DIFFUSE PHOTORECEPTORDYSTROPHIES
Computer averaging of numerous responses
and the optimal use of frequency filters can
aid in the detection of very small responses
previously obscured within the noise level
of the recording procedure in various patients with progressive diffuse photOreceptor dystrophies.54,IZZ Small-amplitude
ERG
30-Hz flicker responses may be useful for
noninvasively
monitoring
the progression of
retinal degeneration in patients with retinitis pigmentosa and other diffuse photoreceptor-cell diseases. A notable number of
such patients have ERG amplitudes to a
30-Hz flicker stimulus that are less than
1.0 pV. These small microvolt responses
are, however, subject to the inherent variability in ERG recordings. Particular attention to the intrusion of various potential
sources of noise is mandatory
ambiguous
interpretation
before an un-
of such small sig-
30
nals can be made. The ultimate general

usefulness of obtaining these small signal
responses for patient management will become more apparent after their use becomes
more widespread at a number of different
testing centers and more data become available as to how well they correlate with visual function, as determined
by an evaluation of daily living skills and psychophysical
measures.
1.8.1
Dystrophies
1-8-1.1Retinitis Pigmentosa The rod-cone dystrophy retinitis pigmentosa (RP) was first
described, as seen through the ophthalmoscope, by van Trigt in 1853 while working
with Donders in Utrecht, the Netherlands.
The name retinitis pigmentosa was first used
in 1857 by Donders. This term encompasses a group of genetic diseases that generally present with recognizable phenotypic
Figure 1-17 Characteristic

bone-spicule-like
retinal
changes as
observed in patient
with RP.
impairment.
Initial visual symptoms include difficulty
with night vision, peripheral vision, and,
about 1.5 million

be affected.
Rod-Cone
pigmentary
retinal pigmentary changes (Figure 1-17).

Patients develop progressive photoreceptorcell degeneration and, consequently, visual
Although
people are estimated
patients
characteristically
to
show
all genetic patterns. In most instances, patients with either the autosomal recessive
or the X-linked recessive form have nondetectable or very reduced ERG responses at
an early age. When responses are obtained
using standard recording procedures, they
are elicited most often bya high-luminance
1-8
Diffuse
Photoreceptor
Dystrophies
31
Figure 1-18 ERG recordingfrom
patient with
X -linked recessive Rp,

showing greater degree
of impairment in cone
function
compared to
rod/unction.
stimulus and include either minimal or appreciably subnormal a- and b-waves.

Of interest, Cideciyan and Jacobson124
observed negative ERG waveforms in 7 patients with RP. This finding indicates that,
at least in a subset of such patients, dysfunction occurs not only at the photoreceptor-celllevel,
but also at
cedures. In those patients with recordable

responses, approximately
50% showed
recordings in which the responses from rods
were more favorably retained than those
from cones (Figure 1-18), while in an approximately equal percentage, cone amplitudes were relatively less severely affected
than rod amplitudes.
The autosomal dominant
varieties
of RP
not infrequently
have a later onset of symptoms and a less rapid progression than the
X-Iinked recessive types. When ERG
recordings are measurable, in at least some
subtypes, they are either predominantly

or
exclusively from remaining cone receptor
cells (Figure 1-19). Nevertheless,
in earlier
stages, some patients with autosomal dominant disease manifest subnormal, but recordable cone and rod ERG responses.
However, several subtypes of autosomal
dominant inheritance are seen with varying
degrees of severity. 126On the basis of rod
sensitivity relative to cone sensitivity, determined by perimetric dark-adapted absolute-threshold
measurements to a shortand long-wavelength
stimulus, at least two
subtypes of autosomal dominant RP are
identified.127,128 ERG recordings done in
conjunction
with these psychophysical
measurements of absolute threshold may
provide supplemental
information
to better
facilitate categorization of patients with
dominantly
inherited RP.129Autosomal recessive and isolated (or simplex) RP patients can be similarly
categorized
using
32
perimetric dark-adapted absolute-threshold

measurements.128,130
In all three genetic forms, cone and rod
responses (when present) can be prolonged
in implicit time.131-133 However, a prolonged
dark- or light-adapted
b-wave implicit time
is not necessarily a characteristic property
of the ERG in all RP patients.82,133-135prolonged cone b-wave implicit times to a single-flash stimulus are likely to be apparent,
particularly when rod function has become
appreciably impaired. In this regard, a rod
influence on cone b-wave implicit time has
been postulated.79 The 30-Hz flicker response may also show a prolongation
of
cone implicit time. Sandberg et al136also

demonstrated
a prolongation in the darkadapted cone a-wave implicit time in RP
patients, a finding that the authors interpreted as consistent with shortened cone
outer segments found in these patients. In
the early stages of autosomal dominant RP
with reduced penetrance, a prolongation of
cone b-wave implicit time can be noted
even in the presence of normal cone amplitudes.132 Patients in the early stages of autosomal dominant RP with complete penetrance can show cone b-wave responses that
are initially normal in both amplitude and
implicit
Figure 1-19 ERG recordingfrom patient with

autosomal dominant
Autosomal dominant
RP patient
time.137 Berson and Kanters138
Normal
b
RP. Remaining responses under both

photopic and scotopic
levels of adaptation
primarily
system.
from cone
are
+Jc-
loo"vL
2Oms
1-8
noted, at least in some families with autosomal recessive RP, that both a reduced cone
b-wave amplitude and a prolonged implicit
time can precede detectable abnormalities
in the rod system.
In some instances, patients with a socalled delimited form of RP have surprisingly substantial ERG responses under
both light- and dark-adapted conditions
(Figure 1-20). These patients seem to have
a more favorable prognosis compared to
those with more extensive reductions in
ERG amplitudes. Although reported relatively infrequently,
one author134 indicated
that they may comprise as many as 17% of
patients with RP.
In addition to its value in diagnosis,
ERG testing provides a means of monitoring progression of this group of disorders
and evaluating the efficacy of intervention
in therapeutic trials. In a natural history
study by Birch et al,139 60% of patients with
RP showed a decline in cone ERG amplitude and 64% a decline in rod amolitude
Diffuse
Photoreceptor
Figure 1-20 Two patients from same family
with so-
called delimited form of autosomal dominant

demonstrating substantial
and rod b-wave implicit
33
Dystrophies
Rp,
ERG response. Cone

times are normal.
34
over a 4-year period. These patients lost an

average of 13.3% of their remaining cone
amplitude to a 31-Hz flicker stimulus per
year and showed a 12% annual decline in
the dark-adapted log v maxresponse of the
ERG. An earlier natural history study54 determined a rate of 17.1 % in the annual decline to a 30-Hz flicker stimulus, whereas in
a treatment trial on the efficacy of vitamin
A for patients with Rp, the placebo group
was found to have a 10% annual decline to
a 30-Hz flicker stimulus.14 Both of these
natural history studies54,139 further documented that patients with autosomal dominant RP have, as a group, a less lapid rate
of progression than do those with other
genetic subtypes.
Of note, in determining
progression of
ERG responses in patients with various
retinal disorders, careful consideration must
be given to the short-term intervisit variation in the measurement of ERG parameters. For example, in the study by Birch et
al,139a change of 41% in rod ERG amplitude and 37% in cone amplitude to 31-Hz
flicker was necessary before progression
was considered statistically significant at
the 95% confidence limit. This compares to
the 31% change to a 0.5-Hz dark-adapted
maximal response and 44% change to a
30-Hz stimulus at the 99.5% confidence
limit reported by Berson et al54 in RP
patients.
In at least some patients with RP, a reduction in ERP amplitude has been recorded
in the absence of ophthalmoscopically
visi-
pigmentary retinal degeneration. This notion awaits experimental

verification.
The carriers ofX-linked
recessive RP
often show fundus changes. These include
a golden metallic-luster
appearance within
the posterior pole (referred to as a topetollike reflex), local areas of peripheral pigmentary changes (including pigment atrophy
and bone-spicule-like
pigmentary clumping), fundus changes seen in high myopia,
and, on occasion, extensive and diffuse pigmentary degeneration, as seen in affected
male patients.142 Approximately
86% to
90% of carriers can be identified
by reductions in ERG amplitudes.135 Bright stimulus
flashes have been demonstrated
as most
effective for carrier identification
by ERG
criteria.143 The presence of a prolonged 30Hz flicker stimulus b-wave implicit time in
carriers was found to be a particularly useful
measure by some investigators.I44,145
An appreciable increase in knowledge of
the molecular defects that result in the clinical phenotypes of RP facilitates correlation
between genotypes and phenotypes and
improves the classification of RP. For each
mode of genetic transmission, more than
one and even several genes have been
identified.
At the time of writing, 23 distinct chromosomal loci have been reported.
For 12 of these loci, the actual causative
genes and specific mutations have been
identified.l46 However, a large number of
genes have yet to be identified.
Molecular defects underlying various genetic subtypes of RP can exert their effects
ble bone-spicule-like
fundus pigmentation
or arteriolar narrowing.141 Theoretically,
reductions in ERP amplitudes might be more
through at least three distinct

mechanismsl46;
apparent than reductions in ERG amplitudes in patients with very early stages of
1. The shedding
and renewal of photore-
ceptor outer segments

2. The visual transduction
3. The metabolism
functional
cascade
of retinol
(vitamin
A)
1-8 Diffuse PhotoreceptorDystrophies 35
The first group includes mutations in the

genes for rhodopsin and peripherin/RDS,
which result, most frequently by far, in au-
membrane domain had intermediate

of visual function.
tosomal dominant transmission. Mutations

in the rhodopsin gene are responsible for
1-8-1-2Allied Disorders Syndromes that are associated with pigment dystrophy similar to
RP have variable degrees of abnormal electrophysiologic
function. In the Bardet-Biedl
and Bassen-Kornzweig
syndromes, as well
as in Ref sum disease, the ERG is often affected early and generally severely, with responses either markedly subnormal, minimally recordable, or nondetectable.
A different pattern of ERG change may
approximately
25% of all cases of autosomal
dominant RP and 4% to 5% of all RP patients.147 More than 100 different pathogenetic mutations in the rhodopsin gene
have been identified
in patients with RP.
Rhodopsin mutations that cause autosomal
recessive RP are very infrequent. The second group involves patients with autosomal
recessively transmitted disease and includes
mutations in both the (X- and 13-subunits
of cyclic guanosine monophosphate
phosphodiesterase (cGMP PDE), as well as
the cGMP-gated cation channel (CNCG)
genes. The third group of patients with
mutations affecting retinol (vitamin A) metabolism includes those with mutations in
the cellular retinaldehyde-binding
protein
(CRaIBP) and retinal pigment epithelium
protein (RPE65) genes. In addition to these
three categories, 20% of families with Xlinked RP were found to have mutations in
a guanosine triphosphatase (GTPase) regulator (RPGR) gene1481ocated at Xp21.1
(RP3). A second gene for X-Iinked RP has
been identified at the Xpll.3locus (RP2).149
Sandberg et al150showed that the severity of disease among patients with autosomal dominant RP and a mutation in the
rhodopsin gene depended on the location
of the mutant amino acid alteration within
the opsin molecule. Patients with mutations altering the intradiscal domain tended
to have better visual acuity, larger visual
fields, better dark-adapted sensitivity, and
larger ERG amplitudes than those with mutations that altered the opsin molecule
within the cytoplasmic domain. Patients
who showed a mutation altering the trans-
levels
...
be
observed
in patients
with
Alstrom
syn-
drome compared to those with the BardetBiedl syndrome. Cardinal features of AIstrom syndrome include a congenital and
progressive cone-rod retinal dystrophy and
infantile obesity in the absence of polydactyly.151 Additional features, among others,
include infantile cardiomyopathy,
sensorineural deafness, type 2 diabetes mellitus
with hyperinsulinemia,
and acanthosis
mgncans.
Patients with the Bardet-Biedl
syndrome
most often manifest a rod-cone dystrophy,152 although a cone-rod phenotype has
also been reported.153 A bull's-eye-Iike
macular lesion, retinal bone-spicule-like
pigmentary clumping, and polydactyly
are
other features that distinguish this syndrome from Alstrom syndrome.
Patients with congenital hearing loss and
RP (Usher syndrome) also have considerable
reductions in ERG amplitudes. The degree
of functional visual impairment can vary, depending on the type of Usher syndrome.154
In Bassen-Kornzweig
syndrome, abnormal ERG recordings have been reported in
children whose fundi were still normal.155
Of interest is the observation that patients
36
with Bassen-Kornzweig
syndrome, in addition to those with Ref sum disease, tend not
to show the delays in ERG b-wave implicit
time that can be noted in patients with typical Rp, in whom systemic biochemical defects are not characteristically identified.156,157
In Bassen-Kornzweig
syndrome, in which
patients show low-to-minimallevels
of serum
vitamin A, parenteral supplements of watersoluble vitamin A increase the electrical activity from both rods and cones in some
cases with less severe fundus changes.158-160
Early treatment with vitamins A and E may
retard the development
and progression of
retinal photoreceptor-cell
degeneration in
this disorder.161,162
Patients with Ref sum disease accumulate phytanic acid in the blood, as well as in
a variety of tissues, including the RPE, because of an absence or deficiency of the enzyme phytanic acid a-hydroxylase,
which
converts phytanic acid to a-hydroxyphytanic acid. Ocular symptoms and signs include night blindness, restricted peripheral
vision, impairment
of central acuity, pigmentary retinal changes (which show a phenotype similar to RP), posterior cortical lens
opacities, and thickened corneal nerves.
Systemic findings include chronic polyneuropathy, cerebellar ataxia, increased cerebrospinal fluid protein, neurogenic hearing
impairment,
and cardiomyopathy.
In some
patients, anosmia, skeletal malformations,
and skin changes that can resemble ichthyosis are observed. A low phytol, low phytanic acid diet may be useful in delaying
the course of the retinal degeneration. ERG
amplitudes show moderate-to-marked
reduction in rod and cone amplitudes, with
rod function affected more severely. In advanced cases, ERG responses are often
nondetectable.
Additional
discussions of
Ref sum disease, as well as the Bardet-Biedl,
Bassen-Kornzweig,
and Usher syndromes,
are available in other references.123.163-167
A distinct form of autosomal recessive
pigmentary rod-cone retinal dystrophy has
been observed in association with nanophthalmos and angle-closure glaucoma. ERG
findings in younger patients with this disorder show nondetectable
rod responses,
with near-normal cone b-wave amplitudes,
but considerably delayed b-wave implicit
times. Older patients show severely diminished or nondetectable
ERG cone and rod
responses.168,169
In the mucopolysaccharidoses-particularly, Hurler (MPS I-H), Sanfilippo (MPS
III), and Scheie (MPS I-S) syndromes-an
associated pigmentary retinopathy causes
ERG amplitudes to vary from subnormal to
nondetectable.
Morquio and MaroteauxLamy syndromes are not generally associated with pigmentary retinopathies,
and the
ERG amplitudes are usually normal. Patients with Hunter syndrome may have either normal or abnormal ERG recordings,
depending on the presence or absence of
a pigmentary retinopathy. More detailed
discussions of ERG findings in the mucopolysaccharidoses,
in addition to their classification and characteristics, are available
elsewhere.170,171
The variants of classic RP also show diverse patterns both morphologically
and
electrophysiologically.
Previously, the term
retinitis pigmentosa sine pigmento was used to
describe patients who clinically appeared to
have a normal retina despite documented
diffuse abnormalities of photoreceptor-cell
function. This term is now appropriately
regarded as confusing because it implies a
distinct disorder rather than either a less extensive stage or a variant in expression of
1-8
RP. Patients
previously
described
as having
retinitis punctata albescens have a progressive

retinal degeneration with night blindness
and peripheral visual field loss. The retina
characteristically
shows generally diffuse,
white, punctate lesions located deep within
the retina. Not infrequently,
pigment
clumping with a bone-spicule-like
configuration is also present. 172The sine pigmento
and punctata albescens groups generally
have significantly
diminished
or absent
ERG responses. When present, responses
have prolonged b-wave implicit times. Either sine pigmento or punctata albescens
may occur in a patient when other family
members show the typical RP fundus appearance.
Unilateral RP refers to a pigmentary retinal degeneration associated with minimal or
nondetectable
ERG responses in the affected eye, while the other eye is clinically
and functionally
normal. Henkes173 noted
the importance of obtaining electrophysiologic studies on the apparently normal eye
to assure that it is also functionally
normal.
Carr and Siegel174 emphasized the probable
secondary inflammatory,
traumatic, and vascular causes in most cases of presumed unilateral RP. These authors presented cases of
ophthalmic artery occlusion that simulated
unilateral RP. Kandori et al175also stressed
the importance of ophthalmic artery occlusion as causing pigmentary retinopathy and
reported 2 cases with a secondary, apparently vascular cause of pigmentary retinopathy. Kolb and Galloway176 noted the absence of a positive family history in these
cases and, like Henkes,173 reported subnormal electro-oculograms
(EGGs) in the normal eyes of patients with clinically apparent
unilateral RP. Thus, most authors believe
that true unilateral RP is a rare entity
because of the following:
Diffuse
Photoreceptor
1. The absence of a family
Dystrophies
history typical
37
of
the other classic forms of RP

2. Known
traumatic,
vascular, and inflam-
matory causes in some cases of unilateral

pigmentary
retinopathy
3. Abnormal ERG and/or EOG values in

the apparently normal fellow eye of some
patients
with unilateral-appearing
RP
Perhaps a more appropriate term for this

disorder would be unilateral retinal pigmentary degeneration. 166
Sector RP is infrequently
encounterec;!,.
The fundus has local areas of constricted
retinal vessels and bone-spicule-like
pigment clumping around or within the quadrant of these vessels. The disease is characteristically bilateral and symmetric, 'with
the abnormality most frequently residing in
the inferior and nasal quadrants and producing corresponding defects in the superior and superotemporal
visual fields. The
ERG is generally subnormal, similar to that
found in the eatlier stages of some forms of
autosomal dominant RP. In contrast, however, is the presence of normal cone and rod
implicit times in the sector form (Figure
1-21).156,157The alteration in the ERG amplitude is, in most cases, proportional to the
extent of ophthalmoscopically
apparent
retinal involvement.
This disease is most
frequently inherited as an autosomal domi,nant trait and is slowly progressive. Although the disease is clinically limited to a
sector of the retina, functional impairment
can frequently be demonstrated by psychophysically
determined visual thresholds
even in clinically normal-appearing
quadrants.l77 Thus, this disorder would better be
termed "asymmetric"
rather than "sector"
if consideration is given to functional im-
38
Figure 1.21 ERG responsesfrom patient

with sector RP. As in
patients with so-called
delimited Rp, cone and
rod b-wave implicit
times are normal.
pairment
rather than to the clinical
fundus
appearance.
Leber congenital amaurosis is a clinically
and genetically heterogeneous group of primarily autosomal recessive disorders that
represent a congenital form of diffuse photoreceptor-cell
disease. Patients, in general,
show retinal changes phenotypically
similar
to those seen in RP. This entity is not rare
and is an all-too-frequent
cause of congenital blindness associated with retinal disease
in children. Although some degree of pigmentary change is apparent in these patientS, even at an early age, it is important
to consider this diagnosis in all infants
whose behavior and physical findingsincluding nystagmus, an oculodigital
sign,
and photoaversion-suggest
poor vision
even in those whose retinas appear clinically normal.
Once poor vision is suspected, an ERG

recording that shows either a nondetectable
or a markedly reduced amplitude can prevent needless and often costly neurologic
and radiologic examinations looking for a
"central" cause of the blindness. This ERG
can often be obtained with only topical
anesthetic and therefore general anesthesia
is rarely justified to record an ERG in these
infants or even in most young children.
Other ocular findings may include keratoconus and/or cataract. 178The majority are
hyperopic. In certain patients, unless an
ERG is obtained, an erroneous diagnosis of
macular coloboma or congenital toxoplasmosis may be made because of the presence of a large atrophic-appearing
macular
lesion.179 Some children have associated
neurologic or psychiatric disturbances, including mental retardation. A summary of
the clinical findings observed in patients
with Leber congenital amaurosis, as well as
1-8
those with juvenile and early-onset forms of

RP, can be found in a review of these disorders by Heckenlively
and Foxman.180
Mutations have currently been identified in four genes in association with Leber
congenital amaurosis that may account for
approximately
36% of autosomal recessive
forms of this disease.181,182These include
those that encode for
1. A retinal pigment epithelium-specific
65kDa protein, RPE65183,184
2. A retina-specific
guanylate
cyclase
(RetGC)185
3. A cone-rod
homeobox
is expressed in developing
protein,
which
and mature
photoreceptorsl86-188
4. A photoreceptor/pineal
expressed protein
termed aryl hydrocarbon interactingproteinlike ]182
Diffuse
An additional
Photoreceptor
Dystrophies
39
locus for this disease has
been assigned to chromosome 14q24.189

The RPE65 and RetGC mutations are also
associated with severe early-onset childhood retinal
dystrophy.
1.8.2 Cone-Rod Dystrophies

Patients with cone-rod dystrophy typically
show reduced visual acuity, color vision
deficits,
visual field impairment
(including
central or paracentral scotomas, midperipheral partial or complete ring scotomas, or

peripheral restriction), and reduced ERG-#
cone and rod amplitudes (Figure 1-22). In
some patients, nystagmus and a complaint
of photoaversion may be present. Cone-rod
dystrophy is a genetically heterogeneous
condition, with autosomal dominant, autosomal recessive, and X-Iinked recessive
modes of transmission
occurring.
patient with
cone-rod dystrophy.
Note that cone responses
are barely detectable,
while rod responses, although appreciably impaired, are considerably
more preserved than
cone responses.
40
A phenotypic
diversity
also exists among
patients with cone-rod dystrophy. This includes differences in the extent of fundus
pigmentary changes, differences in the
degree of central versus peripheral cone
threshold elevations on psychophysical
testing, the presence of central versus midperipheral scotomas, and whether cone
ERG amplitudes are more extensively or
equivalently
reduced compared to rod ERG
amplitudes. 190-196
Fundus changes range
from nonspecific mottling or mild atrophicappearing changes of the retinal pigment
epithelium
(RPE) in the macula to grossly
evident atrophic-appearing
macular changes
that can show a bull's-eye appearance. Peripheral retinal changes include hypopigmentation or both hypopigmentation
and
pigment clumping (Figure 1-23). Optic disc
pallor and disc vessel telangiectasia have
also been reported.194
When there is extensive impairment
of
cone and rod function as determined
by the
Figure 1-23 Extensive

degenerative pigmentary
changes in patient with
cone-rod dystrophy.
Some degree of phenotypic similarity
to bone-
spicule-like pigment
changes seen in patients
with RP is apparent.
ERG, patients have attenuation of the retinal arterioles. At this more advanced stage,
patients may specifically complain of poor
night vision. When clinically apparent lesions are limited to the macula, the fundus
phenotype can be indistinguishable
from
that seen in patients categorized as having
cone dystrophy. From a nosologic perspective, in individual patients, there can be
difficulty
in confidently
diagnosing a cone
dystrophy versus cone-rod dystrophy because some individuals in families diagnosed
with a cone dystrophy can show a generally
mild reduction in rod ERG amplitudes.
At least some patients previously described as having inverse Rp, in which pigmentary atrophy and clumping are observed predominantly
in the macula, were
likely to have had a subtype of cone-rod
dystrophy. Patients with cone-rod dystrophy may be differentiated
from those with
characteristic features of RP and other rodcone dystrophies by their initial complaints
1-8
of impaired
central vision rather than nyc-
talopia, by pigmentary changes that are

more apparent in the macular region than
in the mid peripheral retina, and by cone
ERG impairment
that is greater than or
equal to rod impairment.153.190,191
An autosomal dominantly
transmitted
disorder, described in a single family by
Oeutman197 as benign concentric annular
macular dystrophy, was subsequently considered to likely represent a subtype of
cone-rod dystrophy.198 However, thefindings of subjective night blindness, elevated
rod absolute thresholds on psychophysical
testing, evolution of fundus changes to include bone-spicule-like
pigmentary clumping, as well as the ERG and peripheral-field
abnormalities,
also suggest a subtype of autosomal dominant RP. This disorder in a
single family probably should
sidered as a distinct nosologic
Miyake et al199described 4
tients who showed a bull's-eye
not be conentity.
male pamacu-
Diffuse
Photoreceptor
Dystrophies
41
lopathy (Figure 1-24) and the unique feature of a negative ERG, in which the
single-flash dark-adapted maximal whitelight stimulus showed a normal a-wave but
reduced b-wave amplitude (Figure 1-25).
The cone single-flash ERG response
could also show a negative configuration.
Another feature in these patients was reduced or absent OPs and elevated rod final
thresholds on dark adaptation. These patients showed certain similar fundus features and, in one respect, ERG recordings (b-wave amplitude more reduced
than the a-wave) similar to those seen in
-#
patients described as having benign concentric annular macular dystrophy.197,198

The patients of Miyake et al199also showed
some findings similar to those in patients
with a type of cone-rod dystrophy, except for the negative dark-adapted ERG
waveform and the cone responses, which
were either normal or mildly reduced in
amplitude.
Figure 1-24 Bulls-eyeappearing macular lesion as seen in patient

with cone-rod dystrophy. Also note attenuation of retinal at1erioles.
42
c
o
in
>
:0
--~
o
o
:j.
0)
"1::)
~
"5.
E
<
40
80
Figure 1-25 ERG recordings from patient with

cone-rod dystrophy shown in Figure 1-24.
Roth ( AJ lihotoliic and (BJ -,cotoliic reslionses
120
160
0
Time (ms)
40
80
120
160
show negativewaveform. In this patient, OPs were

not reduced.
1- 9 Stationary
Cone
Dysfunction
Disorders
43
people. These patients are similar to some

cases of acquired cone dystrophy in having
STATIONARYCONE DYSFUNCTIONDISORDERS
1-9-1 Congenital Achromatopsia
Congenital achromats are classified as typical (rod) and atypical (cone) monochromats.
Such patients have a nonprogressive visual
disorder and therefore would best be described as having a cone dysfunction
rather
than a dystrophy, which implies a progressive deterioration
of function. The term
monochromat reflects these patients' perception of all colors as shades of gray. The rod
photoaversion,
nystagmus, decreased visual
acuity, and poor color perception. Generally,
they have a normal fundus or only minimal,
nonspecific pigment changes within the
macula. The photopic electrical activity of
the ERG is generally nondetectable,
while
scotopic responses remain either normal or
minimally
subnormal (Figure 1-26).200,201
The incomplete rod monochromat
is
similar in characteristics to the complete
form, except for less extensive involvement. Photoaversion and nystagmus are
-#
monochromat, who can show either complete or incomplete involvement,

is the
form most frequently seen clinically, al-
generally less apparent. Although visual

acuity is usually in the range of 20/60 to
20/80, it can be as good as 20/40. ERG pho-
though the prevalence
topic responses are markedly
is only 3 in 100,000
reduced in
Figure 1.26 ERG recordingfrom patient

with congenital achromatopsia. Cone responses are nondetectable, while rod amplitudes are at lower range
of normal.
44
amplitude, although, in certain instances,

less extensively than in the complete
monochromat. The incomplete and complete forms probably represent variations
of one genotype because, in some families,
the members may alternatively
manifest
the complete or the incomplete form. Missense mutations have been identified
in
the a-subunit of the cone photoreceptor
cGMP-gated cation channel in patients afflicted with congenital rod monochromacy.zoz
Pokorny et alzo3 identified
at least four
forms of achromatopsia with autosomal recessive inheritance based on color-matching
experiments:
1. In type I (typical rod monochromats),
there is no evidence of cone function.
2. In type II incomplete achromatopsia,
color matches are mediated by rods and
middle-wavelength
(M) cones.
with typical rod monochromism.24 On

ERG testing, female carriers for this trait
can show abnormal cone function, which
includes reduced amplitude, prolonged
30-Hz flicker implicit time, and reduced
ERG flicker-fusion
frequency.2os-2o8 The
condition is inherited as an X-Iinked recessive trait. Male patients with this disorder
show alterations in the red- and green-cone
visual-pigment
gene cluster.209-211 In isolated instances, some blue-cone monochromats may show an atrophic-appearing
macular lesion.209,211
The atypical, or cone, monochromat is
characterized by normal visual acuity and
the absence of nystagmus and photoaversion. In this rare condition (affecting approximately
1 in 100,000 to 1 in 10,000,000
people), cone outer-segment
function is
probably normal. There appears to be a
transmission defect involving cones that
4. In type IV, color matches are mediated
leads to a defect in chromatic perception.

These patients maintain a normal quantity
of photoreceptors.
Generally, patients have
a normal ERG to a white-Iight
stimulus, attesting to the notion of a postreceptoral,
or
by rods, L-cones,
transmission,
3. In type III incomplete achromatopsia,

color matches result from contributions
from rods, long-wavelength
(L) cones, and
M -cones.
and short-wavelength
defect.212
(8) cones.
1-9-2 Congenital Red-Green Color Deficiency
A unique group of patients with incomplete achromatopsia are those in whom the
blue cones are minimally involved or not
involved. These blue-cone monochromats
have abnormal ERG amplitude responses
similar to those of complete achromats, because blue cones contribute only negligibly
to the standard full-field
ERG. However,
with specialized spectral ERG techniques,
it is possible to differentiate
between patients with this X-linked disorder and those
Congenital red-green color defects can affect either the long-wavelength

cones
(protan defect) or the middle-wavelength
cones (deutan defect). The protan defect
can be either partial (protanomaly)
or complete (protanopia). A similar classification
system exists for the deutan defect, which
can be either partial (deuteranomaly)
or
complete (deuteranopia).
Collectively,
these disorders affect about 8% of the
United States male population of European
ancestry. The responses to white-Iight,
fullfield flash stimuli are normal under both
1-10 Stationary Night-Blinding
photopic and scotopic levels of adaptation.

Of note, the initial portion of the darkadapted cone-mediated
response to orangered light (x-wave) is generally absent or
of minimal amplitude in protanopes and
protanomals, but is present in deuteranopes
and deuteranomals.
Disorders
45
traced through 11 generations. Traditionally, findings of the fundus examination in

all groups are normal, although the optic
disc has been described
as tilted,
pale, or
dysplastic.214
The scotopic ERG responses are predictably those most severely affected. However, photopic (cone) responses, although
reported as normal in amplitude in some
STATIONARYNIGHT-BliNDING DISORDERS
1-10-1 Congenital Stationary Night Blindness
patients, not infrequently

show a selective
reduction in the b-wave amplitude.215-217
Although some investigators216 have found
normal photopic b-wave implicit times,
others215,217
Autosomal recessive, X-Iinked recessive,

and autosomal dominant forms of congenital stationary night blindness (CSNB)
all occur. The autosomal recessive and
X-Iinked patients are generally myopic
(-3.5 to -14.5 diopters) and have a history
of poor night vision. The visual acuity of
patients with the X-Iinked form is between
20/40 and 20/200. Those patients with the
autosomal recessive form who have a decrease in visual acuity (to between 20/40
and 20/80) are usually also myopic. However, some of the patients reported with
both the X-Iinked and the autosomal recessive forms have normal visual acuity and
are not myopic. Furthermore,
in some instances, patients may not complain of night
blindness.213 In this circumstance, a definitive diagnosis can be made only by characteristic b-wave amplitude changes on fullfield ERG recordings. Patients with visual
loss frequently manifest nystagmus. Patients with the autosomal dominant form
are generally not myopic and tend to have
normal visual acuity. One subtype with a
dominant mode of inheritance is known as
the Nougaret type, named for Jean Nougaret,
the first affected member in a French genealogy with autosomal dominant CSNB
have
reported
patients
...
with
prolonged photopic b-wave implicit times.

In the X-linked and autosomal recessive
forms, a negative ERG pattern is observed,
with the scotopic a-wave larger in amplitude than the reduced scotopic b-wave
(Figure 1-27). Noble et al218also described
an electronegative
ERG waveform in a
family with autosomal dominant CSNB.
An important observation is the approximate equality of b-wave implicit times under
both photopic and scotopic conditions to a
similar-intensity
stimulus in many patients
with CSNB of either X-linked or autosomal
recessive inheritance. Normally, the scotopic b-wave implicit time is at least twice
as long as that of the photopic b-wave. Thus,
in this ERG pattern (Schubert-Bornschein
type), a negative ERG is found with an essentially normal scotopic a-wave noted,
along with a reduced b-wave that consists
of a predominantly
cone component, because, in these patients, the rods contribute
minimally
if at all to the b1-wave amplitude
or the formation of a b2 component. However, in patients with high degrees of myopia, a reduction in a-wave amplitude compared to normal individuals may be apparent,
46
Figure 1.27 Selective

b-wave reduction to
high-Iuminance
stimu-
Ius as characteristically
seen in myopic patient
with CSNB. This negative ERG pattern
is
found in CSNB patients

who are referred to as
having Schubert-Bornschein type.
although not as extensive as the reduction

in b-wave amplitude.
In a second pattern (Riggs type) noted in
some cases with CSNB, the scotopic b-wave
exceeds the a-wave, but is still reduced in
amplitude. The scotopic a-wave amplitude
is most often observed as mildly subnormal.
Although the cone component appears normal, there is a defective development
of
the rod contribution
to the scotopic b-wave.
The result is a reduction in bl amplitude
and a failure of normal bz formation. The
photopic and scotopic implicit times, unlike
those found with the Schubert-Bornschein
pattern, are more similar to the normal time
relationships anticipated under photopic
and scotopic conditions.
Patients with CSNB appear to have a

normal amount or density of rod visual pigment in situ and, in the Schubert-Bornschein
type, a normal a-wave. Further,
the rod
photopigment-regeneration
kinetics are entirely normal. In such cases, the photoreceptor cells are therefore intact and the primary defect does not reside within the
outer segments of these cells, but rather in
the transmission of their visually evoked
signal.
Carr et al219studied a patient with autosomal recessive CSNB and another with autosomal dominant CSNB. By fundus reflectome try studies, both patients manifested a
normal concentration
and regeneration of
rhodopsin. In the autosomal recessive form,
the scotopic a-wave was normal while the
scotopic b-wave was reduced in amplitude;
1-10 Stationary Night- Blinding Disorders
a normal EGG light rise was seen. In the

autosomal dominant form, the EGG light
rise was abnormal and all ERG responses,
both photopic and scotopic a- and b-waves,
were suppressed. These authors concluded
that the disorder probably reflected a defect in transmission of the ERG wave potentials. For the autosomal dominant form,
this defect possibly resides at the level of
the photoreceptor
inner or outer segment.
Alternatively,
a defect could reside in a
breakdown of the mechanism whereby
quantal absorption is converted to an electrochemical receptor potential, quite possi,bly from a defect in one of the light-activated enzymatic stages in the transduction
process. The recessive variety, the authors
speculated, possibly has a defect in, or just
distal to, the bipolar-celllayer.
In the N ougaret form of autosomal dominant CSNB with a normal-appearing
retina,
a defect has, in fact, been demonstrated in
the a-subunit of rod transducin (Gly38Asp).22o
ERG testing demonstrates that rod function can be present, although subnormal,
and that there is a slight impairment
of
cone function.221,222 An early description of
affected members from this pedigree noted
complete loss of rod function and normal
cone function.223 The ERG findings in
these patients can be simulated by partly
light-adapting
the normal retina, a finding
in accord with the notion that the mutant
rod transducin protein functions in a constitutively active fashion in the dark that would
desensitize rod photoreceptor
cells.222 It is
not surprising, based on the defect in the
phototransduction
enzymatic pathway, that
both a- and b-wave ERG amplitudes are
reduced under scotopic conditions.
Other subtypes of patients with CSNB
and a normal-appearing
fundus have been
47
identified
in whom ERG a- and b-wave amplitudes are both reduced (Figure 1-28).224-227
Two different mutations in the rhodopsin
gene, Ala292Glu224 and Thr94Ile,227 and a
mutation in the cGMP phosphodiesterase
13-subunit gene225 have been identified
in
some of these patients.
Miyake et al52 classified patients showing a Schubert-Bornschein
ERG pattern
into complete and incomplete subtypes,
based on psychophysically
measured
thresholds and ERG amplitudes. In the
complete
thresholds
form, absolute psychophysical

are mainly
cone-mediated,
..
the
rod ERG responses to a dim short-wavelength (blue) flash are absent, and the cone
ERG amplitude is only moderately reduced. In the incomplete form, absolute
thresholds, although elevated above normal, are rod-mediated;
the rod ERG responses, although reduced in amplitude,
are still measurable to a dim short-wavelength flash, while the cone ERG is
markedly subnormal. Therefore, in the incomplete type, the rod system is less affected and the cone system more impaired
than in the complete form. In the incomplete type, the OPs are more frequently
recordable than in the complete type. Further, incomplete-type
patients show an exaggerated increase in 30-Hz flicker ERG
amplitude and a characteristic change of
waveform shape (separation phenomenon)
during the light adaptation following 30
min of dark adaptation.228 Many patients in
the complete group have high or moderate
myopic refractive errors, while those in the
incomplete group tend to have mild myopic
1-10 Stationary
or hyperopic
refractive
errors. The short-
wavelength-sensitive
(8) cone ERG to a
full-field stimulus was found to be nondetectable in 2 patients with the complete
form of C8NB.229
To date, no pedigree has convincingly
shown a complete and an incomplete type
in the same family. ERG recordings, in
addition to psychophysical
measurements,
are of obvious value in distinguishing
these
two distinct subtypes. Mutations in an
L-type calcium-channel
<XJ-subunit gene at
Xpll.23
in patients
with the incomplete form of C8NB.230,23J
This finding provides further evidence of
genetic heterogeneity
with the complete
form, which was mapped to Xpll.4.232
Miyake and Kawase233 reported a selective reduction in the amplitude of the OPs
in female carriers ofX-Iinked
recessive
C8NB. This observation should be of practical value for the determination
of the carrier state of females at 50% risk in families
with this disorder.
An acquired type of night blindness,
with ERG recordings similar to those seen
in patients with C8NB, has been reported
in patients with cutaneous malignant melanoma.234,235Characteristics of this disorder,
referred to as the melonomo-ossocioted retinopothy (MAR) syndrome, include a rapid
onset of night blindness, accompanied by a
constant sensation of shimmering or pulsating light. A selective reduction in the amplitude of the b-wave in the dark-adapted
ERG is a distinctive finding in such patients.
Examination
of their retinas does not disclose any characteristic abnormalities.
In
1 patient, the use of vincristine was believed
Night-Blinding
to account for the findings,
Disorders
49
because, in the
perfused cat eye, this drug can cause a selective reduction in the ERG b-wave.236
However, in 3 human patients treated with
therapeutic doses of intravenous vincristine, no changes in cone-mediated
ERG
responses were observed.237 Nevertheless,
in other reports, chemotherapeutic
agents
were not found to be the cause of acquired
night blindness in cutaneous melanoma patients.235,238In one report,239 the sera from
2 MAR patients were found to produce
heavy immunostaining
of rod bipolar cells.~
An impairment
in signal transmission
that is specific for retinal on-pathways may
be a primary defect in patients with this acquired form of night blindness, as has been
reported in patients with CSNB who manifest a selective reduction in ERG b-wave
amplitudes.24o Accordingly, a general defect
in synaptic transmission between photoreceptor cells and depolarizing bipolar cells
could account for the abnormal rod and
cone ERG responses in patients with these
night-blinding
disorders.238
A defect in signal transmission
from pho-
toreceptors to on-type bipolar cells was also

believed to account for the symptom of acquired unilateral night blindness associated
with a negative ERG waveform in a patient
reported by Fishman et al.241Their patient
showed no evidence of a systemic malignancy or cutaneous melanoma and had a
normal-appearing
retina. Another 3 patients
with acquired unilateral night blindness,
normal retina appearance, and negative
ERG waveform have also been reported.242,243r
50
1-10-2 Oguchi Disease

Patients with Oguchi disease have an early
history of defective night vision. The majority of the relatively rare cases of this autosomal recessively inherited disease are
from japan, although, even as early as 1963,
Franceschetti
et al244reported 32 European
cases. The vision and peripheral fields in
these patients are generally normal or only
slightly impaired in daylight; however, with
dim illumination,
they have a manifest defect in visual sensitivity. The photopic
ERG functions are generally normal or occasionally subnormal, while the scotopic aand b-waves have been reported as diminished in amplitude.24.1 Because the reduction in b-wave amplitude is more extensive
than in the a-wave (in fact, normal scotopic
a-wave amplitudes have been reported246),
a negative ERG pattern with high-Iuminance stimuli is observed.247 Miyake et
al245found that both the on- and the offresponses of the photopic ERG were normal in Oguchi disease, unlike patients with
the complete form of CSNB, who show a
reduced on-response. OPs have been reported variously as normal or reduced in
amplitude.245.248
The disease is characterized by a yellowish phosphorescent-Iike
discoloration, most
often in the peripheral retina. In most cases,
this fundus discoloration reverts to a normal
appearance after several hours of dark adaptation (Mizuo-Nakamura
phenomenon).
The kinetics of the process of dark adaptation do not coincide with the return to nor-
mal fundus coloration.246.249 Rhodopsin kinetics, including both concentration

and
regeneration as measured by fundus reflectometry, are normal.249 With prolonged periods of dark adaptation, most, but not all,
patients with Oguchi disease manifest an
improvement
in dark-adaptation
thresholds
and ERG amplitudes to normal or nearnormal values. Rod and cone b-wave implicit times are normal after appropriate periods of adaptation. However, using computer averaging techniques and a longwavelength stimulus, a delay in rod implicit time may be demonstrated.246
Mutations in the genes coding for arrestin (retinal S-antigen) and rhodopsin-kinase
in patients with this
disease.247.250,251
The site of the retinal disorder and the nature of the photosensitive
pigment responsible for the Mizuo-Nakamura phenomenon
are not yet known. It
seems reasonable to suggest that the normal process of dark adaptation is compromised in patients with this disorder, at least
in part, by abnormal function of the postreceptoral cellular elements responsible for
generating the ERG b-wave.249 Nevertheless, a reduced scotopic a-wave to a high-intensity stimulus also implicates rod photoreceptor-cell
function itself as abnormal
in Oguchi disease.245 This finding is consistent with the mutations in either arrestin
or rhodopsin-kinase
described in these
patients.
1-10-3 Fundus Albipunctatus
The autosomal recessive disorder fundus
albipunctatus
is characterized by an early
onset of nonprogressive poor night vision
and the presence of numerous discrete
dull-white
spots scattered throughout the
fundus, with the exception of the fovea
1-10 Stationary
Night-Blinding
Disorders
51
Figure 1-29 Fundus albipunctatus, with multiple spots of unknown

material scattered primarily throughout deep
retina, with exception of
fovea.
(Figure 1-29). The optic disc and retinal

vessels are normal, and there is no evidence
of peripheral clumping of retinal pigment.
Both cone and rod adaptations follow a prolonged time course of variable severity,
ranging, for the rods, from approximately
45 min to several hours. The severity of
subjective night-vision
impairment,
as well
as the rate of recovery during dark-adaptation testing, can vary between patients and
even between members of the same famiIy, but ultimately
reach normal thresholds.
Correspondingly,
ERG and EGG responses
eventually reach normal values, but only
after a prolonged period of dark adaptation
prior to testing (Figure 1-30). The time
course for ERG recovery follows that ofvisual-pigment
regeneration and psychophysical dark-adaptation
thresholds.252,253
This disorder results from a defect at
some stage in the cycle of both rod and
cone visual-pigment
regeneration, which
has been demonstrated to be prolonged.252.254

However, patients with fundus albipunctatus have normal serum vitamin A levels and
do not show signs of systemic vitamin A deficiency.255 Further, the retinal findings and
visual symptoms do not respond to treatment with vitamin A and zinc.255
Mutations in a gene encoding ll-cis retinol dehydrogenase have been identified
in
patients with fundus albipunctatus.256 This
microsomal enzyme is abundant in the RPE,
where it serves as a catalyst for the oxidative conversion of ll-cis retinol to ll-cis
retinal. Reduced activity of this enzyme
would appear to account for the delay in regeneration of cone and rod visual pigments
observed in this disease.
54
HEREDITARYMACULAR DYSTROPHIES
1.11.1 Stargardt Macular Dystrophy

Stargardt macular dystrophy, or fundus flavimaculatus, was first described in 1909 by
Karl Stargardt, a German ophthalmologist.
Patients with this predominantly
autosomal
recessive disorder characteristically
present,
within the first 10 to 20 years of life, with a
decrease in central vision and bilateral atrophic-appearing
foveal lesions. These lesions may have a beaten-metal appearance
and are associated with a ring, or more extensive garland, of yellow-white
fundus
flecks at the posterior pole and, to a lesser
extent, in the midperipheral
retina (Figure
1-32). The fleck-Iike lesions may be round,
linear, or pisciform (fishtail-Iike).
Impairment in central vision is progressive, with
Figure 1-32 Stargardt

macular dystrophy.
Note atrophic-appearing macular lesion, with
numerous fleck-like deposits throughout retina.
ultimate visual acuity generally reaching

20/200 to 20/400. Initially, only subtle pigmentary mottling within the fovea may be
apparent ophthalmoscopically.
Even with
only these minimal ophthalmoscopic changes,
visual acuity may decrease to levels of 20/30
to 20/50.260,261
Initial investigators preferred the term
Stargardts macular dystrophy when referring
to patients with an atrophic-appearing
foveal lesion and a limited number of fundus flecks and used the termfundusflavimaculatus (first used in 1963 by Franceschetti262) for patients with extensive
fundus flecks with or without an atrophic
foveal lesion (Figure 1-33). Subsequent
studies support the conclusion that this
division into distinct genetic disorders is
likely untenable.
One study263 classified
patients
with fun-
dus fiavimaculatus,
or Stargardt macular
dystrophy, into four levels of severity based
1-11
Hereditary
Macular
55
Dystrophies
Figure 1-33 Fundus

flavimaculatus,
Stargardt
or
macular
dystrophy, with numerous yellow-white

fleck-like deposits
throughout retina,
without atrophicappearing macular
lesion.
on the extent
of fundus changes and elec-
trophysiologic
findings. In general, reduced
ERG cone and rod a- and b-wave amplitudes in patients with Stargardt macular
dystrophy can be predicted by the extent
of clinically apparent fundus pigmentary
changes. Thus, patients with a localized
atrophic-appearing
foveal lesion with a
ring, or a garland, of more extensive fundus flecks show normal cone and rod ERG
a- and b-wave amplitudes. Once initially
present fundus flecks are no longer apparent and diffuse RPE atrophic changes occur,
these amplitudes become reduced.263.264
It is imperative, however, to allow at least
45 min of dark adaptation to appreciate
fully the optimal potential of rod ERG amplitudes, because patients with Stargardt
macular dystrophy can take longer than
normal individuals to recover maximally
dark-adapted
amplitudes
(Figure
1-34).
Occasionally, some patients with a lesion

clinically localized in the macula show a reduction in cone ERG a- and b-wave amplitudes.264 This finding could result either
from a variable expressivity in the severity
of the functional impairment
of cones265,266
or possibly from the presence of a distinct
genetic subtype of the disease.
A histopathologic
report by Eagle et al267
demonstrated
the presence of a lipofuscinlike material in all RPE cells in a patient
with fundus flavimaculatus.
The fundus
flecks corresponded to RPE cells that had
undergone hypertrophy
as a consequence
of particularly extensive accumulation
of
the lipofuscin-Iike
material. The accumula-
56
patient with
Stargardt
macular dys-
trophy. Note that scotopic amplitude
re-
sponses may not reach

normal values unless
ample time is allotted
for dark adaptation.
This period can exceed
30 min, which is usually
sufficient in normal
individuals.
tion of this material in RPE cells and consequent effect on choroidal fluorescence may
at least partly explain the dark choroid reported by Fish et al268in patients with Stargardt macular dystrophy.
A gene associated with Stargardt disease,269 or fundus flavimaculatus,27o has
been mapped to the short arm of chromosome 1. This gene codes for a photoreceptor-specific ATP-binding
transporter protein (ABCR),271 which has been localized to
the disc membrane of retinal rod and cone
outer segments.272.273 Patients with an autosomal dominant form of Stargardt macular
dystrophy have been reported with genetic
linkage
to chromosomes
6q274 and 13q34.275
1-11-2 Best Macular Dystrophy

Best vitelliform
macular dystrophy, an autosomal dominantly
inherited macular disorder first described by Friedrich Best in
1905, presents with a pleomorphic
ophthalmoscopic picture. Typical initial macular lesions, which are most frequently
diagnosed
between the ages of 5 and 15 years, demonstrate a yellow "egg-yolk-like
sunny-sideup appearance" (Figure 1-35). The presence of this macular lesion is still consistent
with visual acuity most frequently
20/25 or
better. Although only a single isolated
foveal lesion is usually present, multiple
nonfoveal foci of yellow egg-yolk-like
lesions can be seen. A vitelliform
lesion can
develop in a previously normal-appearing
macula.276
1-11
Progressive impairment
of visual acuity
tends to parallel a subsequent course in
which the yellow material appears to rupture or become fragmented into a "scrambled-egg appearance." Eventually, the
scrambled-egg appearance is replaced by a
fibrotic (gliotic) hypertrophic-appearing
scar.277,278
In some patients, the yellow material may resorb and subsequently
be resecreted. Infrequently,
in other patients, subretinal neovascularization
may develop.279,28o
Variability in phenotypic expression of the
macular lesion can occur between different
families and within the same family.281,282
Most patients are visually asymptomatic
or
show only slight-to-moderate
visual loss
until between 40 and So years of age.277,278
Peripheral vision remains normal. ERG
cone and rod a- and b-wave amplitudes are
typically normal in patients with Best vitelliform macular dystrophy. However, Nilsson
and Skoo g,283as well as Rover et al , 284reported either absent or small ERG c-wave
Hereditary
Macular
D.fstrophies
57
amplitudes
in patients with this disorder.
The definitive
diagnostic test in this disease is the EOG, which is markedly abnormal in affected patients. Oeutman285 noted
abnormal EOG light-peak to dark-trough
ratios even when lesions were not ophthalmoscopically apparent. Weingeist et al286
observed an abnormal accumulation
of a
lipofuscin-like
material in all RPE cells of a
patient with Best macular dystrophy, a finding also noted by O'Gorman et al287in another patient.
An ERG will not be of any diagnostic
value in a patient with a characteristic egg~
yolk-appearing
lesion. On occasion, a patient with Best macular dystrophy can have
bilateral atrophic-appearing
foveal lesions
that may show some phenotypic
similarities
to other hereditary macular lesions, such as
those seen in Stargardt macular dystrophy
or cone dystrophy. However, the absence of
fundus flecks and a dark choroid, seen in
Stargardt macular dystrophy, as well as a
Figure 1-35 Characteristic

egg-yolk-like sunny-sideup appearance of macular lesion seen in patient
with Best vitelliform
macular dystrophy.
58
markedly abnormal EOG, helps distinguish

patients with Best macular dystrophy from
those with Stargardt macular dystrophy.
The normal ERG and abnormal EGG in
patients with Best macular dystrophy differentiate these patients with an atrophic
foveal lesion from those with cone dystrophy, who, with few exceptions, manifest
abnormal cone ERG a- and b-wave amplitudes, but a normal EGG response.261,266
Mutations in a novel retina-specific
gene
on the long arm of chromosome 11 ( 11 q 13 )
in patients affected
with Best macular dystrophy.288,289 This
gene encodes a 585 amino acid protein
known as bestrophin, which is selectively
expressed in the RPE of the retina.289
1-11-3 Pattern
Dystrophies
The term pattern dystrophies encompasses

a small group of disorders with a distinctive pattern of pigmentary changes in the
Figure 1-36 Pigmented,

butterfly-shaped foveal
lesion in patient with
butterfly dystrophy.
Coul1esyAugust F Deutman,
MD.
retina,290-292 The phenotypic
expression
of
pigmentary changes includes either retinal

pigment clumping or yellowish lesions,
which most frequently have a reticular or
net-Iike configuration,
The designation
butteifly dystrophy was originally used to
describe lesions that showed a radial or
petaloid pattern of distribution
in the macula (Figure 1-36),293 In some patients with
an early stage of pattern dystrophy, only a
nonspecific pigment granularity or mottling
of pigment in the macula may be apparent,291,294,295
These disorders, which can be
transmitted
as either autosomal recessive
or, more frequently, autosomal dominant
traits, include
the descriptive
designations
butterfly dystrophy,293 Sjogren s reticular dystrophy,296 macroreticular dystrophy of the RPE,297

and fundus pulverulentus,298 At least some
patients with a phenotype similar to those
described as having butterfly dystrophy
were found to have mutations in the peripherin/RDS
gene,299
1-11
Hereditary
Macular
Dystrophies
59
Clinical variation of expression regarding the extent of the reticular or net-Iike

pigmentary changes can occur within the
same family.29 One variant of expression
includes a phenotype with similarity to the
egg-yolk-like
lesion seen in patients with
as having new entities, such as central areolar pigment epithelial dystrophy or autosomal
dominant central pigment epithelial and choroi-
Best dystrophy.3o
Initially, visual acuity is either normal or
mildly reduced. The characteristic course
to staphylomatous
or colobomatous-like
(grade 3) in appearance. The appearance
of grade 2 lesions consists of confluent macular drusen in association with RPE atrophy (Figure 1-37).310-318More peripheral
retinal drusen are often encountered in
each of the clinical grades of severity. Generally, the clinical course of the disease is
of visual acuity change is slow and often

less severe than in other macular dystrophies. Over decades, however, central vision impairment
can become clinically significant, particularly when patients develop
extensive atrophy of the RPE and choriocapillaris.31,3o2 Photophobia or metamorphopsia has occasionally been described
as an initial complaint.293 Macular pattern
dystrophy has been observed to occur in association with maternally inherited diabetes
mellitus and deafness, which in turn cosegregate with a mutation in mitochondrial
DNA.303 ERG recordings characteristically
show normal cone and rod amplitudes and
implicit times.290-293.295EoG light-peak to
dark-trough ratios are most frequently either normal or only modestly subnormal.292
dal degeneration.308,309
The macular changes encountered
clinically range from fine drusen (grade 1)
stable, except when choroidal
neovascular
membranes develop. ERG amplitudes

are normal, and EOG light-peak to darktrough ratios have been reported most frequently
as normal or, infrequently,
slightly
reduced.304,306-308.313
This disease has been mapped
to chro-
mosome 6q14-q16.2.314,315 It is present

across the United States, in Central America, and in Europe (including Germany
and France),304,316-318as well as in a British
family.36
1-11-5 Progressive Bifocal Chorioretinal Atrophy
1-11-4 North Carolina Macular Dystrophy

North Carolina macular dystrophy is a dominantly inherited macular disorder that was
initially described in the descendants of
three Irish brothers who settled in the mountains of North Carolina in the 1830s.304-306
The initial report referred to the disease as
dominant macular degeneration and aminoaciduria.34 A subsequent report of this family by Frank et al37 demonstrated that the
aminoaciduria was not genetically related to
the macular degeneration and chose the
term dominant progressive foveal dystrophy to
describe the disorder. Subsequently, other
authors encountered regional branches of
this family and unwittingly
reported them
Progressive bifocal chorioretinal

atrophy is a
rare, autosomal dominantly
transmitted
disease initially described by Douglas et al319
in 33 members of a kinship with 91 individuals from five generations. Patients present
as eatly as 3 weeks of age with an atrophic
lesion both within and temporal to the macula that involves both the RPE and choroidal vessels. The lesion is present essentially
from birth. A second atrophic-appearing
lesion nasal to the optic disc develops subsequently. Additional
ocular findings include
nystagmus, decreased vision, and myopia.
60
Figure 1-37 Macular

grade 2 North Carolina
macular dystrophy.
ERG recordings show subnormal 30-Hz

cone flicker and single-flash scotopic responses.319 The disease has been genetically linked to chromosome 6q.320
1.11.6 Cone Dystrophies
Cone dystrophies represent a heterogeneous group of retinal disorders that can be
inherited as an autosomal dominant,321-323
autosomal recessive,324 or X-Iinked recessive325.326trait. A number of different chromosomallocations
and specific gene
tions have been identified
in various
ilies.327 Patients initially complain of
creased vision and, not infrequently,
mutafamdean im-
pairment of color vision usually within the

first two decades of life. However, there can
be considerable variability in the onset of
visual symptoms, fundus findings, and electrophysiologic
changes.328.329PhQtoaversion
and nystagmus may also occur during the
course of the disease.
On fundus examination,
an atrophic-
appearing lesion in the macula is the most

frequent finding. A bull's-eye configuration
of the atrophic lesion is often encountered
(Figure 1-38). However, in some patients,
the macula may show only minimal changes
or nonspecific mottling of the RPE (Figure
1-39).324 Temporal disc pallor may also be
seen, but only rarely are yellow-white
fiecklike lesions found. A tapetal-like
retinal
sheen has been described in both X-linked
recessive326 and autosomal
dominant330
genetic subtypes. Peripheral pigmentary

changes and a diffusely dark choroid are not
usual features in cone dystrophy. However,
central or pericentral scotomas are found.
Reduction in ERG cone function, as
determined
by single-flash photopic and
30-Hz flicker stimuli, is typical in these patients (Figures 1-40 and 1-41). In most of
them, rod responses are either normal or
only minimally
subnormal, at least in the
early stages. With time, rod as well as cone
responses can show further impairment.331
1-11
Hereditary
Macular
Dystrophies
61
Figure 1.38 Characteristic

bulls-eye-appearing
macular lesion seen in
patient with cone dystrophy.
Figure 1-39 Nonspecific

and small atrophicappearing macular
cone dystrophy.
1-11
Hereditary
Macular
63
Dystrophies
Cone dystrophy
Normal
patients
Patient3
Patient 2
Patient 1
30-Hz
c
o
.00
.>
'0
:---
white
flicker
8f-
Photopic
b
b
I~
a
40
80
120
40
80
120
80
0
40
Time (ms)
120
40
80
120
Normal
b
~
o
.c;;
.>
:0
-->
='0
0
~
0)
-0
E
-0.
E
<.:
a
a
Scotopic
white
flash
a
a
40
80
120
160
40
80
120
160
40
80
120
160
40
80
120
160
Time (ms)
Figure 1-41 ERG (A) photopic and (B) scotopic re-
Note intrafamilial
sponses in 3 patients from family
amplitudes, which may occur in this disordet:
with cone dystroph)
variability,
pat1icularly
in cone
64
At this later stage, the ERG findings can

appear similar to those seen in some patients with cone-rod dystrophy. In isolated
instances, patients have been reported in
whom peripheral cone function was apparently more impaired than central cone
function.331-333 However, other patients
have a primarily central cone dystrophy
because their full-field
ERG cone function
is normal.334
Kellner and Foerster335 described a negative ERG waveform under both light- and
dark-adapted testing conditions in patients
with cone dystrophy. This finding implicates a functional disturbance in the proximal retinal layer either in the cone pathway
or in Muller cells in at least some patients
categorized with cone dystrophy.
A subgroup of patients with cone dystrophy show a supernormal rod ERG b-wave
response to higher-intensity
stimuli and
often complain of nyctalopia.336-341 Such patients show smaller-than-normal
rod amplitildes and substantially
delayed b-wave im-
Figure 1-42 ERG recordin~

from patient with cone
dystrophy and supernormal scotopic b-wave response to higher-intensity
stimuli.
plicit times to weaker-intensity

flashes.
Cone responses to both single-flash and
flicker stimuli are reduced in amplitude,
with delays in implicit times (Figure 1-42).
This unusual pattern of response has been
attributed by some investigators to an abnormality in photoreceptor
cGMP activity,336.338while others attribute the findings
to a disease site proximal to the photoreceptors involving a delay in the activation
of the inner nuclear celllayer.34o
1-11-7 Sheen Retinal Dystrophies
Included in this arbitrary classification
termed sheen retinol dystrophies are the two
autosomal dominantly
transmitted
disorders: fenestrated sheen macular dystrophy
and familial internal limiting membrane
dystrophy. Patients with fenestrated sheen
macular dystrophy initially manifest a yellowish refractile sheen with tiny red fenestrations within the macula.342-346 Occasionally, only the sheen-Iike appearance, which
is located beneath the retinal vessels but
Cone dystrophy patient
1-12
above the RPE, is present, without the red

fenestrations. Abnormal granularity of the
RPE in the macula, as well as in the peripheral retina, can be encountered.346 Visual
acuity is either normal or only slightly reduced,342-346 ERG amplitudes are initially
normal,343 and EOG light-peak to darktrough ratios are generally normal.342
Over time, the fenestrated sheen becomes less apparent and can be replaced by
an annular hypopigmentation
of the RPE
that tends to spare the foveolar region, giving the appearance of a partial or complete
bull's-eye maculopathy.342,343 ERG recordings can show notable reductions in both
cone and rod amplitudes.346 Visual acuity
can show a slowly progressive reduction.343
Polk et al347reported the retinal findings
in a single family with a likely autosomal
dominant trait that was characterized by a
bilateral glistening of the inner retinal surface throughout the posterior pole and was
first diagnosed in middle age. Visual loss
was observed in those patients who developed superficial polycystic retinal edema
and retinal folds. Histopathologic
findings
disclosed an abnormal internal limiting
membrane, with schisis cavities in the inner
retina. A primary defect in Muller cells was
postulated. ERG testing was distinctive in
showing a selective reduction in the b-wave
amplitude. The termfami!ia!
interna!!imiting membrane dystrophy was used to describe
this disorder.
CHORIORETINALDYSTROPHIES
1-12-1 Choroidal
(choriocapillaris)
in the following
forms:
atrophy
Dystrophies
65
areolar
2. Central
3. Peripapillary
4. Diffuse
All can be inherited
as either autosomal
dominant or autosomal recessive traits. The

latter three categories may represent a continuum of the same disease and not separate genetic diseases, because their expression may be interrelated
in some families.
Most frequently, after approximately
age 40
to So years, these patients show a decrease
in visual acuity and, in the diffuse form,
poor night vision. The ERG is subnormal
in the peripapillary
and diffuse forms, becoming nondetectable
with more advanced
disease. Generally, the amplitude of the
ERG parallels the clinically apparent fundus involvement.
Occasionally, however,
cases of central and central-areolar choroidal atrophy show lower amplitudes than
might be anticipated from the extent of the
manifest fundus involvement.
In these instances, consideration should be given to
the diagnosis of cone dystrophy. In contrast
to patients with retinitis pigmentosa, the
implicit times are generally normal in patients with choroidal atrophy.
1-12-2 Gyrate Atrophy
Patients with gyrate atrophy, an autosomal
recessive chorioretinal
dystrophy, generally
present between 20 and 30 years of age
complaining
of poor night vision. Primarily,
the peripheral and midperipheral
fundus
has multiple, initially discrete, irregular, atrophic-appearing
patches of pigment epithelium, choriocapillaris,
choroidal vessels (Figure
Atrophy
Cases of choroidal
can occur
1. Central
Chorioretinu/
and, later, larger

1-43). The lesions
66
tend to become confluent as they extend

both centrally and peripherally. Patients are
frequently myopic, and nearly all develop
posterior subcapsular lens opacities. The
ERG cone and rod amplitudes are usually
either markedly reduced or non detectable.
In addition to night blindness, patients experience progressive impairment
of peripheral and central vision.
Biochemical abnormalities
include 10to 20-fold elevations in plasma ornithine,
hypolysinemia,
hyperornithinuria,
and either an absence or a marked reduction in
ornithine-8-aminotransferase
(OAT) activity in cultured skin fibroblasts and in lymphocytes.348 This results from a number of
different mutations occurring within the
ornithine-8-aminotransferase
gene on chromosome 10.349-351A number of different
point mutations and, less frequently, base
pair deletions have been observed. Pyridoxal phosphate (vitamin ~), administered
orally, can effect a 20% to 50% reduction in
plasma ornithine
levels in some patients,
Figure 1-43 Characteristic atrophic-appearing

areas of RPE and
choroid in patient with
gyrate atrophy of
choroid and retina.
while others are nonresponders

tial reduction of hyperornithinemia
occurs in less than 5% of patients
to 86.352Parlikely
with gy-
rate atrophy.353 Overall, the ERG responses

are better maintained in 86-responsive
patients.354,355
Gyrate atrophy
of the choroid
and retina
is one of the few progressive night-blinding

disorders in which a metabolic defect has
been implicated and for which therapeutic
trials with an arginine-restricted
diet have
been pursued.353,356-3,RAlthough KaiserKupfer et al353believed that this dietary
approach to reducing plasma ornithine was
effective in slowing the rate of disease progression in such patients, this was not observed to occur in patients with gyrate atrophy similarly treated by Vannas-Sulonen et
al357and 8erson et al.35R
1-12-3 Choroideremia
The X-linked recessive chorioretinal
dystrophy choroideremia
was first described in
1-12
1871 by Mauthner.359 Affected males complain of poor night vision within the first 10
to 20 years of life and show bilateral progressive degeneration of the choroid and
retina. Although extensive degenerative
changes of the RPE, as well as the choroid,
become apparent, unlike the pigmentary
changes of the retina seen in retinitis pigmentosa patients, there is little or no migration of bone-spicule-like
pigment into the
anterior
layers of the retina (Figure
1-44 ).
Initially, central vision is normal or

nearly so, but it eventually undergoes progressive deterioration.
Peripheral
vision is
usually moderately depressed even at an

early age, with severe restriction occurring
in the fifth and sixth decades of life. Even
in the early stages of the disease, the ERG
and EOG responses are abnormal.
ERG
Chorioretinol
Dystrophies
67
tients at an early age with a very early stage

of disease, normal ERG amplitudes may be
observed (Figure 1-45). In more advanced
stages, if ERG responses are still recordable, they tend to be primarily residual
cone function. A wide intrafamilial
and interfamilial variability in ERG amplitudes
with age has been observed.36 The fundus
of carrier females may show a "moth-eaten
appearance" of the RPE in the presence of
normal photoreceptor-cell
function as determined by ERG recordings.36o
Initial genetic linkage studies demon-4
strated that a DNA fragment polymorphism
(DXYS 1), located on the long arm of the
X chromosome at the locus Xq13-24, was
reasonably closely linked with the X-Iinked
gene for choroideremia.361,362 Subs~quentIy, the gene that causes choroideremia
was
recordings show a reduction of a- and bwave amplitudes under light- and dark-
isolated and localized to the long arm of

the X chromosome (Xq21).363,364 The cho-
adapted test conditions, with the prolongation of both rod and cone b-wave implicit
times. In isolated instances, in some pa-
roideremia gene encodes a subunit of

the enzyme Rab geranylgeranyl
transferase.365

atrophy of RPE and
choroideremia. Eventually, even more extensive atrophy of choroid
occurs in such patients.
68
Figure 1-45 ERG record-
ing in (A) photopic and
Choroideremia
patient
(B) scotopic conditions

from young patient with
early fundus changes of
choroideremia, demonstrating that normal
ERG amplitudes may
occasionally be observed
in very early stages of
disease.
c
o
.c;;
.>
'0
~
o
o
~
~
"0
.:e
-0.
E
<'=
40
80
120
0
Time
40
80
(ms)
-c:
o
.iii
.>
'0
~
o
o
~
.,
"0
E
0.
E
<
40
80
120
40
L60
Time (ms)
80
120
160
1-14
Hereditary
Vitreoretinal
69
Disorders
1-14-1 X-Iinked Juvenile Retinoschisis

ANGIOID STREAKS
Angioid streaks (Bruch 's membrane disorder) have been associated most frequently
with pseudoxanthoma
elasticum, Paget
disease, and sickle cell disease. The ERG
can be subnormal in more advanced cases.
An abnormal EOG has also been noted in
those cases with more advanced fundus
changes. Franf;ois and de Rouck366 reported
subnormal ERG responses in 14 (46%) of
patients with angioid streaks found in association with pseudoxanthoma
elasticum
Approximately
40% to 50% of patients with
X-Iinked juvenile retinoschisis have peripheral retinoschisis, while foveal microcystic
changes occur in virtually all cases (Figure
1-46). Less frequently, atrophic-appearing
macular lesions are found. The atrophicappearing changes become more apparent
in patients older than 30 or 40 years of age.367
The vitreous is either optically clear or contains fibrous bands. In a small percentage of
patients, retinal detachment or vitreous
hemorrhage can occur. Hyperopic refract~e
errors are most often encountered.367 A
(Groenblad-Strandberg
syndrome). In 8
cases, both cone and rod systems were affected; in 4, only the rods were affected;
and in 2, only the cones were affected.
golden tapetal-Iike fundus reflex, not unlike that observed in patients with Oguchi
disease, has also been described.368,369 Miyake and Terasaki369 noted this reflex to
These changes were found most often in

eyes with advanced disciform macular de-
disappear following vitrectomy with peeling of the posterior hyaloid. The role of an
excess in extracellular potassium, resulting
from a defect in Muller cells, as the cause
of this reflex has been considered.368,369
The ERG has a reduced photopic and
generation. Normal ERG records, however,

were obtained even in the presence of advanced macular degeneration.
scotopic b-wave amplitude, reflecting

tional impairment
in the inner retinal
HEREDITARYVITREORETINALDISORDERS
The four most frequently
tary vitreoretinal
1.
2.
3.
4.
disorders
described
heredi-
include
X-linked juvenile retinoschisis

Goldmann-Favre
syndrome
Wagner disease
Stickler syndrome
Other, less commonly encountered entities

are autosomal dominant neovascular inflammatory vitreoretinopathy
(ADNIV),
autosomal dominant vitreoretinochoroidopathy
(ADVIRC),
and familial exudative vitreoretinopathy
(FEVR). All of these entities
have both vitreous and retinal abnormalities.
funclayers
(Figure 1-47). The a-wave, although not infrequently subnormal in amplitude,37 is

considerably less impaired than the b-wave,
creating a negative ERG pattern. Kellner
et al367observed that the reduction in the
b-wave amplitude
was more apparent
in
dark-adapted compared to light-adapted

recordings. They also observed prolonged
b-wave implicit times in both light- and
dark-adapted test conditions. Of note, however, Sieving et al371observed a normal
ERG recording in a male patient with
70
Figure 1-46 F oveal microcystic changes as characteristically seen in patient

with X -linked juvenile
retinoschisis.
Figure 1-47 ERG record-
ingfrom patient with xlinked juvenile
retino-
schisis, showing selective

b-wave amplitude
reduc
tion under (A) darkadapted and (B) lightadapted conditions.
a
"in
">
:0
-->
='0
0
~
"'
-0
"E
"5.
E
-2:
1-14
documented X-Iinked juvenile retinoschisis. This finding indicates that, in isolated

instances, caution is warranted in relying
on ERG recordings for the diagnosis of
X-Iinked retinoschisis. Table 1-2 lists other
entities that can selectively or predominantly affect the ERG b-wave amplitude
while maintaining
a normal or less severely
abnormal a-wave amplitude. OPs are markedly reduced in amplitude or are not de-
H ereditary
Vitreoretina/
Disorders
fuse, nonspecific retinal pigmentary degeneration with areas of pigment atrophy and
clumping.373 At this later stage, marked impairment of both a- and b-wave ERG amplitudes, as well as EOG ratios, is found.373
Histopathologic
examinations suggest that
the likely primary lesion in X-Iinked retinoschisis occurs initially in the innermost portion of Miiller cells or at the border of the
retinal nerve fiber layer.35,374.375
A gene associated with X-Iinked juvenile retinoschisis (XLRS1) has been identified on the
X chromosome and localized to the region
Xp22.2.376 The severity of ERG abnormaflties was not observed to correlate with the
tectable in retinoschisis patients, while

EOG light-peak to dark-trough ratios are
normal in approximately
90%.367.370.372
In later stages, patients with X-Iinked
juvenile retinoschisis can manifest a dif-
TABLE
1-2
Entities With Selective or Predominant Decrease in b- Wave Amplitude,
Listed by General Category of Disorder
X-Iinkedjuvenile retinoschisis
Oregoneye disease
Oguchidisease
Myotonicdystrophy
Congenitalhereditarystationary night blindness
Cutaneousmelanoma(paraneoplasticsyndrome)
Fleckretina of Kandori
Unilateralacquirednight blindness
Bull's-eyemaculopathywith negativeERG
Retinopathyof prematurity
Conedystrophy(subtype)
Centralretinal artery occlusion
Retinitis pigmentosa(subset)
Central retinal vein occlusion
Autosomaldominantneovascularinflammatory
vitreoretinopathy(ADNIV)
Siderosis
Methanoltoxicity
Familialinternal limiting membranedystrophy
Quininetoxicity
EnhancedS-conesyndrome
Vincristinetoxicity
Dominantoptic atrophy(subtype)
Birdshotretinochoroidopathy
Cisplatintoxicity
~
Canthaxanthintoxicity
Bietti crystallinedystrophy
Glycinetoxicity
Behgetdisease
Vigabatrintoxicity
Neuronalceroid lipofuscinosis(Battendisease)
Ethyl-m-aminobenzoic
acid methanesulfonate
Creutzfeldt-Jakob
disease
(MS-222)toxicity
Duchenneand Beckermusculardystrophies
71
72
type of mutation, while amplitude changes

were found to differ between affected males
within the same family.377
Lewis et al378described 3 female patients
with a familial foveal retinoschisis showing
phenotypic similarity to the foveal lesions
seen in X-Iinked juvenile retinoschisis. The
normal or minimally subnormal ERGparticularly, the absence of a predominant
b-wave amplitude reduction-was
distinctly different from the negative-type
ERG
pattern seen in X-Iinked juvenile retinoschisis. However, Shimazaki and Matsuhashi379 reported a negative-type
ERG in a
mother and daughter, both of whom showed
foveal cystic changes and peripheral retinoschisis. These patients were believed to
have a dominantly
inherited disorder distinct from X-Iinked juvenile retinoschisis.
Peripheral retinoschisis without foveal schisis was noted in a father and daughter in
whom the ERG showed a small reduction
in both a- and b-wave amplitudes without
a predominant
reduction in the b-wave.38o
A reduction in the amplitude of OPs was
also observed. Noble et al381reported foveal
retinoschisis and poor night vision in 2 patients who showed a generalized
dystrophy by ERG recordings.
rod-cone
1-14-2 Goldmann-Favre Syndrome

The Goldmann-Favre
syndrome is an autosomal recessive disease in which patients
characteristically
complain of poor night vision and show atypical peripheral pigmentary degeneration, macular cystic degeneration, peripheral (often inferotemporal)
retinoschisis, posterior subcapsular lens
opacities, an optically clear vitreous with an
occasional vitreous band, and a markedly
abnormal (even nondetectable)
ERG.382
1-14-3 Wagner Disease

Wagner hereditary vitreoretinal
degeneration is a progressive autosomal dominant
disorder in which changes in the vitreous,
retina, and lens are observed. In different
families, either the chorioretinal
or the vitreous changes may be more prominent.
The vitreous changes include avascular
strands or wide condensed bands in an otherwise optically clear vitreous. Posterior
vitreous detachments are common. Some
observers describe a circumferentially
oriented vitreous membrane at the equator as
a characteristic finding. Retinal findings are
variable and include situs inversus of the
optic disc vessels, nasal ectopia of the macula, optic disc pallor, and atrophic-appearing changes of the RPE and choriocapillaris. Perivascular pigment clumping and
hypopigmentation
in the equatorial and
pre-equatorial
retina are described. These
perivascular pigmentary changes not infrequently show a radial orientation.
The family originally reported by Wagner was perhaps unique in that none of its
members was observed to have a retinal detachment. The myopia observecYill this
family was mild. Later reports of Wagner
degeneration described pedigl:ees with high
myopia in which retinal detachment was
common. Additional
subsequent reports described a high prevalence of retinal breaks.
Presenile cataracts and glaucoma have also
been reported with a higher frequency in
patients described as having Wagner disease. ERG recordings can show normal or
mildly to moderately subnormal photopic
and scotopic responses, varying with the extent of apparent fundus involvement.383,384
A nondetectable
ERG is observed only in
the presence of a total retinal detachment.
In those patients classified with Wagner
disease in whom chorioretinal
degenerative
1-14
Hereditary
Vitreoretina/
73
Disorders
changes predominate,
careful and aggressive assessment for systemic findings, such
as orofacial and skeletal changes, needs to
be pursued to rule out a diagnosis of Stickler syndrome. Retrospective
evaluation
of some pedigrees previously reported to
have Wagner disease has resulted in their
reclassification wheu nonocular features
present in the Stickler syndrome were subsequently observed in individual
family
members. Genetic linkage of Wagner disease to chromosome Sq13-14 demonstrates
that it is genetically distinct from Stickler
fied among the various hereditary vitreoretinal disorders. Patients affected with
ADNIV
are usually asymptomatic
in early
adulthood, but have vitreous cells and a selective reduction of the ERG b-wave amplitude that, in the earliest stages of disease, is more apparent in dark-adapted
eyes. Subsequently, patients can show
atrophic changes and pigment clumping
of the RPE, peripheral arteriolar closure,
neovascularization
of the peripheral retina
along the ora serrata ( or occasionally of the
optic disc), vitreous hemorrhage, tractional
syndrome.385
retinal
1-14-4 Stickler Syndrome

In 1965, Stickler et al386described an autosomal dominant syndrome that they termed
hereditary progressive arthro-ophtha!mopathy.
The syndrome is characterized by high myopia, premature vitreous syneresis, frequent
retinal detachments, premature degenerative changes of articular cartilage, and epiphyseal dysplasia. Common ocular findings
include peripheral retinal perivascular pigmentary clumping (often in a radial distribution), nuclear sclerotic cataracts, "wedgeor comma-shaped"
peripheral cortical cataracts, and ocular hypertension
or glaucoma.
Additional
systemic findings include abnormalities of the soft palate, midfacial flattening, sensorineural hearing loss, mitral-valve
prolapse, and the Robin sequence. Mutations in the procollagen II gene on chromosome 12 have been identified
in families
with Stickler
syndrome.387,388
1.14.5 Autosomal Dominant Neovascular

Inflammatory Vitreoretinopathy
Bennett et al38Ydescribed a disorder that
they termed autosomal dominant neovascular
inflammatory vitreoretinopathy (ADNIV).
This disorder is most conveniently
classi-
-#
detachment,
cystoid
macular
edema,
and neovascular glaucoma. In the advanced

stages of the disease, ERG cone and rod
amplitudes can be nondetectable.
This
disease has been subsequently
mapped to
chromosome 11q 13.39
1-14-6 Autosomal Dominant~
Vitreoretinochoroidopathy "
Another disorder that might be classified
among the hereditary vitreoretinal
disorders
has been termed autosomal dominant vitreoretinochoroidopathy (ADVIRC).391-396 patients characteristically
show a circumferential distribution
of peripheral chorioretinal
degenerative changes, which include both
hypopigmentation
and pigment clumping
between the vortex veins and the ora serrata. Generally mild retinal arteriolar narrowing may be seen at more advanced
stages. Retinal neovascularization
has also
been observed.391.392 There is a discrete
delineation between normal-appearing
fundus and more peripheral abnormal fundus
changes. Cystoid macular edema and overall diffuse retinal vascular incompetence
may be found, as can presenile cataracts. A
vitreous traction maculopathy and congeni-
74
Not surprisingly, altered RPE cells were

observed to surround retinal blood vessels
and line the internal limiting membrane.
An extensive preretinal membrane was also
tal nystagmus were found associated with

the disease in one family.396 The vitreous is
typically liquefied, and fibrillar condensation is often apparent. The pigmentary degenerative changes in the fundus are char-
noted.394
acteristically very slowly progressive.

Of interest, in spite of the extensive peripheral pigmentary changes, ERG amplitudes may be normal or only minimally
1-14-7 Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy
(FEVR) was initially described by Criswick
and Schepens.397 Patients with this disorder
subnormal in younger patients and only

mildly to moderately subnormal in older
patients (Figure 1-48).391-393The b-wave
photopic and scotopic implicit times are
typically normal. When ERG amplitudes
are found to be reduced, rod function can
be more impaired than cone function.391.393,394
EOG recordings show a reduction in the
Arden light-peak to dark-trough ratio in
such patients.393.396
Histopathologic
findings in an 88-yearold patient showed focal areas of atrophy of
the RPE and multi focal loss of retinal photoreceptor
cells in the equatorial
region.
Figure 1-48 ERG recordings from 3 members of family
show bilateral abnormalities

of the vitreous
and retina that may closely resemble those
occurring in retinopathy of prematurity,
although FEVR is found in patients who are
full-term and have normal birth weight,
with no history of exposure to supplymental oxygen after birth.
FEVR typically presents in the first decade of life, although neonatal presentation
may be rarely encountered.398,399 Both autosomal dominant and X-Iinked forms have
been observed.398,4oo The autosomal domi-
with ADVIRC
1-15
I nflammatory
75
Conditions
nant form has been linked to chromosome

llq 13-q23.401 In the earlier stages of FEVR,
patients are usually asymptomatic.
Regions
of white, with and without pressure, may be
observed in the peripheral retina in association with vitreous membranes and vitreoretinal traction. An avascular zone in the
peripheral retina, caused by an abrupt termination of peripheral retinal vessels, as
well as both yellow
deposits and pigment
clumping, has been described.

For some affected individuals,
the only
clinically discernible abnormality is the termination of peripheral retinal vessels in the
temporal equatorial region, a feature that
might not be detectable without the use
of fluorescein angiography. In a more advanced stage, the fundus changes resemble
those seen in the cicatricial phase of retinopathy of prematurity, with neovascularization and the development
of a characteristic fibrovascular mass predominantly
in
the temporal retinal periphery. This fibrovascular lesion may lead to traction, resulting in a dragged optic disc and ectopic displacement of the macula. As the disease
progresses, significant loss of vision can
occur from a tractional
and, less common-
ly, a rhegmatogenous
retinal detachment.
Rubeosis iridis, neovascular glaucoma, secondary cataract, and vitreous
hemorrhage
have also been described.

ERG recordings have been reported
as
nal detachment develops and progresses.

EGG ratios are normal in the absence of a
retina.44
The degree to which various inflammatory

conditions of the choroid and retina affect
the ERG most often depends directl~n
the extent of apparent fundus abnormality.
Thus, patients with minimal-to-moderate
fundus involvement
from such conditions
as syphilis or chorioretinitis
of unknown
cause have either normal or generally not
more than moderately subnormal ERG amplitudes. Both a- and b-waves are affected;and implicit times are normal.4s However,
Cantrill et a146noted prolonged b-wave implicit times, moSt apparent under photopic
conditions and with the use of a 30- Hz
flicker
stimulus,
in certain patients
with
chronic pars planitis. Of 13 patients tested,

12 showed absent or reduced scotopic OPs,
9 complained of poor night vision, and 6
had retinal pigmentary changes. Patients
with traditionally
local forms of inflammatory disease of the fundus, including toxoplasmosis and histoplasmosis, manifest normal ERG amplitude and implicit-time
responses. Patients with rubella retinopathy
also show an ERG response within a normal
range, because the disease appears to involve the melanin granules in the RPE
layer of the retina (Figure
showing normal amplitudes under photopic

and scotopic conditions, although diminished GPs may be observed.40z.43 Intuitively, ERG amplitudes would be markedly reduced or even nondetectable
as reti-
detached
INFLAMMATORY CONDITIONS
1-49). However,
76
Figure 1-49 Patient with

rubella retinopathy,
which shows salt-andpepper-Iike pigmentary
changes of retina.
when interocular asymmetric pigmentary

retinal changes of a patient are encountered, the eye with more apparent retinal
changes may be found to show smaller
ERG amplitudes than the less affected eye
tent of clinically obvious disease. Two such

examples are birdshot retinochoroidopathy
and the multiple evanescent white-dot syndrome (MEWDS).
(Figure 1-50).
The less ~xtensive ERG abnormalities,
generally found in inflammatory
disorders
of the choroid and retina, such as syphilis, that lead to degenerative pigmentary
changes can be useful in evaluating these
conditions, which, on occasion, mimic the
fundus appearance of patients with retinitis
pigmentosa. Nevertheless,
in some presumed inflammatory
disorders, functional
impairment
of the retina is more apparent
in reductions of ERG amplitudes than
1-15-1 Birdshot Retinochoroidopathy
might have been anticipated
from the ex-
Birdshot retinochoroidopathy
was initially
described in 1980 and termed such because
of the presence of unusual bilateral multiple discrete cream-colored lesions, without
hyperpigmentation,
at the level of the
choroid and RPE and scattered diffusely
throughout the fundus (Figure 1-51).47
Vitritis, retinal vasculitis, optic disc swelling
or atrophy, and cystoid macular edema are
also encountered. Subretinal neovascularization can occur. A higher prevalence in
middle-aged women has been observed.4O7,4O8
Other descriptive terms, such as vitiliginous
chorioretinitis4O9 and salmon-patch choroidopathy,41Ohave been used. In addition to vitre-
1-15
I nflammatory
Conditions
77
Figure 1.50 ERG recordingfrom

metric fundus pigmentary
patient with asym-
changesfound in associa.
tion with robe!!a. Pigmentary changes were more

extensive in right eye. Note that patients
(A) !ight-
adapted and (B) dark-adapted responseswere of

slightly lessamplitude in eyewith more extensivepigmentary changes(on).
78
Figure 1.51 Multiple

cream-colored lesions
as seen in patient with
birdshot retinochoroidopathy.
-#
ous floaters, photopsia, and a decrease in

central vision, patients may complain of difficulty with night vision and impairment
of
the peripheral visual field.
Reductions in ERG amplitudes have
been reported in most, but not all patients
(Figure 1-52). A prolonged photopic and
scotopic b-wave implicit time is observed,411-413although only amplitude reductions may be apparent during the initial
stages of the disease.414 ERG amplitudes
have been reported to vary from supernormal to nondetectable,
depending on the
severity and stage of the disease.4o8 In general, scotopic responses are more impaired
than photopic responses, while a decrease
in b-wave amplitude has been noted to be
greater than that for the a-wave, suggesting
dysfunction of the inner retina.408,411-413OPs
are either nondetectable
or reduced in amplitude.412 The majority of patients show a
reduction in the EOG light-peak to darktrough ratio.408,412,413,415
An association with
the HLA-A29
antigen, as well as reactivity
to retinal S-antigen, in affected patients
would seem to imply an autoimmune
aspect to the cause of this disease.412,416,417
1-15-2 Multiple Evanescent White-Dot Syndrome
Patients
affected
with the multiple
evanes-
cent white-dot syndrome (MEWDS)

present with an acute, generally unilateral onset
of visual loss associated with the ophthalmoscopic appearance of small discrete white
dots at the level of the RPE or deep retina
(Figure 1-53 ), Granularity of the fovea is
characteristically
found, Some patients manifest an enlargement of the blind spot,418-420
Various authors418,419suggest that patients
with MEWDS should be considered among
the spectrum of patients affected with a
form of acute idiopathic blind spot enlargement,421.422In patients with the latter disorder, not only is an enlarged blind spot observed but also a relative reduction in ERG
amplitude in the affected compared to the
unaffected eye can be found (Figures 1-54
and 1-55),
1-15
I nflommotory
Conditions
Figure 1-52 ERG (A) pho

topic and (B) scotopic
responsesfrom patient
with birdshot retinochoroidopathy depicted in
Figure 1-51. Note selective reduction in b-wave
amplitude.
Birdshotretinochoroidopathy
patient
Normal
Scotopic blue flash
c
o
"U;
">
'0
~
0
~
0>
"0
E
-0.
E
<
Scotopic white flash
a
0
a
40
80
120
160
O
Time
(ms)
40
80
120
160
79
80
Other clinical findings in MEWDS i9clude vitreal cells, retinal vascular sheathing, and optic disc edema. These findings
gradually regress over several weeks, and
vision returns to normal or near-normallevels.423 However, a protracted enlargement
of the blind spot and the presence of photopsia may persist.418 Electrophysiologic
studies during the acute stage show initial
\
reduction
in
ERG
tudes, followed
a- and
b-wave
by subsequent

MEWDS,
showing nu-
merous white spots at

!eve! of RPE.
Gass425described a clinical syndrome that

occurs predominantly
in young women and
is characterized
by
1. Acute deterioration
of outer retinal
in one or more zones
function
in one or both
eyes, usually accompanied

2. Initially
minimal
by photopsia
or absent fundus
ampli-
recovery
(Figure 1-56). Early receptor potential

recordings are similarly found to show an
initial reduction in amplitude, with subsequent recovery.424
1-15-3Acute Zonal Occult Outer Retinopathy
changes
3. Reduction in cone and rod ERG amplitudes
4. Permanent visual field loss, which is
often associated with the late development
of pigmentary changes in the fundus
1-15
120
75
I=F:::::
105
~ 35
V4c
60
~
11/(
of patient with enlarged

blind spot syndrome
from (A) affected right

eye and (B) unaffected
165L /
r--"'
left eye.
15
180
195
\/~\
,~
xx
2'0\
330
22~
-2~~-..~,~~,.-
Conditions
Figure 1.54 Visual fields
"' 45
1"-
I nflammatory
81
82
Figure 1-55 ERG responsesfrom patient with enlarged
Note modestly reduced amplitudes in affected right eye
blind .\pot syndrome shown in Figure 1-54.
compared to thosefrom unaffected left eye.
B
MEWDSpatient
100 ~VL
OD
Figure 1.56 ERG recordings from patient with MEWDS.
(A) Initial
OS
reduction in amplitude
showed recovery 1 year later (B).
20ms
in affected left eye
1-15
Most patients retain good visual acuity. The

fundus pigmentary changes include both
depigmentation
and hyperpigmentation,
which can show a bone-spicule-like
configuration. Narrowing of the retinal vessels
may be observed in patients with more
marked impairment
of photoreceptor-cell
function and diffuse retinal pigmentary degeneration. ERG amplitudes generally vary
from normal to markedly subnormal, with a
delay in b-wave implicit time. In some patientS, cone ERG function is observed to be
more reduced than rod function.425,426 One
report427 emphasized an interocular asymmetry in ERG amplitude as a distinctive
feature in this syndrome. A reduction in the
EGG light-peak to dark-trough ratio may
be found.
From his study of 13 patients, Gass425
provided clinical evidence
notion that these patients,
to support the
referred to as
having acute zonal occult outer retinopathy,

represent part of the spectrum of a single
disorder. The phenotypes included in the
disorder are MEWDS,
acute idiopathic
blind spot enlargement syndrome, acute
macular neuroretinopathy,
and pseudopresumed
ocular histoplasmosis
syndrome.
tested showed either moderately
Patients with pseudo-presumed
ocular
histoplasmosis syndrome (P-POHS), also

described as multifocol choroiditis, show
chorioretinal
scars similar to those observed
in presumed ocular histoplasmosis syndrome (POHS), but also show an inflammatory response in the vitreous and anterior
chamber.428,429These patients have a negative reaction to a histoplasmin skin test and
do not show calcified granulomas on chest
x-ray films. In one study,429 13 of 29 eyes
83
or se-
patients with P-POHS.431

1-15-5
Beh~et
lushi
Behl;;et
Disease
Behl;;et,
disease,
multisystem
ized
volvement
intestine,
vessels,
among
and
others.
complex
main
in
the
iritis
with
the
Middle
addition
arteries
and
ing
both
inflammatory
of
Kubota
the
OPs
ERG
OP
in
the
patients
loss
is
exclusively
b-wave
veins,
Cruz
et
initial
also
al,433
de-
as
in
Behl;;et
by
often
flash
disease.
This
either
in
initially
as
loss
the
reduction,
predominantly,
Normal
well
that
change
with
amplitude.
were
vitre-
variable
observed
followed
or
ocular
affect-
papillitis,
and
Kubota,S3
was
mu-
scarring.
al,432
and
of
genital
vasculitis
cells,
et
The
recurrent
uveitis,
retinal
chorioretinal
Adachi
most
East.
lesions
the
anterior
is
Far
are
of
to
include
ous
grees
ulcers
immunevasculitis
aphthous
and
In
system,
an
It
and
hypopyon,
tisskin,
occlusive
features
mouth,
and
is
feature.
characteristic
in-
joints,
nervous
with
pathologic
and
the
organs
disorder
character-
and
central
This
disease,
its
prevalent
tudes
other
the
Huis
oral
lesions,
several
including
blood
illness
skin
of
sues,
by
inflammation,
ulcers,
most
dermatologist,
described
intraocular
mucosal
as
Turkish
initially
inflammatory
by
findings
Histoplasmosis Syndrome
Conditions
verely reduced ERG amplitudes, which,

with the exception of 1 patient, involved
both cone and rod function. EOG ratios
may be either normal or reduced.429,43o
P-POHS patients are predominantly
women
with myopia.430,431An acute and symptomatic enlargement of the blind spot has
been described as a manifestation
in some
cosa.
1-15-4 Pseudo-Presumed Ocular
I nflammatory
ERG
the
ERG
ampli-
observed.433.434
of
84
The development
of ERG changes is, not
surprisingly, correlated with the duration of
the disease and the severity of the retinal
changes. A factor V Leiden mutation occurs
with an increased prevalence in patients
with Beh~et disease who develop ocular
findings and, in particular, retinal vasoocclusive
changes.435
1-16-1 Sickle Cell Retinopathy

In patients with sickle cell retinopathy,
ERG a-wave, b-wave, and OP amplitudes
were found to be normal in the absence of
peripheral retinal neovascularization.
However, these ERG components were reduced
in amplitude compared to normal when
peripheral retinal neovascularization
was
present.436
1-16-2 Takayasu Disease
The chief characteristics
less) disease are
of Takayasu (pulse-
usually of both eyes in fe-
males around 20 years of age

2. Arteriovenous
anastomoses around the
optic disc, with aneurysm-Iike
vascular dilation and small hemorrhagic spots unassociated with any inflammatory
conditions
3. Impaired
vision, with later development
of cataract
4. General circulatory
ing undetectable
without appreciable
amplitudes, are
both a- and b-wave
reduced or even
nondetectable.
1-16-3 Carotid Artery Occlusion

The effect of carotid artery occlusion on
ERG a- and b-wave amplitudes depends on
the extent and severity of the occlusion, its
CIRCULATORYDEFICIENCIES
1. Involvement
creased or absent OPs,

effect on a- and b-wave
seen. With progression,
amplitudes can become
disturbances,
includ-
radial pulses
The disease represents a primary aortitis,

with spread to the surrounding vessels. In
the early stages of pulse less disease, de-
location, and the degree of collateral circulation that has developed via branches of
the external carotid artery and through the
circle of Willis by way of the anterior communicating artery. With occlusion of the internal carotid artery, a reduction in both aand b-wave amplitudes can be found. The
a-wave reduction is generally relatively less
than that seen in the b-wave, which is more
sensitive to ischemia. Krill and Oiamond437
found a consistently smaller b-wave, associated with insufficient
blood flow through
the carotid artery. These changes are less
likely to be seen if ample collateral flow
through the circle of Willis and/or vertebrobasilar system has been established.
Collateral flow from anastomosis between
branches of the external carotid artery and
the ophthalmic artery can result in a reversed blood flow through the ophthalmic
artery and a relative state of ischemia,
which in turn causes a reduction in a- and
b-wave amplitudes.438
Johnson et al439emphasized
delays in
ERG a- and b-wave implicit times, as well

as in the 30-Hz flicker response, in patients
with venous stasis retinopathy, which is
found in association with carotid artery stenosis. These patients were also found to
have a reduction in retinal sensitivity, as
determined by elevations in the half-saturation constant of their intensity-response
function (see Section 1-5-2).
1-16
1-16-4 Central and BranchArtery

and Vein Occlusions
Retinal circulatory disturbances affect the
ERG b-wave potential (Figure 1-57). Both
decreased scotopic b-wave amplitude and
diminished or nondetectable
GPs accompany central retinal artery occlusion (CRAG).
Henkes440 noted this b-wave reduction in
21 of 24 cases, and Karpe and Uchermann44l
reported similar findings in 15 of 16 cases.
Flower et al442reported an increased susceptibility
to hypoxia of the light-adapted
compared to the dark-adapted b-wave in a
patient with CRAG. Central retinal vein occlusion (CRVG) can cause a similar reduction in the ERG b-wave amplitude. Karpe
and Uchermann441 studied 73 cases ofCRVG
and found a reduced scotopic b-wave ampli-
Circulatory
Deficiencies
85
rude in 44 cases and a normal or increased

scotopic b-wave amplitude in 29 cases. A
reduction of the scotopic b-wave amplitude
in patients with CRVO was also noted by
Eichler and Stave.443 In CRVO, Ponte444
observed that a favorable prognosis correlated more closely with a supernormal or
normal ERG than with either a subnormal
or a negative ERG, which was presumably
associated with a greater
Karpe and Uchermann441
correlation between the
wave amplitude and the
degree of hypoxia.
found no definite
initial size of the bsubsequent visual.
acuity after photocoagulation

therapy in patients with CRVO.
In branch artery occlusion (BAO), there
is generally either a slight b-wave reduction
or a normal ERG response. Ponte444 reported the ERG normal in 52%, subnormal
Figure 1-57 ERG recordingfrom patient with

GRAO. Note selective
reduction of b-wave
amplitude
left eye.
in affected
86
Figure 1-58 Patient

inferotempora!
with
BVO.
in 38%, subnormal
negative
in 8%, and su-
pernormal in 2% of patients with BAD.

Ponte noted no alteration in the ERG in
61% of patients with branch vein occlusion
(BVD), while 32% had a subnormal negative pattern; the finding of a supernormal
response was exceptional, seen in only 1%
of cases (Figures 1-58 and 1-59). In BVD,
the visual prognosis correlated directly with
the effect on DP amplitudes.
Johnson et al445compared eyes having
CRVD that developed iris neovascularization with eyes that had not developed neovascularization. Those developing iris neovascularization
had a significantly
reduced
ERG amplitude and an increase in the
stimulus luminance required to elicit a response equal to one half the maximal potential response (0'). All eyes with neovascularization showed large delays in implicit
times for the a-wave, b-wave, and 30-Hz

flicker responses. These authors concluded
that the implicit-time
delays and amplitude
reductions were more sensitive in ascertaining the presence of iris neovascularization
than was either the ERG b-wave/a-wave
amplitude ratio, as advocated by other
investigators,446 or fundus fluorescein
angiography.
From their study of 25 patients, Larsson
et al447also emphasized the value of a prolonged 30-Hz flicker b-wave implicit time
as a good predictor of rubeosis in patients
with CRVO, particularly if obtained within
2 weeks of the onset of visual symptoms.
Reduction in 30-Hz flicker b-wave amplitude was also noted to be a useful criterion
for predicting the development
of rubeosis.
Using single-flash ERG stimuli in their
study of patients with nonischemic CRVO,
Kaye and Harding448 observed that the
b-wave implicit time was the parameter
most significantly
associated with subse-
1-16
Circulatory
~
o
o
~
0)
"0
oE
"15.
E
<
87
Figure1-59ERG recordingsfrom patient with

inferotemporal BVO
illustrated in Figure
1-58. Notesmallreduction in b-wave amplitude in (A) photopic
and (B) scotopicconditions in affectedright eye
comparedto unaffected
left eye.
c
o
in
0>
=0
Deficiencies
88
quent development
of rubeosis, followed
by the b-wave/a-wave amplitude ratio and
then the b-wave amplitude. Neither a-wave
amplitude nor implicit time was a useful
1-16-5 Hypertension and Arteriosclerosis
predictor.
In a prospective study of 83 individuals with CRVO, Johnson and McPhee449
showed, paradoxically, that the ERG photoreceptor-derived
a-wave in ischemic eyes
with CRVO can be not only delayed in tim-
tients. In patients with systemic hypertension and mild hypertensive retinopathy,

ERG amplitudes can be either supernormal
or normal. Reduction in OP amplitudes may
occur prior to, or be more apparent than,
reductions of a- or b-wave amplitudes.453,454
Those patients with evidence of more se-
ing but also reduced in amplitude. Thus,

the outer, as well as the inner, retina may
not function normally in such patients. A
subsequent study by Johnson and Hood45
found that, as a group, patients who developed iris neovascularization
showed an apparent 2-fold (0.33 log) loss in the a-wave
sensitivity (Iog S), but not in amplitude, in
the affected
eye compared
with the nonin-
volved fellow eye.

This loss in photoreceptor
sensitivity accounted for approximately
one third of the
elevation in log K, the semisaturation
constant of the b-wave intensity-response
function, observed in these patients. Changes in
the log K of the b-wave were more predictive for the development
of iris neovascularization than were changes in log S for the
a-wave. Breton et al45l emphasized that
ERG amplitude and b-wave/a-wave ratio,
as well as half-saturation
intensity (Iog K or
a) and 30-Hz implicit time delays, were of
value as predictors of rubeosis in CRVO patients (Figure 1-60). These authors noted
that a multiple discriminant
analysis, combining information
from several ERG parameters, facilitated separation of CRVO
patients in whom rubeosis would develop
from those in whom it would not.
In patients with systemic hypertension

and
a normal fundus, Henkes and van der Kam452
found supernormal responses in 9 of lS pa-
vere hypertensive
retinopathy frequently
have either subnormal a- and b-wave responses or subnormal b-wave amplitudes.
Henkes and van der Kam452 further noted
that ERG b-wave amplitude reduction occurs in patients with retinal
changes without associated
tension. Occasionally, both
are subnormal. The b-wave
arteriosclerotic
arterial hypera- and b-waves
amplitude re-
duction secondary to hypoxic retinal changes

is generally appreciated more under darkadapted than under light-adapted conditions.
TOXIC CONDITIONS
1-17-1 Chloroquine and Hydroxychloroquine
The most common therapeutic use of
chloroquine and hydroxychloroquine
is iQ
the management and prophylaxis of malarial fever, rheumatoid arthritis, and systemic
lupus erythematosus.
Both drugs have a
high affinity for binding to melanin granules and therefore tend to accumulate in
the choroid, ciliary body, and RPE.
The ocular side effects associated with
prolonged use and/or high doses of chloroquine diphosphate
(Aralen,
Resochin),
1-17
Toxic
Conditions
89
-c:
o
-u;
->
'6
>
"0
0
~
0}
-0
-E
-c.
E
cot
Figure 1-60 ERG recordings from patient with ischemic

CRVO of left eye, illustrating
duced b-wave amplitude,
amplitude
( A) predominantly
with delayed implicit
duced OP amplitudes.
re-
(B) reduced JO-Hzflicker

time, and (a) re-
90
chloroquine
sulfate (Nivaguine),
chloroquine
(Plaquenil)
1. Impaired
central vision
or hydroxy-
include
2. Peripheral
field depression
3. Attenuated
retinal vessels
4. Both atrophic and granular pigmentary

changes of the macula, with the formation
of a characteristic
bull's-eye
appearance
5. In some cases, eventual peripheral

mentary changes and optic atrophy
pig-
Visual loss can progress even after the

discontinuation
of these drugs. Not infrequently, verticillate,
whorl-Iike changes in
the corneal epithelium
are encountered.
The reported incidence of chloroquine-induced retinal toxicity has varied, depending
on the definition
of retinopathy
and the
methods used for its detection. The incidence is probably from less than 1% to
6%,4-0-0-459
particularly if adherence to currently recommended
maximal daily dosages
of 250 mg of chloroquine or 400 mg of hydroxychloroquine
are maintained. The
development
of macular changes has been
reported to occur more frequently with
the use of chloroquine than with hydroxychloroquine. This finding may partly reflect the higher dosages of chloroquine that
were used when this drug was initially introduced. Nevertheless,
macular lesions
can also develop in a small percentage of
patients who use hydroxychloroquine.
In the stage of chloroquine retinopathy
when degenerative changes are clinically
apparent only in the macula, the ERG is
usually normal or occasionally subnormal to
a small degree. With more advanced and
extensive
disease, when peripheral
pigmen-
tary changes also become apparent, the ERG

is usually moderately subnormal, while nondetectable or minimal responses are obtained
in patients with advanced retinopathy.46
The cone ERG function initially tends to
be affected more than the rod function.
However, Weiner et al461observed diffuse
photoreceptor-cell
disease, as evidenced
by marked reduction in ERG amplitudes,
with preferential loss of rod function, in
2 patients treated with hydroxychloroquine.
The ERG is not an effective test to determine a minimal degree of functional impairment of the retina in cases of early chloroquine or hydroxychloroquine
toxicity.462-464
Static perimetry testing of the centrall 00 is
more likely to ascertain early functional impairment than is a test of diffuse retinal cell
dysfunction
such as the ERG.
1-17-2 Chlorpromazine
Siddal1465 described a dusky, granular appearance to the fundus from fine pigment
clumping in patients receiving chlorpromazine (Thorazine).
A few patients had a
more coarse pigment clumping, while 1 patient had actual pigment migration. The
toxic level of chlorpromazine
causing abnormal retinal pigmentation
was estimated
to be 2400 mg per day taken for 8 to 12
months. The pigment accumulation
became less apparent or resolved as the dos~
age was reduced or the drug discontinued.
Retinal pigmentary changes from the use of
chlorpromazine
are significantly
less severe
than the coarse plaques of pigment deposition seen in thioridazine
(Mellaril) chorioretinopathy
(discussed in Section 1-17-3).
Chlorpromazine
probably has significantly less toxic effects on the retina than
1-17
either thioridazine
or chloroquine. Alkemade466 found that 15 of99 patients given
chlorpromazine
developed retinopathy.
The incidence of retinopathy
increased
with greater daily dosages and longer duration of treatment. The drug has a selectivity for melanin-containing
cells of the choroid particularly and is only slowly eliminated from the body.
Boet467 cited Rintelen's findings of no
abnormalities
either in the fundus, on dark
adaptation, or of the visual fields in patients
receiving chlorpromazine.
Boet also discussed the findings of Baumann in 35 schizophrenic patients treated with chlorpromazine. No abnormalities
in dark adaptation,
visual fields, color vision, or fundus examination were noted in 24 cases. Of the remaining 11 cases, 9 had slight abnormalities
in visual fields and dark adaptation that
were attributed
to opacities
or the patient's
mental condition.
of the media
Fundus
pathology, however, was not present. The

other 2 patients apparently had slightly exaggerated pigment mottling. Busch et al468
in 1963 found no ocular abnormalities
in
363 patients treated with chlorpromazine
and promethazine
hydrochloride.
Only
visual acuity and fundus examination results were recorded in this study.
Although final conclusions on the effects
of chlorpromazine
on the ERG await further extensive reports, it appears that toxic
effects on the photoreceptors
are not an
early consequence of treatment with chlorpromazine. It might be anticipated that, in
later stages, associated with coarse pigment
clumping and migration, the ERG would
show reductions in amplitude, as noted in
thioridazine
retinal toxicity.
Toxic
Conditions
91
1-17-3 Thioridazine
Thioridazine
(Mellaril) was introduced in
1959 in clinical trials for the treatment of
psychoses. Patients receiving relatively
high doses of the drug can experience decreased visual acuity and night blindness.
Both central and ring scotomas have been
noted. In the earlier stages, a pigmentary
mottling appears in the macular and perimacular regions. Later, extensive degenerative changes of the RPE, photoreceptors,
and choriocapillaris are seen (Figure 1-61).469
The ERG shows various degrees of dimin..
ished photopic and scotopic a- and b-wave
responses, which correlate with apparent
fundus changes,
Potts470 reported that the uveal pigment
is the ocular tissue that most highly concentrates this phenothiazine
derivative. As
a consequence, the choriocapillaris,
RPE,
and photoreceptors
undergo
degenerative
changes, which can progress for several

years, even after the discontinuation
of
therapy.471.472In contrast, Appelbaum473
studied 77 patients receiving thioridazine
and found no pigmentary retinopathy
suggestive of drug toxicity. ERG recordings,
however, were not obtained in this study.
An additional report474 suggested that even
in patients with clinically apparent degenerative pigmentary changes, a late progressive loss of visual function, as determined
by sequential ERG measurements, was not
inevitable. Nevertheless,
progressive reduction of ERG amplitudes can be demonstrated over time in at least some patients
(Figure
1-62).469.475
92

atrophy of RPE and
Mellaril-induced
retinal
toxicity. Nummulat;
or
coin-shaped, lesions are

characteristic, at least at
some stage.
Normal
loo~vL
20ms
Photopic white
30-min scotopic
white
30-minscotopic
blue
Figure 1-62 ERG recordings obtained during 9 years
10 years. N ote progressive decrease in amplitude
after patient had discontinued Me!!ari! for more than
despite discontinuation
of drug.
1-17
Toxic
93
Conditions
While opinions differ, 1600 mg of thioridazine per day is probably a safe therapeutic dosage, and 800 mg per day for approximately
20 months is probably a maximally safe maintenance dosage to avoid a
degenerative chorioretinopathy.
A phenothiazine preparation closely allied to thio-
to involvement
of extensive areas of pigment atrophy. Burns further found a disturbance of certain visual functions, as demonstrated by abnormal scotopic ERG a- and
ridazine is NP-207. This experimental

drug, which is the chlorine analog of thioridazine, was found to produce night blind.
1.17.5 Quinine
ness, loss of visual acuity, and a severe pigmentary retinopathy with reductions in
ERG amplitude.476
b-wave amplitudes,
Quinine
is a cinchona
Henkes
et al477indicated
that even with
prolonged administration
of indomethacin
(lndocin), ophthalmic side effects rarely
occur. They did report, however, the case
of a 38-year-old man who, during the use
of indomethacin,
noted a deterioration
of
visual acuity, visual fields, and dark adaptation and showed a reduced scotopic ERG
b-wave amplitude and EOG light-peak to
dark-tfough
ratio. Pigmentation
was scattered throughout the retina. After discontinuation of therapy, these visual functions
improved over a period of several months.
alkaloid
and
used in the
treatment of malaria and nocturnal

cramps. Acute poisoning induces a
drome known as cinchonism, usually
after attempted abortion or suicide.
ings in this syndrome
1-17-4 Indomethacin
dark adaptation,
perimetry.
include
muscle
synseen
Find-
tinnitus,
headache, nausea, gastrointestinal

upset,
tremor, and hypotension. Adverse effects
usually occur with ingestion in excess of
4 g, although idiosyncratic sensitivity is
documented.
Death has occurred with ingestion of 8 g. Visual symptoms usually
occur within 2 to 24 hours after ingestion.
The fundus changes in the initial stages
of quinine toxicity are characterized by retinal edema, causing a grayish white fundus
appearance with a cherry-red macula. Visual
acuity is decreased and peripheral fields are
the incidence of ocular changes was noted

between those patients receiving indomethacin and those not receiving the drug.
The longest time any patient received the
restricted. Pupillary dilation is a consistent

feature of acute poisoning. Although a transient subnormal ERG response of both aand b-wave amplitudes is apparent if testing is done within the first 12 to 18 hours,
the ERG is most frequently normal when
recordings are obtained after 24 hours.
Initial reports attributed the disease profile of the early stages to involvement
of
medication was 5 years. Burns479 reported

ophthalmic side effects of indomethacin
that, in addition to subepithelial
corneal
deposits, included an abnormal fundus
the ganglion cells, but subsequent findings

by Cibis et a148in rabbits suggest that there
is an early effect on the ERG from involvement of the outer layers of the retina. In
appearance
the later stages in human patients,
Rothermich478 reported an ophthalmologic

study of 263 arthritic patients, 111 of whom
received indomethacin.
No difference in
in 15 of 34 patients.
Moreover,
6 patients showed paramacular depigmentation varying from a mottled appearance
visual
94
acuity improves, as does peripheral field

vision. At this stage, however, the arterioles
become progressively attenuated and the
optic disc looks pale. Commensurate
with
these changes, the photopic and scotopic
Figure 1-63 ERG re-
ERG b-wave amplitudes are progressively

decreased (Figure 1-63). The flicker-fusion
responses are also abnormal.
After approximately
1 month, the decrease in b-wave amplitude becomes stable.
sponsesfrom patient
with quinine retinal tox
icily, showing predominant or exclusive reduction in b-wave amplitudes under (A) photopic and (B) scotopic
conditions.
c
o
u;
0>
'0
>
=1.
8
~
0)
"0
oE
"5.
E
."
40
80
120
40
O
Time
80
120
(ms;
40
80
120
160
0
Time (ms)
40
80
120
160
1-17
With time, the b-wave may slightly increase

in amplitude, although rarely to normal values. Moloney et al481emphasized that cone
ERG function remains more impaired than
rod function. Generally, the a-wave and
the EGG stay essentially normal, although
Fran<;ois et al,482 as well as Bacon et al,483
reported abnormal EGG findings in 3 cases
and 1 case, respectively, of quinine toxicity.
Moloney et al481reported
marked EGG impairment
a patient with
initially who
demonstrated
slow recovery
over a 2-year period.
of function
can be visible
Methanol is a toxic substance that is widely

used as an industrial solvent and in automotive antifreeze. It can be absorbed through
the skin, respiratory tract, and gastrointestinal system. In the latter mode, individuals
have ingested methanol in the form of
home-brewed
alcohol. Methanol poisoning
can result in permanent blindness and even
death. Methanol is primarily oxidized to
formaldehyde
and subsequently
to formic
acid, which is likely to be the primary toxic
metabolite. Formic acid directly inhibits
mitochondrial
cytochrome oxidase and can
lead to the degeneration of cells in the
retina and optic nerve.
The ocular changes of methanol toxicity
occur after a latent period of about 12 to 40
hours after ingestion.484,48s Those afflicted
complain of reduced vision and, not infrequently, photoaversion.
Hyperemia and
edema of the optic disc are the earliest ophthalmic signs and occur with the onset of
visual symptoms. Peripapillary
retinal edema, which extends along the retinal vascular arcades, develops subsequently, as
may engorgement of the retinal veins.48s
In the acute stage, the most common visual field change is a cecocentral scotoma.
In those with severe toxicity, optic atrophy
Conditions
1 to 2 months.
95
Of in-
terest, the optic discs may become markedly cupped, closely resembling those seen in
glaucomatous optic atrophy.484 Substantial
restriction of the visual field can result.
The ophthalmologic
symptoms and findings likely result from the effects of methano1 on the axons and oligodendrocytes
of
predominantly
the retrolaminar portion of
the optic nerve. The acute hyperemia and
swelling of the optic disc result from axoplasmic stasis and mechanical compression
because of swollen oligodendrocytes.486,487
Optic
1-17-6 Methanol
within
Toxic
atrophy ensues from progressive
demyelination.
Methanol can also cause anatomic changes
in photoreceptor
cells and affect Muller cell
function.485,488 Retinal Muller cells are particularly sensitive to the effects of formic
acid. This action on Muller cells likely explains the greater effect of methanol toxicity on the ERG b-wave compared to its effect on the a-wave amplitude (Figure 1-64).
However, because methanol can also be directly toxic to rod and cone photoreceptor
cells, it is understandable
why the ERG
a-wave, as well as b-wave, amplitude may
be reduced.
In acute methanol poisoning, Karpe3
noted an increased a-wave and a reduced
b-wave amplitude. Potts et al489confirmed
this observation in rhesus monkeys. However, Ruedemann49o found a distinct reduction in both a- and b-wave amplitudes, as
well as increased implicit times.
1.17.7 Gentamicin
The retinal toxicity
of intravitreally
injected
gentamicin (Gentamycin)
in the rabbit eye
has been assessed by several investigators.
Marked reductions in ERG amplitudes can
be found, although the dosage at which
96
Figure 1.64 ERG recordings under (A) photopic

and (B) scotopic conditions in patient with
methano!-induced
reti-
na! toxicity. Note predominant
reduction
in b-wave amp!itude,
giving negative ERG
waveform.
1-17
retinal toxicity
occurs has differed
between
reports.491-493 Palifieris et al492found an intravitreal injection of as little as 0.1 fig to

be toxic to the rabbit retina.
1-17-8 Ethyl-m-Aminobenzoic Acid
Methanesulfonate
acid methanesulfonate (MS-222) is a veterinary anesthetic
commonly used for immobilizing
fish or
amphibians. The finding of retinal toxicity
was observed in an ichthyologist
who had
chronic occupational skin exposure to the
substance.494 Exposure to the drug was associated with decreased vision, photOphobia, and photopsia. The retina appeared
grossly normal, with no evidence
of pig-
mentary change. ERG photopic and scotopic amplitudes were notably reduced.
The b-wave amplitude to a high-intensity
stimulus showed a greater reduction compared to the a-wave amplitude. OP amplitudes were also reduced. After discontinuation of contact with MS-222 for 7 months,
vision returned to normal and ERG amplitudes improved.
1.17.9 Cisplatin
Marmor495 reported a negative-type
ERG
waveform in a 68-year-old woman with
ovarian cancer who inadvertently
received
an overdose ( 480 mg) of cisplatin (Platinol),
an antineoplastic
agent. A negative-type
scotopic response, with a normal a-wave
amplitude but reduced b-wave, was observed. A reduction in the cone b-wave
amplitude, as well as scotopically obtained
OPs, Was also observed. Using an extendedduration flash procedure, on-responses were
observed to be markedly reduced, while
off-responses were essentially normal. Toxicity from cisplatin is apparently another condition that can cause a negative-type
ERG.
Toxic
Conditions
97
Kupersmith
et al496described the development in 3 patients of a maculopathy
with both hypopigmentation
and hyperpigmentation in the eye ipsilateral to an intraarterial infusion of cisplatin. The 8 patients
treated also received an intravenously
administered regimen of carmustine. A diffuse-flash ERG showed cone and rod responses that were reported as being within
the normal range, as was the EOG recorded
in 1 patient.
1.17.10 Glycine
Creel et al497reported photopically
obtained ERG abnormalities
in 4 patients
who had undergone transurethral resection
of the prostate when glycine was used as an
irrigating fluid. These abnormalities
included a reduction in b-wave amplitude,
loss of OPs, and marked reduction in the
30-Hz flicker amplitude. The patients experienced a temporary, but marked reduction in visual acuity. The fundus, on examination, was normal. Glycine is known to
function as an inhibitory
neurotransmitter.
During prostatectomy, excessive absorption
of the glycine irrigating solution can lead to
marked
elevation
of serum glycine,
possible consequences
in some patients.
with
to the visual system
1-17-11 Canthaxanthin
Canthaxanthin
is a carotinoid pigment that
has been used as both a food coloring and
an oral tanning agent. The ingestion of this
substance can result in the development
of
crystalline deposits in the retina. Arden et
al498noted the development
of a generally
small, but discernible reduction in the scotopic and, to a distinctly less noticeable ex-
98
tent, photopic b-wave amplitude, which

was dose-related and most notable with
higher-intensity
stimuli. These authors
speculated that the ERG b-wave change
was likely due to a direct effect of this compound on Muller cells. Hamois et al499observed that canthaxanthin
retinopathy may
be at least partly reversible after the drug is
discontinued.
1-11-12 Vigabatrin
Vigabatrin
is an antiepileptic
drug that in-
creases brain gamma-aminobutyric

acid
(GABA) by inhibiting
GABA transaminase.
GABA is an inhibitory
neurotransmitter
at
different postreceptoral retinal sites. It
plays a role in the regulation of horizontalcell coupling. An accumulation
of GABA
can be found in amacrine cells.
Bilateral concentric visual field restriction and blurred vision have been described
with the use of this drug.soO-so3ERG recordings show retinal cone-system dysfunction,
including a prolonged b-wave implicit time
and preferentially
reduced b-wave amplitude. Cone a-wave and rod function have
been reported as normal. However, markedly reduced or non detectable cone OPs
are reported, consistent with impairment
of
highly GABA-ergic amacrine cells.sol,SO2
Oaneshvar et also4 observed ERG abnormalities in 4 of 10 patients. AI14 showed reduced b-wave amplitudes to scotopic testing. Only 1 patient showed a reduction of
the 30-Hz photopic flicker ERG, while OPs
were normal in all 10 patients. No delays in
implicit time were observed in either photopic or scotopic responses. EGG lightpeak to dark-trough ratios were reported as
either normalSO1,SO4
or abnormal.so4
1-17-13 Deferoxamine
Deferoxamine
(also known as desferrioxamine) is a chelating agent used to treat
iron storage disorders, like hemosiderosis,
which can result from multiple transfusions
such as those used in patients afflicted with
r3-thalassemia major. The use of, initially,
intramuscular
or intravenous and, more recently, subcutaneous infusion has been
shown to increase the urinary iron excretion
substantially in these patients. Deferoxamine (Desferal) has also been used in patients with rheumatoid arthritis, on the
premise that iron deposits in synovial membranes may be contributing
to the inflammatory response and the occurrence of anemia in these patients. By removing iron
from the synovial membranes, deferoxamine may decrease the inflammation,
replenish bone-marrow iron stores, and lessen the
anemia.505 The drug may also playa role by
inhibiting
iron-promoted
peroxidation
from
free radicals generated
by phagocytic
cells
in the inflamed rheumatoid joint.506,507

Ocular signs and symptoms that can
occur with the use of this substance include
blurred or decreased visual acuity, impaired
color vision, and night blindness. Optic
neuropathy, pigmentary retinopathy, or, infrequently, both have been described. The
development
of cataracts, as well as central
and peripheral visual field defects, has also
been reported.506-510 Hearing loss can also
occur with the use of this drug.510 The retinal pigmentary
changes involve
a stippled,
mottled, or "salt-and-pepper-like"
appearance of the macula, resulting from a mosaic
pattern of depigmentation
and hyperpigmentation, as well as areas of pigment clumping in the midperiphery.
It is relevant that,
on occasion, pigmentary retinal changes can
occur in patients who are visually asymptomatic.510 Optic nerve atrophy may become
1-18
clinically
apparent
as a consequence
of the
optic neuropathy.
Most significant is that when deferoxamine is discontinued,
most patients experience either a complete or a partial improvement of their visual function.sO6-S13 N evertheless, a progression in the pigmentary
retinal changes without further deterioration of visual function was observed to
occur despite discontinuation
of the drug.so9
Abnormal ERG amplitudes and reduced
EOG light-peak to dark-trough ratios have
been reported.SO6-S09.S11,SI2
Improvement
in these measures of visual function are
often seen when deferoxamine
is discontinued. ERG rod function tends to be more
impaired than cone function in some patients.so7 Prolonged ERG implicit times, in
addition to reduced amplitudes, have been
observed.so9
Vitamin
A Deficienry
and
99
Retinoids
observed in either the isolated rod response

or the light-adapted
cone b-wave amplitude. Implicit times for both dark- and
light-adapted
responses were reported to
be normal.
In their study of 6 patients who ingested
100 mg of sildenafil, Kretschmann et alS16
observed an increase in the dark-adapted
rod b-wave implicit time, with a normal amplitude 1 to 3 hours after ingestion. The
maximal dark- and light-adapted
b-wave
amplitudes, as well as the implicit times,
were unchanged from baseline. A large
number of such patients, treated with different dosages, need to be investigated before firm conclusions can be drawn about
the type and frequency of ERG changes
that occur with the use of sildenafil. Furthermore, the long-term consequences
the use of this drug, if any, need to be
firmly
of
established.
1-17-14 Sildenafil
Sildenafil citrate (Viagra) is an oral treatment
for erectile dysfunction.
The drug acts as a
relatively selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme in the
corpus cavernosum of the penis that breaks
down cyclic guanosine monophosphate
(CGMP).514 In vitro studies have shown that
sildenafil is approximately
10% effective as
an inhibitor of the enzyme PDE6, which is
found in retinal photoreceptor
cells, compared to its effect on PDE5. The recommended dosage is 25 to 100 mg.
Two reports on ERG findings in patients
treated with sildenafil found different results. In their study of 5 subjects who took
100 mg of sildenafil, Vobig et al.115reported
a 37% and 23% reduction in both a- and bwave amplitudes, respectively, in the maximal dark-adapted ERG response; 6 hours
after ingestion, the response returned to
baseline. No reduction
in amplitude
was
VITAMIN A DEFICIENCYAND RETINOIDS

Vitamin A deficiency and its association
with night blindness has been recognized
since the time of ancient Egypt. Ohanda517
studied scotopic responses in patients with
vitamin A deficiency. Subnormal-to-nondetectable responses were noted in patients
with xerosis and night blindness. After vitamin A administration,
symptoms resolved
and ERG values returned to normal. Small
dot-Iike white deposits, which may develop
in the mid peripheral or peripheral retina
and not affect the macula, also usually resolve after proper vitamin A therapy.518 In
general, children below the age of 15 years
are particularly prone to develop night blindness as a result of vitamin A deficiency.
100
In albino rats, Dowling519 found an initially more marked reduction of the a-wave
to threshold
stimuli
that was associated
with a decline in rhodopsin concentration

in the rod outer segments and was eventually followed by a b-wave reduction. Dowling noted a linear relationship between the
rhodopsin concentration
and the logarithm
of the stimulus luminance necessary to produce a threshold ERG response. In the
early stages of vitamin A deficiency in humans, a reversal of initially reduced ERG
amplitudes occurs when parenteral vitamin
A is administered
(Figure 1-65). In 1966,
Genest520 reported that both a- and b-waves
of the ERG were equally affected by decreased vitamin A blood serum levels in humans. Genest did not note the initial selective a-wave reduction reported by Dowling
in his experiments with albino rats.
Patients with vitamin A deficiency and
night blindness associated with chronic alcoholism and liver cirrhosis or secondary to
malabsorption do not show the appreciable
delays in b-wave implicit times seen in
some patients with retinitis pigmentosa.521,522
Further, after vitamin A administration,
cone function recovers more quickly than
rod function in the central retina, compared
to the retinal periphery, where rod function
recovers more quickly, possibly due to rodcone rivalry for vitamin A.521,523
Retinoids, which are derivatives of vitamin A, are used for the treatment of dermatologic disorders,
such as acne and psoriasis.
One such derivative, isotretinoin (13-cisretinoic acid), was reported by Weleber et

al524to cause abnormal retinal function, with
the complaint
of poor night vision and a re-
duction in ERG amplitudes most apparent

under scotopic conditions. A similar reduction, primarily in rod-mediated
ERG amplitudes, was reported with the use of fenretinide, a synthetic retinoid.525 Abnormal rod
photoreceptor-cell
function, observed on
ERG testing in 2 patients treated for basalcell carcinoma, returned to normal rapidly
after cessation of therapy with fenretinide.525
OPTIC NERVE AND GANGLIONCELL DISEASE

Some authors claim that the presence of
centrifugal efferent fibers in the optic nerve
has an inhibitory
effect on the ERG. Thus,
apparently as a consequence of the interruption of this inhibitory
effect, the ERG
in some optic nerve diseases has been reported as supernormal. Other investigators
have noted that surgical sectioning of the
optic nerve, without disturbance of the retinal circulation,
has no apparent
effect on
the ERG amplitude.

Because the ganglion cells do not contribute to the flash-elicited
full-field
ERG
response, an essentially normal ERG is obtained in most eyes blinded by glaucoma.
Further, patients with infantile amaurotic
familial idiocy (Tay-Sachs disease), a diso~der known to involve the retinal ganglion
cells, have a normal ERG.
Some investigators have noted a lowered
critical flicker-fusion
frequency associated
with the retrobulbar neuritis of multiple
sclerosis. Furthermore,
Fazio et al526emphasized that if proper gender and agesimilar controls are used, reduced flashevoked ERG amplitudes and associated
prolonged implicit times can be encountered in eyes with advanced glaucomatous
optic nerve damage. Secondary ocular is-
1-19 Optic Nerve
chemia or vascular disease, in addition to

retrograde degeneration of bipolar and photoreceptor cells (secondary to increased intraocular pressure), was considered
ble explanation.
and Ganglion
Cell Disease
Of interest, Weleber and Miyake527 reported a negative ERG waveform, most

apparent under scotopic conditions, in two
families affected with a familial (likely autosomal dominant) form of optic atrophy.
a possi-
Figure 1-65 ERG responsesfrom patient

with systemic vitamin
A deficiency before and
1 week after high-dose
oral vitamin
0:
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-->
::!.
o
o
~
0)
-0
~
-0.
E
""'
A supple-
mentation. Note improvement in ERG

amplitudes under both
(A) photopic and
(B) scotopic conditions.
40
80
120
40
80
120
Time(ms)
80
120
Time
(ms)
40
80
120
c
o
";;;
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-->
::!.
o
o
~
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-0
~
-0.
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40
80
120
160
40
160
101
40
80
120
160
102
ERG recordings
have been reported
in
patients with optic nerve hypoplasia.s28.s29

The majority of these patients showed normal photopic and scotopic ERG amplitudes.
Occasionally, some patients show a small
reduction in amplitude, possibly as a consequence of accompanying degenerative
chorioretinal
changes.S28
OPAQUELENS OR VITREOUS
Particularly dense lens opacities can reduce
the ERG a- and b-wave amplitudes. When
present, the amplitude decrease is associated with a comparable increase in implicit
time, both relating to the resultant decrease
in effective stimulus intensity. It takes a
more intense stimulus
to reach the same
amplitude and implicit time compared to

an eye with clear media. Lens opacities do
not appear to modify the OPs. Patients with
mild or possibly even moderate degrees of
vitreous hemorrhage generally have normal
or only moderately subnormal ERG a- and
b-wave amplitudes. As with lens opacities,
the implicit times are prolonged because of
the apparent decrease in stimulus intensity
reaching the photoreceptors.
With longstanding vitreous hemorrhages, a marked
reduction of ERG amplitudes is always possible because of the ever-present threat of
siderotic changes occurring within the retina
secondary to blood-breakdown
products.
Fuller et al530reported that ERG recordings elicited by a very high-intensity
(bright-tlash)
stimulus could be of value for
predicting postvitrectomy
improvement
in
visual function of diabetic patients with vitreous opacities. However, nondetectable
preoperative ERG responses have been reported in patients with dense vitreous opacities who showed appreciable improvement
in visual function after vitreous surgery.S31,S32
Further, results from a bright-flash-elicited
ERG need to be interpreted with particular
caution in patients who have undergone extensive panretinal photocoagulation.
Exposure of eyes with clear media to a very highintensity flash stimulus should be avoided
because it is likely to evoke unwarranted
discomfort.
DIABETIC RETINOPATHY
The most frequently reported ERG abnormalities in patients with diabetic retinopathy include a reduction in b-wave amplitude and a reduction or absence of OPs. For
the most part, reductions in b-wave amplitude are noted in eyes with proliferative
retinopathy. However, a reduction in scotopic b-wave amplitude may be observed
in insulin-dependent
diabetic children,
even in the absence of clinically or angiographically apparent diabetic retinopathy.533
These amplitude reductions likely represent a quantitative
measure of overall inner
retinal ischemia and/or hypoxia. Chung et
al534studied ERG function in 65 patients
with diabetes. They measured ERG amplitudes as a function of stimulus intensity,
and a Naka-Rushton-type
function was fit
to b-wave amplitudes in order to measure
retinal sensitivity. The ERG-measured
retinal sensitivity tended to decrease (ie, log
K t ) as the severity of diabetic retinopathy
increased. However, the eyes of diabetic
patients without visible retinopathy
did not
showa significant ERG sensitivity loss. Significantly prolonged b-wave implicit times
were found in all stages of retinopathy
and
1-21
in eyes of diabetic
patients
without
clini-
cally apparent retinopathy.

Reduced OP amplitudes have been
noted at early stages of retinopathy, when
ERG a- and b-wave amplitudes are normal,535 while delayed OP implicit times
have been reported as an early functional
abnormality in eyes with mild or even no
retinopathy.536 The most consistent change
is a significant increase in the OP1 implicit
time.533 Yonemura and Kawasaki537 have
emphasized a selective delay in the implicit
time of OPs, in the absence of amplitude
reductions, as an early functional change of
the retina in diabetic patients. Bresnick and
Palta538 noted a delay in the 30-Hz ERG
flicker implicit time, which became progressively more prolonged with increasing
severity of retinopathy. These authors also
showed that the summed amplitudes of
OPs decrease, and implicit times in some of
these potentials increase, as the severity of
diabetic retinopathy increases.538-540 Bresnick et al541reported a lO-fold higher rate of
progression to high-risk characteristics of
diabetic retinopathy, as defined by the Oiabetic Retinopathy
Study, in eyes with reduced OP amplitudes compared to eyes
with normal amplitudes at study entry.
Later changes in both a- and b-wave amplitudes, with more severe cases of diabetic
retinopathy, are probably related to associated arteriosclerotic
changes, vitreous hemorrhages, and, frequently, to retinal detachments present in the advanced stages of
diabetic retinopathy. A useful review of the
ERG findings in diabetic patients with various stages of diabetic retinopathy
is available in an article by Tzekov and Arden.533
Oeneault et al542used ERG amplitudes
and implicit times to document the benefits of multiple-dose
daily insulin therapy to
conventional
once-a-day injection of insulin
in streptozotocin-induced
diabetic rats.
Diabetic
Retinopathy
103
The effect of panretinal photocoagulation on ERG amplitudes in diabetic patients has been addressed in several publications. Lawwill and O'Connor543 reported
an average 10% reduction in a- and b-wave
amplitudes when approximately
20% of the
retinal area was photocoagulated.
In general, the percentage decrease in ERG amplitude was less than the total area photocoagulated. Wepman et a1544reported findings
in 10 diabetic patients who had argon laser
photocoagulation
burns to 15% to 18% of
the retina. A mean reduction of 61% in the
rod b-wave amplitude, a 35% decrease in.
the photopic (cone) b-wave response, and a
39% decrease in the combined scotopic rod
and cone response to a bright-Iight
stimulus
were observed. Reduction of the ERG following laser treatment was positively correlated with the total area of retina destroyed,
provided that at least 7% to 10% of the
retina had been treated. Patients with larger
pretreatment
b-wave amplitudes (>300 \lV)
showed the greatest decrease in ERG amplitude, while patients with smaller pretreatment amplitudes ( <200 \l V) showed
the smallest amplitude change.
Therefore, the total area of photocoagulation may be less reliable in consistently
predicting the degree of postphotocoagulation reduction in ERG amplitudes than is
the size of the ERG amplitude prior to
treatment. Those with more reduced pretreatment ERG amplitudes likely have a
greater degree of microangiopathy.
Photocoagulation of less viable regions of the
retina would not be expected to contribute
to a reduction in ERG amplitudes, in contrast to destruction of normal-functioning
retina. The disproportionately
large percentage reduction in ERG amplitudes compared to the area of photocoagulation
ob-
104
served by Wepman
et a1544contrasts with
the findings of Lawwill and O'Connor,,"43

but is consistent with the findings of Ogden
et al545and Frank.546
Franchi et al547reported an improvement
in OP amplitude after panretinal argon laser
photocoagulation
in patients with proliferative diabetic retinopathy. They advocated
determining
an OP/ERG amplitude quotient in patients before and after photocoagulation treatment to evaluate the functional status of the retina following laser
treatment.
MISCELLANEOUSCONDITIONS
1-22-1 Retinal Detachment
In general, the amplitudes of both a- and
b-waves are related to the degree of retinal
detachment. Karpe and Rendahl548 have reported subnormal ERG values in the normal eye when the contralateral eye has a
retinal detachment. In an eye with a detached retina, the ERG deteriorates in relation to both the size of the detached area
and the decrease in retinal function. A nondetectable or minimal response implies a
total or large detachment, respectively, with
a poorly functioning
retina.
There is, however, some disagreement
as to whether these responses imply a poor
prognosis for successful reattachment and
ultimate return of visual function. Both
Rendahl549 and Jacobson et al550indicated
that the amplitude of the ERG response is
of some prognostic value, while Schmoger55l
and Fran~ois and de Rouck552 did not place
significant prognostic value on the ERG
response.
1-22-2 Silicone Oil and Sulfurhexafluoride Gas

Silicone-oil injection into the vitreous cavity for the management of complicated retinal detachment was introduced in the United
States by Cibis et al553in the early 1960s.
Frumar et al554reported their findings on
the effects of intravitrealliquid
silicone or a
mixture of 20% sulfurhexafluoride
(SF6 )
gas and air on retinal function in a series of
patients who underwent vitrectomy for recent rhegmatogenous
retinal detachment.
In the early postoperative period, a reduction of both a- and b-wave amplitudes was
observed. This reduction was likely partly
related to the vitrectomy itself, but mainly
to the silicone oil or SF6 gas. A recovery of
ERG amplitudes was observed in all patients and was accelerated by absorption of
the gas or removal of the liquid silicone.
The authors opined that the relative ERG
amplitude reductions were due to the insulating effect of the tamponading agents and
observed that these reductions were similar
for both gas and liquid silicone.
Similar findings on the effects of silicone
oil on ERG amplitudes were observed by
other authors.555"';';6 Of interest, Meredith et
al557did not observe any sustained reduction of ERG amplitudes or significant histopathologic changes of the retina in pigmented rabbits following vitrectomy and
intraocular silicone-oil injection. Eyes undergoing vitrectomy alone showed a transient decrease in b-wave amplitude of 31 %,
a finding similar to that observed by Declercq et al558after intraocular surgical injury to the rabbit eye.
Doslak5,';9 proposed a theoretical model
from which he concluded that it was not
until at least 50% of the vitreous was replaced with silicone oil that a small reduction of the ERG amplitude would be observed. It was further theorized that this
reduction would increase nonlinearly as the
1-22
percentage of silicone oil was increased in

the vitreal cavity. According to the model,
if the replacement of vitreous was particularly extensive, little, if any, ERG amplitude
would be measurable even if the retina
were otherwise normal.
1.22.3 Thyroid and Other Metabolic Dysfunctions
Several investigators have noted the bioelectrical activity of the retina to be increased in patients with hyperthyroidism
and reduced in patients with myxedema.
Particularly in thyrotoxic exophthalmos,
both a- and b-waves of the ERG were reported as significantly
supernormal. Wirth)6
substantiated this finding of supernormal
responses and emphasized the generally
high correlation with the plasma proteinbound iodine. The ERG is said to be a sensitive test in hyperthyroidism,
being supernormal even when the basal metabolic rate
and protein-bound
iodine may still retain
normal values.
Peatlman and Burian561 noted that the
supernormal ERG amplitudes in patients
with hyperthyroidism
tend to diminish significantly in the course of treatment. Conversely, they reported that myxedematous
patients with initially subnormal amplitudes showed an increase in ERG response
while receiving thyroid treatment. These
authors suggested that the ERG may be a
reasonably reliable, objective means of estimating the success of medical and surgical
therapy in thyroid disease.
Wirth.)6 stated that the adrenal medulla
had no influence on the ERG, noting that
patients with a pheochromocytoma,
as well
as those injected with 1 mg of epinephrine
(Adrenalin),
still had normal b-wave amplitudes. ]T Pearlman, MD, and HM Burian,
MD (unpublished
data), however, recorded
a selective b-wave enlargement in patients
with an adrenal pheochromocytoma.
Pa-
Miscellaneous
tients with Gushing
Conditions
disease and patients
105
re-
ceiving exogenous corticosteroids

can manifest a supernormal ERG.562 Zimmerman
et
al563recorded an increase of approximately
200% to 300% for both photopic and scotopic a- and b-wave amplitudes in subjects
with normal eyes who received 40 mg of
prednisone daily for 3 weeks. Negi et al564
could not demonstrate a similar effect of
betamethasolie
or dexamethasone in their
study on albino rabbits. However, these authors demonstrated
an increase in both the
b- and c-wave following the intravenous ad..
ministration
of AGTH (adrenocorticotropic
hormone) in the rabbit.565
Aldosterone was found by other investigators to increase the ERG b-wave, but decrease the c-wave amplitude in the rabbit.566 An increase in ERG amplitude in
primary aldosteronism was also noted by
Wirth and Tota.562 These investigators also
noted that an intravenous injection of aldosterone in rabbits could increase the
ERG b-wave amplitude by 45%. A summary of ERG abnormalities
in various endocrine and other metabolic disorders is
available in a review by Wirth.567
Patients afflicted with hepatic failure
and accompanying hepatic encephalopathy
can manifest functional abnormalities
of the
retina best demonstrated
by ERG recordings. These functional changes, which correlate well with the degree of encephalopathy,568 were thought to result from altered
neurotransmitter
levels and impaired retinal
glial-neuronal
interaction as a consequence
of Muller cell damage caused by elevated
ammonia levels. The ERG changes included
reduced a- and b-wave amplitudes, with
prolonged implicit times for both cone and
rod responses. Reduced amplitude and delayed implicit
time for OPs were observed
106
to be the most sensitive indicators of retinal

dysfunction, with abnormal findings occurring even in those with less advanced stages
of hepatic encephalopathy.
It is noteworthy
that patients did not complain of impaired
visual function and that normal serum vitamin A levels were maintained. Only
nonspecific RPE mottling and irregular
macular reflexes were observed on fundus
examination.
1-22-4 Parkinson Disease
Ellis et al569reported their f\ash-evoked
ERG findings in 7 patients with idiopathic
Parkinson disease. Subnormal scotopic and
photopic amplitudes were observed in the
Parkinson patients compared to control patients. An increase in ERG amplitude and a
reduction in implicit time were observed in
some of the Parkinson patients shortly after
the administration
of levodopa.
1-22-5 Myotonic Dystrophy

Myotonic dystrophy is a dominantly
inherited systemic disease recognized by weakness of facial and distal muscles, sternocleidomastoid muscle wasting, frontal balding,
dysarthria, and percussion or grip myotonia.
Ocular findings in Steinert myotonic dystrophy include cataract, low intraocular
pressure, and, less frequently, macular
and/or peripheral pigmentary changes. Both
the systemic and the ocular findings result
from an expanded and variable number of
trinucleotide
(CTG) repeat sequences in
the myotonin protein kinase gene.S70
Burian and BurnsS71 obtained ERG data
on patients with myotonic dystrophy and
noted an average b-wave reduction of
40% to 45%, even in those patients with
no or minimal ophthalmoscopically
visible
changes. A reduction in scotopic b-wave

amplitude was also reported by Cavallacci
et al,572who additionally
found a prolonged
scotopic b-wave implicit time. Stanescu and
Michiels573 noted a reduction of the photopic as well as scotopic b-wave amplitude,
in addition to a delayed scotopic b-wave
implicit time. Creel et al574did not observe
a reduction in single-flash photopic
tudes or prolonged scotopic implicit
amplitimes
in their patients with myotonic dystrophy.

These authors did note reductions in ERG
scotopic b-wave amplitudes to dim blue
and red flashes prior to the development
of
ophthalmoscopically
detectable
changes
and in some neurologically

asymptomatic
patients with minimally
expressed myotonic dystrophy. The reduction in b-wave
amplitude in patients with myotonic dystrophy differs from the normal ERG amplitudes found in patients with myotonia congenita, another autosomal dominant
disorder
of skeletal muscle.575
1-22-6 Duchenne and Becker
Muscular Dystrophies
Duchenne
muscular
dystrophy
(DMD)
is
a fatal X-Iinked recessive neuromuscular

disease resulting from mutations in a gene
that alters the structure and function of a
427-kD (kD = kilodalton)
cytoskeletal protein termed dystrophin, which
is expressed
in a number of tissues, including muscle,

brain, and retina. Alterations in dystrophin
can cause either a severe expression of neuromuscular disease, such as DMD, or a
milder
allelic form, Becker muscular
dys-
trophy (BMD).
Abnormal negative ERG responses have
been recorded from patients with DMD or
BMD. These result from a defect in signal
transmission between photoreceptor
cells
and "on" (or depolarizing)
bipolar cells,
1-22
as also noted in patients
with CSNB
and
melanoma-associated
retinopathy.576,577 Patients with DMD or BMD, however, do not
have any corresponding functional visual
complaints, such as night blindness. Abnormal findings are not apparent on ophthalmologic examination. Although the presence of a normal a-wave and an impaired
b-wave is similar to the morphologic appearance of the ERG waveform seen in patients with some forms of CSNB, patients
with DMD have a more selective impairment of OPz, particularly under photopic
conditions, while patients with CSNB can
show reduction or absence of all OPS.577
Pillers et al578identified
dystrophin in the
outer plexiform layer of the human retina.
This finding, coincident with the observation of an abnormal b-wave amplitude in
patients with DMD or BMD, suggests that
dystrophin is required for normal retinal
electrophysiology.
The term Oregon eyedisease has been
used to refer to a small group of patients
who, in addition to DMD or BMD, also
manifest
a glycerol
kinase deficiency
and
congenital adrenal hypoplasia. This disorder seemingly represents a contiguous-gene

deletion syndrome resulting from a deletion
at Xp21.579 Patients were found to show a
negative-configuration
ERG with a reduced
b-wave amplitude in the dark-adapted
state. Of 5 reported patients, 1 showed nystagmus, an albinotic-appearing
fundus, iris
transillumination,
and macular hypoplasia.
Miscellaneous
Conditions
107
1. Heart block (associated with a cardiomyopathy)

2. Cerebellar
dysfunction
3. Cerebrospinal
with ataxia
fluid protein
above
100 mg/dL
Other features, such as weakness of limb,
facial, and neck skeletal muscles primarily,
exercise intolerance, sensorineural deafness, small stature, less than average intelligence, dental anomalies,
respiratory
distress
(Adams-Stokes attacks), abnormal electroencephalographic

tracings, and atrophy of
cortical central nervous system tissue seen on
computed tomography (CT) scanning may
also be observed.580,583,584M uscle biopsy in
such patients shows ragged red fibers by
light microscopy, with the use of a Gomori
trichrome stain, and fine structural changes
of their mitochondria,
including variable
size, abnormal vacuoles, ring-shaped cristae,
and paracrystalline
inclusion bodies.584,585
Bastiaensen et al584reported
tinct forms of this disorder:
1. An infantile
three dis-
form, characterized
by an
early onset and a severe course, with rapid

progression and multisystem
involvement,
particularly of the retina, heart, and central
nervous system
2. A juvenile
form, with onset in the second
decade of life
3. An adult form, with onset in the third
decade of life or later
The latter two forms are characterized
by a
1.22.7 Kearns-Sayre Syndrome
generally slower and more benign course,

with less widespread expression in various
The Kearns-Sayre
tem mitochondrial
organs. However, the three forms appear

to be the expression of the same mitochondrial multisystem
disorde(.
syndrome is a multisysdisorder characterized
by the onset before age 20 of blepharoptosis, progressive external ophthalmoplegia,

pigmentary retinal degeneration, plus at
least one of the followingS8-s82:
Mullie et al586identified
three patterns
of retinopathy
in patients with mitochon-
108
drial myopathy
generation
and pigmentary
(Figure
retinal de-
1-66):
1. One form, the most frequently
encoun-
tered, shows a "salt-and-pepper

phenotype," with stippled areas of hypopigmentation and hyperpigmentation
of the RPE.
As a group, patients show good visual function overall.
2. A second form, seen with considerably
less frequency, shows attenuated retinal
vessels and a notable degree of pigment
clumping, which, to a limited extent, can
have a bone-spicule-like
configuration,
not
unlike that observed in patients with retinitis pigmentosa. However, these pigmentary
changes, unlike those seen in typical retinitis pigmentosa, are most dense at the posterior pole of the fundus. This clinical observation is consistent with the histopathologic
findings of Eagle et al,587who noted degeneration of the RPE and photoreceptor
cells
to be most marked at the posterior pole.
Therefore, none of these patients shows
fundus features compatible
forms of retinitis
pigmentosa.
Figure 1-66 Pigmentary

retinal degeneration resulting in diffuse stippled areas of hypopigmentation of RPE in
patient with KearnsSayre syndrome.
with classic
3. A third, less frequently
seen phenotype
presents with a generalized atrophic appearance of the RPE and choriocapillaris.

In isolated instances, some patients can
manifest a more regionalized atrophy of the
RPE and choriocapillaris,
ent in the peripapillary
often most apparregion.
Patients with the second and third subtypes

often show considerable impairment
of visual function, with markedly reduced visual
acuity, optic disc atrophy, and attenuated
retinal vessels.
ERG amplitudes are most frequently
subnormal in patients with the KearnsSayre syndrome.s82-s84,s86In most patients,
both cone and rod a-and b-wave amplitudes are reduced (Figure 1-67). Mullie et
al,s86 however, described patients in whom
only the cone-mediated
flicker response
was reduced. The extent of amplitude reduction often parallels the severity of fundus subtype described by Mullie et al, with
patients in group 3 showing the greatest reduction in amplitude. Nevertheless,
even
those in group 1, with salt-and-pepper-like
1-22
Miscellaneous
Conditions
Figure 1.67 Substantial
reduetion in ERG amplitudes under (A) pho.

topie and (B) seotopie
eonditions in patient
with Kearns-Sayre
syndrome depicted in
c
o
.0;
.>
'0
-->
::!.
o
o
~
0)
"0
,2
~
E
Figure 1-66.
40
80
120
80
40
120
Time (ms)
B
Normal
Kearns-Sayre syndrome patient
Scotopic
blue
flash
?
o
in
.>
'0
--::;..
o
~'
~~-.
~ ~ -~~ ~a
o
~
0)
"0
~
-0.
E
<I:
Scotopic white flash-
~
-a
40
80
120
160
O
Time
(ms)
40
80
120
160
109
110
changes, often show a reduction in amplitude.586 However, Ota et a1585.588

observed
patients with mitochondrial
myopathy and
a salt-and-pepper
retinopathy who showed
normal ERG cone and rod amplitudes, and
Bastiaensen et a1584found a subnormal
scotopic, but normal photopic response in
1 patient.
EOG
patients
pearance
In more
light-peak to dark-trough ratios in

with a salt-and-pepper
fundus apare either normal or subnormal.585.586
advanced stages of the disease,
once a notable
rod amplitudes
reduction in ERG cone and

are found, EOG ratios are
abnormal. However, accurate measurement

of the EOG ratio is often precluded by external ophthalmoplegia.
Deletions in mitochondrial
DNA
(mtDNA)
have been described in patients
with the Kearns-Sayre syndrome.581.582.585.
589.590
There is a significant difference in the
relative proportion of deleted to normal mitochondria in different tissues. The greatest
proportion of mitochondrial
deletions occurs
in skeletal muscle, and the smallest proportion in smooth muscle.581 Mitochondria
play
a pivotal role in energy production in tissues and cells, and it is the mitochondrial
DNA that is responsible for generating this
energy through encoding oxidative-phosphorylation enzymes in conjunction
with
the nuclear genome. It would be anticipated that mitochondrial
DNA mutations
should have the greatest consequences for
highly energy-dependent
tissues, such as
muscle, brain, and retina.
1-22-8 Neuronal Ceroid Lipofuscinoses
The neuronal ceroid lipofuscinoses represent a group of progressive, hereditary neurodegenerative
disorders with clinical
fea-
tures that include deteriorating

psychomotor function, myoclonic seizures, ataxia,
progressive visual loss, and premature
death.591,592Diffuse degeneration of cone
and rod photoreceptor
cells, as well as optic
nerve atrophy, accounts for the marked visual impairment
in such patients. Initially,
in certain patients, an atrophic-appearing
macular lesion, which can have a bull's-eye
configuration,
is noted within the first
decade of life (Figure 1-68). Later in the
disease, more diffuse pigmentary degenerative changes of the retina are noted.
Characteristic
is the abnormal accumulation of autofluorescent
lipoproteins
within
Iysosomes.
The infantile-onset
(Hagberg-Santavuori
disease), late infantile-onset
(Jansky-Bielschowsky disease), and juvenile-onset
(Batten-Mayou or Spielmeyer-Vogt
disease) are
the most frequent forms encountered clinically. In each of these autosomal recessively
transmitted
subtypes, ERG a- and b-wave
amplitudes under photopic and scotopic
testing conditions are reduced in amplitude
early in the course of the disease (Figure
1-69).593-595Eventually, ERG waveforms
become nondetectable.
A selective reduction in the scotopic ERG b-wave amplitude
has been noted in at least some heterozygotes for the juyenile-onset
form.596 An
adult-onset form, called Kufs disease, does
not present with visual findings.
In the infantile-onset
form, Weleber592
noted that the earliest ERG manifestation
is a marked loss of the scotopic and photopic b-wave amplitude, with either normal
or more relative preservation of the a-wave
amplitude. In the late infantile-onset
form,
rod responses were found to be either normal or mildly abnormal and thus better preserved than in the infantile- and juvenileonset forms. Rod implicit times, however,
were prolonged. Cone b-wave amplitudes
.22 Miscellaneous
111
Conditions
in patients with the earlier stages of the late
a-wave and, to an even greater extent,
infantile-onset
form were markedly reduced,
with prolonged implicit times. Patients
with the juvenile-onset
form showed extensive ERG amplitude reduction even when
tested initially, with essentially no isolated
rod-mediated
response and marked loss of
wave amplitude to a maximal dark-adapted

stimulus. Cone responses were markedly
subnormal in amplitude for both a- and
b-wave amplitudes. A gene that maps to
chromosome 16p12.1 has been isolated in
patients with the juvenile-onset
form.597
b-

juvenile-onset form of
neuronal ceroid lipofuscinosis. Depicted are
bulls-eye-appearing
macular lesion, extensive reflexes from internallimiting
membrane,
and temporal optic disc
pallot:
Figure 1-69 ERG recordings from patient with

Batten disease. N{}te
substantial
loss of both
photopic and scotopic

responses in only 2
years.
112
1-22-9 Retinal Degeneration

With SpinocerebellarAtaxia
An autosomal dominantly
transmitted disorder, retinal degeneration with spinocerebellar ataxia has also been referred to as
olivopontocerebellar atrophy. In an initial classification by Konigsmark and Weiner,598
olivopontocerebellar
atrophy was classified
as type III cerebellar ataxia, while in a subsequent classification of cerebellar ataxia by
Harding,599 it was considered as type II.
The cardinal clinical sign in these patients is ataxia resulting from cerebellar atrophy. However, deterioration
of neurologic
function also results from degenerative
changes in the spinocerebellar
tracts, as
well as brain stem structures. In addition
to progressive ataxia, other clinical findings
include intention tremor, dysarthria, dysmetria, choreoathetotic
movements, progressive ophthalmoplegia,
and pigmentary
retinal degeneration. Ptosis and internuclear ophthalmoplegia
may also be
found.
Figure 1.70 Atrophic-appearing macular lesion,

as well as diffuse hypopigmentation
anterior
to retinal vascular arcades, in patient with

retinal degeneration and
spinocerebellar ataxia.
A variable difference in the age of clinical onset is often encountered.6o The disease has a more virulent course, with severe
neurologic symptoms, often resulting in an
early death, in patients affected in infancy.
Those with an adult onset have a more protracted course. The appearance and extent
of retinal involvement
also depends on the
age of clinical onset.600 Patients with an
early onset of neurologic symptoms show
fundus changes that involve both the macula and the peripheral retina (Figure 1-70),
while those with an adult onset tend to
manifest an atrophic-appearing
macular lesion exclusively. Attenuated retinal arterioles and optic disc pallor can be observed in
patients with more diffuse early-onset disease, but are less likely to be seen in those
with only a macular lesion and a later onset.
Patients with more diffuse retinal pigmentary changes, which manifest as a mottled or granular appearance to the retina,
show marked reduction in both a- and bwave ERG amplitudes involving both cone
and rod function.601,60Z ERG changes in
1-22
some patients with a later onset of symptoms can be observed in certain affected
Retinaldegenerationwith SCApatient
Normal
30-Hz
white
flicker
113
Figure1.71ERG recordingsfrom patient with

retinal degenerationand
spinocerebellarataxia
shown in Figure 1-70.
ERG a- and b-wave
amplitudes in this patient wereconsiderably
more reducedunder
(A) photopic compared
to (B) scotopictest
conditions.
o
o
~
"'
-0
,2
0.
E
Photopic white flash

b
a
a
40
80
120
O
Time
c
o
.00
.>
'0
>
::!.
o
o
~
0)
"0
.E
-c.
E
<
Conditions
ophthalmoscopic
findings.6o3 One report601
suggested that the earliest changes may be
observed in cone function (Figure 1-71).
However, in individual patients, cerebellar
atrophy can occur when ERG function is
family members who have no neurologic

manifestations
and have a normal ophthalmologic examination61 or show only subtle
c
o
.c;;
.>
'6
Miscellaneous
(ms)
40
80
120
114
still normal.6l As might be anticipated,

those with an earlier disease onset are likely
to show the most severe impairment of elec-
atrophy
trophysiologic
function.
Histopathologic
findings disclose diffuse
and extensive degenerative changes of the
photoreceptor
cells, involving both rods and
cones. Changes are most prominent in the
macula.6l,6o2 An intercellular
variability in
Section
the melanin content of the RPE cells is observed and likely accounts for the granular
appearance to the fundus.6l,6o2
An analysis of different kindreds has revealed evidence of genetic anticipation,
in
which subsequent generations manifest an
earlier onset and more severe disease than
do earlier generations.604 Retinal degeneration with spinocerebellar
ataxia has been
mapped to chromosome 3p604 and the gene
has been cloned.6s
1-22-10 Tay-Sachs Disease
Also initially called infantile amaurotic familial idiocy, Tay-Sachs disease was first described clinically by Tay in 1881 and both
clinically and pathologically
by Sachs in
1887. The disease is a hereditary cerebromacular degeneration associated with
lipoidal degeneration of ganglion cells of
both the retina and the central nervous system. The disease most commonly affects
Jewish children of Eastern European ancestry, with a female predilection
of approximately 3 to 1. In patients with this disorder,
there is an absence of the enzyme hexosaminidase A in serum, leukocytes, and skin
fibroblasts, among other tissues. The characteristic fundus picture is a cherry-red spot
in the macula, resulting from the deposition
of lipid material in ganglion cells. Optic
is also present. Because cells proxi-
mal to the bipolar-celllayer

are involved,
the ERG is typically normal, as noted in
1-19.
1-22-11 Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob
disease is a rare spongiform encephalopathy
related to prions that
may be familial, idiopathic, or iatrogenic
(following treatment with human growth
hormone, corneal transplantation,
or a dura
mater graft). Patients develop a progressive
dementia. Myoclonic,
ramidal, or cerebellar
pyramidal, extrapysigns may also occur,
as can characteristic electroencephalographic changes. The disease is uniformly

fatal, and meaningful treatment is not currently available.
De Seze et a166reported their findings
in IS patients diagnosed with definite and
in 9 with probable Creutzfeldt-Jakob
disease. ERG recordings were obtained in 19
of the 24 patients using a hand-held photodiode device. A decrease in the b-wave amplitude under photopic conditions was observed in 17 cases. The a-wave under photopic conditions was only mildly reduced in
amplitude, and therefore a decrease in the
b-wave/a-wave ratio was noted in 14 of the
19 cases. These changes in predominantly
or exclusively b-wave amplitude were observed in the presence of a normal appearance to the retina on ophthalmoscopic
examination and were similar to previously
reported findings by Renault and Richard,67
who also observed a reduction in b-wave
amplitude in 3 patients. Although the predominantly
b-wave changes reported by
De Seze et al were for photopically obtained
responses, based on histopathologic
changes
in the retina, it is likely that similar b-wave
changes would be found, as well, in recordings obtained
scotopically.
1-22
1-22-12 Intraocular Foreign Bodies

The time and rate of ERG changes associated with the retention of an intraocular
foreign
body depend on
1. The nature of the metal (its alloy

content)
2. The degree of encapsulation
3. The size of the particle
4. The location
5. The duration
within
the eye
Iron and copper affect the ERG rather rapidly. Aluminum

only rarely produces a
pathologic ERG, and then usually after a
relatively long duration. Metallic particles
in the lens or anterior segment generally do
not cause significant electrophysiologic
changes. The inciting particles generally reside in the vitreous, ciliary body, or retina.
Ocular siderosis is caused by the retention of an iron-containing
intraocular foreign body. Clinically, patients can experience blurred vision and show pupillary
mydriasis, iris heterochromia,
iron deposition on the corneal endothelium
and beneath the anterior lens capsule, and lens
opacification.6B These changes are induced
by chemical reactions between iron particles and ocular tissues. The process of oxidation of either the nonionized or the ferrous forms of iron to the ferric state likely
plays the detrimental
role in siderosis.
The earliest fundus changes noted in
patients with retained intraocular iron particles (siderosis bulbi) include a patchy pigmentary degeneration in the retinal periphery, with pigment clumping. These changes
are associated with a corresponding
depression in peripheral visual fields and elevated
thresholds on dark-adaptation
testing. The
earliest ERG findings in patients with siderosis bulbi from retained iron particles may
be a transient supernormal response.60B,609
Miscellaneous
Conditions
115
With progressive intraocular changes, a negative pattern is eventually followed by a

nondetectable
cases (Figure
response in the most severe

1-72). Rod function is charac-
teristically more impaired than cone function. The extent of rod impairment
is most
readily apparent with the use of low-intensity stimuli, which isolate rod function.610
In at least one study,610 the cone b-wave implicit
time did not exhibit
any significant
change during the development

of siderosis. Caution in initial interpretation
is warranted, because a traumatically
induced
retinal edema from the foreign body may
produce a subnormal ERG, with subsequent normalization
of the response when
the edema has resolved.
The ERG changes induced by the foreign body pass through the stages of a transient supernormal response, a negativepositive response, a negative-negative
response, and, finally, a nondetectable
response. The ERG changes are reversible
in the negative-positive
and early negativenegative stages (b-wave amplitude not reduced beyond 50% of the other eye ). In the
somewhat more advanced negative-negative stage (b-wave amplitude reduced beyond 50% to 75% of the other eye), it is still
possible to stabilize the response or prevent
further deterioration
by removing the foreign body.611 The initially greater effect of
the siderotic changes on the ERG b-wave
compared to the a-wave supports the conclusion that the earlier changes from iron
toxicity produce more damage to the inner
retinal structures than to the outer retina.
In studies on rabbits, Oeclercq et al558
showed that most of the siderotic
retinal
116
Figure 1-72 Reduction in

ERG amplitudes in patient with siderosis from
retained intraocular
foreign body. Reduction
in b-wave amplitude
is
somewhat more apparent than a-wave.
damage demonstrated
by the ERG occurred within the first week. In a subsequent report, Oeclercq et al612demonstrated that foreign-body
removal after 1
week did not result in normalization
of
ERG amplitudes in the same rabbit model.
Magnetic iron particles have the most toxic
effects on the retina. Generally, nonmagnetic iron particles, which are stainless
steel, do not affect the ERG as markedly.
As noted in Section 1-20, recurrent vitreal
hemorrhages from any source may cause
retinal damage and corresponding
ERG
changes similar to those produced by an
iron foreign body, likely due to iron liberated from erythrocytes.
1-22-13 Myopia
The ERG is normal in simple myopia, in
the absence of degenerative myopic fundus
changes. The ERG response is normal in
more than 20% of patients with degenerative (high} myopia. In approximately
75%
of cases of degenerative myopia, the amplitude of the b-wave is subnormal.613 In general, there is a direct correlation between
the amplitude of the b-wave and the degree
of myopia, with patients who have approximately 7 diopters or more of myopia already
manifesting subnormal b-wave amplitudes.
There is, however, no relationship between
visual acuity and b-wave amplitude. If the
ERG pattern in patients with myopia is either negative or markedly reduced in amplitude, the myopia may be associated with
an inherited retinal disorder, that is, CSNB
or retinitis
pigmentosa.
1.
1.22.14
Three
general
found
in albinism:
2. Autosomal
3. X-Iinked
modes
recessive
dominant
recessive
of inheritance
may
be
oculocutaneous
oculocutaneous
or autosomal
recessive
ocular
The oculocutaneous
groups include both
tyrosinase-positive
and tyrosinase-negative
individuals.
Krill and Lee614 found that oculocutaneous and ocular albinos showed
an increased ERG response in the darkadapted state that was greater for the oculocutaneous albinos. Flicker-fusion
frequencies and light-adapted
responses were
normal. The responses of female carriers for
ocular albinism were not significantly
different from those of a control group. The
increased scotopic responses tended to become more normal in some older albinotic
patients, commensurate with an increase in
ocular, as well as skin, pigmentation.
Internally reflected light, because of its lack of
absorption by sparse or absent pigment
melanin granules, was believed to account
for the supernormal scotopic responses. All
groups of patients
with albinism
had normal
EOGs.
Subsequent studies by Bergsma and
Kaiser-Kupfer615 of a family with autosomal
dominant oculocutaneous
albinism and by
Tomei and Wirth616 of a group of ocular albinos did not find supernormal ERG amplitudes. Similarly, Wack et al617found normal
ERG amplitudes in 9 tyrosinase-positive
oculocutaneous
albinos. Only at high flash
luminances, and primarily after dark adaptation, did tyrosinase-negative
oculocutaneous albinos show increased ERG amplitudes. A summary of various gene mutations obtained in patients with albinism is
available
Conditions
117
1-22-15 Taurine Deficiency
Albinism
1. Autosomal
2 Miscellaneous
in a review by Spritz.618
Taurine is an amino acid abundantly concentrated in the outer segments of rods and
cones. Cats fed a casein diet develop a selective decrease in plasma and retinal,taurine levels, resulting in a retinal photoreceptor-cell degeneration and associated
reduction of ERG amplitudes.619,62o In children receiving long-term parenteral nutrition, reductions in plasma taurine levels can
be accompanied by generally mild and reversible ERG abnormalities,
including primarily prolonged implicit times and small
amplitude
reductions.621,622
1-22-16 Bietti Crystalline Dystrophy

Patients with Bietti crystalline dystrophy
generally present in the third decade of life
with visual impairment
and glistening crystalline-like
lesions at the posterior pole of
the retina (Figure 1-73). About one third of
patients can also show crystals in the superficial stromal layer of the paralimbal cornea.
A degree of phenotypic heterogeneity
exists in these patients, with some showing
diffuse photoreceptor-cell
impairment,
as
evidenced by a markedly reduced to nondetectable ERG amplitude, and others
showing a more regional or localized disease, in which ERG amplitudes can be either minimally or mildly to moderately abnormal. However, Jurklies et al623followed
a single patient over a period of 30 years
who initially showed low-normal cone and
rod ERG responses, but subsequently
showed substantial disease progression and
the development
of a nondetectable
ERG
response. The EGG light rise in this, as
well as a second, patient was reduced. In
some patients with abnormal ERG ampli-
118
Figure 1-73 Glistening

cr)istalline-like
lesions
at posterior pole of
retina in patient with
Bietti crystalline dystrophy. Fundus also shows
atrophic-like changes of
RPE and patchy atrophic change of choriocapillaris
vessels. Clump.
ing of retinal pigment

is also apparent.
tudes, an electronegative-type
ERG recording has been observed (Figure 1-74).623-626
In patients with the more diffuse type of
Bietti dystrophy, night blindness and symptoms related to a loss of peripheral visual
field are noted, while in the more localized
type, symptoms related to paracentral scotomas predominate.
In both the diffuse and
the more localized type, RPE and choriocapillaris loss are notable features.627 This
disorder is likely transmitted
as an autosomal recessive trait, although families with
autosomal dominant transmission have
been reported.628,629
Wilson et al,630 as well as Jurklies et al,623
demonstrated inclusions of crystalloid deposits in circulating lymphocytes
similar to
those seen in the cornea, suggesting that
this disorder may represent a systemic abnormality of lipid metabolism.
1-22-17 Cancer-Associated Retinopathy

A small percentage
of patients
with various
forms of cancer can develop a paraneoplastic syndrome in which tumor-specific

antibodies are produced that in turn recognize
specific proteins and subsets of neurons in
the human retina.631-633 Two of these currently identified
retinal proteins are recoverin,634-636a 23-kD protein located in photoreceptor cells, and enolase,637 a 46-kD
protein. The most frequently encountered
tumor that is associated with what has been
termed cancer-associated retinopathy is smallcell carcinoma of the lung.631,638However,
cancer of the cervix, endometrium,
ovary,
colon, prostate, breast, and other sites have
been similarly associated.631,639
Patients with cancer-associated retinopathy experience visual symptoms that often
precede or are concurrent with the tumor
diagnosis. These symptoms can include
photopsia, photosensitivity,
light-induced
glare, decreased visual acuity, loss of color
1-22
vision, and nyctalopia.631,64o Visual testing

can disclose diminished visual fields, including ring or central scotomas, impairment of color vision, decreased central vi-
Miscellaneous
Bietti crystallinedystrophypatient
Normal
30-Hzwhiteflicker
a
.c;;
.>
'0
>
=1.
Photopicwhiteflash
40
80
120
0
rime (ms:
119
sion, and progressive dysfunction of both

rods and cones as determined
by notably
reduced or nondetectable
rod and cone
a- and b-wave ERG amplitudes.631,636,640-642
8
~
0>
""
~
"5E
<
Conditions
40
80
120
Figure1-74ERG recordings under (A) photopic

and (B) scotopicconditions in patient with
Bietti crystalline dystrophy illustrated in Figure
1-73. Noteelectronegative response:b-wave
amplitude is relativeli
more impaired than
a-wave.
120
Fundus findings characteristically

include
attenuated retinal arterioles, with limited,
electrophysiologic,
if
any, clinically apparent retinal pigmentary

changes. Cells in the vitreous humor are
commonly
found.64
studies, patients
can
demonstrate an absolute or a relative hypersensitivity of their S (short-wavelength,

or
blue) cones.64.1The phenotype can manifest
different degrees of severity in some in-
1-22-18 Enhanced S-Cone Syndrome
stances, including those changes reported

as occurring in the Goldmann-Favre
syndrome.646 It has been proposed that pa-
A group of patients have been described

who complain of poor night vision and show
degenerative pigmentary changes in the re-
tients with the enhanced S-cone syndrome

have many more S cones than occur in the
gion of the vascular arcades, a maculopathy

that can often be cystoid in appearance, and
a distinctive change on their ERG recordings (Figure 1-75). Characteristically,
the
dark-adapted ERG shows either no response or a markedly reduced response to
low-intensity
stimuli, while large and delayed responses to high-intensity
stimuli
are obtained under light-adapted
conditions
(Figure 1-76). In such patients, the waveforms are similar under light- and darkadapted conditions to high-intensity
stimuli.643,644On psychophysical,
as well as
Figure 1.75 Degenerative

pigmentary
retinal
changes as seen in patient with enhanced

S-cone syndrome.
normal retina and that these cones replace

some of the normallongand middle-wavelength cones and many of the rods.647 Gene
mutations in a nuclear receptor, NRZE3,
appear to be responsible for this developmental anomaly.648
1-22-19 Pigmented Paravenous
Retinochoroidal Atrophy
Pigmented paravenous retinochoroidal
atro.
phy likely represents several different disorders, both genetic and acquired, that result in a similar funduscopic
appearance.
122
The
Electroretinogram

pigmented paravenous
retinochoroida/ atrophy.
Characteristic is predi/ection for both hypopigmentation and hyperpigmentation
to OCCUI:
ally normal, as are the retinal arterioles, although narrow retinal arterioles have been
observed.
The disease has been described as being
either stable or progressive and occurring in
both children and adults. Many reported
cases were asymptomatic
and were found to
be affected on routine ocular examination,
while others presented with visual impairment, including decreased visual acuity,
nyctalopia, or peripheral visual field defects. Electrophysiologic
testing has similarly yielded variable findings. Although familial cases have been reported,649-65l these
are by far the exception, with most reported
cases involving only an isolated family member. Two reports652,653describe discordant
ocular findings in monozygotic twins.
There are reports of pigmented paravenous retinochoroidal

atrophy associated
with, and conceivably caused by, tuberculosis, syphilis, and sarcoidosis.654,655The initial case reported by Brown,655 from Copenhagen, was a 47-year-old man with a positive reaction to tuberculin and a significant
family history of tuberculosis. Foxman et
al656demonstrated
the development
of fundus changes typical
nous retinochoroidal
of pigmented paraveatrophy in a patient
afflicted with rubeola.

ERG amplitudes have been variously
described as normal,657,658generally moderately to markedly, but occasionally mildly
subnormal649,651,652,654,656,659-670
or nondetectable (Figure 1-78).650,654One report650 noted
patients with decreased photopic, but normal scotopic responses. EOG light-peak to
dark-trough ratios are most frequently
reduced,649,651,662-664,666-668
but occasionally
have been reported as normal.649,660,669
1-22
Miscellaneous
123
Conditions
Figure 1-78 ERG recordings under (A) photopic

and (B) scotopic conditions in patient with pigmented paravenous
retinochoroidal
c
o
"in
">
'6
>
=0.
0
O
~
0)
"0
E
0E
Note reduction in amplitudes, particularly
::1.
0
O
~
"'
"'
E
0.
E
"'
under
scotopic conditions and to

JO-Hzflicker
-c:
o
c;;
'>
'0
>
atrophy
shown in Figure 1-77.
stimulus.
124
5. Granit R: The components of the retinal action potential and their relation to the discharge
in the optic nerve. J Physiol (Lond) 1933;77:
207-240.
SUMMARY
The ERG can provide important diagnostic
information on a number of retinal disor-
6. Noell WK: The effect of iodoacetate on the

vertebrate retina. J Cell PhysioI1951;37:283-307 .
ders, including, among others, congenital

stationary night blindness with myopia,
achromatopsia, X-Iinkecl juvenile retinoschisis, and Leber congenital amaurosis.
7. Bush RA, Sieving PA: A proximal retinal component in the primate photopic ERG a-wave.
Invest Ophthalmol Vis Sci 1994;35:635-645.
Electroretinography
is also of value in monitoring disease progression in such disorders
as retinitis pigmentosa, choroideremia,
and
cone-rocl dystrophy. Additionally,
the ERG
is of potential value in determining
retinal
toxicity associated with the use of such
drugs as thioridazine
or in vitamin A deficiency, as well as for ascertaining possible
retinal toxicity from a retained intraocular
8. Dowling ]E: Organization of vertebrate retinas. Invest OphthalmoI1970;9:655-680.

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it is vital for each investi-
11. Ripps H, Witkovsky P: Neuron-glia interaction in the brain and retina. In: Osborne NN,
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eases. New York: Harper&

Lambert
function.
KP, et al:
rod phototransduc-
from the two-branched
Invest Ophthal-
mol 1970;9:600-617.
Krill
of human
saturation
AE: The electroretinogram
oculogram:
kinetics
systemic
be-
epithelial
hypoxia.
Invest
Vis Sci 1987;28:1888-1904.
Straub W: ERG in acute and chronic

tions. In: Fran~ois ], ed: The Clinical
Electroretinography.
Symposium
intoxicaValue of
in Ghent,
1966.

Straub W: Unilateral
Nakajima
retinitis
pigmentosa.
In:
A, ed: Retinal Degenerations, ERG, and
Optic Pathways. Proceedings

sium of ISCERG
of the 4th Sympo-
in Hakone,
1965. Jpn J Oph-
thalmoI1966;10(suppl):27B-281.
Thorner
MW, Berk M: Flicker
Onhthalmol19h4:71
:RO7-RI.').
fusion Test. Arch
Suggested Readings
Vinken
PJ, Bruyn
GW, eds: Neuroretinal
Degener-
ations: Handbook of Clinical Neurology. Amsterdam: North-Holland

Weleber
Publishing
RG, Eisner A: Retinal
physiological
studies.
Go; 1972; vo113.

function
In: Newsome
and
DA, ed:

Young RS, Price J, Waiters JW, et al: Photoreceptor responses of patients
ary night blindness.
Zrenner
with congenital
ApplOpt
station-
1987;26:1390-1394.
E, ed: Special Tests of Visual Function:
Basic Problems and Clinical Applications.
Basel:
S Karger AG; 1984; vol 9 of Developments

Ophthalmology.
in
155
GeraldAllen Fishman,MD
The electro-oculogram
(EGG), a term introduced by Margl in 1951, measures a
standing or resting potential of approximately 6 m V (m V = millivolt)
that is always
present between the cornea and the back of
the eye. The current flow is oriented such
that voltage at the cornea is positive relative
to the posterior pole. The amplitude of this
potential is altered by changes in retinal illumination,
an observation made initially
by the Swedish physiologist Alarik Frithiof
Holmgren in 1865. The existence of this
potential was discovered in 1849 by Emil
DuBois-Reymond,
a professor ofphysiology in Berlin. However, it was not until
1954, when Riggs2 reported abnormal values in a case of a retinal pigmentary degeneration, and 1956, when Fran~ois et a13,4reported abnormal findings in various retinal
diseases, that measuring this standing potential began to have value as an objective
clinical test for retinal function.
In 1962, Arden and FojasS noted that the
potential after an intravenous infusion of

20% mannitol, while Yonemura et aJ7noted
a similar reduction in this potential after an
intravenous injection of acetazolamide...
These drugs were believed to be useful for
the study of patients with diffuse pigmentary retinopathy
(mannitol) or with poste- .
rior pole retinal degeneration (acetazolamide). In both the catS and the human,9
hypoxia of the retina has been shown to
produce a rise in the standing potential,
while a sudden restoration of oxygen produces an abrupt fall. This finding is likely
due to changes in potassium concentration
in the subretinal space, presumably as a result of changes in the metabolic rate of the
sodium-potassium
pump in the photoreceptor-cell inner segments.!O Timolol, a
beta-adrenergic
antagonist, was observed to
cause a decrease in the EGG potential in
the steady state.!!
most valuable information

was obtained not
by the absolute amplitude values of the
standing potential (which also varied considerably with levels of illumination,
electrode placement, magnitude and velocity of
visual excursion, eye prominence, and the
corneoretinal
potential itself), but rather by
a comparison of the amplitudes under lightand dark-adapted states. Kawasaki et al6
noted a reduction in the human standing
157
158
The Electro-Oculogram
""
RECORDINGPROCEDURE
\
1\
\\
0 /rl/Yr...,,--
,
vi
e
\~\
'1
)(
"f---\'
"
(.)
[i)
Figure 2-1 F rontal view of electrode placement for

recording EGG responses. Four recording electrodes
are positioned at medial and lateral canthi; ground
electrode is placed on forehead.
The standing potential, which is an overall

mass response, is measured clinically by
using silver-silver
chloride or gold-disk skin
electrodes attached with tape near the lateral and medial canthi of both eyes and employing conducting electrode paste or jelly;
a similar electrode on the forehead serves as
a ground (Figure 2-1). In the electrophysiology laboratory at the University of Illinois at Chicago, the patient sits erect in a
lighted room, with the head supported by a
chin rest, and looks into a diffusing sphere.
Three small dimly lit red fixation lights are
placed in the patient's line of vision, so that
the center light serves for central fixation
and the others allow an excursion of 30 as
the patient looks from right to left at the
approximate rate of 16 to 20 sweeps per
minute (Figure 2-2). Although the pupils
should be dilated to standardize the procedure, a pupil diameter of any value >3 mm
will likely show little clinically significant
variation in the EGG response.
During the initial preadaptation period
of approximately
15 min, the patient is exposed to continuous room light or bowl
background levels while baseline recordings are periodically obtained. The intensity of the light exposure during this preadaptation period should be between 35
and 70 lux units.12 The skin electrodes are
connected to a polygraph recorder, an oscilloscope, or a digital computer, and ocular
movement is recorded as an electrical potential difference between the electrodes at
the medial and lateral canthi (hence the
term electro-oculogram). This difference in
turn is used to monitor the effects of changes
in illumination
on the standing potential.
2-1
After the standardized period of light

adaptation, all lights are turned off and responses from saccadic eye movements are
recorded for 15 min under a dark-adapted
condition. After this allotted time, adapting
lights from within a diffusing sphere or
other light-adapting
source are turned on
and responses are recorded for another 15
min under light-adapted
conditions. It is
suggested that alternating eye excursions
occur every 1 to 2.5 s (equivalent to a complete back-and-forth
cycle every 2 to 5 S).12
Arden and Kelsey13 indicated that at
least 2500 trolands should be used to obtain
optimallight-adapted
responses. With a dilated pupil, this corresponds to an adapting
luminance of at least 50 cd.m-2 ( candela per
meter squared). With an undilated pupil, an
adaptation luminance of 500 cd.m-2 is required.14 Weleber and Eisner15 suggested
that, with dilated pupils, 20 foot-Iamberts
(approximately
70 cd.m-2) of full-field
illu-
Figure 2-2 Fixation
Recording
Procedure
159
lights and ocular excursions used
during recording of EGG potentials.
160
Lights on
15 min
15 min
Lightsoff
Lightson
Lp
Figure 2-3 EGG potentials
recorded as subject looks
from right to left between fixation lights under darkand light-adapted conditions. Lp = light peak. D, =
dark trough.
mi nation is both adequate for obtaining a

light peak and well tolerated by patients.
A suggested standard if the pupils are dilated is to use a stimulus intensity in the
range of 50 to 100 cd.m-2, while a range of
400 to 600 cd.m-2 is recommended
if testing
is performed with undilated pupils.12 Sample recordings are taken at approximately
1-min intervals under both light- and darkadapted conditions. Figure 2-3 outlines this
response sequence.
Although the amplitudes of the saccadic
ocular movements between the fixation
points remain constant, the recorded responses progressively decrease in the dark,
reaching a trough in approximately
8 to 12
min. With light adaptation, there is a progressive rise in amplitude, reaching a peak
in approximately
6 to 9 min. The ratio of
the light peak (Lp) to dark trough (DJ is
then determined to evaluate the normalcy
of the response. Although there is a definite
variation, requiring each laboratory to establish its own set of normal values, most
investigators find that normal patients have
ratios of 1.80 or greater. Values of 1.65 to
1.80 are probably marginally subnormal,
while a ratio of < 1.65 is considered distinctly subnormal.
The reproducibility
of ratios in patients
can vary, although some investigators maintain that a difference of more than 0.20 in
.2 Components
repeated testing of normal patients is unusual. Thus, there is an acceptable testretest variability of up to 10% of the lightpeak to dark-trough ratio.16 Jones et al17
noted that males had, on average, a 0.21
lower EOG ratio than did females when
they compared 25 normal subjects of each
sex who were of a similar age range and had
a similar range of refractive errors. These
authors also reported that 95% of eyes retested from 20 subjects showed an intersession variability of 0.6 or less for the
EOG ratio.
Hanson and Fulton 18recorded corneoretinal potentials in 23 full-term human infants who were between 4 and 48 weeks of
age (median age: 12 weeks). They used a
procedure that incorporated vestibularly
induced horizontal eye movements through
30 to 40 of visual angle; 5 adults were also
tested with this procedure. The EOG parameters assessed included measurement of
both the light-peak and dark-trough amplitudes, time to reach each of these amplitudes, and the Arden light-peak to darktrough ratios. They observed that under
these testing conditions, light-induced
changes in the EOG measures were similar
in infants and adults. Further, no clear systematic age-related changes were noted in
any of these measures in the infants. The
EOG amplitudes and Arden ratios were
similar to those previously reported by
Trimble et al19 on 3 infants, aged 5 through
21 months, using a similar recording procedure. These findings suggest that the corneoretinal potential is adult-like soon after
birth.
In 1993, a standard, approved by the International Society for Clinical Electrophysiology of Vision (ISCEV), was published
that describes the basic technical aspects of
EOGrecording.12
The availability of this
and Origins
of the EGG
161
information
should better facilitate reproducible and comparable EOG measurements. This publication addresses issues
such as
1. Basic technology,
including
light stimula-
tioll, skin electrodes, light source, and electronic recording equipment

2. Clinical
protocol,
which
discusses pupil-
lary dilation, electrode placement, saccades,

preadaptation,
dark phase, light response,
measurement of the EGG, normal values,
and reporting the EGG
An appendix describes the recording
EGG fast oscillation.
of the
COMPONENTSAND ORIGINS OF THE EOG

From the preceding discussion and illustrations, it is apparent that the EGG response
has two components: one light-insensitive,
the other light-sensitive.
The light-insensitive component depends on the integrity of
the retinal pigment epithelium
(RPE), as
well as some extraretinal sources, such as
the cornea, lens, and ciliary body. This
light-insensitive
component, accounting for
the dark trough, is not influenced by previous retinal illumination
and thus is independent of the functional status of the retinal photoreceptors.
The light-sensitive
component, or slow light rise of the EGG,
appears to be generated by a depolarization
of the basal membrane of the RPE that is
not directly related to any change in retinal
potassium concentration.2 This depolarization of the basal membrane results in an in-
162
crease in the electrical potential across the

RPE cells (transepithelial
potential). Intact
photoreceptor
cells are, however, also necessary to generate this response. Further,
this light-rise response requires that physical contact be maintained between the
photoreceptors
and the RPE; thus, the response is not retained in the presence of a
detached retina.
A contribution
from inner nuclear layer
cells is suggested by the finding that the

light rise can be reduced after occlusion of
the central retinal artery, which theoretically should have no direct effect on potentials arising from the RPE or photoreceptors.21 The light rise, and thus the EOG
light-peak to dark-trough ratio, do not correlate with the degree, pattern, or even
presence of melanin in RPE cells. In the
arterially perfused cat eye, an increase in
extracellular calcium was demonstrated to
cause a decrease in the light peak by 85%
to 90%.22
The amplitude of the light-sensitive
EGG component increases with increasing
levels of retinal illumination
in the range of
1 to 1000 foot-Iamberts.
At the higher levels
of illumination,
the ratio manifests more
variability. The EGG light rise is not mediated exclusively by the rod or cone systems,
because normal values are generally obtained in congenital achromats and in patients with congenital stationary night
blindness. Further clinical and basic science investigations
are necessary to define
more precisely the entire physiologic basis

of the various EOG components.
Of note, hyperpolarization,
rather than
depolarization,
of the basal membrane of
the RPE has been measured by EOG
recordings as a slight, fast, and transient decline in voltage of the transepithelial
potential after light onset. This fast oscillation
contrasts with the light rise or slow oscillation seen after light onset and relates to
changes in potassium concentration
in the
retina.23 Kolder and Brecher24 observed the
presence of fast oscillations of the EOG potential when light and dark cycles were alternated at approximately
1.1 min each.
Contrasting with the slow dark-trough and
light-peak oscillations of about 12.5 min
each used for the determination
of EOG
light-peak to dark-trough ratios, the amplitude of the fast oscillations increases in the
dark and decreases during the light phase.
A duration of between 1 and 1.25 min was
determined as the most optimal duration
between repeated light stimuli.2s The amplitude of the fast oscillations depends on
light intensity.26 The clinical value of measuring the fast oscillations is under investigation, because different retinal disorders can
selectively impair either the fast oscillations, the slow oscillations, or both.27.28
Weleber29 observed that the fast oscillations were preserved in patients with Best
macular dystrophy, but abnormal even in
the early stages in patients with retinitis
pigmentosa (RP).
Kawasaki et al6 noted that the amplitude
of the EOG, after stabilization in the dark,
can be reduced by an average of 43% subsequent to the intravenous injection of a
hypertonic solution of 20% mannitol. This
finding, referred to as the hyperosmolurityinduced response, is directly attributable
to
alterations in function at the level of the
2-4
Hereditary
Macular
Dystrophies
163
RPE and thus could serve as an objective

quantitative
test for selectively determining
the function of RPE cells. Similarly, the
function of these cells can be monitored
by measuring the reduction in EGG amplitude following the intravenous injection of
500 mg of acetazolamide (Diamox).7 The
acetazolamide response reflects primarily
the function of RPE cells in the posterior
pole of the fundus and thus can be abnormal in at least some patients with RPE
changes associated with macular degeneration while remaining normal in patients
with RP. Although both the acetazolamideinduced response and the hyperosmolarityinduced response measure functional alterations at the level of the RPE, they appear
to measure different aspects of cell function. An abnormal hyperosmolarity-induced
response has been reported in isolated
cases of Stargardt disease,3o fundus flavimaculatus and fundus albipunctatus,31 and
Best dystrophy, as well as in pattern dystrophy.32 A normal response was observed in a
patient with X-Iinked juvenile retinoschisis.3 Normal responses to Diamox were observeQ in individual patients with either
Stargardt disease or X-Iinked retinoschisis.3
A summary of nonphotic standing potential
responses in various retinal diseases is available in a review by Kawasaki et al.33
THE EOG IN RETINAL DISORDERS

Although the various components of the
EOG are not precisely understood, their
variability in various disease states provides
both a better understanding
of, and a way
to measure, retinal malfunction.
The following sections describe the deviations
from normal caused by various disorders.
HEREDITARYMACULAR DYSTROPHIES
2-4-1 Stargardt Macular Dystrophy
The clinical features seen in patients with
Stargardt macular dystrophy, or fundus flavimaculatus, are described in Section 1-11-1
of Chapter 1. Although initial investigators
reported abnormal EOG ratios in the majority of patients with fundus flavimaculatus,34
subsequent studies showed that abnormal
ratios were consistently found primarily ia
advanced stages of the disease.35 Further,
the recording procedure (full-field
bowl
versus a flat-surfaced view box) was found
to influence whether normal or abnormal
EOG responses were obtained.36
2.4.2 Best Macular Dystrophy
Best vitelliform
macular dystrophy manifests an appreciably reduced EOG ratio not
only in patients at an early stage of evident
disease,37-42 but also in those who have inherited the gene yet show no clinically apparent funqus changes.43,44 In instances
when only one eye manifests a clinically
apparent retinal lesion, both eyes show reduced EGG ratios.37,38 Further, normal
EGG ratios help distinguish patients with
other disorders, such as adult-onset foveomacular pigment epithelial dystrophy45 and
pseudo-Best dystrophy,46 that manifest
vitelliform
lesions phenotypically
similar to
those seen in Best dystrophy. Weleber29
found that not only was the EGG slowoscillation light-peak subnormal, but also it
was delayed in reaching its peak in patients
with Best macular dystrophy.
164
243
The
Electro-Oculogram
Pattern Dystrophies
In pattern dystrophies, EOG light-peak to

dark-trough ratios are most frequently either normal or modestly subnormal,47-54 but
occasionally, marked reductions have been
observed.,)4,.)5 Nevertheless,
in most instances, a normal or only slightly reduced
EGG ratio is a useful distinguishing
feature
between patients with pattern
and those with Best dystrophy
dystrophy
when the di-
agnosis is uncertain because of a possible

overlap in the clinical phenotypes of these
genetically different disorders. The pattern
dystrophies are described in greater detail
in Section 1-11-3 in Chapter 1.
2-4-4 Drusenof Bruch's Membrane

A dominantly
inherited genetic disease,
drusen of Bruch's membrane includes patients who present with yellow or yellowwhite deposits generally, but not always,
most distinct and most numerous in the
macula. Both interfamilial
and intrafamilial
variations in expression are frequently encountered. Patients described in the ophthalmic literature with Hutchinson- Tay
choroiditis, Holthouse-Batten
superficial
chorioretinitis,
Doyne honeycomb retinal
dystrophy, malattia Leventinese,
and familial choroiditis all likely have a form of dominantly inherited drusen. The German word
druse means "nodule" and refers to areas of
clear crystallization
in rocks. Drusen can
result either from a known genetic trans-
mission or, apparently, as a consequence of

aging. However, a clear distinction
between
familial drusen and age-related drusen is
sometimes difficult to make, and some observers question whether such a distinction
is necessarily valid.
Over time, either an atrophic-appearing
lesion or an exudative change associated
with the development
of choroidal neovascular membranes can develop in the macular region. A mutation in a fibrillar-like
extracellular matrix protein has been identified in families with malattia Leventinese
and Doyne honeycomb retinal dystrophy.s6
Although initial studies reported reduced EGG light-peak to dark-trough ratios
in patients with dominantly
inherited familial drusen of Bruch's membrane,s7 subsequent investigations
showed that the majority have EGG ratios in the normal range,
particularly if a full-field
bowl, rather than
a flat-surfaced view box, is used for the
recordings.s8 Sunness and Massof59 also reported normal EGG finding in patients
with drusen as part of age-related macular
degeneration when a focal EGG procedure
was used. Electroretinogram
(ERG) amplitudes are characteristically
normal in patients with familial
drusen.
2-4-5 Membranoproliferative Glomerulonephritis

Membranoproliferative
glomerulonephritis
(MPGN) is a form of progressive chronic
glomerulonephritis
with an onset usually in
childhood. It presents as hematuria and
proteinuria. Three distinctive types have
been identified.
In MPGN type II, electron-dense deposits are characteristically
observed in glomerular capillary and extraglomerular basement membranes of the
kidney. Similar electron-dense
material has
been identified
in Bruch's membrane and
2-,,) Diffuse
in the choriocapillaris.6
Clinically,
sions appear as bilateral,
yellow, drusen-Iike
these le-
lesions, most dense at the posterior pole,

but also extending into the midperipheral
retina.61 Other clinical features include62
1. An increased susceptibility
2. Partial lipodystrophy
3. Higher
Additional
velopment
prevalence
Dystrophies
165
Best macular dystrophy. ERG cone and

rod recordings show subnormal cone and
rod a- and b-wave amplitudes.69
for infections
DIFFUSE PHOTORECEPTORDYSTROPHIES
of diabetes mellitus
retinal findings include the deof subretinal neovascular mem-
branes, detachment of the RPE, and central

serous retinopathy.62-6)
EOG ratios may be normal or subnormal,62,66while ERG amplitudes have been
described as normal.66 Not surprisingly,
patients with abnormal EOG findings are
more likely to show an extensive retinopathy and, in one report, a higher frequency
of subretinal neovascular membranes.62 Vision in patients with MPGN is usually not
affected unless choroidal neovascularization,
subretinal fluid, and/or a detachment of the
RPE occurs.61,62
2-5-1 Rod-Cone Dystrophies

'I'hc EGG is often abnormal in patients
with RP. In early stages, variable results are
obtained when attempting
to evaluate th~
diagnostic sensitivity of the EGG compared
to ERG amplitudes. Although in later stages
the two tests generally parallel each other in
severity of impairment,
Gouras and Carr70
noted that abnormal EGG ratios paralleled
abnormal cone ERG functions and both
were preceded by abnormal rod ERG functions in patients with early RP. In patients
with RP and appreciable reductions in
ERG rod and cone function, measurement
of EGG ratios provides little if any important additional
2-4-6 Ectodermal Dysplasia, Ectrodactyly,

and Macular Dystrophy
'l'he main features of this rare syndrome,
abbreviated
syndactyly
malities of
teeth, and
terior pole
Photoreceptor
as EEM syndrome, include

or split hands and feet, abnorthe hair (hypotrichosis)
and
pigmentary changes of the posof the retina.67-69 The ocular
changes include decreased central vision

associated with both hypopigmentation
and pigment clumping primarily in the
macular region. Choriocapillaris
atrophy is
also observed, while the optic disc, retinal
vessels, and peripheral retina are characteristically normal. The EOG light-peak to
dark-trough ratio is markedly reduced,
similar to that observed in patients with
diagnostic
information.
2-5-2 Cone and Cone-Rod Dystrophies

Abnormal EGGs have been noted in some
patients with acquired cone and cone-rod
dystrophies.71,72 Congenital achromats tend
to have normal EGG values. Similarly, patients with progressive diffuse cone dystrophy tend to show normal EGG light-peak
to dark-trough ratios, while those with diffuse rod, as well as cone, disease show a reduction in EGG ratios.
166
CHORIORETINALDYSTROPHIES
STATIONARYNIGHT-BLINDING DISORDERS
2.6.1 Congenital Stationary Night Blindness
The EGG appears normal in autosomal
re-
cessive and X-Iinked recessive congenital

stationary nyctalopia with the SchubertBornschein type of ERG waveform.73 A
reduced light rise occurs in the autosomal
dominant form with the Riggs type of
Patients with choroideremia,

gyrate atrophy, or diffuse choroidal atrophy show abnormal EGG values. Generally, the abnor.
mal values are noted at an early stage of
disease and often parallel the extent of
diminished
ERG amplitudes.
ERG waveform.
INFLAMMATORYCONDITIONS
2-6-2 Oguchi Disease

Although a normal EOG light-peak to darktrough ratio in patients with Oguchi disease
was observed by Carr and Ripps,74 Miyake
et aJ75found abnormally low EGG ratios in
all 6 patients whom they studied. Combining these 6 patients with 15 additional patients from ten previous reports, these authors observed that EGG ratios were reduced overall in 20 of 21 patients
Oguchi
As with the ERG, local inflammatory

disease does not affect the EGG. In the presence of diffuse, generally chronic chorioretinal inflammation,
the EGG light-peak
to dark-trough ratio is subnormal. The degree of subnormality
usually correlates with
the extent of clinically apparent disease and
its noted effect on the ERG.
with
disease.
2.6.3 Fundus Albipunctatus
CIRCULATORYDEFICIENCIES
In patients with fundus albipunctatus,

the
EGG will not show a notable light rise if
Occlusive disease of the cent tal retinal artery and its effect on the EGG light rise
have been mentioned in Section 2-2. cir-
the procedure is performed in the usual

manner, with a period of dark adaptation of
approximately
15 min. However, a normal
light rise and EGG ratio will be found if a
dark-adaptation
period of several hours is
obtained
prior to light exposure.
culatory
thalmic,
deficiencies in the carotid, ophand choroidal vessels would be ex-
pected to affect the EGG ratio, although

Ashworth 76reported the EGG to be normal
in 3 of 4 eyes on the side of a carotid occlusion. In 5 eyes with hypertensive
retinopathy, also evaluated by Ashworth,76 the EGG
was clearly abnormal in 3. Normal or abnormal findings are likely to depend on the degree of induced
retinal
hypoxia.
2 -10
2-10-1 Chloroquine and Hydroxychloroquine

findings
in EOG, as well as ERG,
recordings, such as a reduction in the lightpeak to dark-trough ratio and reduced amplitudes, respectively, have been reported
in patients receiving antimalarial drugs, such
as chloroquine
and hydroxychloroquine,
which are also used for arthritis. These
changes tend to occur after prolonged administration
of the drugs and when funduscopic evidence
of foveal and, not infre-
quently, peripheral retinal pigmentary

changes are already in evidence. Thus,
these electrophysiologic
tests are not likely
to identify patients who are developing
retinopathy
at a sufficiently
early stage to
warrant their use in monitoring
patients for
signs of eatly retinal toxicity. As noted in
the discussion on the ERG and toxic conditions {Section
1-17 in Chapter
1), static
perimetry testing of the central 10 provides a more reliable means of monitoring

such patients.
Pinckers and Broekhuyse77 reported that
subnormal EOG ratios were recorded in
only 37% of patients with known retinal
toxicity and bull's-eye maculopathy as the
consequence of treatment with chloroquine
or hydroxychloroquine.
Gouras and GunkeJ78 also observed that the EOG was not a
sensitive indicator of mild degrees of chloroquine retinopathy, particularly in patients
no longer receiving chloroquine therapy.
Pinckers and Broekhuyse77 suggested that
an undetlying
systemic disorder, such as
rheumatoid
arthritis,
Conditions
167
bute to an abnormal EOG ratio, independent of the use of these drugs. They noted
the EGG to be subnormal in 20% of patients. Therefore, the interindividual
and
TOXIC CONDITIONS
Abnormal
Toxic
may in itself contri-
intraindividual
variability of the EGG, as
well as its questionable diagnostic sensitivity, precludes
its value as a means of pre-
dictably diagnosing early functional impairment or in monitoring for progressive retinal deterioration
in those patients receiving
these drugs.
2-10-2 Didanosine
Oidanosine (2',3'-dideoxyinosine)
is a
purine analog with antiretroviral
activity
that has been used in the treatment of patients with human immunodeficiency
virus
(HIV) disease. Observed toxic effects include pancreatitis, peripheral neuropathy,
optic neuritis, and retinopathy. The retinopathy has been reported mainly in children,79,8o but also in adults.81 The retinal
lesions first appear as patches of RPE mottling in the midperipheral
retina, Subsequently, the mottling evolves into more circumscribed lesions, with both RPE and
choriocapillaris
atrophy, and still later the
lesions develop into retinal pigment clumping at their margins,
Of 94 children being treated with didanosine and monitored by Whitcup et al,79,8
4 developed retinal lesions attributed to its
use, The authors noted that visual acuity
remained normal. The lesions progressed
while the patients were taking didanosine,
even when the dosage was reduced. However, progression
appeared to stop when the
168
drug was discontinued.

EGG measurements were obtained on 3 of the 4 children:
2 had normal EGGs, while 1 showed a reduced light-peak to dark-trough ratio. This
same patient showed a modest reduction in
the maximal dark-adapted ERG response,
while the rod-isolated and cone single-flash
and flicker responses were normal.79 In this
patient, when the drug was discontinued,
the EGG ratio returned to normal. Histopathologic findings on the retina from 1 of
the 4 patients showed multiple areas of
RPE loss, some of which areas were partly
circumscribed
by hypertrophy
or hypopigmentation of the RPE. Partial loss of the
2.10.3 Deferoxamine
Abnormal EOG light-peak to dark-trough
ratios have been reported with the use
of deferoxamine,
a chelating agent, also
known as desfemoxamine.83-86 (For a more
detailed discussion, see Section 1-17 in
Chapter 1.) In isolated patients, abnormal
EOG ratios have been reported in the presence of normal ERG responses.83,86 Overall,
EOG function is more impaired than ERG
amplitudes.83.84.86 As with ERG amplitudes,
EOG ratios often improve after deferoxamine is discontinued.
choriocapillaris
and neurosensory retina was
also noted in the areas of RPE cell degeneration. Transmission electron microscopy
showed numerous membranous lamellar inclusions and cytoplasmic bodies in the RPE
cells.82 These histologic findings support
the hypothesis that didanosine initially and
primarily affects the RPE, a hypothesis
consistent with the abnormal EGG ratio observed in 1 of the 4 children who showed
clinical signs of retinal toxicity. N evertheless, the true value of electrophysiologic
testing in patients treated with didanosine
remains to be better defined. It would
seem, however, that patients being given
high dosages warrant ongoing and careful
monitoring with fundus examination (with
dilated pupils) and indirect ophthalmoscopy and possibly periodic EGG measurements when early signs of a possible toxic
retinopathy
are suspected.
OPTIC NERVE DISEASE

As might
be anticipated,
primary
disease of
the optic nerve does not affect the EOG

light-peak to dark-trough ratio. In fact, transection of the optic nerve proximal to the
entrance of the central retinal artery does
not diminish the EGG response to light.87.88
MISCELLANEOUSCONDITIONS
2-12-1 Retinal Detachment
As with the ERG, the degree of retinal
detachment is reflected in a progressively
abnormal EOG ratio. This abnormal ratio
indicates the necessity for maintaining
the
physical contiguity of the rod and cone
outer segments and the RPE for proper
generation of EGG responses.
2-12-2 Silicone Oil
Thaler et alHYrecorded EGG measurements
before, shortly after, and up to 4 months
following
the removal of intravitreal
sili-
2 -12
cone oil in 6 patients treated for retinal

detachment. An increase in the standing
potential was observed in all eyes after removal of the silicone oil. The use of silicone oil resulted in the absence of measurable fast oscillations and virtually no recordable slow oscillations. The authors speculated that this impairment
in development
of the light rise resulted from alterations of
the retina and photoreceptor-RPE
interface
from the pre-existing retinal detachment.
Foerster et a19noticed that the baseline
EGG standing-potential
amplitude was low
as long as silicone oil was present in the vitreous, but increased to at least twice the
initial value after the oil was removed in
12 patients treated for complicated retinal
detachments. However, an appreciable increase in the light peak from baseline occurred in only S of the 12 patients after the
silicone oil was removed. Followup studies
did not show a notable recovery in these
two EGG measures.
2-12-3 Diabetic Retinopathy
Henkes and Houtsmuller91 reported that an
abnormal EGG may occur in patients with
diabetes before changes in either the fundus or the ERG amplitude are apparent.
The EGG allegedly deteriorates with the
duration of diabetes and, consequently,
with the severity of the retinopathy. This
area has not, however, been extensively investigated. Kawasaki et al6 reported an abnormality in the hyperosmolarity-induced
response to intravenous mannitol in patients with diabetic retinopathy.
2.12.4 Intraocular Foreign Bodies
Patients with retained intraocular iron particles (siderosis bulbi) show EGG abnormalities, Because the number of cases studied
M iscellaneous
169
Conditions
has not been extensive, it is unclear how

early in disease progression these EOG
changes might be observed. Some investigators maintain that the EGG is a sensitive
way of monitoring the early changes of
siderosis. Good and Gross92 conclude that
the EGG is a better indicator of visual prognosis than is the ERG.
2.12.5 Myopia
Because histologic changes occur in degenerative myopia in both the RPE and the
choroid, an abnormal EGG ratio is antici-4
pated and, in fact, is found in some patients
with the typical fundus changes associated
with progressive high myopia. However,
Thaler et al93 noted a linear decrease of the
light peak with increasing axial length of
the eye, even in the absence of clinically
apparent degenerative changes in the retina
associated with myopia.
2-12-6 Choroidal Malignant Melanoma
A reduction
in the EGG light-peak
to dark-
trough ratio in patients with choroidal melanoma was first reported by Ponte and Lauricella.94 Subsequent investigators noted
similar findings,95-97 and two studies have
suggested that EGG measurements may be
useful in differentiating
between a choroidal nevus and a malignant melanoma.95.97
A reduction in the EGG light-peak to darktrough ratio may be observed in the presence of a choroidal melanoma with or without the occurrence of a retinal detachment
and is independent
of whether the clinically apparent size of a tumor is judged as
small or large. Further studies are necessary
to determine the physiologic basis for these
observations.
170
8. Linsenmeier
Effects
SUMMARY
RA, Mines
of hypoxia
AH, Steinberg
and hypercapnia
peak and electroretinogram

Ophthalmol
The EOG has been applied widely to the

study of various retinal disorders. Its use in
hereditary macular diseases, such as Best
macular dystrophy and the various pattern
dystrophies, is particularly appropriate. Its
value in the various stationary and progressive night-blinding
disorders seems questionable, because the ERG either provides
more diagnostically
definitive
information
or allows the investigator to predict what
the EGG findings are likely to be.
RH:
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gram findings.
eye. Ophthalmologica
P, Scheiber
94. Ponte F, Lauricella
New clinical
based upon the standing
of the eye. Br J OphthalmoI1962;46:
Goldberg
A, Heilig
of myopia
potential
function
diseases: electroretinogram
(free radical)
1988; 196:204-209.
93. Thaler
GB, Barrada A, Kelsey ]H:
test of retinal
449-467.
91. Henkes
SUGGESTEDREADINGS
of the eye. Doc
In: Krill
Hereditary
Diseases. Hagerstown,
AE,
Retinal and
MD:
Harper
&
Row; 1972;1:227-295.
Marmor
retinal
MF: Clinical
pigment
electrophysiology
epithelium.
of the
Doc Ophthalmol
1991;76:301-313.
Marmor
MF, Laurie
M: Light-induced
responses of the retinal

Zinn
KM, Marmor
Epithelium.
electrical
epithelium.
In:
MF, eds: The Retinal Pigment
Cambridge,
Press; 1979:226-244.
pigment
MA: Harvard
University
Suggested Readings
Potts AM: Electrophysiological
measurements.
In: Potts AM, ed: The Assessment of Visual Function. St Louis:
cy
Mosby
Reeser F, Weinstein
Co; 1972:187-206.
GW, Feiock
KB, et al: Elec-
tro-oculography
as a test of retinal function: the
normal and supernormal
EOG. Am J Ophthalmol
1970;70:505-514.
Steinberg, RH: Monitoring
communications
tween photoreceptors
and pigment epithelial
cells: effects of "mild"
Ophthalmol
Weleber
systemic
hypoxia.
be-
Invest
Vis Sci 1987;28: 1888-1904.
RG, Eisner
A: Retinal
function
and
physiological
studies. In: Newsome DA, ed:
Zrenner
E, ed: Special lists of Visual Function.
Basel: S Karger AG; 1984; vol 9 of Developments in Ophthalmology.
175
David G. Birch, PhD
The retinal cone system in humans is spatially heterogeneous. The density of cone
photoreceptors
and the composition of cells
in the cone pathway change substantially
with eccentricity. The focal and multifocal
electroretinograms
(ERGs), two techniques
deriving from distinctly different traditions,
have arisen in response to this spatial heterogeneity. The focal ERG represents an
extension of full-field
ERG technology. It
uses a focal test stimulus centered within a
steady surround to elicit submicrovolt
responses from regions as small as 3. The
focal ERG is used primarily to test the integrity of the fovea. This chapter reviews
focal ERG methodology
and shows that
the focal ERG can be useful for discriminating vision loss due to macular disease
from vision loss due to causes other than
maculopathy.
The multifocal
cross-correlational
ERG uses a powerful

approach to derive re-
sponses from dozens of focal locations

across the central 40 or so of retina. After
describing techniques, recording procedures, and normative data, the chapter reviews recent insights into retinal diseases
derived from this novel approach. Finally,
the chapter outlines the promise of the
multifocal ERG as a sensitive diagnostic
indicator of inner retinal disease.
THE
FOCAL
ERG
The conventional
full-field
(ganzfeld) ERG
is a mass response to diffuse illumination
of
the retina and is abnormal in amplitude
only when large areas of the retina are functionally impaired. Although cone density is
highest in the fovea, the total number of
cones in the macula (a region approximately 5 mm or 20 in diameter) represents
only 9% of the total cone population.l,2 As a
result, diseases limited to the macula typically do not produce full-field
ERG abnormalities. The focal ERG (also calledfoveal
ERG) has evolved as a method for providing an objective measure of the functional
integrity of the macula.
With the advent of computer averaging,
several techniques have evolved for recording the small responses from localized retinal regions. While the techniques differ in
detail, each has had to deal with the
lem of stray light. The challenge for
focal ERG is to record the response
focal test stimulus while eliminating
probthe
to the
the re-
sponse to light, which is inevitably scattered outside the focal test area. Each tech-
177
178
TheFocal and Multifocal Electroretinogram
nique has also had to isolate the response

from foveal cones by suppressing the large
response from rods. Generally, these two
technical challenges have been met by
using a temporally modulated test stimulus
stimulus to mask stray light and enable direct visualization of the fundus during testing. The Maculoscope from Diagnosys
LLC is a commercial device employing
many of the same principles.
surrounded by a steady background.

Full-field
domes can be modified to
record focal ERGs, either by mounting a
Grass photostimulator
behind a 4 aper-
3-1-1 Recording Procedure
ture3 or by mounting a stimulus array

within the dome.4.5 A commercially
available modification
for the LKC Technologies system uses a 10 array of light-emitting diodes to elicit a focal response from
the macula. The background light from the
full-field
dome ensures that the response is
cone-mediated
and masks stray light. In
general, the focal stimulus should be dimmer than the background.6.7
Focal ERGs have also been recorded
through modified fundus cameras.8-10 An
infrared television fundus camera can be
used to monitor the location of the stimulus
relative to the macula. The stimulus, background, and fixation target are mounted
within the optics of the fundus camera and
provide adjustable stimulus size, frequency,
and intensity. Miniature versions of the
conventional
ERG, complete with a-wave,
b-wave, and oscillatory potentials can be
recorded with stimulus sizes as small as 5.
An effective method of testing with direct visualization of the fundus is tbe handheld stimulator-ophthalmoscope
first described by Sandberg and Ariel.l1 This
device produces a white flickering (42-Hz)
stimulus of 3 or 4 centered within a steady
10 white annular surround. The intensity
of the annulus is higher than that of the
Regardless of the device used to elicit focal

responses from the patient, the challenge is
to record reliable sub microvolt responses to
the stimulation.
Responses are recorded
from the anesthetized (0.5% proparacaine
hydrochloride)
and dilated (2.5% phenylephrine hydrochloride
and 1% tropicamide)
eye, typically with a bipolar contact-lens
electrode. A cup electrode attached to the
forehead serves as a ground. After amplification, either analog or digital filtering is
used to enhance that component of the response that is locked in time to the stimulus. Typically, more than 200 responses are
averaged on-line with a computer employing an artifact reject to eliminate sweeps
containing voltages >1 pV (pV = microvolt),
presumably due to blinks and eye movements. The examiner controls data acquisition so that ERGs are acquired only when
the test is centered on the retinal area of
interest (Figure 3-1 ).
With a hand-held device like the stimulator-ophthalmoscope,
the focal ERG is easiest to record if the patient is reclining. It is
helpful to begin with a quick examination
of the fundus while the contact lens is on
the eye. Retinal landmarks and the appearance of the foveal avascular zone should be
noted. The examiner then asks the patient
to look directly at the small central test
spot. If the patient fixates eccentrically or is
unable to see the test spot, the examiner
asks the patient to look at a reference point
on the ceiling and visually places the flickering test on the fovea.
3-1
The
Focal
ERG
179
3.1.2 Normal Values

Normal
values for the focal ERG vary with
recording parameters and stimulus configuration. Table 3-1 shows mean normal amplitude values for stimuli centered on the
foveola as a function of stimulus diameter,
repetition rate, and retinal illuminance.
Clearly, there is no established standard for
the focal ERG, and each laboratory should
establish norms for its particular system.
In determining
whether a focal response
lies within the normal range, the examiner
should also consider the patient's age.12,13
There is a significant decrease in cone
ERG amplitude with age in the fovea, but
not in the parafovea. Therefore, the regression lines relating each measure to age have
significantly
different slopes. This leads to
an age-related change in the ratio of foveal
to parafoveal amplitude and should be considered when using the ratio as an index of
normalcy. Implicit time (or phase) criteria
can be used in conjunction
with amplitude
criteria to increase the sensitivity of the
focal ERG to abnormal
macular function.14
3.1.3 The Focal Rod ERG

Two techniques have been successfully
used for recording the focal rod ERG. In
the dark-adapted eye, the problem of light
scatter is greater than for the focal cone
ERG because an annulus or background to
mask the stray light cannot be used. However, the small focal rod b-wave response to
a test spot 30 in diameter can be distinguished from the larger, but slower, straylight response.15 The stray-Iight response
can be ignored, or it can be eliminated by
subtracting the matching rod response to
a dimmer, full-field
flash. Alternatively,
focal rod a-waves can be isolated with a twoflash paradigm to stimuli 40 in diameter.16
Figure 3-1 Representative focal ERGs from normal

subject. Each trace shows four cycles of response, with
stimulus onset indicated by vertical spikes. Two repetitions of each average are shown to demonstrate importance of consistent phase relationships between
stimulus and response. Representative responsesfrom
normal subject were obtained from fovea and parafovea {midway betweenfovea and optic disc). Data in
occluded condition were obtained with stimulus falling
on eyelid.
Redrawn with permission of Kluwer Academic Publishers
from Birch DG, Fish GE: Focal coneelectroretinograms:
aging and macular disease.Doc OphthalmoI1988:69:
211-220.
180
The Focal and Multifocal
Electroretinogram
TABLE3-1
Normal
r)
Valuesfor
Focal
ERG
Stimulus
Repetition
Rate Illuminance Amplitude Reference
(trolands)
(IIV)
(Hz)
42
4.8
0.31
12
3.2
0.66
38
42
4.8
0.43
22
3.2
1.27
21
10
40
3.4
5.6
20
10
30
3.4
5.4
20
10
10
3.4
7.8
20
10
3.2
2.88
21
15
3.2
4.96
21
3
3.75
3.1.4 The Focal Cone ERG in Retinal Disorders

The corneal response to focal luminance
modulation originates primarily in the photoreceptor and inner nuclear layers of the
retina. Low stimulus rates produce a transient ERG with a waveform
similar to that
of the full-field
ERG, including a-waves,
b-waves, and oscillatory potentials.7,8 High
repetition rates produce a sinusoidal response localized with photoreceptor
and
bipolar contributions.17 Clinical studies have
shown that the focal ERG is normal in patients with optic nerve disease18 and amblyopia.l0 Because the focal ERG is unaffected
by diseases of the ganglion cell layer and
optic nerve, it is useful for discriminating
eyes with macular disease from eyes with
visual acuity loss due to other causes.
To evaluate the diagnostic value of the

focal ERG, responses in eyes with maculopathy were compared to responses in eyes
with reduced visual acuity due to causes
other than maculopathy (including amblyopia, cataract, and optic neuropathy).19
When both amplitude and implicit time of
the focal ERG were used as criteria, the
overall accuracy for discriminating
maculopathy from other causes of visual loss was
87%. The focal ERG was highly specific,
because 96% of eyes without maculopathy
had normal focal ERGs. Sensitivity was also
high, because 85% of eyes with maculopathy had reduced and/or delayed focal
ERGs. Thus, for a patient with visual acuity <20/40, a normal focal ERG makes it unlikely that the visual acuity loss is due to
macular disease. A possible exception may
be in eyes with aphakic cystoid macular
edema, where 65% of the patients tested
had normal focal ERG amplitudes.2
Because the focal ERG is generated exclusively by macular cones, there tends to
be a correlation between focal cone ERG
amplitude and Snellen visual acuity in patients with retinal disease involving the
macula (Figure 3-2).12,19Reduced focal ERG
amplitudes have been reported in most patients with central serous retinopathy7,21
and in virtually all patients with either Stargardt disease or retinitis pigmentosa with
visual acuity <20/40.4,22 However, focal cone
ERGs may also be reduced in eyes with
macular disease retaining visual acuity
>20/40.12 One possible explanation for this
finding is that a relatively small number of
healthy cones in the foveola may be sufficient to support good visual acuity, whereas
a normal focal ERG requires healthy cones
throughout the fovea. While reducing the
overall correlation between visual acuity
and foveal amplitude, these false positives
3-1
have prognostic
implications,
because these
The
Foco/
ERG
181
0.35
eyes typically lose vision over time.

In nonexudative
age-related macular
degeneration (AMD), there is a significant
relationship between focal ERG amplitude
and severity of the fundus lesion, as indexed by the Wisconsin AMD grading system.23 However, even eyes with minimal
fundus abnormalities
and normal visual
acuity had lower than normal focal ERG
amplitudes, again suggesting that focal
ERG abnormalities
may precede the detectable morphologic change typical of
more advanced disease. Similarly, it has
been reported that focal cone ERGs can
be delayed in implicit (peak) time prior to
any amplitude decrease in fellow eyes with
normal visual acuity in patients with unilateral neovascular AMD.24 The findings suggest that these patients can have foveal
cones that are normal in number but that
function abnormally.
It remains to be determined whether
the focal cone ERG will be of prognostic
value in identifying
eyes at high risk for
neovascularization.
Early macular dysfunction has also been detected with the focal
ERG in non-insulin-dependent
diabetes
mellitus before the appearance of diabetic
retinopathy.25 Because these patients were
not observed prospectively, the prognostic
significance for the development
of diabetic retinopathy is not known. It is possible that the focal ERG abnormality is a
secondary manifestation
of metabolic
derangement.
Focal cone ERGs may be of value for
identifying
fellow eyes of patients with unilateral macular holes that are at risk for hole
formation.26 In addition, the implicit time
of the preoperative focal ERG may be useful for predicting postoperative visual acuitv after macular hole sur!!erv.27
0.30
0.25
~
"'
"0
~
~
E
"'
ro
~
.z
0.20
0.15
0.10
0.05
0.00
Figure 3-2 Relationship
between focal cone ERG am-
plitude and Snellen visual acuity in 134 eyeswith

retinal disease involving
macula. Shaded area reP11
sents :t1 standard error of mean for foveal amplitudesfrom
normal eyes.

from Birch DG, Fish GE: Focal coneelectroretinograms:
aging and macular disease.Doc OphthalmoI1988:69:
211-220.
182
Electroretinogram
The focal cone ERG can be used to assess macular function in eyes with opacities.28 Because of its Maxwellian
view optics, the stimulus enters the pupil as a very
small l-mm)
beam. In most eyes with
cataract, the examiner can effectively move
around the pupil while keeping the test on
the macula until a relatively clear view is
obtained. Clear optics are not essential in
this test because the stimulus is relatively
large (3) and minimally affected by light
scatter or blur. An abnormal focal cone
ERG amplitude is not likely to be caused
by the cataract, but should alert the physician and patient to the possibility of coexisting
macular disease.
THE MULTIFOCALERG
Traditional focal ERG technology is an extension of full-field
ERG technology, in
that similar recording and signal-averaging
techniques are used for both. The difference is in the size of the stimulus. In principie, it would be possible to record focal
ERGs from multiple regions across the
retina to determine the topography of retinal sensitivity. In practice, however, time
constraints limit recording to two or three
locations and preclude screening large retinal regions by sequential mapping. Furthermore, the sehsitivity of the focal technique with sequential recordings is compromised by the difficulty
of separating
true variation among retinal regions from
variability in the responses over time.
An innovative
solution
tions of the traditional

record simultaneously
to these limita-
focal ERG is to
from multiple retinal
areas. This powerful technology, originated

by Erich Sutter in the early 1990s, was
made possible by the advent of powerful,
yet affordable computers and high-intensity
display monitors. The technique is new
and, to a certain extent, still experimental;
for example, very few papers have addressed such issues as trial-to-trial
and intersubject variability. Nevertheless,
the
current interest in, and potential of, the
technique are sufficient to warrant an
overview at this time.
The stimulus for the multi focal ERG is
presented on a video monitor and consists
of one of a large number of available arrays.
In general, the elements in an array are
scaled with eccentricity
so that focal retinal
responses with approximately
equal signalto-noise ratios are produced across the field
in normal subjects. At any given moment,
about 50% of the locations in the array are
at a high luminance (white) and the other
locations are at a low luminance (black).
The stimulation rate is the number of times
per second that the display is changed and
is a multiple of the frame rate of the video
monitor (typically, 75 Hz). With every
change in stimulation,
each element in the
array has a probability
of 0.5 of being light
or dark. Each element in the array is stiniulated with the same pseudo-random
sequence of light and dark, called a maximumlength sequence(or m-sequence), but this sequence is lagged by different amounts for
each location. Because the m-sequences are
lagged by different amounts for each element in the array, the responses associated
with these elements are effectively uncorrelated when the lags are much greater than
the duration
of the response.
3-2
The local response for each element
in
the array is computed as the cross correlation between the m-sequence and the response cycle. This response, the first-order
component, can be thought of as the average response from a particular retinal area
unaffected by stimulation at any other region, that is, a linear approximation
of the
response of the small retinal region. A nonlinear response, the second-order component, represents temporal interactions
between flashes when the lags are short
relative to the duration of the response.
The traditional output from the multifocal test is a topographic display of miniature
waveforms. Although these responses bear
a superficial resemblance to the fuIl-field
ERG in showing both a negative and a positive peak, they do not match the fuIl-field
waveform in complexity
or implicit time
(Figure 3-3). This is due primarily to differences in stimulus parameters between the
two
The Multifocal
ERG
183
3.2.1 Recording Procedure

Methods for recording the response are
similar to those for more traditional ERGs.
Typically, the eye is dilated and a ground
electrode is attached to the forehead. The
contralateral eye is occluded with light
pressure to suppress blinks. Prior to insertion of the recording electrode, the cornea
is anesthetized with proparacaine hydrochloride. The recording electrode itself is
typicallya
bipolar contact-lens electrode,
although a variety of electrodes have been
used successfully, including the DawsonTrick-Litzkow
(DTL) fiber electrode, the
Hawlina-Konec
(H-K) loop scleral electrode, and the gold-foil electrode. Many investigators test visual acuity at the distance
used for response recording after inserting
the electrode. When necessary, the vision of
the patient can be corrected for best acuity
by placing a large-diameter
lens in front of
the test eye prior to recording.
The entire multifocal recording
time
depends on the particular m-sequence

and stimulation rate; 8 minutes is a typical
et al29 simulated the traditional full-field
condition of a single flash on a background
by establishing a background luminance
for the multifocal ERG and slowing the
m-sequence with interjecting
7 frames at
the background luminance. Under these conditions, there was excellent agreement between the waveforms (including oscillatory
potentials) and implicit times of the multifocal ERG and full-field
ERG. The negative wave of the multifocal ERG appears to
reflect the same components as the a-wave
of the full-field
ERG, and the cellular basis
of the positive waves of the multi focal ERG
appears to be similar to that of the positive
components of the full-field
ERG.
duration. Because eye movements, blinks,

and losses of fixation can saturate amplifiers
and completely overwhelm tiny focal responses, most investigators use multiple
overlapping recording segments of approximately 30-s duration. These are separated
by brief rest periods and joined off-line to
reconstruct the complete cycle of response
to the m-sequence. Any segment containing a substantial
and repeated.
artifact can be discarded
184
TheFocal and Multifocal Electroretinogram
Radius25
~
White
~""
Frame
-1
~
I
-I..
Cross
correlation
.
..\. .J... "'~ .,..J., 01..
J., ..,...,
Jo..
J.,
""'
~"",.\.0.\.0Jo...
-~~.'
\...f\,
."V'-"r~..'...'..\.
.A. .A.
,..
~ .~I,.. J.yo -iIt' -i'V'
..\.,A..
~
\.~.''~~~~
~~~~~..'...'~.fI,.\.0""'
.,... ~~ 0.\.~ 0.\.'""'01..
.J.,'""'""" ,., ""'
,
.J'v
I Summedmultifocal(all areas)
Black = 2 cd.m-2
White = 400 cd.m-2
10
20
30
40
50
60
Time (ms)
3-2
Figure 3-3 Comparison of full-field

paradigms.
(A) Forfull-field
at fixed inter stimulus interval
and multifocal
cone ERG, briefflashes

( ISI) are presented as
increments of intensity (~/) on background (B). Cone

a-wave and multiple positive peaks associated with
b-wave are shown. (B) Typical display employed in
multifocal paradigm.
Each hexagon in display is
stimulated by same sequence of black and white, but

sequence is lagged by different lengths for each location. F or comparison to full-field
The Multifocal
ERG
185
tricity. The population range-:t2

SO
(SO = standard deviation)-of
response
density was 0.42 log unit, similar to that of
standardized full-field
electroretinography.33 Responses obtained from eyes with
myopia should be interpreted with caution,
because reduced amplitudes and prolonged
implicit times are significantly
correlated
with refractive error.34
ERG, 103 focal
ERGs were summed to produce response at bottom.

Redrawn with permission of Cambridge University Press
from Hood DC, Seiple ~ Holopigian K, et al: A comparison of the componentsof the multijocol and ful/-jield ERGs.
Vis Neurosci 1997;/4:5.13-544.
3-2-2 Normal Values

Because the multifocal approach is so new,
relatively little has been published on the
range of normal values and the test-retest
repeatability
of the technique. Based on results from 20 normal subjects, Parks et al30
reported that the spread of normal for multifocal ERG amplitudes is comparable to
the spread in the full-field
ERG. The lower
limit of normal (Sth percentile) in the central area was 27.5 nV/deg2 (nV = nanovolt)
3-2-3 The Multifocal ERG in Outer

Retinal Disorders
Because the gold standard for topographit
retinal sensitivity profiles is the Humphrey
perimeter, it is not surprising that studies of
regional sensitivity loss in retinal disease
have compared the multifocal outcome to
static perimetry. However, the multifocal
ERG has at least two possible parameters,
amplitude and implicit time, for comparison to the field sensitivity profile. Hood et
ai35 emphasized that increases in implicit
time may correlate better than decreases in
amplitude with perimetric sensitivity loss
under some conditions.
The multifocal ERGs in Figure 3-4A
are from a patient with retinitis pigmentosa
compared to a median value of 55.8 nV/

deg2. They also reported that coefficients of
repeatability
based on two tests per subject
ranged from 18% in the central area to 31 %
in the outer ring of the array.
These results are in general agreement
with a second study reporting that the aver-
whose full-field
flicker ERG was small
(7 pV) and very delayed (42 ms).35.36The
sensitivity values in Figure 3-4B were obtained by modifying the Humphrey
analyzer so that the test spot fell in the center
of the 103 hexagons in the multifocal ERG
age coefficient of variation across all regions

was 22%.31 Population response variability
was evaluated in So normal eyes.32 The amplitude of local responses showed a falloff,
with eccentricity
similar to that of the
human cone density profile. Converting to
the logarithm of amplitude yielded roughly
similar variance for responses across eccen-
associated with markedly reduced amplitude. A second typical finding is illustrated
array. The multifocal ERGs are typical for

retinitis pigmentosa patients with only central vision preserved. F or many of these patients, abnormal visual field sensitivity is
186
The Focal and Multifocal Electroretinogram
Figure 3-4 Comparison
of multifocal
ERG responses,
H ulnphrey field sensitivity, and implicit
...;.~--'"
~~.".1.-.,.Jt"",
tient with retinitis pigmentosa and severefield constriction. (A) Individual

from
multifocal
103 retinal locations. (B) Visualfieldsformodi-
~~
..,..-,
ERG responses
fied Humphrey threshold program. Number at each

point is log of ratio of patient:r threshold to mean
,11-~
and dark gray regions signify values >1.0 log unit.

Three points identified as NoN are fixation
wJlJ.iI}~...,,-r"'-'..+-~~vVvV.-A-,.101..IJf.
calculated by subtracting mean implicit

trols from implicit
time for con-
time for patient:r response at each
location. Black hexagons indicate that response did

not reach criterion signal-to-noise
ratio. Clear regions
signify that delay was <1.7 ms, light gray regions indicate that delay was between 1.7 and 3.4 ms, and
dark gray regions signify that delay was >3.4 ms.
Modified with permission of Elsevier Sciencefrom Hood
DC, Holopigian K, Greenstein~ et al: Assessmentof local
retinal function in patients with retinitis pigmentosa using
the multi-focal ERG technique.Vis Res 1998;38:/63-/79.
Also modified with permission of Optical Societyof America
from Hood D, LiL: A techniqueformeasuring individual
multifocal ERG records. In: YagerD, ed: Noninvasive Assessment of the Visual System. Washington,DC: Optical
Societyof America; 1997;11:33-41.
;.-~
,~,
-,p...1.v.I.--,.--\."4-..'...+
~..-'~,.J...,;.-.10
point and
on blind spot. ( C) ERG delay fields
",<"
",",+~~~J\rw~~v"
gions are within 0.5 log unit of mean, light gray regions indicate values between 0.5 and 1.0 log unit,
\'fII.~~.,.,JI~...~-~
threshold of control group for that point. Clear re-
two points falling
".
times in pa-
--"...~
~~
"'*-
3-2
in Figure
3-4C. When responses from re-
gions of depressed visual sensitivity
can be
measured, they are always delayed. The

numbers in Figure 3-4C are the delays in
milliseconds of the responses that could be
reliably measured. (The hexagons in Figure
3-4C without numbers are associated with
responses below a criterion signal-to-noise
ratio.) Note that the central responses have
normal timing, although the full-field
ERG
was delayed. This example is representative of findings in patients with retinitis
pigmentosa. Cone implicit times typically
are delayed relative to normal subjects in
peripheral locations, but normal in implicit
time within the central retina.35-37 These
findings are consistent with previous results
from full-field
and focal ERGs.5,22,38
Figure 3-5 shows the results from a second patient. This patient had a relatively
large, but markedly delayed full-field
flicker ERG. Again, regions of depressed
sensitivity are always associated with delays
in the multifocal ERG, but two additional
findings
are illustrated
here:
1. Regions of near-normal sensitivity can

also show delays. Notice that the region of
near-normal sensitivity is larger than the region of near-normal timing. These regions
of abnormal timing, but near-normal sensitivity tend to be near the boundaries of regions of normal sensitivity, suggesting that
delayed multifocal ERGs may be indicators
of early local damage.35
2. Some patients
can have relatively
large,
although delayed multifocal ERGs in regions of profoundly depressed sensitivity.

In the patient shown in Figure 3-5, relatively large responses are obtained from regions with losses in sensitivity or 1.5 to 3.0
log units (15 to 30 dB). While the physiologic basis for this finding is unclear, it does
The Mu!tifoca!
ERG
187
indicate that the multifocal ERG amplitude

in a particular region is not necessarily a
good predictor of perimetric sensitivity. On
the other hand, all areas with delayed ERG
implicit time
Thus, timing
ERG appear
local damage
with retinitis
had reduced field sensitivity.

changes in the multifocal
to be an early indication of
to the cone system in patients
pigmentosa.35
Diseases such as Stargardt macular dystrophy,39 occult macular dystrophy,4 and

AMD with geographic atrophy41 produce
focal regions in the macula where the mul-l
tifocal ERG is nondetectable.
At more peripheralloci,
ERG responses from patients
with Stargardt disease approach those of
normal subjects, and implicit times are not
markedly delayed at any eccentricity. This
is in contrast to implicit times in AMD,
which appear to be prolonged in all but patients with an early stage of the disease.
These preliminary
results suggest that the
multifocal ERG may be of considerable use
in Stargardt disease, which may be a major
diagnostic problem in some children
the age of IS, and in AMD, in which
under
the
full-field
ERG has been of little value. It
remains to be determined whether the dynamic range of amplitudes and test-retest
repeatability
in patients with Stargardt disease or AMD are sufficient for the technique to be of value in monitoring progression and intervention.
The multifocal ERG can be recorded simultaneously
from detached and attached
retina prior to surgery and can be used to
assess functional recovery after corrective
surgery.42 Unlike visual acuity and visual
field sensitivity, which recover after suc-
188
The Focal and Multifocal Electroretinogram
Figure 3-5 Comparison of (A)multifocal

ERG responses, (B) Humphrey field sensitivity, and (0) implicit times in patient with retinitis pigmentosa and
moderate field constriction. See legend for Figure 3-4
for details.
M odijied with permission of ElstVier Sciencefrom H ood
DC, Holopigian K, Greenstein~ et al.. Assessmentof local
retinal function in patients with retinitis pigmentosa using
the multi1ocal RG technique.Vis Res 1998;38:163-179.
Also modified with permission of Optical Societyof America
from Hood DC, Li L: A techniquefor measuring individual
multijocal ERG records. in: YagerD, ed: Noninvasive Assessment of the Visual System. Washington,DC: Optical
ov\-A-oJ\-J\
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-Av'\./I...A""v'\-.1\,.fI..,!\
-.J\.J\,f\-v\~"""\1\~--1\-Y\
~-A.J\~"",..j\
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-A-1\-('-~.(;.-(\r~..J'
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Societyof America; 1997;11:33-41.
.J\..f...J\..J\-J\
3-2
cessful detachment surgery, the multifocal

ERG shows evidence of spatially extensive
retinal dysfunction.
Reattached areas have
very low ERG responses, despite showing
almost normal sensitivity to light, suggesting that the multifocal ERG is extremely
sensitive to residual functional deficits. It is
hypothesized
that low multifocal ERG responses may be related to persistent complaints of abnormal color and light perception in these patients.42
The importance
of the kind of topo-
graphic analysis made possible by the multifocal ERG is evident in an analysis of a

patient with enhanced S-cone syndrome
(ESCS). ESCS is a rare retinal disorder
characterized by a profound loss of rod
function and by large-amplitude
S-conemediated electrical responses that dominate the light-adapted
ERG.43-45 Marked
differences between central and peripheral
multifocal ERG responses in ESCS suggest
that there are different distributions
of S,
M, and L cones in these regions and that S
cones may feed into different pathways in
the center and periphery.46 Based on current available evidence, it seems likely that
S cones in these patients replace only a few
M and L cones in the center and feed into
the usual S-cone pathways. Thus, impairment of visual acuity and color vision may
be limited. In the periphery, however, S
cones appear to replace rods entirely and
usurp the neural pathways of the rods.
Thus, the waveform characteristics of the
S-cone-mediated
signal in the periphery is
rod-Iike, and the patients with ESCS are
severely night-blind.
There are several problems with using
the multifocal ERG in patients with widespread retinal disease. One is that testing
with current systems is limited to the centra150 of retina (25 isopter). At most, this
The Multijocal
ERG
189
covers about 35% of the entire cone population. Thus, it is theoretically

possible for a
patient to have a normal multifocal test despite degeneration in the far periphery. Another problem is that the dynamic range of
each response may be limited, making it
difficult to record peripheral responses in
some patients with retinitis pigmentosa.
According to one study,47 there were no detectable multifocal responses in a substantial proportion of patients with retinitis pigmentosa. Only 27 of 111 patients showed a
detectable response anywhere in the test
area; of these 27, several had detectable responses in the central region only. Thus, for
patients with widespread retinal disease,
the multifocal ERG may be of greatest clinical value in assessing focal retinal function
at the posterior pole.
3-2-4 The Multifocal ERG in Inner
Retinal Disorders
Perhaps the greatest promise of the multifocal ERG lies in its potential as a sensitive
diagnostic indicator of inner retinal disease.
In glaucoma, early damage appears to be restricted to the ganglion cell layer. Visual
field testing reveals focal areas with elevated thresholds, but field loss appears to
occur only after substantial ganglion cell
loss.48 In diabetic retinopathy, neovascularization and its complications
likely result
from the release of angiogenic factors from
ischemic areas of the retina. F or both diseases, sensitive new tests are needed to detect subclinical retinal changes before irreversible damage occurs.
190
Electroretinogram
Contributions
from the ganglion cell
layer and from the optic nerve fibers are
present in the multi focal ERG and may
prove to be of appreciable value in detecting and monitoring early retinal abnormalities in patients with glaucoma or diabetes.
Inner retinal contributions
are most evident
in the second-order component of the multifocal ERG. In contrast to the first-order
component, which is essentially the mean
local response to all the flashes occurring in
a stimulus cycle, the second-order component represents the temporal interaction
between two focal flashes. Just as the
first-order component derived from the
m-sequence
is related to the full-field
ERG,29 the second-order response component is most closely related to the pattern
ERG49 (see Chapter 4). In diabetic patients
with retinopathy, the amplitudes of the second-order component were significantly
lower than normalso and implicit times were
significantly
increased.so,.'1 Amplitudes
of
the first-order component were reported to
tifocal ERG abnormalities,

prior to clinically apparent retinopathy, presumably reflect changes to the nonlinear dynamics of
the inner retina and occur before detectable
impairment
of the outer retina.
Sutter and Bearse49 have isolated an
inner retinal component in the multi focal
ERG whose implicit time increases with
the distance from the optic nerve head. It
may be related to a more substantial component in the nonhuman primate that can
be eliminated
by blocking
all sodium-based
action potentials with tetrodotoxin

(TTX).,'2
Unfortunately,
this component is extremely
small in humans and requires extensive,
high-quality
records and sophisticated processing for extraction. It may be possible to
enhance the relative contribution
of the
inner retinal component by decreasing the
contrast of the stimulus.53
As shown in Figure 3-60, there is more
variation in waveform with distance from
the optic nerve head with 50% than with
100% stimulus contrast, suggesting that the
be reduced in some patients with nonproliferative diabetic retinopathySO but, more

typically, local response amplitudes showed
no consistent relationship to fundus abnor-
inner retinal component
saturates at some
malities.s1 Of particular interest, amplitudes

of second-order, but not first-order, components were significantly
lower than normal
in patients without retinopathy. These mul-
least some patients with early glaucomatous

damage (Figure 3-6) show reductions in
this inner retinal component and delays in
intermediate
contrast and then is obscured
by outer retinal contributions
at high contrast. Preliminary
evidence suggests that at
implicit time due to waveform changes.54

To date, however, attempts to identify a
quantitative
measure that reliably
discrimi-
nates patients with glaucomatous damage

from normal have not been successful.54 It
remains to be determined whether this approach can be used in the clinic for the detection and management of early diabetic
retinopathy and glaucomatous damage and
whether
the multifocal
more effective
approach will prove
than existing
techniques.
3-2
""'~.l\--J\.--A..""""
.J\
",,",-A,.1'..r.1'..r.,J\..,.f...,-A-.J\...,A
11,...J\...J\.-.J\.-.J\--.J.-.J'\fv.J\...JI...,
J\.,.J\-"",.J\---J\-.J\
fI.-.J,.-.j.,..",",J\..
.J\,.J\.,..A-~./\-..J\.,.v'..,~.J.,...J.,..
4"","".J\
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4--t1..J'w,J\.."""-,\.",,"~'V\...J\.,.j\..,
~""".J\
.J\,..J\
r-.,.",,,",.J\,...J\--~-I'v-.t
/\-.J\...,J1.,.J\.,.J'..,""-.J,...j'."
.J\.,.J\"..r..,.!\...J\..",
fI
.J\
J\.-.Jw
f\...J\.,-v\..~..t\.-
~.;V-.J\I'-.Jv.~~
4vov~'I/1,
fII"""",,.v\.."fv-.'Ii'v"~
.J\r.t.fY\.""'.Jv...J\,.1./'vo..Jv..""".Jv..-fv\
~.Jv.""'..JI
Jv-.Jv-Jv-.I!-(.~..I\t-.Jv-
v\..y\..Jv..Jlt.v'\r-.A,.Jy-~.Jv-~
Jv--.Jv,...fv--.A,...A;..-N.J\A~-.J\t.~~
Jv,...,
"v-Jy..J\f'~Jv-"""Jy-..JIt.
.J..,..J..,..Jv,,""".J\"."""Jv-.J,f.~Jy.~
.V---J\II.yII.,.Jv-.Ar-~.JIr,~w"",
.Jv.o,Jv...J'v."",,"""'-..1\.-.~.l\...~
VV...J\.,.~.J\A.J\IIo~
Figure 3-6 (A) Multijocal
ERGs obtained with
.\.timulus contrast of 50% in normal human subject.

(B) Pattern employed in multijocal
(a) Multijocal
recordings.
ERGs from patient with primary
open-angle glaucoma (POAG). (D) Black curves are

responsesfrom parts A and C averaged over groups
shown in part B. Red curves are same-group averagesfor nearly 100% contrast stimulus. Calibration
markers indicate 120 n V and 60 ms.
Redrawn with permission of E/sevier Sciencefrom Hood
DC. Greensteint; Frishman L. et a/: Identifying inner retina/ contributions to the human mu/tifoca/ ERG. Vis Res
/999:19:228.,;"-2291
The Multijocal
ERG
191
192
Electroretinogram
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as a clinical
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Bankes JL: The foveal electroretinogram.

Trans Ophthalmol
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St Louis:
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Identifying
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L, et al:
contributions
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full-field
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MA, Jacobson SG, Berson EL: Foveal
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195
Graham E. Holder, PhD
The pattern electroretinogram

(PERG) is
the retinal response to a structured stimulus, such as a reversing black-and-white
checkerboard or grating. It is a powerful
clinical tool, allowing both an objective
evaluation of macular function and a direct
assessment of retinal ganglion cell function.
Thus, the PERG enables an enhanced interpretation
of the cortical visual evoked
potential (VEP) to the same or a similar
stimulus. It has been convincingly
demonstrated to make a substantial contribution
to disease diagnosis and patient management.l The PERG is a small response, and
its recording is technically more demanding
than other visual electrophysiologic
tests.
This chapter addresses both the technical
issues involved in PERG recording and the
use of the PERG in clinical practice. The
International
Society for Clinical Electrophysiology of Vision (ISCEV) has issued
guidelines for PERG recording,2 and practitioners are strongly encouraged to comply
with the ISCEV recommendations.
PERG could provide an objective index of

macular function, the PERG was more extensively applied to clinical practice only..
after the development
of commercially
available corneal recording electrodes that
do not interfere with the optics of the eye.5,6
A case report in the human7 suggested
inner retinal origins for the PERG, and further interest became focused on the PERG
when Maffei and Fiorentini8 reported experimental changes in the
optic nerve section in the
served progressive PERG
tion synchronous with the
histologic retrograde degeneration to the

retinal ganglion cells, such that the PERG
became undetectable
when ganglion cell
degeneration was complete. They concluded that the PERG was generated at an
inner retinal level, in relation to the retinal
ganglion cells. Subsequent
clinical human population9
experimental
of the PERG
work, both in a
and in a primate
model,l confirms that much

reflects ganglion cell function,
but that there is probably
also a significant
contribution
from more distal retina. The
origins of the PERG are discussed in detail
in Section 4-2-6.
HISTORICAL BACKGROUND
Riggs et al3 first documented
PERG following
cat. They obamplitude reducdevelopment
of
the ability
of a
contrast-reversing
stimulus to evoke a retinal response. However, although Lawwil14
demonstrated in the early 1970s that the
197
198
ThePattern Electroretinogram
THE PERG WAVEFORMAND ITS DETERMINANTS

4-2-1 The Normal Waveform and Its Relationship
to Stimulus Parameters
In the initial guidelines for PERG recording, the ISCEV recommended
that the routine clinical PERG stimulus should be a
high-contrast reversing checkerboard of low
temporal frequency 6 reversals/s). The
morphology of the response to this stimulus
in a normal adult is shown in Figure 4-1.
Time(ms)
Figure 4-1 Normal
PERG. Note larger N95
component, measured from the peak of P50.
The waveform consists of a prominent positive component, P50, with a larger later
negative component,N95.11
In many subjectS, a small earlier negative component,
N35, can be identified.
When obtained
using the ISCEV recommendations,
P50 is
typically 2.5 to 5.0 llV (llV = microvolt).
The larger N95 (N95:P50
ratio >1.1 in the
author's laboratories) is typically 3.5 to

6.5 llV. The nomenclature
is based on standard clinical neurophysiology
practice,
whereby components are identified
by their
polarity and approximate expected latency.
Measurement
of the P50 component of
the PERG should be of amplitude, measured peak-to-peak
from the trough of N35,
and peak latency. Some workers measure
N95 amplitude peak-to-peak from P50,
whereas others use measurement from
baseline. Accurate assessment of baseline
may be difficult, and peak-to-peak
measurement circumvents the problem of accurate baseline identification.
Peak-to-peak
measurement further avoids the potential
problem of how to describe a negativegoing component that starts above the baseline (positive), but fails subsequently
to
cross the baseline. It is acknowledged
that
N95 measured this way includes a contribu-
4-2 The PERG
Waveform
and Its Determinants
199
tion from PSO, but the PERG has complex

generators and it is doubtful whether baseline-to-peak
criteria are physiologically
any
more meaningful. The ISCEV guidelines
suggest peak-to-peak amplitude evalua-
2/s
tion.
The accurate assessment of N9S latency
is often precluded due to its broad shape,
and N9S latency is not usually thought to
be a useful parameter. In a clinical setting,
use of the N9S:PSO amplitude ratio assists
the distinction
between a primary N9S
component reduction and a reduction concomitant to reduction in PSO. As with all
electrophysiologic
parameters, it is necessary for each individual
laboratory to establish its own normative
data.
14/s
4-2-1-1Stimulus Rate Berninger and Schuurmans12.13documented the effects of stimuIus rate. Typical recordings are shown in
Figure 4-2. As stimulus rate is increased,
the P50 and N95 components merge into a
sinusoidal waveform, dominated by the
N95 component. As the steady-state waveform is approached (>7 reversals/s, 3.5 Hz),
it becomes impossible to distinguish the
two main components.
4-2-1-2Check Sizeand Spatial Frequency Berninger and SchuurmansI2.!3 also investigated
the effects of check size on the PERG. P50
failed to show spatial tUning, reaching maximum amplitude with increasing check size
up to approximately
45 minutes of arc and
remaining at a similar amplitude level with
further check size increase. The N95 component reached a maximum, but then reduced in amplitUde as check size further increased. Spatial tuning
retinal ganglion
is associated with
cells, and it was concluded
that N95 is a contrast-related
component
Figure 4-2 Effect of stimulus rate on PERG. As stimuIus rate increases and steady-state wavefo171l appears,
individual components merge and amplitude of response is more similar
to that of P50.
to that of N95 component than
200
arising in the ganglion cells, but that P50 is

probably generated more distally with a significant luminance contribution.
Each and Holder14 were unable to fully
confirm these findings, and pointed out potential difficulties
in interpreting
the data
obtained with very large checks. The basic
conclusions were supported when a small
visual field was used, but there was little
low spatial-frequency
attenuation with a
large field. Hess and Eaker15 showed that
the 8-Hz steady-state PERG exhibits spatial tuning, in keeping with postreceptoral
origins, and this was confirmed by Porciatti
et al.16 The reader is reminded that the
steady-state PERG is dominated by the
N95 component. The ISCEV PERG guidelines recommend a check size of approximately 0.8.
Figure 4-3 Effect of contrast on PERG. As contrast

increrlses, PSO amplitude
increases.
4-1-2-3Contrast A linear relationship between

PERG amplitude and stimulus contrast is
usually assumed,15,17-19and the use of a
maximum contrast stimulus is recommended by the ISCEV for this reason (Figure 4-3). However, a subsequent reportZO
described linearity only at low temporal frequency, but increasing nonlinearity
with increasing temporal frequency. This was observed with both full-field
and perifoveal
stimulation.
4-2-1-4Field Size PSO increases in amplitude
with visual field size. One report21 described a logarithmic relationship.
Others
confirmed increase in PERG amplitude
with increase in field size, but did not
quantify the relationship.22 A clinical
study23 examined different stimulus field
sizes in unilateral maculopathy and related
the findings to clinical indices of macular
function. The authors suggested that the
4-2 The PERG
Waveform
201
Figure 4-4 Gold-/oil

electrode
best relationship
between
PERG
and static
perimetry occurred with 6 and 10 fields,

rather than the 20 field also examined. A
field size of between 10 and 16 is recommended
by the ISCEV.
4.2.2 Recordingthe PERG

4-2-2-1RecordingElectrodes The PERG should
be recorded with electrodes that contact
the cornea or nearby bulbar conjunctiva.
This does not include contact-lens electrodes or any other electrodes that degrade
image quality on the retina by interfering
with the optics of the eye. Typical electrodes are the Dawson- Trick-Litzkow
(DTL) thread electrode,5 the Arden goldfoil electrode,6 and the Hawlina-Konec
(HK) loop electrode.24 (These electrodes
are described in Chapter 1.) Similar to its
use in full-field
ERG recording, the goldfoil electrode is probably more stable than
the DTL, with the DTL having a tendency
in position.
to slip down into the lower conjunctival

fornix. PERG amplitude is 20% higher if
the DTL electrode is across the cornea at
the level of the lower lid, rather than in the
fornix.25 Thus, any change in electrode position during recording will result in increased variability. The gold-foil electrode
is more difficult to use in inexperienced
hands, but experience
and the appropriate
precautions during data acquisition give stable, reproducible

recordings. A detailed discussion on the techniques of gold-foil electrode use has appeared elsewhere.26 The
leads are attached to the skin below the
eyes with tape and are positioned such that
the electrodes do not touch the skin above
the tape and, if possible, avoid touching the
lower eyelashes (Figure 4-4). When viewed
202
The Pattern
Electroretinogram
laterally, a blink from the subject should result in negligible movement of the electrode. Thompson and Orasdo27 published
details on the use of the OTL electrode.
The three electrodes referred to above
can all be used comfortably without the use
of topical anesthesia, and it has been suggested that the use of topical anesthesia is
contraindicated
for PERG recording.28 It
is possible to record a PERG with surface
electrodes, and this may be useful in the
patient, perhaps a child, who cannot tolerate the presence of a corneal electrode.
However, surface electrodes cannot be
recommended
for routine use due to the
low amplitude, reduced signal-to-noise
ratio, and relatively high variability of the
recordings.
4-2.2.2 The ReferenceElectrode The reference
electrode for the PERG should be positioned at the ipsilateral outer canthus. Berninger29 elegantly showed that the position
of the reference electrode is critical if contamination from the cortically generated
pattern YEP is to be avoided. He demonstrated marked contamination
of the PERG
from the cortical YEP if an earlobe or midforehead reference electrode was used.
This contamination
affected the N95 component, but there was no significant effect
on P50. Although not all authors have been
able fully to confirm Berninger's findings,3
the ISCEY recommends that reference
sites other than the ipsilateral outer canthus should not be used.
It is standard practice in the author's laboratories to position the reference electrode
at the outer canthus such that the lead runs

horizontally
back and rests on the patient's
ear. This is more comfortable for the patient, creates a
and minimizes
ally significant
graphic artifact
lead hanging
stable recording position,

the chance of the occasionproblem of electromyoarising in relation to the
down unsupported.
4-2-2-3RecordingTechniquesand Equipment There

are marked technical difficulties
in recording the PERG due to the small signal size
and the high amplitude of potential artifact
from eye movement and blink. These difficulties can largely be overcome by the use
of stringent recording techniques and attention to detail. Although important in all aspects of electrophysiology,
technical factors
are particularly pertinent to the recording
of the PERG and therefore merit detailed
discussion.
The small PERG amplitude necessitates
computerized
signal averaging, a technique
involving the presentation of multiple stimuli to enable computerized
extraction of a
small time-Iocked
signal from higher-amplitude biological noise. There is thus a need
for equipment
suitable for averaging and a
high-quality
pattern stimulator (high resolution, fast refresh rate). Many laboratories
that regularly record VEPs should have appropriate equipment.
However, amplifier
characteristics are of critical importance in
PERG recording. The amplifiers should return quickly to baseline following a very
high amplitude, saturating artifact such as a
blink, and this should happen as a function
of amplifier design rather than through software. Some amplifiers "lock up" when presented with such an artifact, thus extending
the recording time, and, worse, some even
pass zero or flat-Iine amplitude data to the
4-2 The PERG
averaging stores during this period. This

latter property results in PERGs of artifactually low amplitude.31.32
The software should have an on-line
ar-
tifact-reject
system to minimize the effects
of unwanted artifacts, such as eye movement or the burst of muscle activity that
may occur in conjunction
with swallowing
or chewing. The ISCEV recommends that
this should usually be set for 100 f1V or less.
The patient
should be instructed
to avoid
such actions while data are being acquired.

The practice of "interrupted
stimulation" can be used to minimize the effects of
blinking
efficient
and eye movement. Although any

artifact-reject
system will reject
the very high amplitude signal associated

directly with a blink, there is a period during recovery from blink when there is an artifactually
fall within
contaminated
signal, which may
the artifact-reject
window. This
leads to higher variability. The patient

should be instructed to concentrate on the
stimulus for 4 or 5 seconds, to keep perfectly still "like a statue," and not blink.
Averaging is then suspended and the patient is told to blink quickly and gently a
few times and then again to concentrate on
the fixation spot and not blink. Averaging is
restarted when inspection of the raw data
reveals a stable baseline.
process is repeated until
been obtained. This will
eraging the responses to
This stop-start
a stable PERG has
usually involve avapproximately
150
reversals, but more will often be necessary

if there is a poor signal-to-noise
ratio. A
minimum of two trials should be performed
to confirm reproducibility.
Of additional importance is the use of a headrest. It is essential that the patient's head remain still to
avoid the small eye movements that would
be needed to correct fixation if head move-
Waveform
and Its Determinant.
203
ments were to occur. The patient should

be asked to rest the head gently backward
against the headrest throughout the recording session, with the chin slightly down, to
help maintain
the most stable recording
situation.
The PERG is sensitive to defocusing33-35
and the patient should be wearing a refraction appropriate for the viewing distance.
Any tint to the spectacles should be noted,
as this may influence the PERG due to the
effect on stimulus luminance. The ISCEY
recommends that the PERG should routinely be recorded binocularly; if there is
better visual acuity in one eye, this eye will
maintain fixation and accommodation.
Also,
there is less trial-to-trial
variability with
binocular recording than with monocular
recording.3
The YEP should always be recorded
with monocular stimulation,
and some authors advocate simultaneous monocular
YEP and PERG. This can be satisfactory,
particularly in suspected functional visual
loss, which is addressed in detail in Section
4-3-5. In most other circumstances, particularly in the distinction
between retinal and
optic nerve disease, and in macular assessment, binocular PERG recording is preferable. Monocular registration is necessary in
the patient with strabismus and, during
PERG recording, a patient should always
be under observation to ensure that a latent
squint does not manifest.
Small lateral eye
204
movements may fall within the artifactreject window and influence the PERG in
an undesirable manner. An example of the
use of monocular registration appears in
usually taken as evidence of at least reasonable macular function. It has been reported
that the PERG reaches adult values by S to
6 months of age.37 Elderly people show a
Figure 4-5.
lower overall PERG amplitude compared

with a young-adult
population, and age-related normative data should be obtained.
There are contradictory
reports in relation to latency in the transient PERG, with
some authors suggesting that it increases
with age,38.39but others suggesting that no
age-related latency increase occurs.40 It is
possible that PERG changes are associated
with age-related loss in the ganglion cell
population,41 and one report42 ascribes the
alterations in PERGwith
aging to retinal
changes. The steady-state PERG shows a
significant reduction in amplitude with age,
combined with a mild phase shift.43.44 Por-
4-2-3 Pupil Diameter

It is usually assumed that there is no significant effect of miosis on the P50 component
of the PERG,29,36 but there may be an effect on the N95 component.29 It is important, if miosis is pilocarpine-induced,
that
the short-term effects of accommodative
spasm are considered.36 It is not clear
whether this was taken into account in one
report of P50 amplitude change following
miosis induced
by pilocarpine.35
4.2.4 Age
Clinically, the recording of the PERG in
children is limited both by their ability or
willingness to fixate and concentrate and by
their ability to tolerate corneal recording
electrodes. Although the author has successfully recorded PERGs using gold-foil
electrodes in a 3-year-old child, this is very
much the exception rather than the rule.
Usually, PERGs can be clearly identified
in
young children using surface electrodes and
appear of similar magnitude to those obtained in adults using similar techniques,
but the limitations of surface electrodes
prevent accurate quantification
or comparison. The presence of any significant PSO
component under such circumstances is
ciatti et al44 suggested that the effects of

age-related miosis could not explain the
amplitude change, but that the mild phase
shift is probably related to pupillary changes.
The studies by Korth et al39 using Maxwellian view, and the greater effect on low
spatial-frequency
stimuli observed by
Trick,4o similarly suggested that age-related
miosis is not the primary cause of the agerelated PERG
amplitude
reduction.
4-2-5 Reliability of the PERG

There must be acceptable trial-to-trial
and
test-retest reproducibility
before a test can
have clinical utility. The technical issues
discussed above are of crucial importance in
recording the PERG, and stringent precautions should be taken throughout recording
to ensure the highest possible technical
standards. Some authors claim that the trialto-trial variability of the PERG is too great
for it to be a clinically useful tool45 or even
that the gold-foil electrode is unsatisfac-
4-2 The PERG
Waveform
205
4
05
>
6
"'
~O
-0.
E
<
-2
-4
0
50
rime (ms)
100
Time (ms)
B
4
4
OD
as
~
0)
0)
"0
E
-0.
E
<x:
~o
-0.
E
-2
-4
-4
0
50
100
Time(ms)
Figure 4-5 ( A) Apparent N95 reduction in right eye
of this patient results from latent squint, giving eye
movement during binocular
recording, Note appa-
rent positive baseline drift in trace from right eye.
50
100
Time(ms)
(B) Right eyecan maintain fixation when left eyeis
occluded,and PERG then has normal waveform. Visual acuity is 20/20 in both eyes.Carifulobservation
of patient during data acquisition is recommended.
206
tory.46 However, these are isolated reports

and have not been confirmed by other
authors.47 In particular, studies that stringently controlled for technical variablesI4.25.31
report variability equivalent to other electrophysiologic
tests. The importance of
technique and technical factors in the
recording of clinical PERGs cannot be
overemphasized.
4-2-6 Originsof the PERG

The initial experimental
studies on the origins of the PERG concentrated on the P50
component, presumably reflecting its superficial similarity to the b-wave of the
ERG. Maffei and Fiorentini8 suggested
from their feline experiments
that the
PERG is generated in relation to retinal
ganglion cell activity. The same group
reached similar conclusions following optic
nerve section in a primate model,48 in
which they also observed PERG extinction.
In apparent contradiction,
two reports49,SO
appeared that failed to find complete extinction of the PERG in the human following optic nerve resection. The case described by Harrison et al,'jois of particular
importance. Despite the development
of
total optic atrophy clinically, the PERG in a
patient following surgical optic nerve resection was still recordable 30 months later.
There was approximately
70% reduction in
amplitude, but the PERG was not totally
extinguished.
The authors noted a shortening of the P50 component latency. A similar
shortening of the positive component latency following optic nerve section was reported in a pigeon model.,'j1 Those authors
drew the conclusion that preservation of

P50 indicated that the pigeon PERG was
not generated in the ganglion cells, but
their comments apply only to the positive
compon~nt, as analysis of the N95 component was not presented.
It was later demonstrated
by Tobimatsu
et al52 that the effect of optic nerve section
in the cat could be more marked on the late
negative component (analogous to the
human N95) than on the positive component. The reader is reminded that differences exist, for example, between cat and
primate PERGs,53 and caution should be
exercised when extrapolating
from animal
models to the human.
Some reports54,55 examining spatial tuning characteristics of the PERG failed to
demonstrate low spatial-frequency
attenuation of the P50 component, suggesting a
(partial) non-ganglion-cell
origin. The experiments of Berninger and Schuurmansl2,13
examined both P50 and N95 components.
The authors suggested that N95 is contrastrelated in relation to the ganglion cells, but
that P50 is at least partly generated more
distally and possibly related to stimulus luminance. Hess and Baker,15 using the N95dominated steady-state technique, also observed spatial tuning and concluded that
the 8-Hz PERG has postreceptoral origins.
Riemslag et al56 initially proposed that the
PERG is simply a summation of localluniinance changes, but later concluded that at
least 50% of the PERG is contrast-related
for check sizes subtending less than 120
min of arc.,)7
Additional
experimental
evidence for a
ganglion cell origin for N95 in the human
came from Orasdo et al,58 who extracted a
pattern-specific
response (PSR59) from the
PERG. They demonstrated a significant
correlation between the amplitude of the
4-3
negative PSR (N95 equivalent) and the volume of the ganglion cell layer. Current
source density analysis also implicated the
ganglion cells in PERG generation.6O,61 The
early clinical reports33,62 of differences between the focal ERG and the PERG suggested different sites of origin, but the
PERG data did not include analysis of N95.
When the clinical relevance of N95 was
recognized, it became apparent that P50
and N95 may be selectively affected in
macular and optic nerve disease, respectively.11,63-6,1These data are in keeping with
the two components having different cellular origins. The clinical findings in human
optic nerve dysfunction
are addressed in
detail in Section 4-3-2. A report66 that a residual P50 is still present in end-stage human
dominant optic atrophy, even though scanning laser ophthalmoscopy
demonstrated
apparent total loss of the ganglion cell layer,
further suggests that some of P50 has origins distal to the ganglion cells. Shortening
of latency was also noted, paralleling the
observations of Harrison et al,1following
surgical optic nerve resection.
That some of the PERG does not reflect
ganglion cell function received further support from the work of Viswanathan et al,IO
who used tetrodotoxin
(TTX) experimentally to block spiking cell activity in a primate model. They observed severe reduction in N95, but retention of a reducedamplitude
P50 component,
providing
phar-
macologically derived data in concordance

with the clinical observations of Harrison et
al' and Holder et al.66 At the time ofwriting, it can be postulated that N95 is ganglion cell-derived
and, although much of
P50 has ganglion cell origins, some is generated more distally. It is unknown where the
part of P50 that is not generated by the ganglion cells arises.
Clinical
Applications
207
CLINICAL APPLICATIONS
4-3-1 Macular Dysfunction
The PERG allows an objective assessment
of macular function and is sensitive to macular dysfunction.
The PERG
should be
considered in conjunction
with the fullfield (ganzfeld) ERG. The ERG is unaffected by disease confined to the macula
and, conversely, a patient with generalized
retinal dysfunction
sparing the macula w~
have an abnormal ERG but a normal PERG.
Following the initial findings of Lawwil14 in the early 1970s, it was not until the
early 1980s that subsequent clinical reports
of PERG changes in macular dysfunction
appeared. This probably relates to the introduction into clinical practice of the DTL
and gold-foil electrodes.\6 The first reports
that examined the PERG in macular dysfunction concentrated on the P50 component and found reduction of this component, which was undetectable
in severe
cases.49,67-69This view did not change
when the N95 component was included
in the analysis, with all later reports confirming P50 involvement
in macular dysfunction.9,11,65,70The N95 component usually shows reduction concomitant with that
affecting P50 such that there is no reduction in the N95:P50 ratio. Occasionally,
there may be better preservation of N95
than P50.70
208
4-3-1-1Macular Assessmentin Retinal Degeneration

The full-field
ERG is normal in disease
confined to the central retina, and the additional objective assessment provided by the
PERG allows a more complete quantification of retinal function. Patients with rodcone dystrophy may have almost nondetectable ERGs, but a normal PERG, consistent with the sparing of central retinal
function in some patients. This corresponds
clinically with classical retinitis pigmentosa
(RP, rod-cone dystrophy), in which the patient may have profound peripheral visual
defect, but function in the remaining central field may be unaffected or affected to a
minimal degree. Such patients have normal
visual acuity. When visual acuity is affected,
the PERG is almost invariably abnormal,
and most patients with a visual acuity of
20/40 or worse show either extinction or severe reduction in the PERG. However,
there are some patients with electrophysiologic abnormalities,
but no clinical evidence
of central retinal involvement.
In particular,
abnormal PERGs and increased color-contrast thresholds71 can be found in the presence of normal Snellen visual acuity.72 This
is presumed
to reflect early central retinal
involvement.
Long-term
followup will determine to
what extent these data have prognostic significance. It is anticipated that the objective assessment of central retinal function
provided by the PERG will facilitate counseling and management of RP patients.
The PERG
abnormality
is usually that of
PSO amplitude reduction not accompanied

by latency change, but latency shift may
also be present if there is associated macular edema. Others have also described the
possible preservation of the PERG in
RP.73-75Any retinal dystrophy with central
retinal involvement
is likely to have an abnormal PERG. In addition to the more
common genetic causes of Rp, loss or reduction of the PERG in the retinal dystrophies due to mutations in RetGC76 and
GCAP77 has also been described. Typical
findings in retinal dystrophy are illustrated
in Figure 4-6.
4-3.1.2 Other GeneralizedRetinal Diseases Similarly
to the role of the PERG in retinal dystrophy patients, the PERG has a general use
in the objective assessment of macular
function, with the ability to document the
severity of macular dysfunction
and sometimes to detect asymptomatic
macular involvement.
Patients
with X-Iinked
juvenile
retinoschisis, congenital stationary night

blindness (CSNB), birdshot retinochoroidopathy, and the like, may have PERG abnormalities in which the severity of PERG
reduction parallels the degree of symptomatic central retinal dysfunction.
However,
the PERG can also demonstrate macular
dysfunction
in the absence of symptoms or
signs of central retinal disturbance. Representative findings in CSNB and birdshot
retinochoroidopathy
are shown in Figures
4-7 and 4-8, respectively. Other authors also
report PSO amplitude changes in X-Iinked
retinoschisis, as well as Sorsby fundus
dvstronhv.78
4-3
Clinical
Applications
209
Scotopic rod
Maximal
Photopic
5001
400
300
200
100
11
~
0)
"0
.E
"0.
E
<
100
50
c
500
400
300
200
100
0
100
~
0)
"0
.E
-0.
E
<
150
100
50
0
Figure4-6 ERGs and PERGs from 3 patients with

rod-cone dystrophy-retinitis pigmentosa. (A) In this
patient, whosevisual acuity is 20/20, there is almost
completeextinction of both rod and coneERGs, but
PERG is normal, suggestingthat central retinal function is not significantly compromised.(B) This patient
has relatively mild visual acuity reduction (20/30),
but marked PERG P50 reduction. Generalizedcone
function, although markedly abnormal, is betterpre-
50
Time(ms)
100
Time(ms)
served than in patient in paTt A, but abnormal

PERG confirms central retinal dysfunction. (a) In
this patient, with visual acuity of 20/120, both maximal and coneERGs show slightly betterpreservation
than in paTt A patient, but PERG is nondetectable
and visual acuity is severelyreduced.Complementary
nature of ERG and PERG in assessment
of global
and central retinal function is demonstrated.
(D) Normal control.
210
A
Scotopic
Maximal
rod
PERG
~
0>
-0
.E
"6.
E
<1:
100
150
400
100
200
50
100
100
50
100
c
150
400
100
200
50
o
o
Figure 4-7 ERG findings
100
Time(ms)
in this patient are representa-
tive of CSNB. (A) Right eye. Visual acuity is 20/40.

(B) Left eye. Visual acuity is 20/60. (0) Normal
con-
trol. There are nondetectable rod ERG; negative maximal ERG; relatively minor changes in both amplitude and implicit
time of cone flicker ERGs; and
broadened a-wave with reduced b:a ratio in photopic

ERG. Long-duration
stimulation
response, with significant
shows ERG on-
b-wave reduction, but nor-
mal o.ff-response in keeping with selective involvement

of depolarizing
hyperpolarizing
photopic pathways and sparing of

cone pathways.
50
Time(ms)
100
Time(ms)
200
Time (ms)
4-3.1.3 Macular Dystrophies The PERG is of

particular use in macular dystrophies, in
which the full-field
ERG is normal unless
there is peripheral retinal involvement.
As
part of a prospective series, a large number
of patients with Stargardt macular dystrophy (or fundus flavimaculatus)
have been
examined.79,8 The diagnosis in these patients was supported by fundus autofluorescence imaging, by which flecks can more
clearly be identified
than with either direct
ophthalmoscopy
or slit-Iamp biomicroscopy.
The PERG is usually nondetectable,
even
when visual acuity is reasonably well preserved, suggesting more widespread macular dysfunction
than that implied
or autofluorescence
examination.
by clinical
In most
maculopathies,
there is a reasonably good
relationship between the magnitude of the
PERG reduction and the degree of visual
acuity loss.
4-3
Clinical
211
Applications
Figure 4-7 (D,E) Although maculas show

no significant visible
abnormality,
PERG
demonstrates marked
central retinal dysfunction.
212
3o-Hzflicker
Scotopic rod
Photopic
150
100
1001
50
5q
100
50
O
-2
-4
150
150
100
100
50
50
50
100
0
0
100
PERG
150
50
50
c
150
100
50
0
50
Time(ms)
Figure 4-8 This patient has HLA-A29

retinochoroidopathy.
20/200-.
positive birdshot
(A) Right eye. Visual acuity is
(B) Left eye. Visual acuity is 20/200-.
(a) Normal
subnormal;
control. Rod ERGs from both eyesare

there are negative maximal
(feature often found in this condition)

delayed 30-Hzflicker
responses
and mildly
and photopic ERGs. Although
100
Time
(ms)
visual acuity is not significantly reduced,PERG from

right eyeshowsnondetectablePSOcomponentwith
someresidual N9S, and PERG from left eyeis slightly
betterpreserved but of globally reducedamplitude.
Patient went on to develop visual acuity lossfrom
cystoid macular edema.
4-3
In many patients
with Stargardt macular
dystrophy, the full-field

ERG is entirely
normal (Figure 4-9). A previous report on
Stargardt macular dystrophy also described
PERG abnormalities,81 but the diagnostic
criteria were poorly defined and it is possible that the patient population included
other types of macular dystrophy. It is
known that Stargardt macular dystrophy is
related to mutations in the ABCR gene,8Z,83
located in the short arm of chromosome 1.
The effect on photoreceptors
may be secondary to retinal pigment epithelial dysfunction.84
PERGs are nondetectable
in advanced
stages of the macular dystrophy phenotype
associated with a peripherin/RDS
172 mutation, and may be abnormal prior to the
development
of acuity loss.8s Fundus autofluorescence imaging is also abnormal at
an early stage.
Clinical
Applications
nopathy.89,90 Nesher and Trick,91 in a series

of 58 diabetic patients, found the steadystate PERG to be more sensitive than the
transient PERG in the detection of early diabetic maculopathy. However, abnormalities were present only when there was
background retinopathy. PERGs and assessment of color-contrast sensitivity were
used as objective measures in a study of the
different effects of argon and diode laser
treatment in diabetic patients requiring
panretinal photocoagulation.92
Clinical evaluation showed no significant differences..
between the two treatment options. There
was, however, a tendency for less reduction
in color-contrast sensitivity and PERG after
diode laser photocoagulation,
suggesting
that this was a viable alternative to argon
laser treatment and may be a less harsh
mode of treatment.
4-3-1-5Other Macular Dysfunction PERG
4-3-1-4Diabetes There is conflicting

evidence
in relation to the incidence of a PERG abnormality and its significance in diabetes.
An early report by Arden et al86 suggested
that the PERG is a sensitive indicator of
maculopathy and could show changes prior
to the development
of preproliferative
retinopathy. Coupland87 found that PERGs
could be abnormal in diabetic patients with
background retinopathy, but were always
normal in those with no photographic
evidence of retinopathy. Other authors88
found no evidence of abnormal PERG in
patients with either normal fundi or microaneurysms only.
There are, however, reports that describe a significant correlation between
PERG amplitude and the duration of diabetes in patients with either no observable
retinopathy or minimal background reti-
213
abnor-
malities have been described in other

causes of macular dysfunction,
but usually
with small groups or isolated cases. Central
serous retinopathy (CSR) can give not only
PSO amplitude reduction but also latency
change.7o One report described continuing
visual acuity loss and PERG abnormality
in
CSR associated with systemic lupus erythematosus, despite fluorescein angiogram appearances suggesting resolution ohhe
CSR.93 Age-related macular degeneration
(AMD) has received little attention, but abnormal PERGs are a consistent feature.
Birch et al94 found the PERG to be a sensi-
214
A
~
Scotopic
Maximal
rod
Photopic
400
-;;;-0
300
.~
-0.
E
<1:
200
100
100
B
::;;:
400
';j;'
"0
300
~
-0.
E
<1:
200
100
100
100
c
~
400
--;;;
"0
300
E
"15.
E
200
100
{J
100
Time(ms)
Figure 4-9 Stargardt
100
Time(ms)
macular dystrophy. ( A) Right eye.
Visual acuity is 20/200. (B) Left eye. Visual acuity is

20/120. (0) Normal
control. This patient has normal
ERG, but nondetectable PERG,

function
confined to macula.
in keeping with dys-
50
Time(ms)
tive measure of function in AMD patients

with untreated subfoveal neovascular membrane during a 12-month followup period.
Nonspecific
transient PERG abnormalities
have been described in patients with macular hole95; abnormalities
of the second harmonic component of the steady-state
PERG also occur.96 PERG abnormalities
in Fuchs heterochromic
cyclitis have been
reported.97
4-3.2 Optic Nerve Disease
Given the putative
ganglion
cell origins of
the PERG, it is not surprising that much re

search has examined the effects of optic
nerve disease on the PERG. In general, although an oversimplification,
optic nerve
disease is usually associated with a normal
P50 component, but there may be an abnormality of the N95 component.
4-3
Clinical
Application.l'
215
Figure 4-9 (D,E)
Note
kyperfluorescent
flecks
on fundus
autofluores-
cence Imaging.
Parts D and E courtesy
Noemi Lois, MD.
216
4-3.2.1 Optic Nerve Demyelination The initial
re-
ports of the PERG in optic nerve demyelination were not optimistic that the PERG
would be of value. A variable incidence of
abnormality was described,33,69,98-101but at
that time attention was concentrated on the
P50 component.
Porciatti
and yon Berger99
noted that the "negative after potential"

(N95) seemed to be more affected than the
main positive component, but did not further address this issue. Some authorslO2,103
concluded that the PERG contributed
no
significant
information.
Absent PERGs
were reported in some severely affected

eyes,69,104but those studies used monocular stimulation. There are profound difficulties in controlling fixation in a severely
affected eye, and those results have not
been confirmed
by studies using binocular
stimulation.
While experimental
data were being
collected that P50 and N95 may have different origins,12,13 clinical data were accumulating
from which similar conclusions
documented pattern YEP delay after an

episode of optic neuritis, the YEP in that
eye was normal 10 years later when the patient presented with optic neuritis in the
second eye. However, the optic disc was
pale and there was an N95 reduction in the
PERG, in keeping with loss of ganglion cell
function. The PERG did not significantly
differ from that previously obtained.
It is possible that the normalization
of
the YEP delay reflects deterioration
from
conduction delay to conduction block, thus
exposing any normally conducting remaining optic nerve fibers, rather than functional remyelination,
but the latter cannot
be excluded. The findings of that study
were extended by a larger series of more
than 300 eyes.9 Eyes with a history of a clinical attack of retrobulbar neuritis are associated with a greater percentage of PERG abnormalities than are eyes with subclinical
demyelination.
It should be noted that the
ability to observe selective reduction in the
N95 component may depend on the use of
were drawn.II,63 When the N95 component

was examined, it was demonstrated
that if
a high-contrast stimulus (Figure 4-11).106

There may be a shortening of P50 com-
the PERG is abnormal in optic nerve disease, the abnormality could be confined to
ponent latency in severe disease, presumably due to the exposure of the shorter la-
the N95 component, with sparing ofP50

(Figure 4-10.)11,64,65In an early study of 200
eyes examining the incidence of PERG abnormality in optic nerve demyelination,
it
tency luminance contribution

to the PERG
by loss of the N95 component. Such P50 in-
was found that 40% of eyes had abnormal

PERGs. Of those abnormalities,
85% were
confined to the N95 component with no
P50 involvement.105 Two eyes had normal
pattern VEPs but abnormal PERGs. In one
of those cases, in an eye with a previously
volvement is usually accompanied by a

greater degree of N95 involvement,
and
there is usually a severe pattern YEP abnormalitY in association with involvement
of
the P50 component.
The steady-state
PERG
also shows
abnormalities
in optic nerve demyelination.IO7-111 Porciattil12 showed that, in patients with optic atrophy secondary to
trauma or optic neuritis, Fourier analysis
of the second harmonic component of the
steady-state
PERG
is the proper measure.
4-3
Clinical
Applications
Time(ms)
Time(ms)
Time(ms)
Time(ms)
Figure 4-10 Patient with optic nerve demyelination.

( A) Right eye. Visual acuity is 20/20. (B) Normal
control. The patient had previously
suffered retrobul-
bar neuritis in right eye, but made good visual recov-
217
ery. Therewas right discpallor: Pattern VEP (positive upward) in this patient showsprofound delay
from right eyecompared with normal control. Note
selectiveloss of N95 in fJatient.
218
Furthermore,
this study found that the
second harmonic component of the fullfield ERG was unaffected, in keeping with
a different site of origin. Readers proposing
to use the steady-state PERG are advised
to consult the ISCEY guidelines.2
Although specific reduction in the N95
component is a more common feature in optic nerve demyelination,
a P50 abnormality
often occurs in the acute phase of optic neuritis.72,lOS,113
In the first week after the onset
of symptoms, there may be marked reduction in P50 amplitude. PSO recovers during
the next 3 to 4 weeks and may return to
normal values, but an N95 component ab-
~
55% C OD
OS
~
20%COD~
OS
v-
Figure 4-11 This figure documents effects of reduction in

stimulus contrast on N951oss present in 2 patients
with high-contrast/high-luminance
stimulus. Note
that, at lower contrast levels, N951oss may not be

present and, indeed, patient in pat1 A has changed
into P50 reduction at 55% contrast.
Redrawn with permission of Elsevier Sciencefrom H older
GE: The incidenceof abnormal pattern electroretinography
in optic nerve demyelination. Electroecephalogr Clin
NeurophysioI1991:78:18-26.
normality may appear. The pattern YEP

may initially show relatively minor latency
change but marked amplitude reduction at
the stage when P50 is markedly reduced.
Over the time scale that an N95 abnormality may develop in the PERG, the YEP
amplitude improves but there is an increase
(a deterioration)
in YEP latency. This finding suggests that the process resulting in
the reversible reduction of the PERG P50
component (perhaps inflammatory
change
distal to the ganglion cells) is independent
of that causing the YEP latency delay (presumed demyelination).
The improvement
in YEP amplitude may reflect resolution of
edema within the optic nerve. The initial
effect on PERG P50 cannot reflect retrograde degeneration to the ganglion cells, as
there has been insufficient
time for this to
occur. As the presumed inflammatory
process resolves with improvement
in both
PERG P50 and YEP amplitudes, so the increasing YEP latency delay reflects the development of demyelination
in the nerve. It
can be presumed that retrograde degeneration may occur during this period, resulting
in the N95 abnormality that may occur 4 to
6 weeks after the acute ohase.
4-3
4-3-2-2Optic NerveCompression PERG
N9S ab-
normality is a common finding in compression of the optic nerve from space-occupying lesions, usually pituitary tumors or
craniopharyngiomas.
Kaufman et alll4,ll5
first suggested that monitoring of PERG
may be useful in optic nerve compression,
and two subsequent reportsll6,ll7 found that
the PERG had prognostic value in relation
to postoperative function following surgical
decompression.
In the largest series to
date,ll7 N9S abnormalities were frequently
observed, in keeping with retrograde degeneration to the retinal ganglion cells, but
PSO abnormalities
were present in severe
disease.
Note the findings shown in Figure 4-12
in a patient with an eye with no light perception following long-term optic nerve
compression by a large, nonfunctioning
pituitary tumor. The blind eye still shows
some remaining PERG, with a shortened
latency PSO, in keeping with the suggestion
that some of the PSO component is generated anterior to the ganglion cells. It is
doubtful whether such a finding would
have been possible if monocular stimulation had been used due to the resulting difficulties in fixation. Perhaps surprisingly,
the PERG has been suggested to be a more
sensitive indicator of optic nerve compression in dysthyroid eye disease than is the
Clinical
219
Applications
tion. This section addresses the findings
in
primary ganglion cell degeneration only.

After an early report of normal full-field
and pattern ERGs in DOA that did not examine the PERG N95 component,119 a
more complete description of the PERG in
DOA was provided by Berninger et al.120
They reported reduction in the N95 component, with none of 7 patients showing abnormalities of P50. YEP abnormalities were
usually also present, but in some patients
the abnormalities were confined to amplitude, with only 2 patients
showing
marke
latency abnormality.
Holder et al66 reported the PERG findings in 13 pati~nts from eight families with
DOA linking to the OPAl locus on chromosome 3q, examined as part of a larger clinical series.121 N95 abnormalities
were observed in the PERGs of younger patients,
but as disease progressed and visual deficit
became more severe, the P50 component
became involved, with mild amplitude reduction. Further increase in disease severity was accompanied by additional amplitude reduction in P50, with accompanying
shortening of latency. In no patient was the
PERG completely nondetectable,
even
though scanning laser ophthalmoscopy
demonstrated
loss of the ganglion cell population in end-stage disease. The findings
in 2 typical patients, 1 with relatively mild
pattern VEP.lI8
disease and 1 with severe disease, appear

in Figure 4-13.
4-3-2-3Optic Atrophy There is a lack of clarity

in the literature between optic atrophy as a
LHON may also show PERG N95 reduction with a normal P50 and normal fullfield ERGs.9 One report of a patient with a
11778 mutation showed recordings taken
3 days after the onset of acute visual loss in
physical sign and primary optic atrophy,

such as Leber hereditary optic neuropathy
(LHON)
or dominant optic atrophy (DOA).
It is known that a pale disc can be associated with primary ganglion cell disease,
ganglion cell dysfunction
secondary to optic
nerve disease, or primary retinal dysfunc-
4-3
the second eye.122 The vision in the first

eye had shown sudden reduction 3 weeks
earlier. There was marked N95 reduction in
both eyes, but no P50 involvement
and no
interocular asymmetry. Clearly, with such a
short history, the abnormality in the more
recently affected eye could not reflect retrograde degeneration, and the N95 loss is
attributed to primary ganglion cell dysfunction. MRI scan data were also presented
which showed an abnormality only in relation to the optic nerve of the acutely affected eye. The different and complementary nature of the structural information
provided by neuroradiology,
tional information
provided
iology, were noted.
and the funcby electrophys-
4-3-2-4MiscellaneousOptic Nerve Dysfunction Amplitude reduction of the N95 component,

with sparing of P50, has been described in
19 of 24 patients with optic nerve head
drusen 123;only 4 of the 24 showed P50 involvement. There has also been a report of
N95 component reduction in optic neuropathy following a bee sting.124 Ischemic
optic neuropathy may also show selective
involvement
of the N95 component, but
there is a higher incidence of P50 abnormality than in optic nerve demyelination.64
4-3.3 Glaucoma
The difficulties
in the management of the
patient with glaucoma, and the search for
an accurate early diagnostic indicator, have
led to more published PERG data on this
subject than any other. Despite this extensive literature, there is little consensus on
the value of the PERG in glaucoma or ocular hypertension
(OHT). As it has been
suggested that loss of more than one third
of nerve fibers can occur prior to the appearance of a visual field defect,125 one of
Clinical
Application:
the main issues is whether the PERG can

assist in identifying
those patients with
OHT destined to convert to primary openangle glaucoma (POAG) at a stage prior to
the development
of irreversible visual field
loss. A wide variation in technique often
precludes accurate comparison between
published studies, and it is hoped that in
future this problem may be resolved by
widespread adoption of the ISCEY recommendations. Differences in risk propensity
between patient populations are another
confounding
factor in the comparison of...
different studies.
After the initial reports33,107.126of PERG
changes in gl~ucoma were published, Papst
et al127described abnormal PERG amplitudes in all their glaucoma patients with
abnormal optic discs and abnormal visual
fields. In addition, they found that the
PERG was a more sensitive indicator of
dysfunction
than was the pattern YEP.
However, other authors were unable fully
to confirm these results. Ringens et al128
exa!llined the relationship between the
PERG and clinical variables in a group of
75 glaucoma patients with normal visual
acuity. There was a relationship between
the PERG and the cup:disc ratio, but not
with intraocular pressure or the extent of vi.
sual field loss. They observed considerable
overlap between healthy individuals and
glaucoma patients, but there was a difference between the mean values of the two
groups. The demonstration
of mean differ-
222
The Pattern Electroretinogram
Pattern YEP
Flash VEP
PERG
-J\
1-
100
200
50
100
100
200
50
100
100
200
50
100
Time(ms)
Figure 4-13 Electrophysiologic findings from 2 patients

ffi'ith dominant
optic atrophy are shown. (A} This pa-
tient has relatively mild disease, with visual acuity of

20/60. Pattern VEP is delayed (P]OO at approximately ]30 ms; upper limit of normal]]
VEP shows no abnormality;
0 ms}; flash
PERG shows normal
P50 component with reduction in N95. (B} Second

patient has end-stage disease, with visual acuity of
countingfingers.
Pattern VEP is nondetectable; flash
VEP is of very low amplitude;
v-
and PERG shows re-
duction in both N95 and P50 components, with shortening of P50 component latent}'. (C} Normal
control.
Time(ms)
ences between groups, although of scientific value, may contribute little to the management of an individual patient. Others,129
controlling carefully for optical factors, also
found no PERG changes as a function of
field loss.
Most of these early reports did not analyze the N95 component. One reportl30
found P50 amplitude reduction, but also increased N95 latency. Other authorsl31 described involvement
of the negative wave
(N95) in glaucoma. Weinstein et al132analyzed the two components individually
in a
glaucoma population. They found specific
effects on the N95 component in both glaucoma and OHT and observed an abnormal-
4-3
Clinical
Applications
223
Figure 4-13 (D.E) Fundi

of both patients show
global disc pallor:
224
ity incidence of 40% in the OHT patients.

With respect to OHT, it is important to remember that many patients do not develop
clinical glaucoma. Various prospective studies report a conversion rate between 0.4%
and 17.4%133-138;10% in 10 years may be
taken as a reasonable figure (RA Hitchings,
personal communication),
but this is inevitably a simplification
because of populations with different risk factors, degrees of
intraocular pressure elevation, and other
factors. A higher incidence rate implies a
diagnostic measure with excess false positives, thus not clinically useful, or, more
likely in the study by Weinstein et al,132a
population more at risk than those in the
cited reports that examined conversion.
Porciatti et al16 used a steady-state
PERG with 16.6 reverals/s (8.3 Hz) in a
comparison of different stimulus spatial frequencies. They found that medium spatial
frequencies, similar to the 1.5 cycles per degree (c/deg) grating stimulus that produced
the maximum amplitude in normal individuals, were affected
in all glaucoma
patients
and most OHT patients. Early steady-state

checkerboard PERG experiments
by Bach
and Speidel-Fiauxl39
used two check sizes,
0.8 and 15.0. The authors concluded that
a combined measure based on responses to
both check sizes, the smaller being more
affected, gave abnormal findings in 43% of
an OHT group. This observation is cQnsistent with the reported spatial-tuning
effects
of the PERG and the domination of the
steady-state waveform by the N95 component. A further report from Pfeiffer and
Bachl40 extended those observations and
included longitudinal
described a reduction
data. The authors

in mean visual field
sensitivity over an average followup

of 20 months in the high-risk OHT
period
patients
with abnormal PERGs compared to those

with normal PERGs. Pfeiffer et al141also
found that all 5 eyes with high-risk OHT
that developed field loss over the study
period had abnormal PERGs, but none of
the 17 eyes with normal PERGs went on
to develop visual field defects.
A subsequent study found a correlation between visual field parameters and
PERG
N95 amplitude,142
but it is difficult
to apply this to a management decision,

such as the possible initiation of treatment,
in a single patient with raised intraocular
pressure. In contrast, Bach et al,143using a
large steady-state stimulus field (26 X
34), reported that 72% of 18 eyes with abnormal PERGs had no visual field defect
within the area covered by the PERG stimulus. The relevance of risk factors had
also been considered by O'Oonaghue
and
colleagues and by Trick and coworkers.
O'Oonaghue
et all44 found (transient)
PERG reduction more marked in highrisk OHT patients. Trick et al145found
that 11;5% ofOHT
patients exhibited
steady-state PERG amplitudes more than
2.0 standard deviations below the normal
mean, but there was no correlation between PERG parameters and either
cup:disc ratio or intraocular pressure.
Korth et all46 added the dimension of
stimulus color. They compared the patternons~t PERGs to red-green color-contrast
stimuli with green-black luminance contrast gratings (0.3 c/deg) in a group of 42
patients with glaucoma of various types and
severity. The PERG data were correlated
with the results of static perimetry and
optic disc morphometry.
Reduced PERGs,
of similar magnitude reduction, occurred
with both types of stimuli. However, although correlations between PERG amplitudes and neuroretinal rim areas were similar, a significant correlation between PERG
4-3
reduction and visual field loss was found

only with the color-contrast stimulus.
Publications have continued to examine
the relationship between PERGs and other
variables. Ruben et a1147,148
compared
PERG with peripheral color-contrast sensitivity (CCS), motion-detection
thresholds
(MOT), and static perimetry in a large population of OHT and glaucoma patients.
There was poor correlation between the
tests, with a relatively low proportion of patients showing multiple abnormalities.
The
authors suggested the possibility of multiple pathophysiologic
mechanisms, perhaps
affecting different retinal layers. The incidence of 40% PERG abnormality
in the
OHT group is much higher than would be
predicted by the conversion studies. Homer
et al149added disc morphometry
to their
protocol. None of their OHT patients in
the interim report of a prospective study
developed field loss over a mean 15-month
followup period, but the PERG and nervehead analyses were found to differ in their
abnormality incidence.
A comprehensive
multivariate
analysis
was presented by Martus et allso in relation
to a group of glaucoma patients. Using psychophysical and electrophysiologic
tests,
they examined the correlation with neuroretinal rim area. Contrast-sensitivity
measurements and blue-yellow
pattern-onset
VEPs showed similar sensitivity (approximately 85%), with PERG lower at about
65%. A specificity of 89% was achieved by
combining the measures. All measures
showed moderate correlation with disc morphometry, but psychophysical
tests showed
a higher correlation with visual field defects
than did the electrophysiologic
tests.
To summarize, the PERG is often abnormal in glaucoma, but there is little clear relationship between the PERG and many of
the other parameters used in the assess-
Clinical
Application.\
225
ment of glaucomatous eyes. Visual field parameters correlate poorly in some studies,
better in others. There is better consistency
in the correlation with the structural information provided by disc morphometry.
Many studies find the incidence of PERG
abnormality in OHT to be significantly
higher than prospective studies examining
conversion to glaucoma would predict. Both
P50 and N95 abnormalities
may occur in
the transient PERG. The steady-state
PERG, an abnormality of which may reflect
either P50 or N95 reduction in the transie~t
PERG, is found by some to be the more
sensitive measure. VEPs to a blue-yellow
pattern stimulus are reported to be more
sensitive than the PERG, but chang~s in
disc morphometry
may be potentially the
best single parameter. A variety of tests,
both electrophysiologic
and psychophysical,
increase abnormality detection.
Additional
functional effects on the neural retina in raised intraocular pressure may
be contributory
factors to the differing
manifestation
of the functional defect present in different patients, even though histologic change occurs only at the level of the
ganglion cells. This is further supported by
recent experiments
in primates where
TTX, which blocks spiking ganglion cell
activity, did not completely extinguish the
PERG, whereas the PERG was abolished
in experimental
glaucoma.l0 Not all of the
measurable functional defects translate into
clinically significant disease, and there may
be additional modifying factors, yet unknown. In an earlier review(O6 of the PERG
in glaucoma and OHT, this author concluded that a long-term prospective study
was necessary before definite conclusions
could be drawn regarding the potential influence of the PERG on the management
226
of OHT.
That need persists at the time of
this writing.
4-3-4 VEP Abnormalities and the PERG
When the initial reports of delayed pattern YEP in optic nerve demyelination
and other optic nerve diseases were published , 1.)1-1.)5
it was at first assumed that a
delayed pattern YEP was indicative of optic
nerve dysfunction.
However, in the early
1980s, with the publication
of reports of delayed pattern YEP in a great variety of retinal diseases , 156-1.)9
it became clear that a delayed YEP was far from pathognomonic
of
optic nerve disease. Subsequent reports
have confirmed that macular dysfunction
regularly gives a delayed YEP, the magnitude of which may be similar to that seen
in optic nerve disease.9,70 A delayed pattern
YEP must not be assumed necessarily to
reflect optic nerve dysfunction.
The electrophysiologic
distinction
between optic nerve disease and maculopathy
is achieved by their different effects on the
PERG. Clinically, it can be difficult to distinguish between central retinal disease
and optic nerve pathology, as both may
manifest visual acuity, central field, and
color vision loss. Equally, a relative afferent
pupillary defect may occur in macular dysfunction.160,161 Furthermore,
macular dysfunction is not necessarily accompanied by
anatomic abnormality. In the author's laboratories, the PERG is recorded whenever
there is a pattern YEP abnormality in a patient with visual symptoms. A normal
PERG, or selective N95 abnormality, confirms optic nerve-ganglion
cell dysfunction.
A severely reduced or extinguished
P50
component suggests macular dysfunction,
and thus the need for a full-field
ERG to
determine whether the dysfunction

is generalized or confined to the central retina.
On many occasions, patients referred by
a neurologist for presumed optic neuropathy have been shown to have retinal dysfunction. Some had normal maculas; others
had subtle alterations that were not revealed during routine neurologic examination. Similar principles apply to the assessment of the patient with disc pallor associated with cone or cone-rod dystrophy
who was originally thought to have neurologic disease. There may not be visible abnormality at the macula, and the retinal
vessels may not show significant abnormality. The diagnosis may be thought to be primary optic atrophy when neuroimaging
studies exclude a compressive lesion. The
pattern YEP is abnormal, but a severe
PERG PSO abnormality confirms macular
dysfunction,
and a full-field
ERG to assess
generalized retinal function is thus performed and may reveal generalized cone
dysfunction.
Use of the PERG also enabled
the delayed YEP that may occur in hypothyroidism to be localized to retinal rather
than optic nerve dysfunction.162 The PERG
during the hypothyroid
phase was both
delayed and reduced compared with that
following restoration of euthyroid status.
The mechanism by which this occurs is unknown.
4-3.5 Nonorganic Visual Loss
Assessment of the patient in whom nonorganic visual loss is suspected and who has
a monocular pattern YEP abnormality is a
situation where simultaneous pattern YEP
and PERG registration has particular advantages. In such circumstances, there may
be an attempt by the patient to influence
the results, particularly if malingering or if
there is pending litigation from which sig-
References
nificant compensation may result. Assuming the patient is cooperative, the PERG
should initially be performed binocularly in
the routine manner. This records what the
PERG should be in the eye with the abnormal YEP. If that PERG is abnormal, then
the dysfunction
is organic and the YEP abnormality is a genuine reflection of disease.
The site of dysfunction
is distal to the retinal ganglion cells if there is a marked P50
abnormality, and optic nerve or ganglion
cell if the abnormality
is confined to the
N95 component. If the PERG is normal
from the "bad" eye with binocular recording, monocular simultaneous YEP and
PERG is performed. If the YEP remains
abnormal in the "bad" eye, and the PERG
remains that obtained under binocular
recording conditions, then the YEP abnormalitY is genuine and reflects optic nerve
dysfunction.
If the YEP remains abnormal
from the "bad" eye, but the PERG differs
227
SUMMARY
Since its introduction
to clinical practice,
the PERG has become an important component of electrophysiologic
diagnosis. The
objective PERG evaluation of central retinal function complements
the full-field
ERG in the assessmeht of patients with
retinal disease. In addition, the gahglion
cell origins of the N95 component of the
PERG allow a direct electrophysiologic
assessment of ganglion cell function in botrr
primary ganglion cell disease and ganglion
cell dysfunction
secondary to optic nerve
disease. The different effects of optic nerve
and macular disease on thePERG
considerably improve accuracy of interpretation
an abnormal YEP, facilitating the electrophysiologic distinction
between
and macular dysfunctioh.
of
optic nerve
markedly from that obtained with binocular registration, then the patient is manipulating
the recording
situation,
perhaps
by voluntary defocusing or inaccurate fixation.

If the patient states that he or she is unable to fixate with the "bad" eye, the following technique may be successful. Obtain fixation binocularly; then patch the
"good" eye, asking the patient to try to
keep the eyes as still as possible. Start data
acquisition immediately
when the "good"
eye has been occluded, and pause as soon
as fixation is observed to drift. It is notable
how often an eye with apparently very poor
visual acuity maintains fixation for at least
5 or 10 seconds. The process is then repeated until satisfactory PERG registration
is achieved. Some malingerers deliberately
move the eye to avoid fixation as soon as
the "good" eye is covered.
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121. Votruba
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GH: The pattern-elicited
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128. Ringens
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A: Pattern
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elec-
149. Bomer TG, Meyer
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140. Pfeiffer
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N, Bach M: The pattern-electroin glaucoma
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J: Little
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Br J Ophthalmo/1992;
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150. Martus
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al: Pattern
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Bickler-Bluth
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151. Halliday
Delayed
AM, McDonald
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M, Horn F, Jonas J: Utility
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The
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ent pathomechanisms
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in compression
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1976;99:
357-374.
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GE: The effects of chiasmal
on the pattern
com-
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156. Lennerstrand
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G: Delayed
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thalmoI1982;60:497-504.
157. Holder
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GE, Chesterton
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]R: The visual

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al: Combined
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E, Kriss A, et al:
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158. Papakostopoulos
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CD:
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F, et al:
1994;8:516-520.
D, Hart CD, Cooper
Electroencephalogr
R, et
assessment
of
serous retinopathy.
77-80.
ST, Arden
Pattern
electroretinogram
contrast
thresholds
glaucoma:
DW, Marsden
AM, Halliday
pattern
]: Vi-
of multiple
Visual evoked
ophthalmology
ST, Hitchings
WI, Mushin
in diagnosis
153. Asselman
278-280.
84-89.
148. Ruben
]:
in optic neuri-
1973;4:661-664.
Electroencephalogr
coma. Graefes Arch Clin Exp Ophthalmo/1993;231:
hypertension
diagnosis.
WI, Mushin
response
AM, McDonald
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correlation
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Electrophysiology
F, et al: A multi-
in glaucoma
visual evoked
152. Halliday
cortical
147. Ruben
M, Horn
Vis Sci 1998;39:1567-1574.
(PRERG)
201-206.
146. Korth
P, Korth
Invest Ophthalmol
155. Holder
145. Trick
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in-
results after 2.5 years. Ger J Ophthalmol
154. Halliday
144. O'Donaghue
abnormalities
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analysis in ocular hypertension:
tis. Lancet 1972;1:982-985.
C, Kaye SB, Brown
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Bach M, et al: Pat-
and computerized
variate sensory model
N, Tillmon
value of the pattern
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]H,
tern electroretinogram
GB, O'Sullivan
F, et al:
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Br J Ophthalmo/1995;79:326-331.
colour
and
of results.
159. Bass S], Sherman

Visual evoked
Invest Ophthalmol
160. Thompson
Pupillary
], Bodis-Wollner
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I, et al:
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Vis Sci 1985;26:1071-1074.

HS, Watzke
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RC, Weinstein
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]M:
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161. Folk JC, Thompson

sual function
nopathy.
in central
serous reti.
162. Holder
evoked
HS, Han Dr, et al: Vi-
abnormalities
GE, Condon
potentials
JR: Pattern
and pattern
grams in hypothyroidism.
visual
electroretino-
Doc Ophthalmol1989;
73:127-131.
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Arden
GB, Vaegan, Hogg CR: Clinical
perimental
evidence
that the pattern
retinogram
(PERG)
mal retinal
layers than the focal electroretino-
gram (FERG).
in more proxi-
Ann iVY Acad Sci 1982;388:580-607.
Bach M, Hawlina
for basic pattern
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and exelectro-
M, Holder
GE, et al: Standard
Doc Oph-
In press.
Baker CL ]r, Hess RF, Olsen BT, et al: Current

source density
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analysis of linear and non-linear
of the primate
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Heckenlively
]R, Arden
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Mosby-
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Hess RF, Baker CL ]r: Human

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GE: The
of Vision. St
1991 :549-556.
pattern-evoked
J Neurophysiol1984;51
pattern
anterior
visual pathway
tionship
to the pattern
personal
clinical
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dysfunction
visual evoked
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:939-951.
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and its relapotential:
of 743 eyes. Eye 1997;11:
924-934.
Holder
GE: Significance
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Maffei
953-955
pattern
visual pathway
L, Fiorentini
sponses to alternating
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in anterior
A: Electroretinographic
gratings
re-
before and after
of the optic nerve. Science 1981;211:
235
Mitchell G. Brigell, PhD
The visual evoked potential (YEP) is a cortical response that is time-Iocked

to a visual
the posterior head regions allow detection

of chiasmal and postchiasmal dysfunction
stimulus event, such as the contrast-reversal of a checkerboard pattern or a flash of

light. It is recorded using surface electrodes
and differential
amplifiers, both of which
are commonly used to record the electroen-
the visual pathways...

In this chapter, YEP methodology
cephalogram (EEG). The amplitude

YEP-3
to 25 pY (pY = microvolt)-is
of the
con-
siderably smaller than that of the ongoing

EEG, which can be as large as>iOO pY. Because of this uhfavorable signal-to-noise
ratio, computer averaging is necessary to
record the occipitally generated YEP. Detailed guidelines for the recording of the
YEP have been published, and those interested in developing a clinical YEP service
are encouraged to consutt these sources.l,2
Although the YEP is a cortically generated response, careful choice of stimulus
can localize visual dysfunction.
Monocular
stimulation
allows the localization of dysfunction to the prechiasmal visual pathway.
When the YEP is used together with the
pattern and flash electroretinogram
(ERG),
an occult visual loss can be attributed to
in
is
briefly reviewed, followed by a review of

the use of the YEP in detecting various diseases affecting the visual pathways in adults
and children. Special emphasis is placed on
differentiating
clinically significant effects
of a disease on the YEP from statistically
significant
difference
effects. A clinically significant

is one in which there is a high
probability
that a patient with a given disease will have a result that is highly unlikely in the normal population (that is,
2 standard deviations [SO] away from the
mean, yielding a probability
of less than 5%
of being normal). A statistically significant
difference
between
groups can reveal the
pathophysiologic
mechanism of a disease.
For example, a patient with a YEP latency that is 2.5 SO above the age-matched
normal mean is most likely to have a demyelinative
optic neuropathy in the presence of a normal pattern ERG and a normal
funduscopic
appearance
(although
such
maculopathy, diffuse retinal degeneration,

optic neuropathy, or functional visualloss.3
Figure 5-1 is a flowchart illustrating the use
of visual electrophysiologic
tests in clinical
decision making. Hemifield
stimulation
and the use of multiple recording sites over
237
238
The Visual Evoked Potential
r-Optic
opacity.
eg, cataract.
corneal opacity
Figure 5-1 Flowchart
of clinical applicationsforvisual
electrophysiologic tests.
Redrawn with permission ofWB Saunders Companyfrom
Brigell M. Celesia GG: Electrophysiological evaluation of the
neuro-ophthalmologypatient: an algorithm for clinical use.
Sem Ophthalmol
1992;7:65-78.
findings can also be seen with early compressive optic neuropathy or mild toxic
optic neuropathy). However, a statistically
significant difference between a group of
patients with dyslexia and normal individuals can be of little clinical significance in
the diagnosis of this disorder if there is a
large overlap between groups. Many studies
in the literature do not differentiate
statistically significant differences from clinically
significant differences. In this chapter, care
is taken to distinguish these results.
5-1
Origins
ofthe
VEP
239
ORIGINS OF THE VEP

The YEP primarily
reflects the electrical
activity generated by stimulation of the

central visual field. Figure 5-2 shows how
the introduction
of a central scotoma reduces pattern YEP amplitude. There are
three reasons for a predominant
contribution of the central visual field to the YEP:
1. The retinotopic
map in striate cortex is
such that the representation

visual field is located nearest
at the occipital pole, whereas
tation of the peripheral field
within the calcarine sulcus.4
2. The foveal projection
of the central
to the surface
the represenis buried deep
is magnified
at the
cortex.5,6 Much of this magnification

is due
to a minimum ofa 1:1 relationship between
photoreceptor
and ganglion cell in the central retina, and a wide area of spatial summation in the peripheral retina, with the
input from many photoreceptors
converging
on a single ganglion cell. Thus, more than
50% of cells in the primary visual cortex
have receptive fields in the central 10 of
the visual field.
3. Small checkerboard stimuli can be resolved only by the central visual field.
Because there is no change in mean luminance with a contrast-reversal
stimulus,
the peripheral field will not be stimulated
by time-Iocked
stray light and a response
from the central visual field is ensured. The
use of larger spatial elements (lower spatialfrequency stimuli) can be used to measure
responses derived more from the parafoveal region. It is therefore generally recommended that both a relatively small (15
min of visual angle) and a relatively large
(60-min)
protocol.
check size be used in a clinical
Figure 5-2 Transient pattern
VEPs recorded from visu-
ally normal adult. Trace at top is typical response to

full-jield stimulation (12-min checks, 12 X 14 field,
2 reversals/s}. P100 component of response isindicated. M iddle trace (-3 O}shows response when central
3 of stimulus is blocked out. Note both reduced amplitlfde and increased latency when central scotoma is
present. Bottom trace (-9} shows response when central9
is blocked out. In this and all subsequent fig-
ures, positive is up unless otherwise indicated.

Redrawn with permission of Churchill Livingstone from
Sokol S: Visual evokedpotentials. In: Aminoff MI, ed:
Electrodiagnosis in Clinical Neurology. 2nd ed. New
York: Churchill Livingstone; 1986:441-466.
240
The surface-recorded
YEP is derived
from open electrical fields generated by

synchronous slow potentials in apical dendrites.7 Simultaneous recording of multiunit
activity in striate cortex and surface potentials in the monkey has demonstrated that
the primary source of the early surface positivity to pattern stimulation
{the P60 in the
monkey, analogous to the PlOO in the human) is in the supragranular layers of the
primary visual cortex.8 Although there are
probably multiple areas of visual cortex that
contribute to each surface-recorded
peak,
measurement of component amplitude and
latency has proved to be clinically useful in
the detection of conduction delays due to
demyelination
of the optic nerve and reduced amplitude
due to optic atrophy
{that
is, axonal degeneration).
VEP STIMULUS PARAMETERS

The YEP is typically recorded in response
to pattern or flash stimuli. Flash stimuli are
produced most frequently with xenon-arc
photostimulators,
with which the luminance, stimulus rate, and wavelength of the
flash can be varied. The flash YEP is quite
variable in waveform between individuals,
lif\1iting its clinical utility. It is often difficult to identify homologous waves in normal individuals,
resulting in high variability
of normative amplitude and latency data.
This variability can be overcome somewhat
by recording data from multiple flash-Iumi-
nance levels and plotting an intensity-amplitude function.9 Also, because, in the normal population, the flash response is quite
similar regardless of which eye is stimulated, interocular asymmetries of the flash
YEP can be used to identify unilateral dy~function in the prechiasmal visual pathway.
Pattern stimuli are usually generated
on a video monitor. The field size, pattern
size, contrast, retinal location, and rate of
presentation of pattern stimuli can be varied. Checkerboards
are used most often in
clinical settings because they generate the
most robust YEP. However square- or sinewave gratings can also be used for certain
applications.l
YEP pattern stimuli are either phase-reversed (also called pattern
reversal, contrast reversal, or counterphase
modulation) or presented in a contrast appearance-disappearance
mode without a
change in mean luminance (called pattern
appearance-disappearance or pattern onsetoffset). In either case, the overall mean luminance of the stimulus is constant, minimizing luminance contamination
of the YEP.
For example, when a phase-reversal
stimulus is viewed, checks are visible at all
times-with
half the checks increasing in
luminance and the other half decreasing.
The net result is a constant mean luminance.ll If the modulation of the checks is
asymmetric-that
is, one cycle of checks is
brighter than the other cycle-the
pattern
YEP waveform will be contaminated
with
luminance responses. In the on-off mode,
the pattern appears for a discrete length of
time (for example, 100 ms) and then is replaced by an unpatterned,
diffuse field of
the same average luminance as the pattern
stimulus.12
YEPs can be recorded under either ttansient or steady-state stimulus conditions.
Transient YEPs are produced when sub-
5-2
stantial intervals
elapse between
stimulus
duced when the brain does not regain its

resting state between stimulus presentations. A practical distinction between the
two is that transient YEPs are evoked by
low stimulus rates, while steady-state YEPs
are evoked by rapidly repetitive stimuli.
The temporal rate at which YEPs change
from transient to steady-state conditions
varies, depending on a variety of factors,
but in general the transition occurs at 6 to
10 presentations per second. An advantage
of recording transient YEPs is that it allows
analysis of specific amplitude or latency
components. A disadvantage of this method
is that it may be difficult to identify homologous components across individuals or
stimulus conditions. Steady-state YEPs are
more easily described in quantitative
terms
a specific number
of
frequency components that can be characterized by amplitude and phase.

In the past two decades, new forms of
visual stimuli have been applied to clinical
testing. Most notable of these are the motion YEp, the sweep YEP, the binocular
beat response, and the multifocal YEP:
1. The motion VEP is generated
Stimulus
Parameters
2. In the sweep VEp, a steady-state,
presentations, allowing the brain to regain

its resting state. Steady-state YEPs are pro-
because they comprise
VEP
by the
onset, reversal, or drift of a grating or dot

pattern. The response generated by the
motion stimulus has different characteristics from other pattern YEPS13 and appears
to be generated primarily by the magnocellular visual pathway. 14.15Asymmetries
in
the motion YEP nasally and temporally
have been found in strabismic patients and
correlate with perceptual asymmetries.16
Thus, the motion YEP may prove useful in
the early detection of strabismic amblyopia
and in the monitoring of its treatment.
sinusoidal
response is generated
241
quasito high-
frequency presentation of a visual stimuIUS.17-19By measurement of the EEG components at harmonic frequencies to the
stimulus frequency, a VEP can be measured
without signal averaging. Changes in the
amplitude and phase of this frequency following response can be measured as a stimulus parameter, such as check size or contrast, is changed. By measurement of the
check size at which the response falls to
noise levels, the sweep VEP has been used
clinically
to estimate
visual
acuity
quickly
in infants and young children.2,21

3. The binocular beat response can be used to
measure binocularity
of the visual cortex in
amblyopic patients.22,23 The beat response
is a nonlinear difference frequency (for example, 2 Hz), which is seen when different
frequencies of stimulation (for example,
16 and 18 Hz) are presented to each eye
dichoptically.
Patients who lack binocular
cells in the visual cortex because of untreated childhood amblyopia do not generate a beat frequency in their VEPs.
4. The multifocal
VEP is a technique
oped to obtain independent
devel-
responses from
multiple areas of the visual field simultaneously.24 A pseudo-random

sequence of stimuli, called a maximum-Iength sequence( or
m-sequence), is used to derive linear and nonlinear components of the VEP. This technique can potentially be used to obtain objective measurement of dysfunction
localized areas of the visual field.
in
242
Figure 5-3 VEP waveforms and wave nomenclature

for (A) pattern-reversal,
(0) flash-stimulus
(B) pattern-onset,
and
conditions. Note that occipital
negative potentials are plotted upward for the pattern-reversal

positivity
and flash responses, whereas occipital
is plotted upward for the pattern-onset
response.
M odified with permission of Elsroier Sciencefrom H arding
GF, Odom J~ Spileers ~ et al: Standard for visual rooked
potentials 1995: the International Societyfor Clinical
Electrophysiology of Vision. Vis Res 1996,:36:3567-3572.
VEP RESPONSEPARAMETERS
The YEP parameter that is of greatest diagnostic utility depends on the questions
being asked and the type of stimulus used
to generate the YEP. If the issue is estimation of a patient's visual acuity, amplitude is
measured and high spatial-frequency

(smallelement) pattern stimuli are used. If a covert demyelinative
lesion of the visual pathway is at issue, then latency (or phase) is key.
Response amplitude is measured from
the peak of one component to the trough of
the preceding component. Amplitude
is expressed in microvolts (JlY). Pattern-reversal
YEP components that are commonly measured include the N75, the PlOO, and the
Nl35 (Figure 5-3). In this nomenclature,
P and N refer to positive and negative voltages recorded at the occipital electrode
with respect to the voltage at the reference
electrode. The number following the letter
refers to the approximate normal component peak latency measured in milliseconds
(ms). A peak latency is the time between
the stimulus event and the voltage peak of
the response. Other stimulus paradigms use
other nomenclatures
for the response components.
3 VEP Response Parameters
243
Although this may seem confusing, it is

intentional
to emphasize that response
peaks obtained in these stimulus paradigms
are not equivalent, but rather have differing
origins and can be affected differently
by
disease states. The flash YEP components
are labeled sequentially
and by their voltage polarity (NI, PI, Nz,...). The patternonset YEP components are labeled CI, CII,
and CIII (see Figure 5-3). Although it is
clinically useful to measure peak components, it is important to note that each component is probably derived from the activity of multiple cortical areas and thus
depends on recording-electrode
location.
(See ReganZ5 for a discussion
of component analysis.)
of the pitfalls
Absolute latency is more reliable than

absolute amplitude. A normal subject
shows a latency variability of 2% to 5%
within and between recording sessions,
whereas amplitude can vary by as much as
25% within and between subjects.z6,z7 Latency is clinically useful because an individual patient's latency can be compared to
age-liatched
norms using statistical probability rules. Relative amplitude is reliable
when comparing interocular differences.z8
Because
parameter,
in subjects
factors that
latency is an important clinical

it has been studied extensively
with normal vision. Important
affect YEP latency include
pupil diameter, age, and refractive error. As

shown in Figure 5-4, a decrease in pupil diameter results in a prolongation of P 100 latency, caused by a decrease in retinal illuminance.z9 Latency decreases by nearly
20 ills when pupil diameter increases from
1 to 9 mill. Thus, pupil diameter, as well as
other factors that reduce retinal illuminance,
such as ptosis or tinted lenses, should be
considered when interpreting
latency of the
Figure 5-4 VEP latency in normal subject for 12- and

48-min checks as function
of pupil
diameter ( upper
scale}. Subjects eye was dilated with 2.5% phenylephrine and tested with artificial
pupils ranging in
diameter from 1 to 9 mm. Lower scale shows effective

retinal illuminance for each pupil
diametet; Data are
bestfit by hyperbolas; respective equations and coefficients of determination
are shown in figure.

from Sokol S, Domar A, Moskowitz A, et al: Pattern evoked
potential latency and contrast sensitivity in glaucoma and
ocular hypertension.In: SpekreijseH, Apkarian PA, eds:
Electrophysiology and Pathology of the Visual Pathways. Hague: Dr W Junk BV Publishers. Doc Ophthalmol
Proc Ser 1981;27:79--86.
244
A
220
220
210
210
200
200
190
190
180
180
';;)
E
~
u
0:
170
160
-;;;
..
170
160
! ..
c:
"'
150
o
~
"-
140
Jg
o
~
Cl.
150
\~;
140
:
130
"
'..',,:..:,
120
~:~
110
110
100
90
100
90
..~='i.~
:r-
III
1
111111II
2 3 456
II
1 111111
2 3 45
Months
10
1 II
20
1111
50 80
Years
Age
Age
Figure 5-5 p 100 latency as function
::~f;
:..~~::...
of agefor ( A) large
(48- and 60-min) checks and (B) small (12- and

15-min) checks. Note that latency for small checks is
longer than for large checks across life span.
Redrawn with permission of Elsevier Sciencefrom Moskowitz A, Sokol S: Developmental changesin the human visual
systemas reflectedby the latency of thepattern reversal VEP.
Electroencephalogr Clin Neurophysiol1983;56:1-15.
YEP. As can be seen in Figure
5-5, P100 la-
tency decreases exponentially

from age
2 months to the 40s and then increases
slightly from the mid 40s to 80 years of
age.30 The functions are the same shape for
large and small check sizes, but absolute latency is longer for small checks.
Figure 5-6 shows YEP latency recorded
with lenses of varying power from two subjects after cycloplegia: RP, a myope; and
JM, a hyperope. The shortest latency was
obtained when optical values equivalent to
their emmetropic
correction were used. In
subjects without cycloplegia, minus lenses
produce a constant latency until the subject
can no longer accommodate.31 Stimulus factors also affect YEP latency. For example,
latency decreases with increasing pattern
size,3z-34 increasing luminance, and increas-
5-4 Clinical
ing contrast.3) It is therefore important to

calibrate the YEP stimulus periodically
to
ensure the validity of normative data and
to make accurate assessment of changes in
patient
status over time.
Use of the VEP in Adults
245
sorbed or reflected by all but the most

dense opacities. Thus, an amplitude reduction of more than 50% or a latency delay of
more than 15 ms is highly
suggestive
of
dysfunction in the central visual field. The

flash YEP may be particularly important in
patients with opacities who are at high risk
for neuronal dysfunction,
such as patients
CLINICAL USE OF THE VEP IN ADULTS
with diabetes, ocular hypertension,

or ocular trauma. Abnormalities
in the flash YEP
5-4-1 Media Opacities
are correlated with poor postoperative visual acuity.37-41 The flash YEP has also
been useful in the selection and timing i'!f
Flash VEPs may be useful for detecting

maculopathy or optic neuropathy in patients with dense media opacities.36 This
response is unaffected by most opacities
because light is diffused rather than ab-
vitreous surgery in eyes with diabetic vitreous hemorrhage.42,43 Scherfig et al43 recorded flash YEPs from diabetic patients
prior to vitrectomy and found that patients
Figure 5-6 p 100 latency

as function
of spherical
power for 12-min checks

for myope ( subject Rp'
black squares) and hyperope (subject JM, red
squares). Both subjects
underwent cycloplegia.
Note that shortest latency is found for each
subjects best optical correction (m slope).
Redrawn with permission
of Elsevier Sciencefrom
Sokol S, Moskowitz A:
Effect of retinal blur on the
peak latent)' of thepattern
evokedpotential. Vis Res
1981:21:1279-1286.
246
with p 2 latencies of less than lOO ms were

significantly
more likely to have improved
vision following surgery than were patients
with latencies longer than 100 ms.
in the absence of any other localizing
infor-
mation can only be interpreted

as indicating dysfunction
in the prechiasmal visual
pathway. The same YEP abnormality in the
presence of a normal pattern
ERG yields
5-4-2 Retinal Diseases
evidence
5-4-2-1Central SerousRetinopathy YEP latency is
5-4-2-3Glaucoma Many early studies reported

large latency delays in patients with primart open-angle glaucoma (POAG). However, these studies confounded effects of
the disease on the optic nerve with latency
effects caused by reduced retinal illuminance induced by miotic pupils as a result
of cholinergic therapy.29 Subsequent studies
that controlled for the effects of miosis reported increased YEP latency in POAG patients to large check sizes.s2 Kubova et als3
found YEP abnormalities
in 29 of 40 eyes
prolonged in patients with central serous

retinopathy.44-46 However, with recovery of
visual function, latency returns to normal.45
This finding is in contrast to latency abnormalities in optic neuritis (discussed in Section 5-4-3-1 ), which persist even after visual
acuity has returned to normal. It is likely
that this latency change is caused by decreased efficiency of cones to capture photons because of their misalignment,
rather
than a more proximal visual disturbance.47.48
In contrast to this hypothesis, it has been
reported that pattern ERG and pattern
YEP changes can persist in some patients
with central serous retinopathy following
resolution of funduscopic abnormalities.49
542-2 Macular Disease Johnson et also tested
patients with optic neuritis, maculopathy,
macular holes, macular cysts, and lamellar
holes. They found that patients with lamellar holes had normal latency, but patients
with macular cysts and macular holes had
prolonged P100 latencies. They also found
a greater prolongation of P 100 latency in
patients with optic neuritis than in patients
with macular holes. Similarly, Shimada et
al)1 reported larger latency delays in patients with optic neuritis than in patients
with macular disease when patients were
matched for visual acuity. Because subtle
changes in macular function can affect the
YEp, a monocular abnormality of the YEP
of retrobulbar
conduction
delays.
of chronic POAG patients to low-spatialfrequency, low-contrast, motion-onset

stimuli, whereas the pattern-reversal
YEP was
abnormal in only 11 of 40 of eyes. The authors interpreted their results as supporting
the hypothesis, proposed by Quigley et al,s4
that large axons of magnocellular
ganglion
cells are primarily affected early in glaucoma. This hypothesis is not uniformly acceptedSs and these YEP results provide
only weak evidence in its support. Although the existence of group differences
between YEP results in POAG patients, ocular hypertensive
patients, and healthy individuals is well established, the clinical
utility of the YEP in glaucoma has yet to be
convincingly
demonstrated.
Early results
with the multi focal YEP seem promising.s6
5-4-3 DemyelinativeOptic Neuropathies

543.1 Optic Neuritis The P 100 latency of the
pattern-reversal
YEP is delayed in patients
with optic neuritis.S7 This prolongation
per-
5-4 Clinical
sists in 80% to 100% of patients,
even after
visual acuity has returned to normal.58 Although an abnormal YEP latency is not
unique to optic neuritis, a markedly prolonged YEP latency in the context of a normal clinical examination and a full visual
field is highly suggestive of a resolved optic
neuritis.
Despite the well-known
clinical sensitivity of the P100 latency to optic neuritis, the
pathophysiology
of the disease is not well
understood. First, it is puzzling that the
YEP waveform remains relatively intact despite the patchy nature of optic nerve demyelination.
This may be the result of temporal integration in the visual cortex.59 Also,
pathologic evidence in multiple sclerosis
suggests that axonopathy is a cardinal feature of sclerotic plaques.60,61 Yet the YEP
amplitude does not show evidence of axonal degeneration. This discrepancy is
probably not due to an insensitivity
of the
YEP to axonal degeneration because, as
discussed in Section 5-4-5, YEP amplitude
is markedly reduced in anterior ischemic
optic neuropathy. The difference may be
attributable
to the populations studied.
The pathologic studies showing evidence
of axonal degeneration have been in patients who had primary or secondarily progressive multiple sclerosis, whereas electrophysiologic studies have been in patients
with optic neuritis who had no other neurologic history or had relapsing/remitting
multiple sclerosis.
54-3-2 Multiple Sclerosis The diagnosis of multiple sclerosis (MS) depends on clinical or
laboratory evidence of the presence of multiple lesions in the central nervous system.
The optic nerve is one of the most common
sites to be involved. Measurement
of the
latency of the response evoked by pattern
247
stimulation provides an objective means of

identifying
demyelination
in the visual
pathways, even when there is no clinical
history of optic neuritis.62,63 Accordingly,
when patients presenting with clinical evidence of a single lesion of the nervous system (especially a lesion below the level of
the foramen magnum) are being evaluated,
YEP studies provide a means of establishing the presence of multiple lesions by permitting the detection of clinically silent
disease in the visual system. Abnormal responses to pattern stimulation
in patients
without
a history
of optic
nerve
involve-
ment and without eye symptoms at the

time of testing indicate subclinical involvement of the visual pathways in patients
with MS. The pattern YEP has been shown
to be more sensitive to resolved optic neuritis than is magnetic resonance imaging,64,65
contrast-sensitivity
testing,58,66 visual acuity
testing,57,67 or Goldmann perimetry.68
A survey of the literature63 yielded an estimate that S 1% of patients with diagnosed
MS had YEP evidence of conduction delays, despite no clinical history of optic neuritis and no clinical signs of optic neuropathy. The high diagnostic yield ofYEPs in
patients with definite MS has been confirmed repeatedly, with a range usually
varying between 70% and 97%. The percentage of abnormal YEPs is lower among
patients in the category of probable MS and
lowest among those with possible MS, commonly ranging between 20% and 40%. The
presence of an abnormal YEP in a patient
with possible MS provides laboratory support for the diagnosis and may avert the
need for extensive and expensive diagnostic testing. Furthermore,
establishing the
diagnosis may put the patient at ease, be-
248
cause many symptoms
are thought
to be
psychosomatic prior to diagnosis.

The pathophysiologic
basis of the YEP
latency increase has been clarified by work
on the effects of demyelination
on saltatory
conduction in axons.69-71 Saltatory conduction depends on voltage changes in the
node of Ranvier. A threshold level of depolarization is necessary for conduction. A
safety factor is present in the node, in that
many more sodium channels are present
than are necessary to reach threshold depolarization. Demyelination
of an axon exposes potassium channels. These potassium
channels cause a current leak, which results
in a delay in achieving threshold depolarization of the node of Ranvier (Figure s- 7).
This threshold delay results in an increase
in latency of the pattern YEP without a decrease in amplitude.
When this current leak exceeds the
safety factor, conduction block results. Reduction in YEP amplitude in resolved optic
neuritis can result from either conduction
block or axonal degeneration. Conduction
blockage results in loss of function, whereas
conduction delay does not produce a loss of
sensitivity. This explains the exquisite sensitivity of the YEP to optic neuritis and MS.
It also explains the lack of correlation between YEP latency and other measures of
visual function. YEP amplitude loss is better correlated with visual field changes and
visual acuity loss.67
In apparent contradiction
to this hypothesis, a number of studies have failed to
show a correlation between YEP latency
and estimated length of optic nerve involvement as measured by MRV2,73 However, it seems probable that MRI abnormalities reflect edema in acute optic neuritis
and fibrosis in older lesioQs and are not a direct measure of demyelination
et al74).
(see Thorpe
543.3 Leukodystrophies A heterogeneous

group of inherited disorders, leukodystrophies are characterized by demyelination
and degeneration of white matter. Many
of these diseases involve lysosomal disorders, including the mucopolysaccharidoses
and lipidoses, and are frequently accompanied by a demyelinative
optic neuropathy.
Age of onset varies from infancy to early
adulthood. YEP latency abnormalities
have
been reported in patients with leukodystrophies with and without evidence of optic
neuropathy.75-77
Adrenoleukodystrophy
is an X-Iinked,
recessively inherited demyelinative

polyneuropathy, accompanied by atrophy of the
adrenal glands, Addison disease, low cortisol levels, and visual impairment.
A number
of studies have reported clinically significant abnormalities
in pattern YEP latency
in patients with adrenoleukodystrophy.77-8o
Kaplan et a18found evidence of visual
pathway demyelination
in 63% of 59 men
with this disease, using pattern YEP and
MRI criteria. Demyelination
was apparent
at any level of the visual pathway, from the
optic nerve to the visual cortex. In another
study, Kaplan et al81 failed to find an effect
on pattern YEP latency of therapies intended to reduce the buildup of long-chain
fatty acids in the white matter of these
patients.
54-3-4 Nutritional Amblyopia The disorder nutritional amblyopia occurs as a result of deficiency in vitamin B complex. Symptoms are
generally a rapid onset of bilateral visual
acuity loss to about 20/200 and cecocentral
scotomas. Visual loss may prec~de sensory
signs of dorsal and lateral spinal-tract in-
5-4 Clinical
volvement and may even precede macrocytic anemia. Nutritional

amblyopia should
be suspected in the elderly and in alcoholics, who are at risk for poor nutrition,
and in patients with pernicious anemia.
There is also likely a toxic component in
patients with tobacco-alcohol ambylopia.
The visual loss is reversible with a well-balanced diet and B complex supplements.
Numerous studies have reported reversible
YEP abnormalities
in symptomatic and
asymptomatic
patients with vitamin
249
B com-
plex deficiencies.82-84
5-4-4 Compressive Optic Neuropathies
In general, the latency of the YEP is prolonged in the early stages of optic nerve
compression, often prior to the onset of visual signs or symptoms. This observation is
supported by pathologic evidence of optic
nerve demyelination
in a balloon model of
optic nerve compression in the cat.85 As the
Figure 5-7 Effect of demyelination
on conduction veloc-
ity. Current leakage to exposed axonal potassium

channels increases time needed to reach threshold depolarization
at node of Ranvier to enable saltatory
conduction. ( A) Upper drawing shows normal conduction across normally
myelinated node. Lower
tracing shows conduction leak due to demyelination.

(B) Stimulation
at stimulus 1 (SI) produces delayed
response because signal must cross demyelinated area

to reach recording electrode. Green arrow represents
position of recording electrode.
Redrawn with permission of Elsevier Sciencefrom Kocsis
JD, Waxman SG: Demyelination: causesand mechanismsof
clinical abnormality and functional recovery.In: Koetsier
JC, ed: Demyelinating Diseases. Handbook ofClinical
Neurology, Series3. Amsterdam: Elsevier; 1985;47:29-47.
Proximal
Demyelination
Distal
250
optic neuropathy becomes clinically apparent, with changes in the visual field and visual acuity, YEP amplitude is affected. If
decompression is achieved in a timely fashion, the YEP and visual function recover.86
The increase in YEP latency in subclinical
compressive optic neuropathy is usually
smaller than that seen in resolved optic
neuritis.8-1
In a study of 88 patients with Graves disease, Salvi et a19reported significantly

prolonged P 100 latencies in 23% of patients.
Patients with visual field abnormalities
had
more prolonged latencies, although a difference between groups was obtained between normal individuals and all patients
with proptosis greater than 21 mm. The authors concluded that the YEP is comple-
5-4-4-1DysthyroidOptic Neuropathy Graves dis-
mentary to visual field testing in identifying patients with ophthalmopathy

and
normal visual acuity.
ease is characterized by proptosis secondary

to an enlargement of the extraocular muscles in patients with disease of the thyroid.
An optic neuropathy can occur due to compression of the nerve at the orbital apex.
Oysthyroid optic neuropathy can severely
affect visual acuity, with 20% of patients
not recovering to better than 20/200.87
Medical therapy with high-dose corticosteroids, radiation therapy, and surgical
decompression of the orbit can all be effective with timely administration.
Setala et al88 recorded pattern YEPs before and after decompression (7 patients) or
retrobulbar irradiation (3 patients) in patients with dysthyroid optic neuropathy.
Prior to treatment, the YEP was abnormal
in all patients, whereas visual acuity was affected in only 5 of 19 eyes. YEP latency improved in 7 of 19 eyes, but deteriorated in
8 of 19 eyes following therapy. YEP change
was correlated with clinical outcome. In a
similar study, Tsaloumas et al89 studied
13 eyes of 10 patients with dysthyroid optic
neuropathy. All patients had abnormal YEP
amplitude and latency values prior to decompression therapy and, in all patients,
amplitude returned to normal limits following therapy. In some patients, latency remained prolonged,
demyelinative
suggesting
changes.
permanent
544-2 Idiopathic Intracranial Hypertension In patients with idiopathic intracranial hypertension (IIH), also called pseudotumor cerebri,
and normal visual fieids (with the exception
of an enlarged physiologic blind spot secondary to papilledema),
an increased group
mean YEP latency has been reported.91
However, few individual
patients have a
clinically significant increase in P100 latency compared to normal control values. In
fact, the consensus is that the YEP is within
normal limits in patients with IIH.63,92
However, Falsini et al93 reported positive
results from steady-state YEP testing in
18 patients with IHH. Stimuli were sinewave gratings ranging in spatial frequency
from 0.6 to 4.8 cycles per degree (c/deg).
An amplitude abnormality was found in
response to at least one spatial frequency
between 1.8 and 4.8 c/deg in 10 of 18 patients. No studies have observed patients
to determine whether YEP abnormalities
are prognostic for subsequent visual field
deterioration.
5-4-5 Anterior Ischemic Optic Neuropathies
In patients more than 50 years of age, anterior ischemic optic neuropathy (A ION) is a
common cause of acute monocular visual
loss. The idiopathic nonarteritic form of
5-4 Clinical
AION
(NAION)
can spare visual acuity if it
is associated with an altitudinal

field defect.
The arteritic form of AION tends to occur
in an older population and is associated
with giant-cell arteritis. In arteritic AION,
visual acuity is severely affected and a
large, dense central scotoma is often found.
Patients with monocular arteritic AION are
at high risk in the contralateral eye and are
treated aggressively with corticosteroids.
In
a randomized trial sponsored by the National Eye Institute, optic nerve decompression was found to be an ineffective
form of therapy for NAION.94 AION has
clinically significant effects on YEP amplitude, but latency is typically unaffected.95
This pattern of results can be useful in differentiating
AION from optic neuritis when
a 30- to 50-year-old presents with acute
optic neuropathy.96
5-4-6 Traumatic Optic Neuropathies
Craniofacial trauma involving the optic
canal or orbital apex can produce transection of the optic nerve and irreversible visualloss. Less severe injury can lead to
optic nerve compression with reversible
damage to the optic nerve if timely decompression is instituted. Pupillary reflexes are
often inaccessible because of periocular
edema and/or motoric pupillary involvement, and patients are often comatose or
sedated. U nder these circumstances, the
flash YEP can provide valuable information
regarding optic nerve integrity.
Cornelius et al97 used the flash YEP to
assist in decisions regarding initiation of
corticosteroids
and/or surgical intervention
to reduce compression of the optic nerve.
Tandon et al98 reported a retrospective
study of 111 patients with blunt head
trauma and indirect optic nerve injury. All
patients were treated with high-dose
pred-
251
nisolone, and 39 were subsequently

surgically decompressed. Overall, 72 of the 111
patients showed improved visual function.
Poor prognosis was associated with no light
perception at presentation, failure to respond to corticosteroids,
absence of a flash
YEP response, and fracture of the optic
canal. Fuller and Hutton99 reported the
flash YEP to be of more prognostic value
than either the flash ERG or ultrasonography in severely injured
eyes.
5-4-7 Toxic Optic Neuropathies

5-4-7.1 Ethambutol A drug used in the treatment of tuberculosis, ethambutol
is known
to cause a toxic optic neuropathy. Although
this effect is thought to be reversible with
prompt cessation of treatment, permanent
visual deficits sometimes result. Subclinical
involvement
of the optic nerve has been
demonstrated in 5 of 14 asymptomatic
patients being treated with ethambutol.100 In
a study of 7 consecutive patients with severe toxicity, 3 did not recover visual acuity
to a level of 20/200.101 Failure of YEP recovery was a poor prognostic sign. In another study, Woung et allOZ found evidence
of residual visual dysfunction
in a majority
of 36 patients with ethambutol optic neuropathy 4 months after cessation of treatment. Latency of the P100 peak of the pattern YEP was abnormal in 10 of29 eyes
tested.
547.2 Cisplatin Maiese et all03 studied
6 con-
secutive patients taking intra-arterial cisplatin: 5 of the 6 had evidence of visual

pathway toxicity, and in 2 an increase in
PlOO latency preceded measurable loss of
visual function by at least 4 months. The
252
authors suggested that the YEP may be

useful for early detection of toxic effects
on the visual pathway.
54-7-3 Deferoxamine An iron-chelation
agent,
deferoxamine
(also known as desferrioxamine) is used in the treatment of sideroblastic anemias and transfusional hemochromatosis. Neurologic and ocular toxicity has
been well described. Triantafyllou
et allo4
reported abnormal YEP latency in 32 of 120
patients undergoing long-term deferoxamine therapy for beta-thalassemia.
The YEP
normalized in 15 of 23 patients, who were
retested following reduction of deferoxamine dosage. A similar pattern of results was
reported by Marciani et alios in a smaller
number of patients. Because other neurotoxicities coexisted, the visual abnormalities were assumed to be related to optic
nerve dysfunction.
However, retinal dysfunction cannot be ruled out as the origin
of the YEP delays because ERGs were not
performed.
5-4-8 Inflammatory Optic Neuropathies
Optic neuropathies are frequent central
nervous system manifestations
of inflammatory disorders, including systemic lupus
erythematosus,
Lyme disease, sarcoidosis,
syphilis, tuberculosis, measles, mumps,
rubella, human immunodeficiency
virus
(HIY) infection, cytomegalovirus
infection,
herpes zoster, and paraneoplastic syndromes.lo6 Many of these diseases present
with acute visual loss and papillitis and can
be mistaken for idiopathic optic neuritis
when the presenting symptom is a visual
disturbance. YEP abnormalities
have been
reported in many of these disorders.l07-113
Pattern YEP latency abnormalities
have
been reported in patients suspected of neurosarcoidosis without clinical evidence of

optic nerve involvement.lo8,lo9 Gott et allo9
found abnormal YEP latencies in 6 of 25
patients with confirmed multisystem
sarcoidosis. The YEP abnormalities
in these
infectious optic neuropathies are nonspecific and of little use in differential
diagnosis. However, YEP testing, along with electrophysiologic
retinal evaluation, may be
useful in localizing the visual disturbance in
complex medical illnesses with ill-defined
visual disturbances.
5-4.9 HereditaryOptic Neuropathies

549-1 Autosomal DominantOptic Atrophy The
neuropathy autosomal dominant optic atrophy has been separated into an infantile or
congeQital form and a juvenile form.114,115
In the juvenile form, onset is insidious and
is usually detected in the first decade of
life. Regardless of age of onset, visual loss is
usually mild-to-moderate,
with approximately 40% of patients maintaining visual
acuity of 20/60 or better and only 15% to
20% having visual acuity of 20/200 or worse.
Disc pallor is subtle, usually involving the
temporal aspect of the disc. Symptoms are
generally symmetric between eyes. YEP
amplitude and latency abnormalities
have
been reported in patients with visual acuity
of 20/30 or worse, but not in unaffected
family members.116,117 The abnormal YEP,
in the presence of a normal ERG, can localize the dysfunction
to the optic nerve in
cases where the diagnosis is unclear.
549-2 LeberHereditaryOptic Neuropathy The disease Leber hereditary optic neuropathy
(LHON)
affects primarily males in their
second to third decade of life. It involves
both eyes either simultaneously
or sequen-
5-4 Clinical
253
tially, with a rapid loss of visual acuity and

dense central scotomas. The fundus is characterized by peripapillary
telangiectatic
microangiopathy and swelling of the nerve
fiber layer. Later in the course of the disease, there is evidence of optic atrophy. Ap-
ties have been presumed to be caused by

optic neuropathy in patients with mitochondrial myopathies, Sartucci et al125reported abnormal pattern ERG PSO components in 13 of 17 patients with biopsyverified mitochondrial
myopathy.
proximately
15% of patients recover some
useful vision. LHON is transmitted mito-
5-4-10 Operating Room Monitoring
chondrially through the female. Six mutations of mitochondrial

DNA have been
identified,
the most common of which is a
guanine-adenine
substitution
at nucleotide
position 11778.118
The pattern YEP is abnormal in LHON,
showing evidence of both conduction delays (increased peak latency) and loss of
optic nerve fibers (decreased amplitude),119
Some studies have reported YEP abnormalities in carriers of the disease and in presymptomatic
individuals,119.120 whereas
other studies have seen YEP abnormalities
only after evidence of involvement
of the
central visual field.121
5-4-9-3Mitochondrial Myopathies Other mutations of mitochondrial
DNA are associated
with progressive myopathy, ophthalmoplegia, and, in some cases, optic neuropathy or
retinitis pigmentosa.122 Ambrosio et al123reported ERG and/or YEP abnormalities
in
17 of 19 patients with progressive external
ophthalmoplegia
and noted ragged-red
fibers on muscle biopsy. Ohtsuka et al124
observed two siblings with a point mutation
in mitochondrial
DNA at nucleotide 8344.
Despite clinical signs of optic atrophy, the
pattern-reversal
YEP was reported to be supernormal in amplitude, and response peak
latency was prolonged. The high amplitude
of the response may have been related to
an occipitally dominant electroencephalographic spike and wave pattern that was
photosensitive.
Although YEP abnormali-
Evoked potentials are frequently used in

the operating room to monitor physiologic
integrity
of the sensory and motor pathways
during surgical procedures involving the

spinal cord, brain, head, and neck.126 The..
use of the YEP has been limited by the disruption of the cortical response by anesthetic agents and the difficulty
in stimulating the visual pathways in the surgical
setting.127,128 Harding et al129reported successful use of the flash YEP in 57 patients
undergoing intraorbital surgery who were at
risk for optic nerve damage. The authors
obtained good waveform identification
with
use of enflurane and nitrous oxide anesthesia, A fiberoptic contact lens was used for
flash stimulation.
The absence of a recordable response for more than 4 minutes during the surgery was correlated with postoperative impairment
of vision, Hussain et
al130reported successful use of flash YEP
latency to monitor visual function during
endoscopic sinus surgery, whereas Jones131
concluded that the flash YEP is too cumbersome and its results are too variable to
be a reliable indicator of optic neuropathy
during anterior skull base surgery.
Stereotactic pallidotomy
is a surgical procedure performed on patients with Parkinson disease who are no longer adequately
controlled by medical therapy. In this procedure, a lesion is made in the ventral
globus pallid us. This area is near the optic
254
tract and visual field defects have occurred

in some cases. Yokoyama et al132and Tobimatsu et al133reported innovative results
using a depth needle electrode to stimulate
the optic tract directly during the surgery.
The amplitude of the YEP recorded at the
surface decreases dramatically as the distance from the optic tract increases. This
information
is used to ensure proper placement of the lesion and to avoid damage to
the visual pathway.
5-4-11 NeurodegenerativeDiseases
5411-1 AlzheimerDiseaseand Other Dementias As
new therapies become available for the
treatment of Alzheimer disease (AD), the
search for reliable biomarkers has intensified. Involvement
of the visual pathways in
AD is controversial. Hinton et al134reported
a loss of large-diameter
ganglion cells in
postmortem histologic evaluation of optic
nerves in patients with AD. This result was
subsequently challenged, as evidence was
provided that the loss of large axons was
age-related.135
The YEP literature is similarly divergent. Some laboratories report robust
changes in the latency of the flash YEP in
AD patients, with sparing of the pattern
YEP.136,137However, other studies find no
electrophysiologic
evidence of dysfunction
to the level of the primary visual cortex,
even in the context of behavioral visual disturbance.138,139 The consensus of these later
studies is that visual dysfunction
in AD
involves primarily visual association areas.
Electrophysiologic
studies in patients with
Creutzfeldt-Jakob
disease have also shown
no evidence of abnormality in the primary
visual pathways to the primary visual
cortex. 140
5411-2 SpinocerebellarDegeneration Carroll et

al141recorded pattern YEPs from 22 asymptomatic patients with Friedreich ataxia:
15 patients had neuro-ophthalmologic
abnormalities, and 14 had abnormal pattern
YEPs. Both latency and amplitude abnormalities were seen, abnormalities
were always binocular, and ERGs were not affected. The authors concluded that visual
abnormalities
are common in Friedreich
ataxia and that the primary abnormality is
axonal degeneration with secondary demyelination.
Perretti et al142found pattern
YEP abnormalities
in 11 of 24 patients with
autosomal dominant cerebellar atrophy (abnormal latency in 6; abnormal amplitude in
4; both latency and amplitude abnormalities in 1). All patients had normal appearance of the fundi, and the authors inferred
dysfunction
of the central visual pathways
based on these findings.
5-4-12 FunctionalDisorders
Pattern VEPs are often requested
in cases
where functional visualloss-malingering

or hysteria-is
suspected. In these patients,
components of the visual examination are
inconsistent with organic pathology. For example, a patient may complain of profound
monocular visual loss in the absence of a
relative afferent pupillary defect. Goldmann perimetry can be spiraling in nature,
and color vision can be intact in the context
of profound visual acuity loss. A normal pattern VEP provides objective evidence of intact function to the level of the primary visual cortex in patients presenting with this
type of examination.3,143
Figure 5-8 shows pattern VEPs recorded
from a patient with documented
disease
and blindness in the right eye, but no disease in the left eye; yet the patient claimed
20/200 visual acuity. Clearly, pattern VEPs
5-4 Clinical
from the left eye were normal. In this case,

a positive finding of a recordable pattern
Figure 5-8 Pattern VEPs recorded from 55-year-old

patient who had aphakia, maculardegeneration,
peripheral
for checks of 6 to 48 min show large amplitude
Baumgartner and Epstein144 reported

that 5 of 15 normal subjects could extin-
Cou11esySamuel Sokol, PhD.
using large fields, large checks, and binocular stimulation.I44-147 Unfortunately,

these
conditions are not optimal for visual acuity
testing, because the highest correlation of
visual acuity and pattern YEPs is found
when small checks and small fields are
used.
Because the YEP can sometimes be suppressed voluntarily, an abnormal pattern
and
retinal degeneration in right eye. (A) Re-
YEP to small checks is helpful in establishing intact visual pathways. However, absent
YEPs in a patient claiming blindness can
pose a dilemma, because this result could
relate either to disease or to voluntary suppression of the YEP.
guish their pattern YEPs voluntarily, using

such strategies as transcendental
meditation, concentration
beyond the plane of the
checks, and ocular convergence. Other
studies have shown that deliberate alteration of the YEP can be minimized
by
255
sults of examination
of left eye were normal, yet pa-
tient claimed visual acuity of 20/200.

normal latenrysignals.
VEPs recorded
(B) Signalsfrom
were nondetectable and not significantly

noise (N). NLP = no light perception.
and
right eye
different from
256
VEP should be interpreted
with caution
in
patients suspected of malingering.

In these
cases, the flash VEP can be used with some
benefit. The flash VEP is reduced in amplitude when an eye with optic atrophy (that
is, axonal degeneration)
is tested. This abnormality is difficult, if not impossible, to
induce voluntarily. Thus, the presence of
flash VEPs of equal amplitude from either
eye in a patient with markedly reduced visual function monocularly and an abnormal
pattern VEP can be interpreted as supportive of a nonorganic visual loss.
The use of long-Iatency potentials, such
as the P300 response, which are influenced
may attenuate the amplitude of sensory

components of the YEP.
Another solution to the problem of testing patients suspected of voluntarily
reducing their YEPs is to
stimuli at a random
If the su bject is not
stimulus is going to
present pattern-onset
interstimulus
interval.
aware of when the
appear, it is more diffi-
cult to be deceptive.
5-4-13 Disordersof the Optic Chiasm,

Optic Radiations,and Visual Cortex
5-4-13-1 The Hemifield VEP and Paradoxical Lateralization Just as monocular
stimulation
by sensory stimuli but not evoked by them,

can eliminate problems of voluntary suppression.148,149The P300 response is
elicited by unpredictable
or infrequent
ize dysfunction
stimuli and cannot be voluntarily

suppressed if the subject is attending to the
task. Vertical gratings would appear 80% of
mal dysfunction
the time (frequent), and horizontal gratings

would appear randomly 20% of the time
(rare). The subject is instructed to count
the horizontal gratings. When the stimuli
are in focus (attend), large sensory responses are present for both horizontal and
vertical gratings and a large P300 wave oc-
left
curs for the rarely presented horizontal gratings. The subject then views the gratings
through a 20-0 positive lens (blur). While
no longer able to resolve the edges of the
gratings, the subject is still able to detect
orientations correctly. Under these conditions, sensory VEP components are attenu-
stimulation
of the left
visual
the highest
amplitude
surface
ated (as predicted), but the P300 remains

intact. Such findings suggest that subjects
who voluntarily
blur or attempt to tune out
a pattern stimulus may be unable to sup-
generators
press their P300 response, although
not occur
they
to the prechiasmal
pathway,
hemifield
tion
the use of lateral
with
trodes,
stimulation,
can localize
visual
field
visual
the right
whereas
activates
will
produce
tion
of the temporal
over
responses
occipital
right
the hemisphere
chiasm
to stimula-
of each eye.
lobe,
field
produces
potential
rather
than
occipitallobe.15
tangential
face of the skull,
within
sulcus.
Paradoxicallateralization
depends
on stimulus
This
variability
hemifield
to chiasmal
the banks
of the
to the sur-
calcarine
parameters
in all normal
YEP
of the
and does
individuals.151-153
in scalp
limits
over
to the stimulated
to the orientation
of the YEP
over
This
of the YEP
ipsilateral
is due
hemi-
pattern-reversal
paradoxicallateralization
field
field
surprisingly,
the left
postchi-
the left
visual
of the
stimulation
of the optic
abnormal
the activated
visual
Due
path-
activates
field
Somewhat
pathways.
of the visual
stimulation
Abnormalities
elec-
and postchias-
chiasm,
pathway,
of the right
sphere.
chiasmal
decussation
way at the optic
visual
in conjunc-
occipital
in the visual
to the partial
asmal
can local-
distribution
its clinical
and postchiasmal
of the
sensitivity
disease.
5-4 Clinical
5413-2 Chiasma!Compression Sellar and parasellar masses stretch the optic chiasm,
which lies over the pituitary gland. Pituitary
macroadenomas are the most common
cause of chiasmal compression. Prolactinsecreting adenomas can enlarge rapidly in
pregnant women and are a common cause
of visual loss during pregnancy. Pituitary tumors that secrete growth hormone cause
acromegaly in adults. Tumors that do not
extend laterally outside the sella can be surgically removed through a transphenoidal
approach. Those with extensive extrasellar
extent are usually surgically approached
transcranially. Prolactin-secreting
tumors
can be treated medically with bromocriptine. Meningiomas
and craniopharyngiomas
are parasellar masses that can compress the
257
present, then the polarity of this bipolar

YEP inverts when the response obtained
with stimulation of the right eye is compared to that obtained with stimulation of
the left eye. This pattern of results is highly
suggestive of chiasmal misrouting and is independent of the lateralization pattern of
the YEP at the occipital surface. Due to the
high incidence of nystagmus in this population, the pattern-appearance
YEP is preferable to the pattern-reversal
YEP.
5-4-13-4Dysfunctionof the Optic Radiationsand
Visual Cortex Postchiasmal visual dysfuncti~
is detectable using the hemifield pattern
YEP. However, the technique is not as
sensitive as formal visual field testing.161
Hemifield
testing can be clinically useful in
optic chiasm.
The bitemporal visual field defects
caused by chiasmal compression often are
subclinical because the binocular field is
only mildly constricted. Visual acuity is not
affected unless the tumor spreads anteriorly
to involve an optic nerve. Hemifield
VEPs
can show latency and amplitude abnormalities with stimulation of the temporal visual
field. 154--156
It is doubtful, however, that
distinguishing
hemianopia secondary to
dysfunction
in the postchiasmal primary visual pathway from visual neglect secondary
to parietal or frontal lobe dysfunction.
The
YEP is normal with stimulation of a neglected hemifield,
despite the patient being
unaware of the neglected stimulus,162,163
whereas little if any YEP is obtained with
VEP abnormalities
are more sensitive than
visual fields to chiasmal dysfunction.
Although VEP abnormalities
have been seen
in some patients with normal visual fields,
the VEP can show no asymmetries in patients with florid field defects due to chiasmal compression.157
5-4-13-5Migraine Three recent studies reported group differences in the pattern

YEP between patients with migraine and
normal controls. All patients were tested interictally. Tagliati et all64 reported normal
latency and amplitude of the midlinerecorded pattern YEP in migraine patients,
but an abnormal scalp distribution
of the response in patients with migraine and visual
aura (classical migraine). Shibata et al165reported increased amplitude of the YEP in
54-13-3 Albinism Misrouting

of optic nerve
fibers at the optic chiasm is an anomaly associated with albinism.lsB There is excessive crossing of fibers at the chiasm. The
most efficient way to detect this anomaly is
to record the YEP referring the left occipital electrode to the right occipital electrode.ls9.16o If misrouting at the chiasm is
stimulation
of a hemianopic
field.
258
patients with classical migraine. However,

Afra et al166reported decreased amplitude
of the pattern YEP in patients with migraine with or without visual aura and an
abnormal adaptation pattern of the YEP
with prolonged stimulation
in all migraine
patients. In no study was the interictal YEP
clinically abnormal in migraine patients.
5413-6 DevelopmentalDyslexia A number of
YEP studies have been performed that
seem to support the hypothesis that patients with developmental
dyslexia have
dysfunction
in the magnocellular
visual
pathway. Lehmkuhle
et al167showed that
the long-range masking effect of a low spatial-frequency,
high temporal-frequency
stimulus on the YEP generated by a low
spatial-frequency
stimulus was absent in
patients with developmental
dyslexia. Liv-
are of scientific interest regarding the origins of dyslexia, they do not indicate any
clinical use for the YEP in the evaluation
of dyslexia.
5-4-13.7Cortical Blindness A number of studies
have reported normal or only mildly abnormal YEPs in patients with chronic cortical
blindness,174-176 However, other studies indicate that recovery of the flash YEP following acute cortical blindness secondary to
basilar artery occlusion or head trauma can
precede clinical signs of recovery and is indicative of a good prognosis for subsequent
recovery of function, 177
,178
CLINICAL USE OF THE VEP IN CHILDREN
magnocellular
pathway of dyslexic subjects.
Selective shrinkage of the magnocellular
layers of the lateral geniculate nucleus had
previously been seen pathologically
in a
single patient with dyslexia who died in a
The infant visual system continues to develop after birth.179 While the retinal rods
are nearly adult-like at birth, the foveal
cones are immature and the ganglion cells
have not moved aside to form the foveal
pit.180.181Myelination
of the optic nerve
continues,182 cell size of the lateral geniculate nucleus increases,183 and the number of
synapses in the occipital lobe first increases
and then decreases as experience strengthens selective connections.184.185 As the in-
motorcycle accident.169
A number of subsequent studies have
failed to replicate these YEP findings, either showing no differences between
dyslexic patients and normal individuals
using similar stimulus conditionsI7.171 or
finding differences with high spatial-frequency stimuli.l72 Borsting et al173sug-
fant's visual system matures anatomically,

the YEP changes as well. Peak latencies of
the flash and pattern YEP decrease as the
pathways myelinate.186-188 P100 peak latency shortens for all check sizes, more rapidly for large checks than for small checks
(Figure 5-9).189-191The pattern-onset YEP
reaches its maximal amplitude at smaller
gested that the magnocellular

defect may
be found only in a subtype of dyslexic patients. In any case, although these studies
check sizes as the visual system matures,192

and infant visual acuity, measured with the
YEP, improves to a Snellen equivalent of
20/20 by 6 months to 1 year of age. The
.
ingstone et al168reported abnormal YEPs to

low-contrast, low spatial-frequency
stimuli
in patients with dyslexia. In both of these
studies, the group mean difference between dyslexic patients and controls was interpreted as s1,1pporting a dysfunction
in the
YEP has also provided
a means of investi-
5-5 Clinical
gating the development
U se of the VEP in Children
259
of many other vi-
sual functions, such as color vision,193-195

scotopic vision,196 stereopsis,197,198and contrast sensitivity.195
5-5-1 Estimation of Visual Acuity in Infants
Assessment of visual acuity in preverbal
children is a difficult but important task.
Because normal visual development
depends on visual experience, it is important
to identify correctable visual dysfunction
at
as early an age as possible. In early studies,
YEP acuity was estimated by measured
transient YEPs to various check sizes. Acuity was estimated by extrapolating
the amplitude versus increasing check-size function to zero or to noise level. This was a
time-consuming
procedure and could not
be performed successfully in many infants.
Subsequently, the sweep YEP procedure
(discussed in Section 5-2) was developed to
provide a rapid, objective estimate of visual
acuity.18,20,21Sweep YEP acuity estimates
have provided important information
in the
diagnosis and treatment of childhood amblyopia (Figure 5-10)20 and have helped to
define the critical role of dietary long-chain
fatty acids on the development
of visual
acuity in newborns.199,200
In normal infants, YEP estimates of visual acuity are generally higher than behavioral forced-choice preferential-Iooking
estimates.201 The YEP may be unreliable in
children with nystagmus or with extremely
abnormal EEGs because of unfavorable signal-to-noise characteristics. Alternatively,
preferenrial-Iooking
techniques may be inappropriate in children with severe motor
dysfunction.
The pattern YEP has been
shown to provide a valid estimate of visual
acuity in preverbal children with various visual and neurologic disorders.20,202,203Bane
and Birch204 found that, in contrast to nor-
Figure 5-9 Development of VEP waveform for

( A) large (60-min)
and (B) small ( 15-min) checks.
Redrawn with permission of EIsevier Sciencefrom M oskowitz A, Sokol S: Developmental changesin the human visual
systemus reflectedby the latency of thepattern reversal VEP.
Electroencephalogr Clin NeurophysioI1983;56:1-15.
260
mal children, children with moderate-tosevere visual impairment

tend to show better visual acuity by the forced-choice preferential-Iooking
technique than by YEP
estimates.
5-5-2 Childhood Amblyopia

and Binocular Function
B
1 !,V
O/LV
ll:[~~~
I
~~,
- ~
0.5
10
15
20
Spatialfrequency(c/degj
Figure 5-10 Steady-state sweep VEP grating acuity estimated from (A) normal eye and (B) amblyopic eye of
anisometropic amblyope using sweep VEP technique.
Stimulus was square-wave grating alternating
at
8 Hz ( 16 reversals/s). Spatial frequency of grating

was swept linearly from 0.5 to 20 c/deg in 13 s.
(A) Amplitude
and (B) phase are shown for each eye.
Upward movement of phase indicates lag ( delay in latency). Straight line, fit by eyefrom peak of each amplitude function,
is extrapolated through 0 flV axis.
Grating acuity of normal eye is 19 c/deg ( Sne/1en

equivalent: 20/30 ); acuity of amblyopic eye is 14 c/deg
( Sne/1en equivalent: 20/40 ). Patient~ Sne/1en acuity
was 20/20 in normal eye and 20/50 in amblyopic eye.
CourtesySamuel Sokol, PhD.
Childhood amblyopia is a loss of visual acuity that occurs during development

because
of a difference in inpur between the two
eyes. The difference in the image between
one eye and that of the other can be caused
by strabismus, anisometropia,
or monocular
occlusion because of cataract, corneal opacity, or ptosis. Physiologic research on animal
models of amblyopia has revealed a great
deal about the causes of childhood amblyopia.205,206Briefly, whereas most cells in the
visual cortex respond to stimulation
of either eye in a restricted area of the visual
field (that is, the cells have binocular-receptive fields), amblyopic animals have monocular visual cortexes, with few cells responding to stimulation of the amblyopic eye. If
the condition causing the amblyopia is
remedied within a critical period of development, cortical binocularity
can be restored. Experiments
in which the nonamblyopic eye is enucleated during the critical
period suggest that there is a competition
for cortical space between the two eyes.207
These results correspond well to the clinicalliterature
on the therapeutic effects of
patching therapy and surgical intervention
for strabismic amblyopia.2s
The pattern VEP has been shown to be
a sensitive detector of amblyopia, and a
number of specialized stimulus techniques
have been developed specifically for this
application.17,209-2Is Odom et al214monitored
VEP visual acuity estimates in both the am-
5-5 Clinical
blyopic and the normal eye during occlusion therapy. The authors were able to
judge improvements
in the amblyopic eye,
as well as deterioration
of the occluded eye.
These results assisted in evaluating the
therapeutic protocol. Amblyopia results in a
reduction of the amplitude of the pattern
YEP primarily in response to small check
sizes, that is, <20 min (Figure 5-11). Pattern
YEP latency is also abnormal in amblyopia.29
However, because the effect is small, latency is not as sensitive a marker of amblyopia as is amplitude.
The binocular beat technique (described
in Section 5-2) has been shown to be a sensitive measure of the binocularity
of the vi-
Use of/he
VEP in Children
261
Figure 5-11 Transient monocular pattern
VEPs from
(A) two normal subjects, TC and HH, and(E)

amblyopic patients, KC and IP Interocular
two
ampli-
tude differences were abnormal for both N75-P lOO

and P 1 00-N135 for KC and Ip, which is compatible
with amblyopia. IPs latency was also abnormal
in
amblyopic eye. Snellen acuity measurements confirmed

VEP results.
Redrawn with permission of University of WisconsinPress
from Sokol S: Alternatives to Sne!len acuity testing in pediatric patients. Am Orthoptic J 1986;36:5-10.
262
sual cortex.22,23 The technique
provides
rapid and quantitative

assessment of cortical binocularity
and may be of prognostic
value regarding the potential for binocular
fusion following therapeutic intervention.
5-5-3 Oculomotor Disorders
Preverbal children with intact sensory pathways but with eye movement abnormalities
may appear to have sensory visual impairment because they cannot fixate or follow.
A normal YEP in a child who does not show
good fixation or following helps rule out
dysfunction
in the primary visual pathway
as a cause of this behavior. In these cases,
the problem usually involves either diffuse
cortical dysfunction
(absence seizures, altered states of consciousness, or abnormal
states of arousal) or oculomotor dysfunction.219 The YEP can also help differentiate
a sensory cause from a motor cause for nystagmus in preverbal infants.
5-5-4 Delayed Visual Maturation
Otherwise-normal
infants who are visually
inattentive
may be suffering from delayed
visual maturation.220--224 These infants fail
to fixate and follow, show normal pupillary
responses, have no nystagmus, and have no
structural abnormalities
of the eye. Eventually, the infants show normal visual behavior, in contrast to infants with cortical visual
impairment.
Although the YEP is not prognostic in delayed visual maturation, it can
be used to monitor visual development.
In
delayed visual maturation, a systematic improvement in the amplitude and latency of
the YEP is seen, as opposed to the repeatedly abnormal or absent YEPs that occur
with cortical visual impairment.
Possible causes of delayed visual development include delayed retinal development, delayed myelination
of the visual
pathways, and delayed dendritic and synap.
tic growth in the visual cortex. Delayed visual development
can also be associated
with delays of other sensory and motor
modalities.225 Because it is possible that infants with grossly abnormal visual function,
no evidence of structural damage to the visual system, and grossly abnormal electrophysiologic responses to visual stimulation
may subsequently
develop normal visual
function, conclusions should be guarded
following a single examination.226,227
5-5-5 Optic Nerve Hypoplasia
Hypoplastic
optic nerves are a common
cause of congenital visual dysfunction.
Although the diagnosis is rarely difficult, visual prognosis is somewhat varied. Borchert
et al228reported a significant correlation between flash and pattern YEP parameters, as
well as extent of hypoplasia, with visual
acuity.
5-5-6 Optic Nerve Gliomas
Optic nerve gliomas cause compressive
optic neuropathies that are frequently detected in childhood. These tumors are frequently associated with neurofibromatosi.s
type 1 (NF -1 ). The value of the YEP in detection of asymptomatic
optic gliomas in
patients with this disease is controversial.
Liu et al229did not find pattern-reversal
YEP abnormalities
in 6 patients with neurofibromatosis
and asymptomatic
gliomas,
despite abnormalities
in the visual examination in 2 of these patients. However,
North et a123reported a sensitivity of90%
and a specificity of 60% of the pattern YEP
in 10 NF -1 patients with asymptomatic
optic gliomas and 20 NF -1 patients without
gliomas.
5-5 Clinical
Use of the VEP in Children
263
5-5-7 Prognostic Value of the VEP
longed flash YEP latencies
in Neurologic Diseases
model of viral encephalitis with histopathologic changes resembling subacute scleros-
Many studies in the pediatric neurologic literature have claimed value of the YEP in
the prognosis of infants with neurologic disease. The flash YEP recorded within the
first days of life has been reported to be
strongly related to neurologic outcome in
term neonates with perinatal hypoxia or asphyxia.231.232 However, this relationship did
not hold for preterm infants.233
In contrast to this latter finding, Kurtzberg234 found prognostic value of the flash
YEP in 79 high-risk preterm infants who
were tested when they reached 40 weeks
conceptional age (CA), which corresponds
to term gestation. This allowed comparison
of the data from high-risk infants with the
data from a normal full-term population. In
the group of 79 high-risk infants, 51% had
normal flash YEPs at 40 weeks CA. The
remaining 49% had abnormalities
that consisted of hemispheric wave-shape asymmetries, amplitude asymmetries, and immature or atypical responses. The validity of
the flash YEP measures was then assessed
by retesting the infants at monthly intervals. The results showed that 92% of the
infants with normal flash YEPs at 40 weeks
CA had normal YEPs during the first 6
months of life and at 1 year. Abnormalities
persisted in more than 50% of the group
with wave-shape and amplitude asymmetries and in the group with immature responses, as well as in more than 75% of the
group with atypical responses. Standard
neurologic and developmental
examinations were most likely to be normal in
infants with normal-term
(40 weeks CA)
flash YEPs.
Pike et al235did not find a relation between YEP and neurologic outcome in 41
patients with acute bacterial meningitis.
However, Ochikubo et al236reported pro-
in a primate
ing panencephalitis.
Flash YEP studies of infants with posthemorrhagic hydrocephalus
have shown
that the latency of the primary positive
wave increases linearly as intracranial pressure increases.237-24oThis relationship is affected by a number of factors, however.
Guthkelch
et al241found that latency
1. Increases in inverse proportion
to the age
at which symptoms appear

2. Is significantly
longer when the head is
enlarged
3. Is longer still when the patient
has ven-
triculitis
They also found that latency did not
change in parallel with changes in ventricular size, but did correlate with evidence of
brain damage. Developmentally
delayed
hydrocephalic
infants had abnormally prolonged latencies, whereas the latencies
recorded from deyelopmentally
normal hydrocephalic infants were normal. The authors concluded that the value of the flash
YEP lies in assessing mental development,
not in monitoring shunt function.
YEP latency has been used in the diagnosis of many forms of leukodystrophies
with onset in childhood (these studies are
summarized in Section 5-4-3-3). As therapeutic interventions
become available for
genetic leukodystrophies,
such as Canavan
disease,242 the YEP should provide a sensitive measure of their effectiveness in halting or reversing
the demyelinative
process.
264
5-6-2 Patient Preparation

Current international
guidelines recommend recording the YEP from a minimum
PRACTICAL GUIDELINES
5-6-1 Instrumentation
A variety of equipment
for recording
VEPs
are available commercially. The systems

should have a minimum of three channels
available for simultaneous recording of
ERG signals and VEP signals from multiple
sites over posterior head regions. On-line
artifact-rejection
capability should be available to eliminate unwanted biological
noise, such as high-voltage electrical artifacts generated by head movement and
muscle contraction, as well as environmental electrical noise generated by AC power
lines. A remote-control
gating switch to interrupt averaging when the patient stops
looking at the stimulus is particularly useful
for testing pediatric patients. The pattern
stimulator should be checked for luminance
contamination.
A quick way to do this check is to face
away from the stimulus monitor and hold
up a sheet of white paper parallel to the
plane of the screen. The room should be
darkened, and the stimulus events should
occur at an intermediate
rate (8 to 10 reversals/s). If the light reflected on the paper
appears to be steady, mean luminance is
constant. If flicker is seen on the paper, the
of three active occipital sites: midline (Oz),

left (0\), and right (02). A midline frontal
electrode (F z)is used as reference for each
of these active sites, and a vertex (CJ electrode is used as ground. Each active electrode is referenced to a frontal electrode to
eliminate signals common to both (for example, electroencephalogram
and AC line
noise). At each electrode position, a small
area of the patient's scalp should be cleaned
with alcohol or abrasive paste. A cup electrode filled with conducting cream is then
taped or glued to the area. If the electrodes
are properly attached, the impedance measured between active and reference electrodes should be less than 50000, (0, = ohm).
Figure 5-12 shows a block diagram of a YEP
recording
system.
5-6-3 Adult Protocol

A large field (at least 150) and two check
sizes are used: small (12 to 20 min) and
large (48 to 60 min). Note that visual stimulus sizes are measured
in units of visual
angle. Visual angle is defined as the angle

subtended by a visual stimulus on the
retina. As viewing distance increases, an object's visual angle decreases. This is illus-
stimulus is contaminated
by a luminance
artifact and the manufactUrer should be
trated in Figure 5-13, along with the equation for calculating visual angle. At a distance of 1 m, a 12-min check measures 3.5
contacted. Methods for calibration ofVEP

stimuli are presented in detail in the calibration guidelines of the International
Soci
mm and a 48-min check measures 14 mm.

Using small and large checks enables both
foveal and parafoveal retinal regions to be
ety for Clinical
tested, thus increasing the diagnostic yield

of the test. The patient's pupils should not
(ISCEV).2
Electrophysiology
of Vision
be dilated.
Latency
norms should be estab-
lished for age-matched controls (20 subjects

for each decade), starting at age 10. A latency
5-6
Practical
Guidelines
265
Figure 5-12 Electrode location and electronic equipment

for recording VEP. F = frontal. p = parietal. T =
temporal. z = midline. 01 = left occipital. O2 = right
occipital. 03 = left parieto-occipital.
parieto-occipital.
10-20 System.
Nomenclature
04 = right
is from International
Modified with permission of EIsevier Sciencefrom Sokol S:

The visually evokedpotential: theory. techniques,and clinical
applications. Surv OphthalmoI1976;21:18-44.
value of 2.5 SO (99% ) above the normal

mean should be used as the criterion for abnormality. Amplitude
is useful only when
comparing interocular differences. The
mean interocular amplitude difference for
normal subjects is calculated, and a cutoff of 2.5 SO above the normal mean is
used.
The YEP should be recorded with
monocular viewing. The untested eye
should be patched or otherwise occluded.
A minimum of two averaged recordings
should be obtained for each stimulus condition for each eye. The patient should be
appropriately
refracted for the testing distance. Because obtaining an adequate signal requires patient cooperation, the patient
and the incoming signals should be carefully monitored during testing. The patient
should be seated comfortably, with jaw and
neck muscles loose to avoid excessive muscle artifact. Patient fixation should be monitored, and testing should be paused if there
is evidence of drowsiness. Responses obtained from each eye should be compared
prior to disconnecting
the patient. If la-
266
8mm
-11-
~
B = tan-l(8/1000j x 60 = 27.50 min
= 27 min, 30 s
B' = tan-l(8/500)
X 60 = 54.99 min
= 54 min, 59 s
and 0.5 m (500 mm). Visual angle (in degrees) is
tency or amplitude is abnormal from the

second eye tested, the first eye should be
tested again to ensure that the abnormal
equal to inverse tangent of ratio of check size to view-
values are not due to poor compliance.
Figure 5-13 Calculation
of visual angle ( 1:1)subtended
by 8-mm check at viewing distances of 1 m (1000 mm)
ing distance. To obtain measurement in minutes of visual angle, result is multiplied
by 60.
5-6-4 Pediatric Protocol

Because the amplitude
and peak latency of
specific components change dramatically

during the first 6 months of life, it is preferable to record transient rather than steadystate VEPs when testing pediatric patients,
unless special techniques (such as sweep
VEPs or binocular beats) are being employed. The patient's fixation must be
monitored. An observer can stand behind
the video monitor used to generate pattern
stimuli and watch for a centered pupillary
reflex. The test room should be dark, leaving only the pattern stimulus for the infant
to look at. As noted, a remote-control
switch,
used to start and stop averaging, depending
on the patient's fixation, is required, as is an
algorithm for rejecting artifacts caused by
head movements. Uncooperative
patients
can be tested while sedated. Wright et al243
showed that pediatric patients can be reliably tested under chloral hydrate sedation.
These investigators found that measure-
5-7
ment of interocular YEP amplitudes was

sensitive to the presence of amblyopia in
sedated patients.
The optimal check size for infants varies
during the first 6 months of life. At 1 month,
checks of 120 to 240 min are optimal; at
2 months, 60 to 120 min; at 3 to 5 months,
30 to 60 min; and at 6 months and older,
15 min. If no response is obtained with the
check size appropriate for the infant's age,
the check size is doubled.
For binocular testing, a check size appropriate for the infant's age is selected first,
and larger or smaller checks are used depending on the outcome (see above). It is
often possible to obtain a check-size series
and estimate YEP acuity. At least five
check sizes should be used to fit a reliable
curve; for example, 7.5,15,30,60,
and 120
min. For infants, an intermediate
(60-min)
check size is used first. If a signal is obtained, a smaller (30-min) check size is
used; if no signal is obtained, a larger ( 120min) check size is used. If signals are nondetectable with any check size, flash stimuli are used. If a repeatable response to
flash stimulation
is obtained, it is assumed
that the patient has vision of at least light
perception.
For monocular testing, patients older
than 6 months are first tested binocularly,
starting with 15-min checks. If necessary,
check size is increased until a reliable
binocular signal is obtained. After a reliable
binocular signal has been obtained, each
eye is tested separately; preferably, the eye
thought to have better visual acuity is
tested first. Because the transient YEP extrapolation technique is too time-consuming for clinical use, an alternative, as described previously, is to measure the
difference in amplitude between the eyes
for one check size. Although a visual acuity
value is not obtained, there is a greater
Summary
267
probability
that some clinically useful information will be obtained from each eye.
Visual acuity estimates using transient
stimulus techniques require a prolonged
test battery. This makes these estimates
unobtainable
in many clinical situations. As
described above, newer sweep techniques
allow a rapid estimate of visual acuity to be
made in infants and other nonverbal or uncooperative
patient
populations.
SUMMARY
The latency of the pattern YEP provides a
sensitive means of detecting subclinical demyelinative
lesions of the visual pathways
in adults and monitoring developmental
changes in infants. The amplitude of the
pattern YEP is usually of greater interest in
children than is latency because it correlates well with visual acuity, particularly for
small size checks. U nlike latency, however,
it is difficult to use absolute amplitude information because of wide intersubject
differences. This drawback can be overcome
by using sweep techniques or, when there
is a question of monocular visual loss, by
measuring the amplitude difference between the eyes for a small check stimulus.
Although some argue that the YEP provides no more information
than does a thorough clinical examination,244 most agree
that the pattern YEP can detect otherwiseobscure or subclinical disease and provide
quantitative
information
unobtainable
by
even the most astute clinician. When used
with other visual electrodiagnostic
techniques, the YEP can provide valuable localizing information
in patients with cryptic
visual loss.
268
10. Bodis-Wollner
The
practice:
1. Harding
GF, Odom IV, Spileers
dard for visual evoked

national
Society
potentials
for Clinical
W, et al: Stan1995: the Inter-
I, Ghialardi
importance
the clinical
relevance
11. Riggs LA, Johnson
2. Brigell
M, Bach M, Barber C, et al: Guide-
cal responses
parameters
vision:
used in clinical
Calibration
electrophysiology
Standard
International
Society
ogy of Vision
(ISCEV).
Committee
for Clinical
of
of the
Electrophysiol-
12. Spekreijse
T: Contrast
H, van der Tweel
evoked
responses
M, Celesia
evaluation
GG: Electrophysiological
of the neuro-ophthalmology
an algorithm
for clinical
LH,
use. Sem Ophthalmol
1973;13:1577-1601.
resentation
5. Daniel
to the cortical
of vision. Brain
D: Motion
adaptation
6. Horton
IC, Hoyt WF: The representation

in human
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potential in optic nerve hy-
gliomas
in
model of viral encephalitis.
J Pediatr 1990;116:702-706.
Brigell
M, Celesia
GG: Electrophysiological
evaluation of the neuro-ophthalmology

patient:
an algorithm for clinical use. Sem Ophthalmol
1992;7:65-78.
Celesia
GG, Brigel1 MG:
dards for pattern

evoked
potentials.
Recommended
electroretinograms
In: Deuschl
stan-
and visual
G, Eisen A, eds:
Recommendations for the Practice of Clinical Neurophysiology: Guidelines of the International

of Clinical Neurophysiology.
Elsevier;
1999:53-67.
Federation
2nd ed. Amsterdam:
Suggested Readings
Chiappa
KH, Hill
evoked
RA: Pattern-shift
potentials:
visual
interpretation.
In: Chiappa
KH, ed: Evoked Potentials in Clinical Medicine.

3rd ed. Philadelphia:
Lippincott-Raven;
1997:
95-165.
Graham
SL, Klistorner
cance of the multifocal

tential
in glaucoma.
A: The diagnostic
pattern
signifi-
visual evoked
po-
CUlT Opin Ophthalmol1999;
10:140-146.
Harding
GF, Odom IV, Spileers
dard for visual evoked

national
Society
ofVision.
W, et al: Stan-
potentials
for Clinical
1995: the Inter-
Electrophysiology
Vis Res 1996;36:3567-3572.
Spekreijse
cording
H, Reimslag
methods
F: Gross potential
in ophthalmology.
re-
In: Carpen-
ter R, Robson I, eds: Vision Research: A Practical

Guide to Laboratory
Methods. Oxford:
versity
Press; 1998.;
Taylor
MI, McCulloch
potentials
in infants
physioI1992;9:357-372.
DL:
Oxford
Uni-
Visual evoked
and children.
J Clin Neuro-
279
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281
OPHTHALMOLOGY
MONOGRAPH2, Second Edition
E/ectrophysi%gic
Testing in Disorders of the Retina,
Optic Nerve, and Visua/Pathway
Circle the letter of the response option
to the question.
Question
Answer
10
11
12
13
14
15
16
17
18
19
20
282
that you regard as the "best"
answer
SELF.STUDYEXAMINATION
The self-study
examination
provided
for each book in the
Ophthalmology
Monographs series is intended for use after
completion of the monograph. The examination for Electrophysiologic Jesting in Disorders of the Retina, Optic Nerve, and Visual
Pathway, Second Edition, consists of 20 multiple-choice
questions followed by the answers to the questions and a discussion
for each answer. The Academy recommends that you not consult
the answers until you have completed the entire examination.
Questions
The questions are constructed so that there is one "best" answer.
Despite the attempt to avoid ambiguous selections, disagreement may occur about which selection constitutes the optimal
answer. After reading a question, record your initial impression
on the answer sheet (facing page).
Answers and Discussions
The "best"
answer to each question
is provided
after the exami-
nation. The discussion that accompanies the answer is intended

to help you confirm that the reasoning you used in determining
the most appropriate answer was correct. If you missed a question, the discussion may help you decide whether your "error"
was due to poor wording of the question or to your misinterpretation. If, instead, you missed the question because of miscalculation or failure to recall relevant information,
the discussion may
help fix the principle in your memory.
283
284
Self-Study Examinatioi
4. In congenital
QUESTIONS
a. An abnormal
Chapter 1
1. Which
red-green
which of the following

true?
of the following
disorders has
flicker
color deficiency,
statements
is
response to a 30-Hz
stimulus
would
be anticipated.
not been observed to show a selective

or predominant
reduction of the ERG
b-wave compared to the a-wave
b. F emale carriers can often show a reduction in ERG amplitude to a 30-Hz

flicker stimulus.
amplitude?
c. ERG responses to white-Iight

full-field
flash stimuli are normal under both
a. methanol
toxicity
b. cancer-associated
photopic
retinopathy
d. Reduction in ERG amplitudes parallels the severity of the color vision
c. siderosis
d. quinine
and scotopic conditions.
toxicity
deficiency.
2. All of the following
statements
are true
except
a. Patients with North
macular dystrophy
ERG response.
Carolina
show a normal
a. syphilis
b. Carriers of the X-Iinked choroideremia gene most often show mildly to

moderately severe reduction in ERG
a- and b-wave amplitudes.
c. Patients with multiple evanescent
white-dot syndrome (MEWDS)
can
show recovery of initially reduced
ERG amplitudes.
d. A normal ERG response is observed
in patients with Tay.:Sachs disease.
3. Rod ERG responses can be isolated in
a dark-adapted subject by which of the
following stimuli?
a. high-intensity
short-wavelength
(blue) stimulus
b. high-intensity
c. low-intensity
white
white
d. moderate-intensity
long-wavelength
s. In which of the following inflammatory

disorders are ERG amplitudes more
likely to be reduced out of proportion to
the clinically apparent retinal changes?
stimulus
stimulus
lO-Hz flicker
(red) stimulus
b. histoplasmosis
c. rubella
d. pseudo-presumed
ocular histoplasmosis syndrome (P-POHS)
Chapter 2
6. All of the following statements
the EOG are true except
about
a. The slow-oscillation
EGG light rise
correlates with the degree of melanIn
in retinal pigment epithelial cells.
b. The EGG light rise is generated by a
depolarization
of the basal membrane
of the retinal pigment epithelium.
c. Intact photoreceptors
are necessary to
generate the light-rise portion of the
EGG.
d. The EGG light-peak to dark-trough
ratio is reduced in occlusion of the
central retinal artery.
Self-Study Examination
7. In which of the following diseases has

the EGG light-peak been found to be
delayed in reaching its peak amplitude?
previous
sequence of flashes.
the full
field ERG.
b. cone dystrophy
c. pattern
b. The response to a particular focal

flash depends to some extent on the
c. The local responses resemble
a. Stargardt macular dystrophy
285
d. Retinal
dystrophy
horizontal
eral interactions
cells produce
lat-
among focal regions.
d. Best dystrophy
8. In which of the following
diseases is
the EOG light-peak to dark-trough

ratio most likely to be reduced?
a. congenital
red-green
b. congenital
achromatopsia
c. rQd-cone
d. Leber
color deficiency
the multifocal
optic neuropathy
a. Regions of decreased field sensitivity

are associated with delays in implicit
time in retinitis
pigmentosa.
may be reduced
in dia-
c. Lower-than-normal
amplitudes
reli-
ably identify ocular hypertensive

patients at risk for glaucomatous damage.
Chapter3
9. Which of the following helps isolate
the focal cone ERG by minimizing
rod
d. Responses reflect temporal

tion between
interac-
two or more focal
flashes.
activity?
a. a slow stimulus
repetition
rate (slow
Chapter4
flicker)
b. long-wavelength
13. Which
stimulation
c. an intense
background
d. prolonged
dark adaptation
or surround
prior to the
of the following
about the PERG

a. The PERG
ganglion
test
the focal ERG likely
disorders is
to be normal?
b. Stargardt macular dystrophy
c. The PERG
retinopathy
11.The
multifocal ERG is said to contain

first- and second-order components for
reason:
a. Each focal hexagon in the display can

be either dark or light at a given time.
generated
in the
is mainly
generated
in the
is solely generated
in the
cells.
d. The PERG
full-field
c. macular hole
is mainly
bipolar cells.
ganglion
a. amblyopia
statements
is true?
cells.
b. The PERG
10. In which of the following
the following
about
betic retinopathy.
(LHON)
d. chloroquine
statements
ERG are true except
b. Amplitudes
dystrophy
hereditary
12. All of the following
is abnormal
whenever
ERG is abnormal.
the
286
Self-Study
14. Which
Examination
of the following
about recording
Chapter 5
statements
the PERG
is true?
a. Clinical PERGs are usually evoked by

low-contrast reversing checkerboards.
b. PERG
recording
is best performed
using non-contact-lens
electrodes.
c. The reference electrode for PERG

should be at the earlobe.
d. PERG
recording
with unilat-
15. Which of the following statements

about the PERG and macular dysfunction is true?
a. Patients with disease confined
the macula have both full-field
PERG abnormalities.
to
and
b. Patients with Stargardt macular dystrophy (fundus tlavimaculatus)

usually have normal ERGs and PERGs.
c. PERG abnormality in macular dysfunction can be confined to the N95
component.
can be useful in identify-
ing maculopathy as the cause of a delayed pattern YEP.

16. All of the following statements about
the PERG and optic nerve disease are
true except
a. The PERG
may be normal in optic
nerve dysfunction.
b. The PERG abnormality in optic
nerve dysfunction
may be confined
to the N95 component.
c. Leber
(LHON)
tectable
hereditary
optic neuropathy
usually gives a nondePERG.
d. Isolated loss of the PERG N95 component can occur in dominant optic
atrophy (DOA).
reveal
a. subclinical
optic neuropathy
b. optic nerve demyelination

c. occipital
lobe dysfunction
d. nothing
should be performed
monocularly in patients
eral visual acuity loss.
d. The PERG
17. Recording an abnormal pattern YEP

in a patient with macular edema may
18. An abnormally prolonged p lOO latency

in response to lS-min checks recorded
from an eye with 20/20 visual acuity
most likely represents
a. a technical
error
b. resolved optic neuritis

c. glaucoma
d. optic neuropathy that spares the
central visual field
19. An abnormal or absent YEP in an infant
who is unable to fixate or follow
a. indicates that the infant should be
tested again 1 month later to verify
replicability
and to rule out delayed
visual development
b. indicates
optic neuropathy
c. indicates
cortical
blindness
d. excludes the possibility

tern vision in adulthood
of useful pat-
20. Which of the following conditions does

not generally cause an increase in pattern YEP latency?
a. adrenoleukodystrophy
b. miotic
pupils
c. nonarteritic
neuropathy
d. malingering
anterior
(NAION)
ischemic
optic
Seif-Study Examination
287
Chapter 2
6. Answer-a. The EOG slow-oscillation
light rise is not affected to any clinically
significant extent by the melanin content of retinal pigment epithelial cells.
ANSWERS
Chapter 1
1. Answer-b. Patients with cancer-associated retinopathy will show a reduction
in both a- and b-wave amplitudes.
2. Answer-b. Unlike carriers ofX-linked
retinitis pigmentosa, carriers of the gene
for choroideremia
most often show
normal ERG amplitudes and implicit
It is, however, generated by depolarization of the basal membrane of these

cells.
7. Answer-d. The EGG slow-oscillation
light rise is not only subnormal but also
delayed in reaching its peak amplitude
in patients with Best dystrophy.
times.
3. Answer-c. Rod-isolated responses can
be elicited by either a low-intensity
blue stimulus or a low-intensity
white
stimulus. Higher-intensity
wavelength (red) stimuli
and longerare likely to in-
clude a cone component
in the response.
8. Answer-c. Patients with diffuse degeneration of photoreceptor

cells, such as
seen in rod-cone dystrophy like retinitis
pigmentosa, will predictably show reduced EOG light-peak to dark-trough
ratios. Patients with nonprogressive
cone dysfunction,
or optic atrophy, show
normal EOG ratios.
4. Answer-c. In X-Iinked red-green color

vision deficiencies, the full-field
flashelicited ERG to either a single flash or
a 30-Hz flicker white-Iight
stimulus is
normal.
5. Answer-d. ERG amplitudes in patients
with histoplasmosis and rubella are
within the range of normal. In syphilis,
ERG amplitudes either are normal or, if
reduced, parallel the extent of clinically
apparent fundus changes. Some patients
Chapter 3
9. Answer-c. An intense background or
surround will saturate the rod-mediated
ERG and help isolate the cone ERG. In
addition,
minimize
the brighter surround helps

stray light, thus ensuring that
the test spot elicits a focal response.

The rod ERG can follow flicker up to
around 20 Hz, so a slow flicker rate will
elicit primarily
rod activity.
Rods are
with pseudo-presumed
ocular histoplasmosis syndrome will show a notable re.
duction in ERG amplitude in the pres-
also most sensitive to short-wavelength

stimulation and require a prolonged period of dark adaptation to reach maximal
ence of a small or at most moderate

number of chorioretinal
scars.
sensitivity.
Se/f-Study Examination
~
Amblyopia typically results
10. Answer-s.
from inappropriate
binocular stimulation during childhood and has a cortical
basis. Both the retina and, therefore, the
focal ERG, are normal in amblyopes.
The focal ERG is often abnormal early
in the course of Stargardt macular dystrophy. Reduced focal ERG amplitudes
have been reported in some patients
with normal visual acuity. Unless a macular hole is extremely small (less than
600 pm in diameter), it too will affect
the focal ERG from the fovea. The
focal ERG is also useful for detecting
early damage within the macula caused
by chloroquine
12. Answer-c. It remains to be determined

whether the multifocal ERG technique
will be useful for identifying
patients at
risk for glaucomatous damage. Investigations to date in diabetic patients,
however, suggest that multifocal responses may be reduced in amplitude
at a time when there is little or no retinopathy. Second-order components resulting from temporal interactions of
flashes reflect primarily inner retinal
processIng.
toxicity.
11. Answer-b. The multifocal ERG would

contain only first-order components if
the response from each retinal region
were simply the average response to all
the flashes. Because of the pseudo-random m-sequence, however, either a
flash or a dark period can precede each
flash. The temporal interactions among
flashes give rise to the second-order
components, which may be useful for
detecting disorders of the inner retina.
The local responses in the multifocal
ERG resemble the full-field
ERG only
if the stimulation
parameters are made
similar between the two tests.
14. Answer-~. The PSO component of the

PERG usually shows a linear increase in
amplitude with stimulus contrast, and a
high-contrast
stimulus is recommended
for routine clinical practice. It is essential that the reference electrode be situated at the ipsilateral outer canthus;
other sites, such as the forehead or ear,
are subject to contamination
from the
cortically generated YEP being recorded via the reference electrode. Binocular stimulation
is usually used for
PERG and has the advantage in patients with asymmetric visual acuity that
the better eye can maintain fixation and
accommodation.
Se/f-Study Examination
15. Answer-d. Patients with dysfunction

confined to the macula have a normal
ERG and an abnormal PERG. Stargardt
macular dystrophy (fundus flavimaculatus) usually has this pattern of abnor.:
mality. The PSO component is primarily
affected in macular dysfunction,
and
macular dysfunction
usually affects amplitude rather than latency. PSO latency
increase can occur, particularly
in serous
detachment or macular edema, but is
relatively uncommon. The reduction in
PERG PSO almost invariably associated
with macular dysfunction
is important
to the distinction
between the delayed
YEP that can occur in optic neuropathy,
in which PSO is rarely involved, and
the delayed YEP that is caused by
maculopathy.
16. Answer-c. The N9S is the component
that is usually selectively affected in
optic nerve dysfunction,
but the PERG
will often be normal. The PSO component is affected only occasionally in
optic nerve dysfunction,
either longstanding severe optic neuropathy or
acute optic neuritis. In the latter case,
PSO may recover. Disorders such as
Leber hereditary optic neuropathy and
dominant optic atrophy affect the N9S
component, usually selective\y, with
PSO involvement
occurring late in the
disease; PSO is always likely to be
detectabl~.
289
Chapter 5
17. Answer-d. Reduced visual acuity due to
macular edema will result in an abnormality of the YEP. Thus, no inference
regarding the health of more proximal
visual pa~hways can be derived from results of this test.
18. Answer-b. Delayed PlOO latency with
normal visual acuity is highly suggestive
of optic nerve demyelination.
Glaucoma
affects the YEP to large checks, and the
YEP is insensitive to changes in the peripheral
visual
field.
19. Answer-a. An abnormal YEP in an infant

can be caused by many factors, including poor cooperation, delayed visual
maturation, abnormal background electroencephalogram,
as well as disease or
disorder of the visual pathways. When
an abnormal YEP is obtained in an infant, the test should be repeated in 1
month before inferring
pathways
intact.
that the visual
are not electrophysiologically
20. Answer-c. Ischemic optic neuropathy

causes wallerian degeneration and decreased YEP amplitude, but does not
affect YEP latency. Adrenoleukodystrophy increases YEP latency caused by
demyelination
of the optic nerve. Miotic pupils reduce retinal illumination,
resulting in an increase in YEP latency.
Malingerers can voluntarily
increase
YEP latency through poor fixation or
accommodation.
INDEX
NOTE: Anffollowing
number
a page number
indicates
a table. Drugs
drug trade name is listed,
indicates
a figure,
and a tfollowing
are listed under their generic
the reader is referred
to the generic
name.
Alzheimer
ABCR (ATP-binding
transporter
protein)
photoreceptor-specific,
macular
Acetazolamide,
chloride,
Achromatopsia,
by, 157,163
ERG affected
(adrenocorticotropic
hormone),
43!
ERG
outer retinopathy,
80-83
ERG in, 80-83

AD (Alzheimer
ADNIY
disease), YEP in, 254

dominant
inflammatory
ERG in, 73
disorders,
Adrenocorticotropic
Age
ERG affected
73-74,
25, 26/, 179
10-11,
ERG
Anterior
Aphakic
vitreoretino-
by, 27-28
affected
by, 202
streaks (Bruch's
ischemic
26/, 27
cystoid
macular
gold-foil
Arden
201/
ratio (light-peak
EOG,
clinical
degeneration
2591 See
use of YEP in
(AMD)
Arrestin
(retinal
in birdshot
in Oguchi
ratio), in
162
66
retinochoroidopathy,
78
disease, 50
Arthro-ophthalmopathy,
ERG in, 88
hereditary
(Stickler
syndrome),73
ischemic
optic neuropathies),
YEP in, 250-251

Albinism
Artifact-rejection
system
for PERG, 203
for YEP, 264
Arylhydrocarbon
ERG in, 117
Leber
YEP in, 257

Aldosterone,
Alstrom
to dark-trough
diet, for gyrate atrophy,
Arteriosclerosis,
in, 213-214
201-202,
S-antigen)
in, 181
in, 187
for PERG,
160-161,
Arginine-restricted
by, 204
edema, focal ERG in,
electrode,
ERG
(anterior
(AlaN),
See Chloroquine
Arden
multifocal
AlaN
disorder),
optic neuropathies
focal ERG
PERG
membrane
180
Aralen.
74!
by, 244, 244/, 258-259,
macular
10/, 11!
179, 180!
ERG affected
by, 179
also Children,
degeneration
202-203
YEP in, 250-251
by, 25-26,
affected
Age-related
in ERG,
macular
ERG in, 69
(ACTH),
dominant
focal ERG affected

YEP affected
of response
in, 105
choroidopathy),
in, 74, 74!
PERG
Amplitude
PERG
YEP in, 248
(autosomal
ERG
for PERG,
by, 105
Adrenoleukodystrophy,
ADYIRC
Amplifiers,
Angioid
hormone
affected
in, 38-39
Anesthesia
neovascular
vitreoretinopathy),
ERG
ERG
YEP in, 248-249
See Age-related
in focal ERG,
(autosomal
Adrenal
AMD.
YEP in, 254
congenital,
YEP in, 260-262,261/
age affecting,
by, 105
zonal occult
Leber
nutritional,
by, 25
ERG in, 43-44,
disease (AD),
Amaurosis,
Amblyopia
childhood,
56, 213
congenital,
affected
Acute
in Stargardt
EOG affected
Acetylcholine
ACTH
dystrophy,
gene,
a page
names; when a
ERG affected
syndrome,
interacting
congenital
protein-like
amaurosis,
1, in
39
by, 105
ERG in, 35
291
292
Index
Binocular
Ataxia
Friedreich,
spinocerebellar,
ERG
with
retinal
in, 112-114,
11~
macular
dystrophy,
dominant
and choroidal
Carolina
Autosomal
Bipolar
Birdshot
neovascular
Blind
BMD
ERG in,
73
dominant
optic atrophy,
dominant
vitreoretinochoroidopathy
(ADYIRC),
in, 74, 74!
ERG
73-74,
stimulus,
different-wavelength
implicit
latencyof,
10, 10!
negative wave of multifocal
of focal ERG,
B
Bardet-Biedl
21, 2~
23!
18, 18/, 19!
syndrome,
ERG
disorder
(angioid
in, 69
(branch
retinal
dystrophy
(BMD),
ERG
concentric
Butterfly
dystrophy,
b-wave
of ERG,
dystrophy,
macular
ERG
in,
circulation/dtugs
56-58,
41
57!
in, 163
ERG in, 56-58

Bestrophin gene, in Best macular
crystalline
dystrophy,
ERG in, 117-118,
119!
117-118,
58
118/, 119!
streaks),
ERG in,
in, 58-59,58!
affecting,
disorders
11!
affecting,
affecting,
diurnal
fluctuations
gender
affecting,
latencyof,
refractive
stimulus
25, 26],
27-28
25
stimulus,
different-wavelength
implicit
dystrophy,
in, 164
1, 2-6, 2], 71!. See also Electro-
affecting,
dystrophy,
ERG in,
41,41], 42/
for ERG, 12
of, 10,10],
with
in,
86], 87!
Bull's-eye maculopathy,
Burian-Allen
electrode,
with constant-intensity
annular
ERG in,
ERG
vein occlusion),
anesthesia
Beh<;:et disease, ERG in, 83-84

Best macular
ERG
111/
ERG in, 35-36

in, 110-111,
106-107
Bietti
of, EGG
membrane
27
amplitude
in, 35
syndrome,
disease, ERG
muscular
EGG
drusen
Bruch's
retinogram
age/retinal development
Batten-Mayou
Benign
(BRYG),
Bruch's
BRYG
20, 21!
180
Bassen-Kornzweig
Becker
26!
ERG and, 183
stimuli,
ERG in,
(BRAG),
vein occlusion
85-88,
stimuli,
with variable-intensity
in, 44
dystrophy),
85-88
membrane,
17, 17!
stimuli,
ERG
muscular
82/
by, 25
85-88, 86], 87!

(branch retinal artery occlusion),
time of, 10, 10/, 11!
with variable-frequency
monochromats,
Branch retinal
development
affecting,
of, 10, 10/, 11!
78,81],
ERG affected
85-88
74/
with
YEP in, 252
syndrome,
106-107
Branch retinal artery occlusion
1, 2-6, 2/ See also Electroretinogram
age/retinal
amplitude
78], 79!
YEP in, 258
systemic,
(Becker
BRAG
a-wave
of ERG,
cortical,
spot enlargement
Blue-cone
inflammatory
Autosomal
76-78,
in, 208,212/
Blood pressure,
59,601
Autosomal
and,
2-6
Blindness,
(North
(ADNIY),
binocularity
ERG in, 76-78,79!
epithelial
dystrophy),
vitreoretinopathy
cells, in ERG,
PERG
pigment
degeneration
macular
dominant
113!
(ABCR) gene,
in Stargardt
56, 213
central
in YEP, 241
of cortical
261-262
degeneration,
ATP-binding
transporter protein
photoreceptor-specific,
Autosomal
beat response,
assessment
YEP in, 254
17, 17!
stimuli,
20, 21!
71!
in, 28
27
time of, 10, 10], 11!

10,10!
error affecting,
duration
with variable-frequency
with variable-intensity
19!
of focal ERG,
180
27
affecting,
24
stimuli,
stimuli,
21, 22], 23!

18-19,
18],
Index
Chlorpromazine,
Cancer-associated
retinopathy,
118-120
Canthaxanthin,
ERG affected
Carotid artery occlusion
by,97-98
EGG
Chorioretinal
ERG in, 84
See also Lens opacities
(CRaIBP),
protein
(autosomal
epithelial
dominant
epithelial
pig-
central
Carolina
pigment
degenera-
macular
dystro-
(CRAG)
in, 85-88,85!
Central
85-88, 89!
serous retinopathy
vein occlusion
(CRVG),
ERG in,
in, 180
PERG
Choroidal
visual field
(cyclic
activity,
in VEP, 239, 239!
guanosine
monophosphate
pigmentosa,
PDE-gated
Cherry-red
amblyopia
delayed
disorders
prognostic
and,
hydrate
sedation,
children,266-267
Chloroquine
EGG affected
ERG affected
by, 167
by, 88-90
melanoma,
familial
(drusen
brane),
EGG
EGG
in, 169
and, 262
Choroidopathy,
disease and,
in
of Bruch's
(pseudo-presumed
Circadian
salmon-patch
ERG in, 93-95,

rhythm,
mem-
ocular histoplas(birdshot
76-78,78/,
in, 208, 212/
Cinchonism,
EGG
ERG in, 83
retinochoroidopathy),
ERG in, 76-78, 79!
PERG
260!
membrane),
in, 164
mosis syndrome),
for VEP testing
65
68!
of Bruch's
in,164
Hutchinson- Tay (drusen
263
Chloral
malignant
Choroideremia,
66-67,67/,
EGG in, 166
multifocal
and, 259-260,
atrophy,
ERG in, 65
and, 262
value in neurologic
in, 208,212/
Choroiditis
259!
and, 262
protocol for, 266-267

visual acuity in infants
retinochoroidopathy),
EGG in, 166
and, 262
optic nerve hypoplasia
(birdshot
of
gene for, 67
disease, 114
function
260-262, 261/
visual maturation
optic nerve gliomas
(drusen
EGG in, 164
ERG in, 66-67,68!
35
use of VEP in, 258-263,
and binocular
oculomotor
(CNCG)
pigmentosa,
spot, in Tay-Sachs
clinical
47
35
cation channel
gene, in retinitis
Children,
superficial
membrane),
(choriocapillaris)
Choroidal
phosphodiesterase)
gene
in congenital stationary night blindness,
in retinitis
Bruch's
76-78, 78/, 79!

ERG in, 76-78, 79!
VEP in, 246
cGMP
66!
in, 166
vitiliginous
in, 213
PDE
ERG in, 66-67,68!

~ene for, 67
gyrate atrophy, 65-66,
Holthouse-Batten
retinal
cGMP
68!
Chorioretinitis
Central
Central
65
ERG in, 65-66
in, 162
PERG
atrophy,
ERG in, 65
EGG
phy), 59,60!
retinal artery occlusion
focal ERG
ERG
in, 166
choroideremia,
66-67,67/,
EGG in, 166
dystrophy
and choroidal
tion/North
ERG
bifocal,
65-68
(choriocapillaris)
EGG
35
areolar pigment
EGG
progressive
dystrophies,
choroidal
gene for, in retinitis
mentosa,
Central
atrophy,
Chorioretinal
retinaldehyde-binding
Central
65
in, 59-60
focal ERG and, 182

Cellular
by, 90-91
atrophy,
ERG in, 65
in, 166
Cataract.
ERG affected
Choriocapillaris
(choroidal)
EGG in, 166
293
of ERG,
94!
28
79!
294
Index
Circulation
Crystalline
dystrophy, Bietti,
ERG in, 117-118,119!
EOG affected
by, deficiencies
ERG affected
by, 25
CSNB.
and, 84-88
Cushing
deficiencies
by, 251-252
Cyclic
PDE-gated
cation channel)
gene, in retinitis
Cone dysfunction
pigmentosa,
disorders,
stationary,
ERG
60-64,61/,
62/, 63/, 64!
night
blindness
1, 2-6, 2/
affecting,
105
guanosine monophosphate
phosphodiesterase (cGMP PDE) gene
stationary
in retinitis
in,
118}; 119!
in, 105
therapy
in congenital
35
43-45
Cone dystrophies,
of ERG,
117-118,
stationary
disease, ERG
corticosteroid
by, 97
VEP affected
(cGMP
See Congenital
c-wave,
Cisplatin
ERG affected
CNCG
and, 166
night
pigmentosa,
blindness,
47
35
Cyclitis,
Fuchs heterochromic,
Cystoid
macular
PERG
in, 214
edema, focal ERG in, 180
EGG in, 165

ERG in, 60-64,
Cone ERG,
Cone monochromat,
Cone-rod
EGG
EOG
dystrophies,
39-41,
39/, 40/, 41/, 42/
ERG in, 14-23,
night
blindness,
45-4 7,
Dawson- Trick-Litzkow
for multifocal
for PERG,
in, 208, 210-211!
Deferoxamine
electrode.
See also Recording
electrodes
for ERG,
11
Contrast-reversal
Corneoretinal
stimuli,
potentials,
Cortical
blindness,
Cortical
visual evoked
electrode,
for ERG,
Counterphase-modulation
Craniofacial
trauma,
stimuli,
by, 105
caused by
compression
caused by, VEP in, 257

See Central
Creutzfeldt-Jakob
retinal
optic nerve
velocity
artery occlusion
disease
ERG in, 44-45
Deuteranopia,
ERG
Developmental
Diabetic
maculopathy,
Diabetic
retinopathy
in, 169
ERG
in, 102-104
vein occlusion
in, 44-45
dyslexia,
EGG
retinal
by, 247-248,
218/
Desferal. See Deferoxamine

Deutan defect, ERG in, 44-45
ERG in, 114

See Central
affected
in, 216-218,217/,
VEP in, 254

CRVO.
by, 203
YEP in, 262
YEP in, 254
Deuteranomaly,
chiasmal
affected
YEP in, 246-249
for VEP, 240
VEP in, 251

Craniopharyngiomas,
PERG
Demyelination,
PERG
by, 168
visual maturation,
conduction
13
optic neuropathy
( desferrioxamine
by, 98-99
Dementia,
See Visual
183
by, 2.12
Delayed
potential.
ERG,
ERG affected
Defocusing,
VEP in, 258
electrode
YEP affected
for VEP, 240
YEP in, 258
PERG
in, 213
focal ERG in, 181

multifocal
PERG
Diamox.
25
201
affected
161
evoked potential
Corticosteroid
therapy, ERG affected
Cotton-wick
EGG
age affecting,
160, 160/, 161
12-13
46/, 48!
Contact-lens
sensitivity,
(Dr), in EGG,
for ERG,
46/, 48!
in, 166
15/, 16/
ERG
Dark trough
42/
stationary
ERG in, 45-47,
CRAG.
conditions
in, 159, 160/
Dark-adapted
in, 165
Congenital
PERG
Dark-adapted
181!
44
ERG in, 39-41,39/,
EGG
62/, 63/, 64!
focal, 180-182,
ERG in, 189-190
in, 213
See Acetazolamide
Didanosine,
EGG
affected
by, 167~168
249/
Index
Diffuse
photoreceptor
dystrophies.
See also
cone, 60-64, 61!, 6~

EGG in, 165
specific type
EOG in, 165
ERG
ERG in, 29-30

Diurnal
fluctuations,
DMD
{Duchenne
DNA,
106-107
mitochondrial,
in ERG,
muscular
{dominant
mutations
in, in KearnsPERG
Dominant
trophy), 59, 601

optic atrophy {DOA),
Dominant
222-2231
progressive
Carolina
Drug
macular
PERG
dystrophy),
retinal
Bruch's
membrane),
toxicities.
in, 219,
dystrophy
dys-
in, 219,
foveal dystrophy
macular
{North
in, 167-168
ERG
in, 88-99
Doyne
honeycomb
of
EOG in, 164
(drusen
EGG
of Bruch 's mem-
in, 164
gyrate atrophy, 65-66,

EGG in, 166
66!
ERG in, 65-66

macular
EGG
in, 163-165
ERG
in, 54-65
North
in, 210-213
Carolina,
pattern,
EGG
ERG in, 59, 60!
58-59, 58!
in, 164
ERG in, 58-59

progressive
bifocal
chorioretinal
atrophy,
ERG
in, 59-60
Drusen
of Bruch 's membrane,
EGG
optic nerve head, PERG

D, {dark trough),
DTL
39!, 42!
in, 165
PERG
59, 601
{drusen
See also specific agent
EGG
63!, 64!
photoreceptor
EGG
and amino-
Carolina
honeycomb
6~
ERG in, 29-30
degeneration
{North
63!, 64!
39!, 40!, 41!, 42!
ERG in, 39-41,
brane),
aciduria
Doyne
ERG in,
110
optic atrophy),
222-2231
macular
Dominant
28
dystrophy),
diffuse
Sayre syndrome,
DOA
in, 60-64,
cone-rod, 39-41,
EGG in, 165
295
electrode.
in EGG,
in, 164
rod-cone,30-39
EGG in, 165
in, 221
ERG
160, 160/, 161
with
See Dawson- Trick-Litzkow
glaucoma,
electrode
Duchenne
muscular
dystrophy
{DMD),
ERG in,
{off-response),
of ERG,
ERG
5, 51
Dystrophies.
optic neuropathy,
YEP in, 250
fundus
ERG in, 56-58

crystalline,
ERG
choroidal
117-118,
in, 117-118,
in, 166
ERG
in, 65
choroideremia,
66-67,
EGG in, 166
ERG
in, 66-67,
gene for, 67
118/, 1191
1191
{choriocapi!laris)
EGG
PERG
in, 54-56,
in, 208
54!, 55!, 56!

56!
focal ERG in, 180
Best, 56-58, 571

EGG in, 163
Bietti
64-65
in, 65
Stargardt, 54-56,
EGG in, 163
ERG
See also specific type
and angle-closure
36
in, 208, 209!
Sorsby fundus,
stimulus duration affecting, 24

Dyslexia, developmental,
YEP in, 258
Dysthyroid
PERG
sheen retinal,
106-107
d-wave
in, 30-39
nanophthalmos
681
atrophy,
67/, 681
65
autofluorescence
215!
multifocal
PERG
Dystrophin,
ERG
imaging
in, 213,
in, 187
in, 210-213,214-215!
in muscular dystrophy,
106
296
Index
in diabetic
retinopathy,
Early receptor potential (ERP), 7-8, 8!

in multiple evanescent white-dot
syndrome,
in diffuse
photoreceptor
80
in retinitis
Ectodermal
pigmentosa,
34
(EEM
syndrome),
EGG
dysin, 165
Electrodes
158, 158!
for ERG,
11-12,12-14
for focal ERG,

for multifocal
for PERG,
(off-response)
for focal ERG,

for multifocal
183
deficiencies,
components
in diffuse
157-175
dystrophies,
in circulatory
stimulus
166
166
photoreceptor
macular
in inflammatory
dystrophies,
dystrophies,
conditions,
165
163-165
166
procedure
in stationary
disorders,
166
167-168
age affecting,
(ERG),
1-155
43-44,
25-26,
anesthesia
affecting,
in angioid
streaks, 69
43!
components
43-45
conditions,
15/, 161
of components
of, 10-11,
101;
11!
normal
values for, 185

disorders,
1881
recording procedure
185-189,
pupil
for, 183
(PERG),
25
electrodes
for focal ERG,

for multifocal
recording
of, 2-9
disorders
(stationary),
197-235.
See also Pattern
electroretinogram
size affecting, 25
recording
65-68
186/,
for, 182
pattern
and origins
c-wave of, 1, 2-6,2/
27, 102
and dark-adapted
27-28
and, 84-88
in cone dysfunction
69-75
75-84
off-responses of, 5, 5!
in optic nerve disease, 100-102
dystrophies,
affecting,
deficiencies
54-65
disorders,
conditions,
in lens opacities,
light-
dystrophies,
26/, 27
of, 1,2-6,2/
circulation
in inflammatory
stimulus
a-wave of, 1, 2-6, 2/

in chorioretinal
macular
vitreoretinal
in outer retinal
for use of, 238!
in achromatopsia,
for, 178, 1791
in hereditary
158/, 159/,
tests. See also specific type
Electroretinogram
180-182,
multifocal,
177, 182-190, 184/, 191/, 192
in inner retinal disorders, 190, 191/
night-blinding
Electrophysiologic
flowchart
for, 158-161,
163
in toxic conditions,
192
disorders,
cell disease, 100-102
14-23,
measurements
of, 161-163
160!
in retinal disorders,
177, 177-182,
in hereditary
with
in optic nerve disease, 168

recording
183
23-28
for, 177, 177-178
in ganglion
of, 161-163
in hereditary
178
ERG,
recording procedure
from rods, 179
(EGG),
in chorioretinal
of, 5, 5!
181/
normal values for, 179, 1801
201-202,201/
Electro-oculogram
29-42
12-14
from cones, in retinal
178
ERG,
dystrophies,
in, 28
for, 11-12,
focal (foveal),
for YEP, 237, 264, 265!
b-wave
d-wave
factors affecting,
for EGG,
origins
fluctuations
electrodes
dysplasia/ectrodactyly/macular
trophy
diurnal
102-104
retinal
183
color deficiency,
error affecting,
disorders,
toxicity
sex (gender)
size of retinal
12-14
for, 11-12
development
in retinal
retinoid
ERG,
procedure
in red-green
refractive
for, 11-12,
178
44-45
27
affecting,
25-26,
26!
28-29, 29!
affecting,
affecting,
99-100
27
area illuminated
affecting,
24
Index
in stationary
cone dysfunction
Fleck
disorders,
night-blinding
stimulus
duration
stimulus
interval
45-53
A deficiency,
opacities,
Focal (foveal)
Enolase,
stimulus
disorders,
retinopathy,
118
Foreign
179
body, intraocular
EGG
affected
by, 169
ERG. See Electroretinogram
ERG
affected
by,
electrode,
Foveal dystrophy,
13
ERP. See Early receptor

ESCS. See Enhanced
Ethambutol,
Foveal
S-cone syndrome
caused by, YEP
(MS-222),
ERG affected
thyrotoxic,
ERG
Eye movement
abnormalities,
in children,
PERG
Fundus
F
Factor V Leiden
mutation,
Familial
choroiditis
Familial
exudative
Familial
internal
brane),
in Beh~et disease, 84
(drusen
EOG
of Bruch's
mem-
membrane
dystrophy,
ERG
in,
PERG
in media opacities,
for operating
pro~nostic
ERG,
158, 159!
242}; 243, 245-246

245-246
room monitoring,
value of, in pediatric
253
neurologic
disease, 263
in traumatic
Fundus
by, 200--201
in multifocal
for EGG,
flavimacularns
trophy
in, 163
of, for focal ERG,
(Stargardt
), 54-56,
macular
dys-
54/, 55/, 56/
optic neuropathies,
251
autofluorescence
multifocal
74-75
Flash YEP, 240-241,
camera, modification
34
52/
focal ERG in, 180

fundus
component,
pigmentosa,
50-51,51/,
ERG in, 54-56,56/

dystrophy,
vitreoretinopathy),
affected
178
178
64-65
size, PERG
albipunctarns,
in, 166
EGG
exudative
in, 214
in, 226-227
in, 50-51,52/
(FEVR),
65
lights,
PERG
of, for focal ERG,
ERG
Fundus
limiting
Fast PIll, 1,2/

Fenestrated
sheen macular
Fixation
cyclitis,
24
visual loss
EGG
Fundus
in, 164
vitreoretinopathy
74-75
First-order
ERG
YEP in, 254-256, 255/

Fundus, changes in, in retinitis
in,262
Field
stimulus,
Functional
YEP
(North
59,60/
ataxia, YEP in, 254
modification
by, 97
in, 105
progressive
dystrophy),
ERG. See Focal (foveal)
Friedreich
Full-field
acid methanesulfonate
Exophthalmos,
(familial
macular
Fuchs heterochromic
in,251
FEYR
115-116,116/
dominant
Carolina
potential
optic neuropathy
181/
for, 178, 179/
EGG. See Electro-oculogram

ERG-jet
180-182,
for, 177, 177-178
Focal rod ERG,
ERG in, 189
in cancer-associated
181/
177,177-182,192
recording procedure
from rods, 179
120, 120/, 121/
ERG in, 120, 121/

multifocal
180-182,
ERG,
normal values for, 179, 180!
ERG in, 105-106
S-cone syndrome,
21, 22/
25
from cones, in retinal
99-100
27, 102
hepatic,
frequency,
Focal cone ERG,
24-25
88-99
in vitreous
Flicker-fusion
age affecting,
23-24
affectin~,
in vitamin
Encephalopathy,
disorders,
affectin~,
in toxic conditions,
Enhanced
53, 53/
ERG in, ,)3
43-45
in stationary
retina of Kandori,
297
183
imaging
in, 213,215/
ERG in, 187
in, 210-213,214-215/
pulvernlenrns,
ERG
in, 58-59
298
Index
Hepatic
G
Ganglion
failure/encephalopathy,
in multifocal
in PERG,
Ganglion
ERG,
190
Hereditary
arthro-ophthalmopathy
syndrome), 73
197, 206-207
Hereditary
cell disease
Gender,
in, 219-221,
222-223!
ERG affected
by, 27
Gentamicin,
ERG affected
Gentamycin.
See Gentamicin
macular
vitreoretinal
Hexosaminidase
ERG
in, 189-190,191/
Glycine,
ERG affected
Gold-foil
electrode,
Goldmann-Favre
by, 97
for PERG,
syndrome,
in ERG,
for focal ERG,
201-202,201/
HLA
leukocyte
(human
gene, in retinitis
cyclase, retinal
congenital
Gyrate atrophy, 65-66,

EGG in, 166
Human
regulator
leukocyte
(RPGR)
pigmentosa,
(RetGC),
35
amaurosis,
39
(HLA),
78
perimetry,
in retinitis
Hurler
multifocal
pigmentosa,
syndrome,
disease, ERG in,
111/
ERG affected
Hawlina-Konec
for ERG,
electrode
14
for multifocal
for PERG,
by, 28
185-187,
ERG
201
YEP, 256
(drusen
EGG
of Bruch's
in, 164
in infants,
prognostic
value of
YEP in, 263
10-111,
Hydroxychloroquine
EGG affected by, 167
ERG affected
by, 88-90
Hyperosmolarity-induced
ERG,
186/, 188!
in, 36
Tay choroiditis
Hydrocephalus,
Hagberg-Santavuori
ERG compared
ERG in, 36
membrane),
H
in birdshot
185
syndrome,
Hutchinson-
ERG in, 65-66
EGG
2-6
with,
Hunter
66!
chorioretinitis
membrane),
anti~ens
Humphrey
gene for, in
in birdshot
78
of Bruch's
in,164
Horizontal
cells, in ERG,
11
electrode
antigens),
superficial
(drusen
for ERG,
ERG in, 83
See Hawlina-Konec
Holthouse-Batten
triphosphatase
Leber
pseudo-presumed,
HK electrode.
11
178
electrode,
Guanylate
dis-
value of YEP in,
Graves disease, YEP in, 250

Guanosine
disorders
in Tay-Sachs
Histoplasmosis
ERG in, 75
72
Grass photostimulator,
Hemifield
69-75. See also
263
optic nerve, YEP in, 262
G-protein,
A deficiency,
ease,114
infants, prognostic
High-risk
in, 221-226
Halothane,
disorders,
specific type and Yitreoretinal
Glomerulonephritis,
membranoproliferative,
EGG in, 164-165
Ground
dystrophies
in, 210-212
Hereditary
YEP in, 246

Gliomas,
54-65. See also
ERG in, 54-65

PERG
by, 95-97
ERG in, 100

PERG
dystrophies,
EGG in, 163-165
Glaucoma
multifocal
in,
(Stickler
specific type and Macular
ERG in, 100-102

PERG
ERG
105-106
cell activity
183
response),
Hypertension
ocular, PERG
systemic,
response
157,162-163
in, 221-226
ERG affected
Hypertensive
retinopathy
EGG in, 166
ERG
in. 88
by, 88
(mannitol
Index
Hyperthyroidism,
ERG
Hyperventilation,
ERG affected
Hypothyroidism
Hysteria,
PERG
in, 105
(myxedema),
nonorganic
Kandori,
by, 25
ERG
in, 105
visual loss and
fleck retina of, ERG
intracranial
tumor
IIH.
Implicit
hypertension
cerebri),
See Idiopathic
(pseudo-
243/, 244/, 245/, 264-265
Leber
congenital
amaurosis,
Leber
hereditary
optic neuropathy
44
ERG affected
10, 10!
in YEP, 243-245,
ERG in, 38-39

(LHGN)
PERG in, 219-221

YEP in, 252-253
See Indomethacin
Indomethacin,
of response
in ERG,
hypertension
10, 10/, Ilt
a~e affecting, 25, 261

Incomplete
achromatopsia,
holes, YEP in, 246
Latency
YEP in, 250
intracranial
time, in ERG,
Indocin.
108/, 109!
255!
Lamellar
Idiopathic
in, 53,53!
Kearns-Sayre syndrome, 107-110,

ERG in, 108-110, 109!
Kufs disease, 110
in, 226-227
YEP in, 254-256,
299
Lens opacities
by, 93
ERG and, 27,102
Infant
focal ERG and, 182
ERG in, 25, 261

visual acuity
in, YEP in estimation
259-260, 2601
amaurotic familial
Infantile
disease),
Inflammatory
idiocy
of,
(Tay-Sachs
of choroid
ERG
in, 75-76
Inflammatory
optic neuropathies,
retinal
cells, in PERG,
Inner
retinal
component,
EGG
YEP in, 252
hypertension,
cerebri),
foreign
ERG,
dystrophy,
familial,
idiopathic
YEP in, 250
Lipofuscinoses,
Liver
failure,
ERG affected
of ERG,
1161
by, 100
neuronal
ERG
PERG
in. 208
ceroid,
110-111,
111/
in, 105-106
peak), in EGG,
160, 160/, 161-162
dystrophy
Macula,
function
focal ERG
disease, ERG in, 110-111,
of retinal
of
in assessment
of, 246
Macular
cysts, YEP in, 246
Macular
degeneration,
multifocal
PERG
age-related
ERG in, 187
in, 213-214
of, 180
of, 207-214
focal ERG in, 181

69-72,701
pigment
ERG in, 58-59
in assessment
YEP in assessment
J
111/
Juvenile retinoschisis,
X-Iinked,
ERG in, 69-72, 70!
macular
PERG
Jansky-Bielschowsky
in Stargardt
55-56
epithelium,
by, 115-116,
i-wave,
160-161,162
Lipofuscin-like
substance,
l'vlacroreticular
ERG affected
ratio, in EGG,
(pseudo-
body
by, 169
160, 160/, 161-162
to dark-trough
ERG in, 110-111,
EGG affected
Isotretinoin,
15/, 16!
peak (Lp), in EGG,
Lp (light
tumor
in, 158, 160, 160!
dystrophy,
in multifocal
optic neuropathy
conditions
ERG in, 14-23,

Light
65
Intraocular
Light-adapted
197
190,191/
limiting
membrane
Intracranial
See Leber
Light-peak
Inner
Internal
hereditary
and retina,
75-84. See also specific type

in, 166
YEP in, 248
LHGN.
ERG in, 100, 114
conditions
EOG
Leukodystrophies,
(AMD)
111/
300
Index
Macular
dystrophies
benign
concentric
annular,
electrophysiologic
EOG,
testing
Maximum-Ien~th
for multifocal
41
in
for multifocal
163-165
Media
54-65.
YEP and, 245-246

Melanoma,
Mellaril.
ERG in, 56-58

cone, ERG in, 60-64,61/,
Carolina,
ERG
pattern,
EGG
59,60!
Meningiomas,
bifocal
Stargardt, 54-56,
EGG in, 163
chorioretinal
atrophy,
Methanol
poisoning,
MEWDS.
See Multiple
compression
imaging
in, 213,
ERG
in, 95, 96!
myopathies
mutations
associated
cystoid,
blue-cone,
focal ERG
in,
Monocular
holes
ERG in, 44
in, 20, 43-44,

registration,
43!
in PERG,
YEP, 241
PERG
MPGN
(membranoproliferative
in, 214
nephritis),
YEP in, 246

MS-222
focal ERG in, 180
Malignant
PERG
choroidal,
nonorganic
EGG
in, 169
visual loss and
in ERG,
sequence)
ERG
in, 36
1,2-6
in methanol
toxicity,
choroiditis
95
(pseudo-presumed
histoplasmosis
255!
by (hyperosmolarity-
response),
by, 97
YEP, 241
Mucopolysaccharidoses,
Multifocal
EGG affected
induced
acid methane-
ERG affected
Mlillercells
in, 226-227
YEP in, 254-256,

Mannitol,
mem-
2051
glomerulo-
(ethyl-m-aminobenzoic
for multifocal
of Bruch's
EGG in, 164
melanoma,
Malingering,
178
203-204,
in, 164-165
M-sequence
(maximum-Ien~th
for multifocal
ERG, 182
YEP in, 246
brane),
EGG
sulfonate),
in, 213
(drusen
50
ERG in, 44
Motion
for focal ERG,
YEP in, 253
phenomenon,
cone (atypical),
rod, ERG
Leventinese
110
with,
focal ERG in, 181
Malattia
white-dot
Monochromats
in, 210-213,214-215!
Maculopathy
diabetic, PERG
value of YEP
evanescent
syndrome,
Mizuo-Nakamura
ERG in, 187
prognostic
ERG in, 105-106
DNA
in Kearns-Sayre
autotluorescence
edema, aphakic
Maculoscope,
caused by,
syndrome
YEP in, 257-258
Mitochondrial
180
Macular
in,263
disorders,
Migraine,
ERG in, 54-56,56!
PERG
in infants,
Metabolic
54/, 55/, 56!
focal ERG in, 180
Macular
chiasmal
Meningitis,
in, 59-60
215!
multifocal
in, 169
YEP in, 257
ERG in, 58-59
fundus
EGG
glomerulonephritis
(MPGN),
EGG in, 164-165
62/, 63/, 64!
58-59, 58!
in, 164
ERG
choroidal,
See Thioridazine
in, 59
progressive
YEP, 241
opacities
focal ERG and, 182
Best, 56-58,57!
EGG in, 163
North
(m-sequence)
ERG and, 27,102
ERG,54-65
PERG in, 210-213
hereditary,
sequence
ERG, 182
157,162-163
Multifocal
ERG,
in inner retinal
normal
syndrome),
177,182-190,
disorders,
ocular
ERG
in, 83
191/, 192
190, 191/
values for, 185
in outer retinal
disorders,
185-189,
186/, 188!
301
Index
recording
stimulus
procedure
Multifocal
white-dot
(MEWDS),
78-80,
in, 78-80, 82/
Neurologic
syndrome
Neuronal
Mylar
ceroid
Newborn,
in, 100
dystrophy,
electrode,
Myopathies,
Night
for ERG,
13
YEP in, 253
in, 169
in, 116
Myotonic
congenital
EGG
46}; 48!
in, 166
ERG
in, 45-47,46};
ERG
PERG
N35 component,
ofPERG,
See also Pattern

N75 component,
242, 24:if See also
Visual evoked
See also Pattern
check size affecting,
NP-207,
potential
ofPERG,
NR2E3
198-199,198!
electroretinogram
199-200
204
in optic atrophy,
219-221
216-218,
217],
N135 component,
Naka-Rushton-type
Negative-ne~ative
of VEP, 242, 24:if See also

potential
function,
19
focal ERG and, 181
Neuritis
optic/retrobulbar,
VEP in, 246-247
PERG
in, 216-218,
Oguchi
2171
(d-wave)
duration
in, 83
(OHT),
disorders,
PERG
in children,
of ERG,
affecting,
in, 221-226
YEP in, 262
5,5!
24
disease, 50
EOG
in, 166
ERG
in, 50
OHT
28,291
ERG
hypertension
stimulus
Negative-positive
ERG, 28,291
Neovascular
inflammatory
vitreoretinopathy,
autosomal dominant (ADNIV),
ERG
in,73
Neovascularization,
YEP in, 262
in, 75
Off-response
199, 1991
ratio, 199
ERG,
S-cone syndrome
YEP in, 248-249
in children,
Oculomotor
and, 199-200
Visual evoked
night
histoplasmosis
ERG
Ocular
rate affecting,
stationary
in enhanced
pseudo-presumed,
2181
origins of, 206-207
amplitude
type of congenital
receptor,
Ocular
219
in optic nerve demyelination,
stimulus
59,601
in optic nerve compression,
spatial frequency
dystrophy,
blindness, 45,47
ERG affected by, 93
Nystagmus,
miosis affecting,
255!
macular
120
Nutritional
amblyopia,
222-224
by, 27-28
in, 59
Nougaret
electroretinogram
ofVEP,
N95 component,
N95:P50
48!
visual loss
Carolina
ERG
198-199,198!
45-47,
in, 226-227
YEP in, 254-256,

North
111!
in, 208,210-211/
Nonorganic
ERG in, 106
in, 105
in glaucoma,
stationary,
Nitrous oxide, ERG affected

Nivaguine.
See Chloroquine
dystrophy,
Myxedema,
110-111,
111/
ERG in, 25, 26!
PERG
ERG
prognostic
lipofuscinoses,
blindness,
ERG in, 106-107
mitochondrial,
Myopia
EGG
in infants,
ERG in, 110-111,
YEP in, 247-249,249/

Muscular
disorders,
value of YEP in, 263
80!, 81!, 82/
sclerosis
ERG
type 1, optic nerve gliomas
in, YEP in, 262
evanescent
Multiple
disease, YEP in, 254
Neurofibromarosis
YEP, 241
Multiple
ERG
Neurodegenerarive
for, 183
for, 182
(ocular
hypertension),
PERG
in, 221-226
Olivopontocerebellar
atrophy (retinal degeneration with spinocerebellar
ataxia), ERG
in, 112-114,
11~
113!
302
Index
Open-angle
glaucoma,
primary
(POAG).
See
toxic, YEP in, 251-252
Glaucoma
Operating
traumatic,
room monitoring,
OPs. See Oscillatory
YEP for, 253-254
potentials
atrophy,
in, 219-221,222-223/
at, in albinism,
in congenital
YEP in, 257
Optic
disc, pallor of, in optic atrophy,
Optic
hypoplasia,
Optic
nerve
ERG
219, 223/
in diabetic
in, 101
of
in hepatic
in, 219,220/
in children
contributions
from, in multifocal
demyelination
conduction
ERG,
velocity
with
affected
249/
PERG in, 216-218,217/,
by, 247-248,
218/
conditions,
dystrophy,
circulatory
107
disturbances,
variable-intensity
in X-Iinked
stimuli,
juvenile
PI component,
of, YEP in, 262
PII component,
PIll
of, YEP in, 262
nerve disease
of ERG,
of ERG,
P50 component,
ofPERG,
1,2!
198-199,198/
electroretinogram
ERG in, 100-102
in optic atrophy,
focal ERG in, 180
in optic nerve compression,
PERG
in optic nerve demyelination,
in, 206,207,214-221
Optic
neuritis
PERG
in, 216-218,217/
YEP in, 246-247

Optic neuropathy
dysthyroid,
YEP in, 250
hereditary,
YEP in, 252
ischemic
PERG
in, 221
YEP in, 250-251

Leber
hereditary
PERG
in, 221
in, 219-221
YEP in, 252-253
219
219
216-218,217!,
218!
origins of, 206-207
spatial frequency
and, 199-200
stimulus
check size affecting,
stimulus
rate affecting,
P100 component,
YEP in, 252-253
inflammatory,
71
of ERG,
See also Pattern
nerve head, drusen of, PERG
85, 86, 89!
18, 19!
retinoschisis,
component,
in, 168
Optic
105-106
75, 77!
YEP in, 246-249

hypoplasia
in retinal
of
104
ERG and, 183
in muscular
190
103
affecting,
failure/encephalopathy,
multifocal
262
47
17, 17!
180
in inflammatory
with optic nerve glioma,
blindness,
stimulus,
retinopathy,
photocoagulation
78
night
YEP in, 249-250
EOG
stationary
in focal ERG,
compression
Optic
gene, in gyrate
66
in birds hot retinochoroidopathy,

of, YEP in, 257
misrouting
gliomas
of, YEP in, 257
Oscillatory
potentials (OPs), 8-9,9!
in Behget disease, 83
chiasm
compression
PERG
dysfunction
eye disease, ERG in, 107
Ornithine-8-aminotransferase
YEP in, 252

Optic
YEP in, 251
radiations,
Oregon
Optic atrophy
ERG in, 101
PERG
Optic
ofVEP,
Visual evoked
199-200
199, 199!
242, 24lf
See also
potential
age affecting, 244, 244!

in optic neuritis, 246-247
pupil
size affecting,
Papaverine,
243-244,
ERG affected
Paradoxicallateralization,
Parkinson
ofVEP,
disease, ERG
256-257
in, 106
Patient
preparation,
Pattern
appearance-disappearance
VEP, 240
243!
by, 25
for VEP recording,
264, 265!
stimuli,
for
303
Index
Pattern
dystrophies,
EOG
58-59,
581
Photomyoclonic
in, 164
ERG in, .)8-59

Pattern
electroretinogram
age affecting,
electrodes
(PERG),
197-235
historical
in ERG,
221-226
background
of, 197
in focal rod ERG,
in macular
dysfunction,
visual loss and, 226-227
waveform
207-214
Photoreceptor
determinants
and, 198-201
1981
in optic nerve disease, 214-221
origins
pupil
204
recording,
recording
201-204, 201/
electrodes for, 201-202,
reference
electrode
reliability
of, 204-206
affecting,
contrast
affecting,
field size affecting,
stimulus
rate affecting,
202
onset-offset
Pituitary
Plaquenil.
for, 202-204,
2051
POAG
for YEP, 240, 242, 242/

(PSR), 206-207
202
YEP
See Pattern
Perimetry,
PERG
gene, in retinitis
open-angle
161
early receptor,
7-8, 8!
8-9, 9!
1,2/
158
237-279
(pseudo-presumed
sis syndrome),
185
ERG affected
Prematurity,
retinopathy
Primary
open-angle
coma
ocular histoplasmo-
ERG
Prednisone,
pigmentosa,
of, ERG in, 25-26
glaucoma
Procollagen
II gene, in Stickler
Progressive
bifocal
(photopic
Photocoagulation,
affected
negative
response),
for diabetic
bv. 103-104
6-7
retinopathy,
(POAG).
See Glau-
See Tolazoline
in, 59-60
ERG
in, 83
by, 105
Priscoline.
in, 105
See
See a/so specific type
corneoretinal,
259
1881
glaucoma).
and, 213
ERG
caused
Glaucoma
P-POHS
with,
185-187,186/,
compression
35
Pheochromocytoma,
PhNR
in infants,
ERG compared
pigmentosa,
Peripherin/RDS
261/
electroretinogram
multifocal
in retinitis
chiasmal
visual evoked,
for visual acuity estimation

PERG.
(primary
receptor,
standing,
260-261,
atrophy,
See Cisplatin
for YEp, 240, 242.1:
detection,
retinochoroidal
See Hydroxychloroquine
Platinol.
oscillatory,
for amblyopia
in Ref sum disease,
by, YEP in, 257
for YEP, 240, 264

Pattern
178
tumors,
Potentials.
response
Grass, 11
paravenous
200-201
243
Pattern-specific
Pattern stimuli
See a/so
120-122, 12~ 123!

ERG in, 120-122, 123f
226, 237
stimuli,
diffuse.
acid accumulation,
Pigmented
199, 1991
stimuli,
Pattern-reversal
for PERG,
in, 29-30
Phytanic
200, 2001
and equipment
YEP and, 197,203,
EOG
ERG
for focal ERG,
216,218/
stimulus
Pattern
dystrophies,
36
in optic demyelination,
techniques
180
179
specific type
in, 165
Photostimulator,
201/
spatial frequency and, 199-200

stimulus check size affecting, 199-200
stimulus
6-7
Photoreceptor-specific
ATP-binding
transporter
protein (ABCR) gene, in Stargardt macular dystrophy, 56,213
of, 206-207
size affecting,
(PhNR),
2-6
in focal cone ERG,
nonorganic
normal,
18
Photopic negative response

Photoreceptor
cells
204
for, 201-202,201/
in glaucoma,
reflex,
Photopic ERG, 14-23, 15/, 16!

in retinal disorders, 28-29, 29!
chorioretinal
syndrome,
atrophy,
73
ERG
304
Index
Prolactin-secreting
adenomas,
pression
during
chiasmal
pregnancy
com-
Refractive
caused by,
YEP in, 257

Protan defect,
Protanomaly,
Resochin.
ERG in, 44-45
ocular histoplasmosis
drome (P-POHS),
Pseudotumor
cerebri
Pupil
intracranial
response),
(Takayasu)
fleck,
Retinal
EOG
YEP in, 250
PSR (pattern-specific
Pulseless
syn-
ERG in, 83
(idiopathic
hypertension),
206-207
Retinal
disease, ERG in, 84
Retinal
Pyridoxal
ERG affected
phosphate,
243/
degeneration
with
66
Retinal
spinocerebellar
in, 112-114,
protein,
11~
113/
cellular
gene for, in retinitis
pigmentosa,
for gyrate atrophy,
by, 25
and, 84-88
(CRaIBP),
and, 243-244,
EOG
Q
Quinine,
85/
circulation,
Retinaldehyde-binding
and, 204
in, 53,53/
in, 162
ataxia, ERG
ERG and, 25
by,
artery occlusion
deficiencies
size
PERG
stage of, ERG affected
25-26, 26/
of Kandori, ERG
ERG in, 85-88,
EOG and, 158, 159-160
YEP latency
See Chloroquine
developmental
ERG in, 20, 44-45
Pseudo-presumed
by, 27
Retina
ERG in, 20,44-45
Protanopia,
error, ERG affected
Ref sum disease, ERG in, 35, 36
35
detachment
in, 168
ERG in, 104

ERG affected
by, 93-95,
94!
multifocal
ERG in, 187-189
in Wagner disease, 72
R
Retinal
Rl component,
of early receptor
Rz component,
of early receptor
Rab geranylgeranyl
transferase
deremia,67
Reattachment
surgery, multifocal
potential,
7, 7!
potential,
7, 7!
gene, in choroi-
for ERG,
11-12,12-14
for focal ERG,

for multifocal
for PERG,
electrode
for ERG,
for PERG,
190, 191/
disorders,
185-189,
11-12
202
associated
with,
186/, 188/
189
in, 208-214
guanylate
Leber
183
color deficiency,
Reference
disorders,
outer retinal
Retinal
201-202,201/
44-45
ERG in
inner retinal
PERG
in cancer-associated
Red-green
29/
YEP in, 246
for YEP, 237, 264, 265!

Recoverin,
ERG in, 28-29,
focal cone ERG in, 180-182,181/
178
ERG,
See a/so specific type
in, 163
problems
Receptor potential,
1,2/
Recording electrodes
158, 158!
disorders.
multifocal
ERG after,
187-189
for EGG,
EOG
retinopathy,
congenital,
118
ERG in,
cyclase (RetGC)
congenital
Retinal
pigmentary
Retinal
pigment
degeneration,
epithelium
in EOG,
161-162
in ERG,
2-6
macroreticular
Retinal
pigment
dystrophy
Retinal
S-antigen
in birdshot
in Oguchi
of, ERG in, 58-59

protein
amaurosis,
pigmentosa,
39
unilateral,
(RPE)
epithelium
gene
in Leber congenital
in retinitis
gene, in
amaurosis,
(RPE65)
39
35
(arrestin)
disease, 50
78
,?7
Index
Retinal
vein occlusion,
Retinitis
pigmentosa
ERG
87!
31], 341;
31,32/
recessive,
in, 181
multifocal
ERG
abnormalities
in,
ERG in, 88
of prematurity,
34-35
form of, 33
EGG
in, 165
ERG
in, 30-35,31],
venous
stasis, ERG in, 84
familial
X-linked
185-187,186],
(simplex)
multifocal
PERG
PERG
X-Iinked
Retinitis
30,31,31],
atrophy,
pigmented
birdshot,
EGG
in, 37
paravenous,
dehydrogenase
retinitis
pigtnentosa,
Retinopathy
acute zonal occult
night
76-78,
78], 79!
diabetic
in, 169
ERG in, 102-104
PERG
in, 208, 209/

focal, 179
RP2/RP3
affecting,
35
in
RPE65
Rubella
ERG
43/
pigment
epithelium
gene
in Leber
RPGR
ERG in, 43-44,
pigmentosa
genes, 35
RPE. See Retinal
outer, 80-83
in, 180
in, 213
and angle-closure
36
Rod ERG,
RP. See Retinitis
gene, in fundus
30-39. See also specific type
nanophthalmos
in retinitis
serous
YEP in, 246
dystrophies,
glaucoma,
in, 80-83
cancer-associated,
EGG
stationary
ERG in, 30-39

with
by, 100
albipunctarns,51
metabolism,
mutations
PERG
47
35
in, 165
Rod monochromats,
ERG affected
focal ERG
night blindness,
pigq1entosa,
217/..
in, 166
Rod-cone
34
ERG
in, 208,212/
central
in, 216-218,
blindness
EGG
albescens,
Retinochoroidopathy,
ERG in, 76-78,79!
ERG
PERG
Riggs type of congenital

37-38,38!
120-122, 1241; 123!

in, 120-122, 123!
ll-cis-Retinol
neuritis,
ERG in, 46
recessive,
Retinoids,
in, 208
in retinitis
188!
36--37
punctata
PERG
69-72,70/
70/
Rhodopsin gene
in congenital stationary
37
Retinochoroidal
Retinol
35
in, 208,209!
unilateral,
ERG
syndrome),
form of, 31-32
sector (asymmetric),
77/
72
juvenile,
Retrobulbar
ERG in, 185-187,186],
sine pigmento,
foveal,
ERG in, 69-72,
188!
pattern, 208, 209!

focal ERG in, 180
isolated
in, 75-76,76/,
Retinoschisis
341; 33!
loss (Usher
in, 25-26
ERG
focal, 180
with hearing
ERG
rubella,
in carriers, 34
multifocal,
in, 189-190
in, 213
hypertensive
EOG in, 166
31-32
chromosomal/molecular
delimited
focal ERG
PERG
33!
autosomal dominant,
autosomal
in, 85-88,86],
(RP), 30-35,30],
305
congenital
amaurosis,
pigmentosa,
gene, in retinitis
retinopathy,
39
39
pigmentosa,
ERG
in, 75-76,
35
76/, 77/
in, 118-120
s
Salmon-patch choroidopathy (birdshot retinochoroidopathy), 76-78, 78}; 79!
ERG in, 76-78, 79!
PERG in, 208, 212/
306
Index
Sanfilippo
syndrome,
S-antigen
(arrestin),
in birdshot
ERG in, 36
retinal
in Oguchi
station.
blindness
S-cone
fundus
response
component,
(STR),
PERG
in multi focal ERG,
disease and, 190
for YEP testing
ERG affected
by, 27
dystrophies,
ERG
in, 84
116!
by, 99
for retinal
affected
by, 168-169
ERG affected
by, 104-105
reticular
detachment
for ERG,
Slow PIII,
ERG
in, 58-59
syndrome
(hereditary
for EOG,
intensity
for ERG,
11
ERG responses. See also

flicker
photoreceptor
responses
dystrophies,
in, 106
arthro-ophthalfor focal ERG,
178
constant-intensity,
17-18, 17/
different wavelengths
(colors) and, 20,21/
and, 23-24
full-field,
24
modification
of, for focal ERG,
29-30
181!
178
and, 24, 24-25

21-23, 22j; 23/
variable-intensity,
18-20, 18/, 19/, 20/
for focal ERG, 177, 177-178
for multifocal
ERG,
182
for PERG
check size and spatial frequency
visual acuity
and, 208
ERG
of, 160
variable-frequency,
focal ERG and, 180-181,

PERG
dystrophy,
Stickler
13
Thirty(30)-Hz
Snellen
YEP, 241
myotonic
interval
1, 2/
in diffuse
45-53.
48/
Steinert
158, 158!
Small-amplitude
in,
in, 208,210-211/
duration
dystrophy,
Skin electrode
for EOG,
ERG
Stimuli
ERG affected
oil injection,
disorders,
mopathy),73
Stimulator-ophthalmoscope,
for YEP, 237
Sjogren's
night-blinding
Steady-state
in, 169
ERG in, 115-116,
EGG
disorders,
ERG in, 45-47,46/,
64-65
Signal averaging
for PERG, 202-203
Silicone
in, 213,215/
214-215/
cone dysfunction
PERG
cell retinopathy,
Sildenafil,
imaging
congenital
EOG in, 166
gas
Siderosis
EGG
flavimacu-
56/
in, 210-213,
Stationary
266-267
ERG in, 65
Sickle
(fundus
54/, 55/, 56/
ERG in, 187
Stationary
in children,
SF6. See Sulfurhexafluoride

Sheen retinal
19-20, 20/
43-45
inner retinal
Sex (gender),
dystrophy
autofluorescence
multifocal
183
Sedation,
YEP in, 254
focal ERG in, 180
Scotopic ERG, 14-23, 15/, 16!

in retinal disorders, 28-29, 29!
threshold
macular
latus), 54-56,
EOG in, 163
degeneration,
112j; 113/
degeneration,
ERG in, 54-56,
ERG in, 189
Second-order
Spinocerebellar
Stargardt
of (enhanced
syndrome),
120, 120/, 121!
ERG in, 120, 121!
Scotopic
disease, ERG in, 110-111
S/R (stimulus/response)
function,
Standing potential,
158
ERG in, 45, 46/, 47

S cones, hypersensitivity
in, 208
ataxia with retinal
ERG in, 112-114,
in, 166
multifocal
199-200
in, 36
type of congenital
ary night
PERG
of PERG,
Spinocerebellar
ERG
Schubert-Bornschein
dystrophy,
Spatial tuning,
Spielmeyer-Yogt
disease, 50
Scheie syndrome,
EGG
78
Sorsby fundus
and,
199-200
contrast and, 200, 200/
in ontic nerve demvelination.
216.218{
Index
field
size and, 200-201
307
interrupted,
203
rate and, 199, 1991
Unilateral
retinal
pigmentary
Usher syndrome,
degeneration,
37
ERG in, 35
for YEP, 237,240-241

for adults,
264, 2661
for children,
267
Vasodilator
latency and, 244-245

luminance contamination
therapy,
ERG affected
Venous stasis retinopathy,

and, 164
VEP. See Visual evoked
Stimulus/response
(S/R) function,
19-20, 201
STR (scotopic threshold response), 6
Viagra. See Sildenafil
Sulfurhexafluoride
Visual acuity, in infant,
(SF6) gas, intravitreal,
retinal
detachment,
for
ERG affected
by,
104-105
Surface-recorded
YEp, 240
Taurine
PERG
reflex,
in retinitis
deficiency,
Tay-Sachs
ERG
Thiopental,
pigmentosa,
34
in, 117
disease (infantile
idiocy),
amaurotic
ERG affected
familial
by, 28
in retinitis
night
Thorazine.
conditions,
diseasc, ERG in, 105

EOG
Tolazoline,
Toxic
75, 771
affected
beat response
assessment
of cortical
in, 241
binocularity
and,
significance
of,
electrodes
by, 25
See also specific agent
flash, 240-241, 24~ 243, 245-246

in media opacities, 245-246
for operating
room monitoring,
in functional
disorders,
254-256,
hemifield,
256
in hereditary optic neuropathies,
ERG
in, 88-99
instrumentation
for, 264
in media opacities, 245-246
Transient
in, 75
motion,241
YEP, 240-241
in children,
Traumatic
ERG
in ERG,
266,267
optic neuropathies,
253
in inflammatory
YEP in, 251-252
YEP in, 251
246-249
for, 237, 264, 2651
in, 167-168
Transducin,
249-250
optic neuropathies,
EGG
Toxoplasmosis,
237-279
neurologic
disease, 263
in traumatic optic neuropathies,
by, 157
ERG affected
conditions.
of, VEP in, 257

(VEP),
250-251
prognostic
See Chlorpromazine
Thyroid
47,
29-30
34
Timolol,
potential
in demyelinative
blindness,
dystrophies,
pigmentosa,
dysfunction
Visual evoked
237-238
in compressive optic neuropathies,
Thirty(30)-Hz
flicker responses
in cone dystrophies,
60, 6~ 631
in inflammatory
Visual cortex,
protocol for, 266-267

clinical versus statistical
degenerative
changes caused by, 91,92!
ERG affected by, 91-93
481
in diffuse photoreceptor
181/
261-262
in children, 258-263
Thioridazine
stationary
of,
2601
and, 208
binocular
ERG in, 100,114
in congenital
by, 98
VEP in estimation
age affecting, 244, 244}; 258-259, 2591

in anterior ischemic optic neuropathies,
disease, ERG in, 84
Tapetal-Iike
ERG affected
259-260,
Visual acuity loss
by, 25
in, 84
potential
focal ERG and, 180-181,
Sweep YEP, 241

in children, 2.')9, 26()j
'I'akayasu
Vigabatrin,
ERG
251
2551
252-253
optic neuropathies,
252
308
Index
Visual evoked
potential
(conI.)
in operating
Vitamin
diseases, 254
room monitoring,
in optic chiasm/optic
disorders,
Vitelliform
253-254
radiation/visual
EOG
cortex
preparation
detection,
PERG
260-261,
estimation
261/
in infants,
guidelines
prognostic
autosomal
259
neurologic
pediatric
surface-recorded,
24~
243/,
74-75
72
73
retinoschisis,
in, 69-72,
PERG
in, 208
69-72,
70!
70!
autosomal
dominant
73-74,74!
neovascular
inflamma-
tory, ERG in, 73

251-252
familial
exudative,
in retinal
Vitreous
optic neuropathies,
ERG in, 74-75
circulatory
opacities,
disturbances,
86, 89!
ERG and, 27,102
2.11
w
in VEP, 239, 2391

affected
Wagner
X,V
Xenon-arc
in, 226-227
VEP in, 254-256,

Visual maturation,
X-Iinked
2551
delayed,
VEP in, 262
mutations
ERG
PERG
deficiencyof,
ERG in, 99-100,

affecting
pigmentosa,
disease,
72-73
by, 200-201
Visual loss, nonorganic
Vitamin
juvenile
ERG
259, 2601
size of, PERG
Vitamin
inflamma-
73
syndrome,
Vitreoretinopathy
autosomal dominant
Visual field
PERG
vitreoretinochoroidopa-
(ADVIRC),
ERG in, 74, 74!
for, 237, 240-241
240
in toxic optic neuropathies,
central,
dominant
Vitreoretinochoroidopathy,
transient,240-241
in children, 266, 267
in traumatic
69-75.
neovascular
syndrome,
X-Iinked
266-267
for, 242-245,
sweep, 241
in children,
disorders,
dominant
Wagner disease, 72-73
244/, 2451
in retinal diseases, 246
steady-state,241
stimulus parameters
Stickler
2661
retino-
79!
Goldmann-Favre
protocol,
57!
78/, 79!
thy, 73-74,74!
exudative vitreoretinopathy,
familial
disease, 263
response parameters
(birdshot
76-78,
tory vitreoretinopathy,
autosomal
recording procedure for, 264-267,265/,

adult protocol, 264-266, 2661
Best, 56-58,
in, 208, 212/
for use of, 264-267
dystrophy,
chorioretinitis
.choroidopathy),
ERG in, 76-78,
and, 197, 203, 226,237
practical
amblyopia
ERG in, 56-58
for, 264, 2651
for visual acuity

PERG
macular
Vitreoretinal
pattern
for amblyopia
deficiency,
in, 163
Vitiliginous
256-258
origins of, 239-240, 2391

paradoxicallateralization
and, 256-257
patient
B complex
caused by, VEP in, 248-249
multifocal,241
in neurodegenerative
metabolism
XLRSl
of, in retinitis
66
11
retinoschisis,
in, 69-72,
69-72,
70!
70!
in, 208
gene, in X-Iinked
juvenile
retinoschisis,
71-72
x-wave,
35
B6, for gyrate atrophy,
101/
photostimulator,
juvenile
of ERG,
in congenital
20, 21!
red-green
color deficiency,
45
z
Zonal occult outer retinopathy, acute, 80-83
ERG in, 80-83

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in Disorders of the Retina, Optic Nerve,

and Visual Pathway

H. Sprague Eustis, MD, Chair

P.O. Box 7424

CLINICAL EDUCATION SECRETARIES

CLINICAL EDUCATION STAFF

Kathryn A. Hecht, EdD

Secretary for Continuing Education

Eachauthorstates that he has no significantfinancial

Referenceto certain drugs, instruments, and other products in

the Retina, Optic Nerve, and Visual

plans for updating

who use LEO

may select to form individualized,

to earn the LEO

Copyright @ 2001 Gerald Allen Fishman,

,ibrary of Congress Cataloging-in-Publication

Gerald Allen Fishman, MD

Components and Origins of the ERG 2

a-, b-, and c-Wavesand Off-Responses2

Measurement of the ERGComponents 10

The ERG Under Light- and Dark-Adapted Conditions 14

Other Factors Affecting the ERG 23

The ERG in Retinal Disorders 28

Diffuse Photoreceptor Dystrophies 29

Stationary Cone Dysfunction Disorders 43

1-10 Stationary Night-Blinding Disorders 45

1-16-4 Centraland BranchArtery and VeinOcclusions 85

4-3-2 Optic Nerve Disease 214

THE VISUAL EVOKED POTENTIAL

Origins of the VEP 239

VEP Stimulus Parameters 240

VEP Response Parameters 242

Clinical Use of the VEP in Adults 245

Clinical Use of the VEP in Children 258

Practical Guidelines 264

Estimationof VisualAcuityin Infants 259

troretinogram (ERG) is the record of a diffuse electrical response generated by neural

ions, principally sodium and potassium, in

ponents in the cat. The PI, PII, and PIll

gren, who initially misinterpreted

of the ERG. An initial

of the ERG are now conven-

Subsequently, the PIll component was

the receptor potential or

negative deflection was designated by the

nent, normally greater in amplitude, was

Ragnar Granit,5 working

Slow Pill potential

Figure 1-1 (A) ERG a- and b-wave response to lO-ms

human eye. Also illustrated

COMPONENTSAND ORIGINS OF THE ERG

dashed-curve fit of receptor model, which provides

to ERG. Note that

peak a-wave amplitude does not represent peak recep-

1.1.1 a., b-, and c-Waves and Off-Responses

tor response, because rod a-wave of human ERG to

origin. (B) ERG a-, b-, and c-wave response to 4-s

whose origins are Muller

The site of origin of the ERG components

cells and retinal pigment epithelium, respectively.

cone or rod retinas of

2. Chemical destruction, with toxins known

ual cell layers