Electrophysiologic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway (Ophthalmology Monographs)

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

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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,

which

continuing

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clinical

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Copyright @ 2001 Gerald Allen Fishman, U sed by permission. Copyright @ 1990 American All rights reserved.

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of Ophthalmology

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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

5 4

in Singapore

3 2

1

Contents

Preface

Xttt

Acknowledgments Chapter 1

XV!

THE ELECTRORETINOGRAM

1

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

v

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

x

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 Suggested Readings 235

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 Suggested Readings 278

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

2

The Electroretinogram

B

A

Pigmentepithelialpotential b c

Time a

-#

Slow Pill potential

0

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

3

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

4

The Electroretinogram

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-

d

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.

5

6

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

7

8

The Electroretinogram

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

A

of the ERG

9

White-Iightstimulus

0: O in > '6

0: O ij) >

~

~

~ 0

C) "' "'

L{) N

B

Rod OPs

Cone OPs

2 0= O u; .> '6 > "LO "'

c o v; > '6

'f.. "" N

0

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.

...

0

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

The Electroretinogram

B

A

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

The Electroretinogram

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

The Electroretinogram

B

c: O in > '6

0 §

~ 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

1-5 The ERG Under Light- and Dark-Adapted

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

The Electroretinogram

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

The Electroretinogram

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

1-5 The ERG Under Light- and Dark-Adapted

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

The Electroretinogram

~ 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

B

A

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

TheElectroretinogram

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

The Electroretinogram

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 Electroretinogram

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

TheElectroretinogram

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

The Electroretinogram

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

TheElectroretinogram

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

The Electroretinogram

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

TheElectroretinogram

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.

Figure 1-22 ERG recordingfrom

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

The Electroretinogram

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

The Electroretinogram

B

c o in > :0 --~ o o :j.

0) "1::) ~ "5. E <

0

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

The Electroretinogram

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.2°4 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

TheElectroretinogram

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 have been identified 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

The Electroretinogram

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 have been identified 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

The Electroretinogram

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

The Electroretinogram

Figure 1-34 ERG recordingfrom

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

TheElectroretinogram

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 ) have been identified 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.3°o 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.3°1,3o2 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.3°6 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.3°4 A subsequent report of this family by Frank et al3°7 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

TheElectroretinogram

Figure 1-37 Macular lesion in patient with 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 lesion in patient with cone dystrophy.

1-11

Hereditary

Macular

63

Dystrophies

A

Cone dystrophy

Normal

patients

Patient3

Patient 2

Patient 1

30-Hz

c o .00 .> '0 :---

white

flicker

~

8f-

Photopic b b

I~ a

40

0

a

a

80

120

0

40

80

120

80

0 40 Time (ms)

120

40

0

80

120

Normal

b

b ~ o .c;; .> :0 --> ='0 0 ~ 0) -0 E -0. E <.:

a a

b

b

b

Scotopic

b

white

flash

a a

a

0

40

80

120

160

0

40

80

120

160

0

40

80

120

160

0

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

TheElectroretinogram

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

The Electroretinogram

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

Figure 1-44 Extensive atrophy of RPE and choroid in patient with choroideremia. Eventually, even more extensive atrophy of choroid occurs in such patients.

68

The Electroretinogram

Figure 1-45 ERG record-

A

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 <

0

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

TheElectroretinogram

Figure 1-46 F oveal microcystic changes as characteristically seen in patient with X -linked juvenile retinoschisis.

Figure 1-47 ERG record-

A

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

The Electroretinogram

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

The Electroretinogram

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.4°4

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.4°s However, Cantrill et a14°6noted 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.4°3 Intuitively, ERG amplitudes would be markedly reduced or even nondetectable as reti-

detached

INFLAMMATORY CONDITIONS

1-49). However,

76

TheElectroretinogram

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).4°7 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

A

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

TheElectroretinogram

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.

B

Birdshotretinochoroidopathy patient

Normal

Scotopic blue flash

b

c o "U; "> '0

~ 0 ~ 0> "0

a

E -0. E <

b

Scotopic white flash

~

a 0

a 40

80

120

160

O Time

(ms)

40

80

120

160

79

80

The Electroretinogram

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

Figure 1-53 Patient with 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

A

120

75 I=F:::::

105

~ 35 V4c

60 ~

11/(

of patient with enlarged blind spot syndrome

\

from (A) affected right eye and (B) unaffected

v

165L /

x

r--"'

left eye. 15

180

195

\/~\ ,~

I

xx

2'0\

330

22~

-2~~-..~,~~,.-

Conditions

Figure 1.54 Visual fields

"' 45

1"-

I nflammatory

81

82

TheElectroretinogram

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.

A

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,

a

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

a

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

a

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

a

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 Electroretinogram

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

The Electroretinogram

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

A

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

The Electroretinogram

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

The Electroretinogram

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

The Electroretinogram

Figure 1-61 Extensive atrophy of RPE and choroid in patient with 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 a148°in 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

The Electroretinogram

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.

A

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 ."

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80

120

(ms;

B

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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

The Electroretinogram

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 Ethyl-m-aminobenzoic 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

The Electroretinogram

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

The Electroretinogram

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-

A

Figure 1-65 ERG responsesfrom patient with systemic vitamin A deficiency before and 1 week after high-dose oral vitamin

0: O ";;; > :0 --> ::!. o o ~ 0) -0 ~ -0. E ""'

A supple-

mentation. Note improvement in ERG amplitudes under both (A) photopic and (B) scotopic conditions.

0

40

80

120

40

0

80 120 Time(ms)

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80

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(ms)

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101

40

80

120

160

102

TheElectroretinogram

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

The Electroretinogram

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

The Electroretinogram

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

The Electroretinogram

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

A

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

0

80

120

80

40

O

120

Time (ms)

B Normal

Kearns-Sayre syndrome patient

b

Scotopic

blue

flash

? o in .> '0 --::;.. o

~'

~~-.

~ ~ -~~ ~a

o ~ 0)

b

"0 ~ -0. E
Scotopic white flash-

~ -a

a

0

40

80

120

160

O Time

(ms)

40

80

120

160

109

110

The Electroretinogram

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-

Figure 1-68 Patient with 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

The Electroretinogram

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.6°o 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

A

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

0

40

80

120

O Time

B

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 examination6°1 or show only subtle

c o .c;; .> '6

Miscellaneous

(ms)

40

80

120

114

The Electroretinogram

still normal.6°l 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.6°l,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.6°l,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.6°s 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 a16°6reported 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,6°7 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.6°B 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

TheElectroretinogram

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

TheElectroretinogram

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

b

a

a

0

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

A

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

The Electroretinogram

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

Figure 1-77 Patient with 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

A

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

B

-c: o c;; '> '0 >

atrophy

shown in Figure 1-77.

stimulus.

124

The Electroretinogram

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. 9. Kline RP, Ripps H, Dowling ]E: Generation of b-wave currents in the skate retina. Proc Natl A cad Sci USA 1978;75:5727-5731. 10. Newman EA, Odette LL: Model of electroretinogram b-wave generation: a test of the K+ hypothesis. J NeuropliysioI1984;51:164-182.

foreign body. For the ERG to provide reliable information, it is vital for each investi-

11. Ripps H, Witkovsky P: Neuron-glia interaction in the brain and retina. In: Osborne NN, Chader G], eds: Progressin Retinal Research. Elmsford, NY: Pergamon Press;1985;4:181-219.

gator to comprehensively establish a normative database and to maintain both stimulus and background-Iight sources appropriately

12. Stockton RA, Slaughter MM: B-wave of the electroretinogram: a reflection of ON bipolar cell activity. J Gen PhysioI1989;93:101-122.

calibrated.

13. Karowski C], Proenza LM: Relationship between Milller cell responses: a local transretinal potential and potassium flux. J Neurophysiol 1977;40:244-259.

REFERENCES 1. Dewar J: The

physiologic

action of light.

Nature 1877;15:433-435. 2. Riggs LA: Continuous records of the electrical

and reproducible activity

of the human

retina. Proc Soc Exp Bioi Med 1941 ;48:204-207. 3. Karpe G: The basis of clinical

electroretinog-

raphy. Acta Ophthalmol1945(suppl

24):1-118.

4. Einthoven

W, Jolly W: The form and magni-

tude of the electrical stimulation

response of the eye to

by light at various

Exp PhysioI1908;1:373-416.

intensities.

QJ

14. Marmor MF, Lurie M: Light-induced electrical responses of the retinal pigment epithelium. In: Zinn KM, Marmor MF, eds: The Retinal Pigment Epithelium. Cambridge, MA: Harvard University Press; 1979:226-244. 15. Arden GB, Tansely K: The spectral sensitivity of the pure-cone retina of the grey squirrel. J Physiol (Lond) 1955;127:592-602. 16. Tomita T, Matsura T, Fujimoto M, et al: The electroretinographic c- and e-waves with special reference to the receptor potential. 16th ISCEV Symposium. Jpn J OphthalmoI1979:15-25. 17. Marmor MF, Hock PA: A practical method for c-wave recording in man. Doc Ophthalmol Proc Ser 1982;31:67-72.

125

References

18. Sieving

PA, Murayama

Push-pull

model

troretinogram: in shaping

K, Naarendorp

of the primate

a role for hyperpolarizing

the b-wave.

F:

photopic

30. Fran9ois

elecneurons

Vis Neurasci 1994; 11 :

Third

and kinetics

LJ: Response

of the cat retina:

component

linearity

the bipolar

of the dark-adapted

cell

LJ: Photoreceptor to the cat electroreti-

a kinetic

model

and

for the early part of the

flash response. J Opt Sac Am 1996;13:613-622. 21. Hood

DC, Birch DG: b-wave of the scotopic

(rod) electroretinogram of human

as a measure of the ac-

on-bipolar

cells. J Opt Sac Am

1996; 13:623-633. 22. Shiells bipolar,

RA, Falk G: Contribution

of rod, on-

cell light responses

retina.

to the

Vis Neurasci 1999;16:

[Analysis

K, Yonemura

of rapid off-response

gram major participation Nippan

D. Nakazato

H, et al:

in electroretino-

of receptor

potential.]

Ganka Gakkai Zasshi 1980;84:1574-1580.

24. Sieving

PA: Photopic

way abnormalities Am Ophthalmal

in retinal

and OFF-path-

dystrophies.

Trans

Sac 1993;91:701-773.

25. Nagata M: Studies of the human

ON-

ERG

retina. Jpn J Ophthalma/1963;7:

PA: Electrical

F oundations of Clinical phia: JB Lippincott;

27. Gills JP Jr: The electroretinogram

after sec-

tion of the optic nerve in man. Am J Ophthalmal

GP, Winkelman

JE: Effect

tion of the optic nerve on histological ation and electrical

activity

a study of centrifugal

Summation

of secdifferenti-

of the retina in dogs:

influences

on the ERG.

1969;157:293-300. JC, Tepas Dl,

of retinal

1980;51:877-886.

signals of the visual

Ophthalmology.

GP, Brownstein hereditary

noschisis:

histopathologic

findings

Philadel-

S, Wang NS, et al:

(juvenile

X-Iinked)

reti-

and ultrastructural

in three eyes. Arch Ophthalmol1986;

104:

576-583. 36. Murayama threshold

K, Kuo CY, Sieving

ERG

retinoschisis:

response

evidence

PA: Abnormal

in X-Iinked

juvenile

for a proximal

STR.

retinal

ori-

Clin VisSci 1991;6:

317-322.

mental

S, Frishman negative

electroretinogram: glaucoma.

LJ, Robson JG, response

of the

reduction

byexperi-

Invest Ophthalmol

38. Spileers

W, Falcao-Reis

The

ERG evoked

human

tor powered

1966;62:287-291.

Ophthalmalagica

re-

Vis Sci 1999;

40:1124-1136.

1958;60:295-302.

29. Armington

threshold

electroretinogram.

1996:1-15.

Congenital

26. Jacobson JH, Gestring

28. Horsten

C: Scotopic

In: Tasman W, Jaeger EA, eds: Duanes

macaque

Arch Ophthalmal

1978;15:297-301.

1989;4:373-377. 34. Sieving

et al: The photopic

ence on the electroretinogram.

GH, Oosterhuis

and the electroretinogram.

33. Aylward GW, Vaegan, Billson FA: The scotopic threshold response in man. Clin Vis Sci

37. Viswwanathan

influ-

of the

1964. Elms-

Vis Sci 1988;29:1608-1614.

96-124: GF: Centrifugal

H, eds:

Proceedings

of the human

Invest Ophthalmol

by pho-

Jacobson

RP, van Lith

gin of the human

on the photopic

HM,

Press; 1966: 191-202.

PA, Nino

sponse (STR)

35. Condon

503-511. 23. Kawasaki

32. Sieving

cortex.

and horizontal

ERG of dogfish

ford, NY: Pergamon

of ERG

destruction

Symposium,

Doc Ophthalmol ProcSer

bipolar nogram:

International

JA: Photocoagulation

20. Robson JG, Frishman cell contributions

In: Burian

31. Schuurmans

electroretino-

gram. Vis Neurasci 1995;12:837-850.

tivity

tocoagulation.

A: Behavior

retinal

Clinical Electroretinography.

519-532. 19. Robson JG, Frishman

J, de Rouck

and EOG in localized

Kropfl

potentials.

WJ, et al:

J Opt Sac Am

F, Smith

R, et al:

by a ganzfeld

red and green light emitting

stimuladiodes.

Clin VisSci 1993;8:21-39. 39. Brown tential

KT, Murakami

of the monkey

M: A new receptor

retina with no detectable

latency. Nature 1964;201:626-628.

po-

126

The Electroretinogram

40. Pak WL,

Cone RA: Isolation

tion of the initial tential.

51. Hirose

and identifica-

peak of the early receptor

retinoschisis

Nature 1965;204:836-838.

41. Goldstein

EB, Berson EL: Rod and cone

contributions

to the human

early receptor

PA, Fishman

to the human timated

poten-

GA: Rod contribution

early receptor

potential

tential

W, Topke

(ERP).

(ERP)

es-

the human

po-

1987;66:35-74.

HB: A new component

electroretinogram.

of

J Physiol (Lond)

D: The oscillatory

electroretinogram.

potential

of the

Acta Soc Ophthalmol Jpn 1963;

66:1566-1584. and potential

tion of disturbances

of retinal

OphthalmoI1981;25:237-252. 47. Peachey NS, Alexander

potentials:

flash effect.

an explanation

his-

use in the evaluacirculation.

Surv

KR, Fishman

GA:

to oscillatory

for the conditioning

48. Korol S, Leuenberger In vivo effects of glycine

Y, Kubota

PM, Englert on retinal

electroretinogram.

U, et al:

ultrastrucBrain

Res

1975;97:235-251. L: Further

studies

of the

chemical sensitivity of the oscillatory potentials of the electroretinogram (ERG), I: GABA and glycine

antagonists.

Acta Ophthalmol

1980;58:

712-725. L: Further

studies of the

chemical sensitivity of the oscillatory potentials of the electroretinogram (ERG), II: glutamate, aspartate,

significance.

dis-

Doc Ophthal-

MA,

Natural

pigmentosa

course of retinitis

three-year

interval.

55. Iijima

Rosner B, et al:

Am J Ophthalmol

over a 1985;99:

H: Distribution

and dopamine

thalmoI1981;59:247-258.

of ERG amplitudes,

latencies, and implicit times. In: Heckenlively ]R, Arden G B, eds: Principles and Practice of Clinof Vision. St Louis:

Year Book;

1991:289-290.

56. Burian

HM,

lens electrode

57. Lawwill

Allen

L: A speculum

antagonists.

Acta Oph-

Mosby-

contact

for electroretinography.

T, Burian

the Burian-Allen

Electroen-

1954;6:509-511.

HM:

A modification

contact-Iens

electroretinography.

electrode

of for

Am J Ophthalmol

1966;6:1506-1509. 58. Dawson proved

WW, Trick

electrode

GL, Litzkow

CA; Im-

for electroretinography.

Invest

Vis Sci 1979;18:988-991.

59. Dawson

WW, Trick

tion of the DTL

GL, Maida

TM:

corneal electrode.

Evalua-

Doc Ophthal-

mol Proc Ser 1982;31:81-88. 60. Hebert ducibility

50. Wachtmeister

S: ERG of Behget's

54. Berson EL, Sandberg

Ophthalmol 49. Wachtmeister

Arch

mol Proc Ser 1980;23:91-93.

human

Vis Res 1987;27:859-866.

ture and averaged

nega-

cephalogr Clin Neurophysiol

Rod and cone system contributions potentials:

with

a new classification.

OphthalmoI1986;104:1013-1020.

ical Electrophysiology

46. Speros P, Price J: Oscillatory tory, techniques

M, et al:

blindness

240-251.

1954; 123:36P-37P. 45. Yonemura

night

ease and its diagnostic

H: The early receptor

44. Cobb WA, Morton

inheritance.

Y, Yagasaki K, Horiguchi stationary

53. Kubota

data. Doc Ophthal-

Doc Ophthalmol

in congenital

recessive

tive electroretinogram:

mol Proc Ser 1982;31:95-102. 43. Muller

52. Miyake Congenital

from monochromat's

studies

ofX-Iinked

Doc Ophthalmol Proc Ser 1977;13:173-184.

tial. Vis Res 1970;10:207-218. 42. Sieving

T, Wolf E, Hara A: Electrophysiologi-

cal and psychophysical

po-

DTL

M, Vaegan, Lachapelle of ERG

electrode.

61. Lachapelle cording

with

the

Vis Res 1999;39: 1069-1070. P, Benoit

the oscillatory

retinogram

P: Repro-

responses obtained

], Little

potentials

with the DTL

]M,

et al: Re-

of the electro-

electrode.

Doc Oph-

thalmoI1993;83:119-130. 62. Grounauer

PA: The new single use ERG

corneal lens electrode and its clinical application. Doc Ophthalmol Proc Ser 1982;31 :89-93.

References

63. Chase WW, Fradkin electrode

NE, Tsuda S: A new

for electroretinography.

PhysiolOpt

76. Peachey

Am J Optom

1976;53:668-671.

64. Arden

GB, Carter

foil electrode:

the horizons

Invest Ophthalmol

during

light adaption.

77. Miyake

Vis Sci

tional change in cone-mediated

Y, Horiguchi

gram in human RM, Coats AC: Gold-coated

Appl Opt

M, Ota I, et al: Adaptaelectroretino-

and carp. Neurosci Res 1988;8

(suppl):S 1-S 13.

Mylar (GCM) electrode for electroretinography. Doc Ophthalmol Proc Ser 1978; 15:339-343.

78. Gouras P, MacKay

C: Adaptation

the electroretinogram.

In: Heckenlively

66. Sierpinski-Bart

Arden

], Moran

et al: Non-corneal

A. Hocherman

electroretinography

atric ophthalmology.

S,

for pedi-

387-388.

clinical

D: The technical

electroretinography.

limitations

of

Doc Ophthalmol Proc

Ser 1982;31:3-12. 68. Coupland pediatric

patients:

PVA-gel,

and non-corneal

M: ERG electrode

comparisons

of DTL

in

Doc

Corneal

PA, Fishman

wick electrode

electroretinograms

GA, Maggiano for recording

MF, Zrenner

electroretinography

E: Standard

flash

71. Weleber

A: Retinal

81. Johnson

MA, Massof

reflex:

an artifact

and

82. Massof

RW, Wu L, Finkelstein

83. Motokawa

73. Armington

of the human

light adaptation

:509-524.

Long-term

of the human

electroretinogram.

Tohoku J Clin Exp Med

technique.]

C]: Growth

the human

cone electroretinogram

adaptation.

Invest Ophthalmol

of

with light

Vis Sci 1989;30:

625-630. 75. Lachapelle troretinogram adaptation.

P: Analysis recorded

of the photopic

elec-

before and after dark

Can J OphthalmoI1987;22:354-361.

and an

G, de Rouck

of the human

A: Pathol-

electroretino-

gram. Br J OphthalmoI1956;40:439-443. 85. Bush RA, Sieving

86. Marmor amplitUde

properties

re-

improved

troretinogram.

J Comp Physiol PsychoI1958;51:1-5. 74. Gouras P, MacKay

light

retina:

tions to the primate

]C, BiersdorfWR:

pigmentosa.

K, Mita T: [Electrical

ogy of the x-wave responses

intensity-

sponses of the human

84. Franc;;ois J, Verriest

Electric

electro-

D, et al:

of electroretinographic

Raven Press; 1988:21-69. HM:

photomyo-

Br J OphthalmoI1982;66:368-378.

Retinal Dystrophies and Degenerations. New York:

72. Burian

RW: The

1942;42:114-133.

DA, ed:

visual system. Arch Ophthalmol1954;51

time and amp

in the clinical

response functions in retinitis Doc OphthalmoI1984;57:279-296.

function

stUdies. In: Newsome

retina.

electroretinogram

implicit

for clinical

( 1994 update ). Doc Ophthal-

RG, Esiner

JR: The human

dark adaptation:

Properties

mol 1995;89: 199-210.

physiological

M: Rod--

in the distal human

potentials.

Arch OphthalmoI1978;96:899-900. 70. Marmor

during

retinogram.

]M:

bright

and early receptor

MA, Berson EL, Effron

Science 1981;212:829-831.

clonic

OphthalmoI1989;71:427-433. 69. Sieving

Mosby-Year

studies. Arch OphthalmoI1969;82:491-498.

fiber,

skin electrodes.

of Vision. St Louis:

cone interaction

80. Brunette

SG, ]anaky

JR,

1991:391-395.

79. Sandberg

67. van Norren

effects on

G B, eds: Principles and Practice of Clinical

Electrophysiology Book;

Metab OphthalmoI1978;2:

GA,

cone system elec-

1989;28:1145-1150.

for clinical

1979;18:421-426. 65. Borda Bp, Gilliam

KR, Fishman

of the human

troretinogram

RM, Hogg C, et al: A gold

extending

electroretinography.

NS, Alexander

et al: Properties

127

Standard

PA: Inner photopic

retinal

contribu-

fast flicker

elec-

J Opt Soc Am 1996;13:557-565. MF, Arden

for clinical

GB, Nilsson

SE, et al:

electroretinography.

OphthalmoI1989;107:816-819.

Arch

128

The Electroretinogram

87. Marmor

MF, Zrenner

E: Standard

electroretinography

(1999 update):

Society for Clinical

Electrophysiology

Doc Ophtholmol

for clinical

International of Vision.

1998-1999;97:143-156.

88. Miiller-Limmroth

W: [The

of the

of the light

nogram.]

Arch Gesomte Physiol 1953;257:35-47.

89. Johnson duration

stimulus

influence

duration

E, Bartlett

on electrical

electroretinogram.

on the electroreti-

N: Effects responses

of stimulus

of the human

Br J Ophtholmol

1956;40;

439-443. 90. Gouras P: Electroretinography: principles.

Invest Ophtholmol

some basic

1970;9:557-569.

91. Rabin AR, Berson EL: A full-field for clinical

electroretinography.

system

Arch Ophtholmol

1974;92:59-63. 92. Kooijman

AC: Light

retina of a wide-angle

distribution

theoretical

on the

eye. J Opt Soc

Am 1983;73:1544-1550. 93. Henkes

HE: The

in measuring

use of electroretinography

the effects of vasodilation.

Angiol-

ogy 1951;2:125-131. 94. Mactier

H, Dexter

electroretinogram

JD, Hewett

in preterm

JE, et al: The

infants.

J Pediotr

1988;113:607-612. 95. Horsten activity

GP, Winkelman

JE: The

electric

of the eye in the first days of life. Acto

Physiol Phormocol Neerl 1965; 13: 1. 96. Zetterstrom

B: The electroretinogram

newborn

In: Wirth

infant.

Eighth ISCERG

of the

A, ed: Proceedings of the

Symposium. Pisa: Pacini Mariotti;

1972:1-9. 97. Fulton adaption

AB, Hansen in human

RM: Background

infants:

responses. Doc Ophtholmol

analysis of b-wave Proc Ser 1982;31 :

191-197. 98. Kriss A, Russell-Eggitt I: Electrophysiological assessment of visual pathway function in infants. Eye 1992;6:145-153.

99. Birch DG, Anderson ]L: Standardized fullfield electroretinography: normal values and their variation with age. Arch Ophthalmol1992; 110:1571-1576. 100. Fulton AB: The development of scotopic retinal function in human infants. Doc Ophthalmol 1988;69:101-109. 101. Fulton AB, Hansen RM: Electroretinography: application to clinical studies of infants. J PaediatrOphthalmol Strabismus 1985;22:251-255. 102. Birch EE, Birch DG, Petrig B, et al: Retinal and cortical function of very low birthweight infants at 36 and 57 weeks postconception. Clin Vis Sci 1990;5:363-373. 103. Mets MB, Smith VC, Pokorny ], et al: Postnatal retinal development as measured by the electroretinogram in premature infants. Doc OphthalmoI1995;90: 111-127. 104. Fulton AB, Hansen RM: Photoreceptor function in infants and children with a history of mild retinopathy of prematurity. J Opt SocAm 1996;13:566-571. 105. Fran9ois ], de Rouck A: Retrolental fibroplasia and ERG. Doc Ophthalmol Proc Ser 1983; 37:287-291. 106. Peterson H: The normal B-potential in the single-flash clinical electroretinogram: a computer technique study of the influence of sex and age. Acta OphthalmoI1968(suppI99):7-77. 107. Vainio-Mattila B: The clinical electroretinogram, II: the difference between the electroretinogram in men and in women. Acta Ophthalmol 1951;29:25-32. 108. Zeidler I: The clinical electroretinogram, IX: the normal electroretinogram-value of the b-potential in different age groups and its differences in men and women. Acta Ophthalmol1959; 37:294-301. 109. Karpe G, Rickenbach K, Thomasson S: The clinical electroretinogram, I: the normal electroretinogram above fifty years of age. Acta OphthalmoI1950;28:301-305. 110. Martin DA, Heckenlively ]R: The normal electroretinogram. Doc Ophthalmol Proc Ser 1982; 31:135-144.

129

References

111. Weleber

RG: The effect

cone and rod ganzfeld Ophthalmol

of age on human

electroretinograms.

Invest

Vis Sci 1981;20:392-399.

112. Lehnert

W, Wunsche

nogram at different

AY, Jacobson SG: Negative

troretinograms

in retinitis

Ophtholmol

H: [The

ages of life.]

124. Cideciyan

electroreti-

GA, Farber MD,

retinitis

Exp OphthalmoI1966;170:147-155.

findings.

Arch OphtholmoI1988:l06:369-375.

113. Pallin

126. Fishman

of the axial length

of the eye on the size of the recorded in the clinical

single-flash

b-potential

electroretinogram.

method

Acta OphthalmoI1969(suppI101):1-57. 114. Padmos P, van Norren generation:

sia. Doc Ophthalmol 115. van Norren tation:

of halothane

re-

anesthe-

Proc Ser 1975;11:145-148.

of halothane

anesthesia.

Doc Ophthalmol

anesthetics

of

on dark adaption.

Proc Ser 1975;11:149-151.

117. van Norren dark adaption.

retards

Proc Ser 1974;4:

DG, Berson EL, Sandberg

nal rhythm thalmol

in the human

MA: Diur-

rod ERG. Invest Oph-

S, Wakakura

dian rhythm

of human

M, Ishikawa

S: Circa-

electroretinogram.

Jpn J

HE:

tory disturbances

Electroretinography of the retina;

gram in cases of occlusion

in circula-

I: electroretino-

of central

retinal

pigmen-

vein

from two-color

Doc Ophtholmol

GB, Carter

RM, Hogg CR, et at: in patients

measurements.

130. Massof

with domi-

Br J OphtholmoI1983;67:

RW, Finkelstein

to cone sensitivity

tosa. Invest Ophtholmol

D: Rod sensitivity in retinitis

pigmentosa.

RD, et al:

in sex-Iinked

retinitis

Arch OphtholmoI1969;81:215-225.

132. Berson EL, Gouras P, Gunkel Dominant

pigmen-

Vis Sci 1979; 18:263-272.

131. Berson EL, Gouras P, Gunkel

retinitis

133. Iijima

pigmentosa

RD, et al:

with

reduced

Arch OphtholmoI1969;81:226-234. H, Yamaguchi

electroretinogram

implicit

S, Hosaka 0: Photopic time in retinitis

what do we mean by these terms? Doc Ophthal-

mentosa. Jpn J OphtholmoI1993;37:130-135.

mol ProcSer

134. Marmor

1982;31:13-17.

122. Andreasson Narrow-band

SO, Sandberg

filtering

MA, Berson EL:

for monitoring

tude cone electroretinograms mentosa. Am J Ophthalmol1988; 123. Sharma RK, Ehinger hereditary

retinal

and future

directions.

427-444.

low-ampli-

in retinitis

105:500-503.

B: Management

degenerations:

pig-

present

retinitis

MF: The electroretinogram

pigmentosa.

of

Surv OphthalmoI1999;43:

pig-

in

Arch OphtholmoI1979;97:

1300-1304. 135. Rothberg

DS, Weinstein

et al: Electroretinography

status

sco-

Proc Ser

405--418.

190-201. and absent ERGs:

D: Subclassifica-

pigmentosa

nantly inherited retinitis pigmentosa: comparisons between psychophysical and electroretino-

penetrance.

G: Subnormal

retinitis

1981;26:219-225.

or one of its branches. Arch OphthalmoI1953;49:

121. van Lith

D: Two forms of

primary

Rod and cone responses

OphthalmoI1983;27:346-352. 120. Henkes

RJ: a

Arch Ophtholmol1985;

Finkelstein

dominant

:.:3. Arden

relative

Vis Sci 1984;25:236-238.

119. Nozaki

pigmentosa:

128. Massof RW, Finkelstein

graphic

1.'55-159. 118. Birch

autosomal

Rod and cone activity

D, Padmos P: Halothane Doc Ophthalmol

127. MassofRW,

topic static perimetry.

D, Padmos P: The influence

various inhalation

KR, Anderson

retinitis

of classification.

tion of retinitis

Invest OphthalmoI1975;14:212-227. 116. van Norren

GA, Alexander

dominant

Dl:

of clinical

tosa. Doc OphtholmoI1981;51:289-346.

D, Padmos P: Cone dark adap-

the influence

profile

103:366-374.

D: Cone pigment

the influence

Autosomal

pigmentosa:

Derlacki

X-Iinked

0: The influence

elec-

Invest

Vis Sci 1993:34:3253-3263.

125. Fishman

Graefes Arch Clin

pigmentosa.

tosa: no discrimination

GW, Hobson

and retinitis between

types. Arch Ophtholmol1982;

genetic

RR,

pigmensub-

lOO: 1422-1426.

130

The Electroretinogram

136. Sandber!!; MA, Sullivan Temporal

PL, Berson EL:

aspects of the dark-adapted

a-wave in retinitis

pigmentosa.

147. Stone EM:

cone

Invest Ophthalmol

Vis Sci 1981;21:765-769.

sponses in retinitis herited.

pigmentosa,

RD: Rod re-

dominantly

in-

Arch OphthalmoI1968;80:58-67.

138. Berson EL,

Kanters

sponses in a family retinitis

with

pigmentosa.

inherited

288-297.

pigmentosa

and cone-rod

140. Berson EL,

Rosner B, Sandberg

MA, et al:

A and vitamin

for retinitis

141. Berson EL, Goldstein

pigmentosa.

literature

Arch

EB: Early receptor

in dominantly

mentosa.

Arch OphthalmoI1970;83:412-420.

inherited

GA, Weinberg

characteristics

retinitis

retinitis

TT:

clinical

IM, Clayton

syndrome:

review.

troretinographic

GA, Derlacki

Ophthalmology

1998;105:

FX, Apathy

PP: Pat-

in Bardet-

Am J Ophthalmol1990;

109:

676-688.

sive cone-rod

pigmentosa.

Dl,

154. Fishman

in carriers of

degeneration.

testing

RD: Progres-

Arch Ophthalmol

retinitis

of

pig-

155. Lamy genital

M, Frezal J, Polonovski

156. Berson EL, Howard the electroretinogram

pigmenrosa.

in families

B: Electroretiwith X-linked

Acta OphthalmoI1990;68:

139-144.

pigmentosa:

A, De long PT, defined

from a mo-

of view. Surv OphthalmoI1999;43:

Pediatrics

J: Temporal

in sector retinitis

aspects of pigmen-

tosa. Arch OphthalmoI1971;86:653-665. 157. Berson EL:

Retinitis

diseases: applications

146. van Soest S, Westerveld

J, et al: Con-

1963;31:277-289.

mentosa. Am J OphthalmoI1979;87:460-468.

diagnosis

et al:

and neuro-oto-

absence of beta-lipoproteins.

145. Andreasson

SO, Ehinger

A, Joseph ME,

ophthalmic

logic findings suggesting genetic heterogeneity. Arch OphthalmoI1983;101:1367-1374.

EA: Elec-

as an aid in detection

GA, Kumar

Usher's syndrome:

Ophthalmology

catriers ofX-chromosome-linked

321-334.

R,

1968;80:68-76. NS, Fishman

144. Berson EL, Rosen lB, Simonoff

lecular point

PT, Coffey

report of 22 cases and

153. Berson EL, Gouras P, Gunkel

of carriers. Arch Ophthalmol1986;

retinitis

et al: Retinitis

lo-

retini-

Vis .S'ci 1995;36:

terns of rod and cone dysfunction

1988;95:677-685.

retinitis

with

in dominant

Invest Ophthalmol

Biedl syndrome.

AB, McMahon pigmentosa:

et al: Rod and cone dysfunction

nographic

C, Dryja

correlates

mutation

152. Jacobson SG, Bortuat

pig-

104:1329-1335. 143. Peachey

expression

1274-1280.

potential

recessive

MA, Weigel-DiFranco

151. Russell-Eggitt et al: Alstrorn

E

OphthalmoI1993;111:761-772.

142. Fishman

retinitis

2. Nat Genet 1998; 19:327-332.

tis pigmentosa.

Ophthal-

S, Dong J, et al: Posi-

1934-1942.

trial of vitamin

supplementation

X-linked

U, Lenzner

of the gene for X-Iinked

cation of rhodopsin

loss in retinitis

mology 1999;106:258-268. A randomized

Am J Hum Genet 1997;61:

tional cloning

TP, et al: Clinical

Fish GE: Yearly

dystrophy.

gene that

with X-linked

149. Schwahn

150. Sandberg lL,

rates of rod and cone functional

X-linked

pigmentosa.

R, et al:

in the RPGR

in 20% of families

pigmentosa

Arch OphthalmoI1970;84:

139. Birch DG, Anderson

of RP

1287-1292.

L: Cone and rod rerecessively

retinitis

M, Wu W, Fujita

of mutations

are identified

the repertoire

1998;19:311-313.

148. Buraczynska Spectrum

137. Berson EL, Gouras P, Gunkel

Expanding

genes. NatGenet

testing.

pigmentosa

and allied

of electroretinographic

Int OphthalmoI1981;4:7-22.

158. Carr RE: Vitamin degenerative

retinal

A therapy syndrome.

may reverse Clin Trends

1970;8:8. 159. Gouras P, Carr RE, Gunkel pigmentosa vitamin

in abetalipoproteinemia:

RD: Retinitis effects of

A. Invest OphthalmoI1971;10:784-793.

References

160. Sperling

MA, Hiles

OA, Kennerdell

]S:

171. Leung

Electroretinographic responses following vitamin A therapy in A-beta-Iipoproteinemia. Am J Oph-

with

thalmoI1972:73:342-351.

7:32-40.

161. Muller

OP, IJloyd ]K, Bird AC: Long-term

management

of abetalipoproteinaemia:

role for vitamin

possible

E. Arch Dis Child 1977;52:

Further

LS. Weinstein

mucopolysaccharidoses.

172. Krill

AE: Flccked

AE, Archer

Birth Defects 1971;

retina diseases. In: Krill

DB, eds: Krills

E, Zaidman

]L,

Eshchar

], et al: Case

173. Henkes

report: abetalipoproteinemia treated with parenteral and oral vitamins A and E, and with me-

of the fellow

dium chain triglycerides.

eds: Clinical

Acta Paediatr Scand

1978;67:796-801. 163. Fishman

GA: Hereditary

retinal

roidal diseases: electroretinogram oculogram

findings.

and cho-

and electro-

In: Peyman

GA, Sanders

OR, Goldberg

MF, eds: Principles and Practice of

Ophthalmology.

Philadelphia:

WB Saunders

Co;

1980;2:857-904.

Hereditary

Retinal and

MD:

Harper

&

tions: vitamin

A, taurine,

and retinal ornithine,

degenera-

and phytanic

acid. Retina 1982;2:236-255. 165. Carr RE, Siegel IM: Testing: A Practical

Visnal Electrodiagnostic

& Wilkins;

166. Pagon RA: Retinitis

Balti-

1982:81-84.

pigmentosa.

Surv Oph-

thalmoI1988;33:137-177.

Does unilateral

eye. In: Burian

retinitis

the Third

International

Elmsford,

NY: Pergamon

pigstudy

Jacobson JH,

Proceedings

Symposium,

174. Carr RE, Siegel IM: mentosa.

HM,

E:lectroretinography.

of

1964.

Press; 1966:327-350... Unilateral

retinitis

pig-

Arch OphthalmoI1973;90:21-26.

175. Kandori

F, Tamai A, Watanabe

lateral pigmentary

degeneration

T, et al: Uni-

of the retina:

hexadecanoic

atactica polyneuri-

acid storage disease (Ref-

sum's disease)-definition,

treatment

genesis (a short review).]

and patho-

Psychiatr Neurol Med

P.lychol Beih 1977;22:11-18. 168. Ghose S, Sachdev

H: Bilateral

retinal dystrophy, a new syndrome?

Br J OphthalmoI1985;69:624-628.

with nanophthalmos,

degeneration,

coma: a new recessive

cystic

and angle closure glausyndrome.

Arch Ophthalmol

1987;105:366-371.

profiles

R, Hanley

and fundus

WB, et al: Elec-

oculi findings

in

disease and allied mucopolysacchari-

doses. Arch OphthalmoI1965;74:596-603.

Finkelstein

in sector retinitis

D: Vision

pigmentosa.

threshold Arch Oph-

thalmoI1979;97:1899-1904. Leber's

R, Mets MB, Maumenee

congenital

amaurosis:

cases. Arch Ophthalmol1987; 179. Margolis

IH:

retrospective

view of 43 cases and a new fundus

finding

rein two

105:356-359.

S, Scher BM, Carr RE: Macular

in Leber's

congenital

amaurosis.

Am J OphthalmoI1977;83:27-31. 180. Heckenlively and early-onset delphia:

JR, Foxman forms of retinitis

JB Lippincott

181. Lotery

pigmentosa.

Co; 1988:107-124.

AJ, Namperumalsamy

SG, et al: Mutation tients with

SG: Congenital In:

JR, ed: Retinitis Pigmentosa. Phila-

Leber

Ophthalmol2000;

170. Gills ]P, Hobson

cases of uniBr J Ophthalmol

1964;48:471-479.

Heckenlively

C], Shek MS, Carr RE, et al: Reti-

NR: Three

degeneration.

177. MassofRW,

colobomas

MS, Kumar

nanophthalmos, pigmentary and angle closure glaucoma:

nal degeneration

1091-1101. 176. Kolb H, Galloway

178. Schroeder

167. Ref sum S: [Heredopathia

troretinography

HE:

really exist? An ERG and EGG

lateral pigmentary

Guide for the Clinician.

more, MO: Williams

169. MacKay

mentosa

report of two cases. Am J OphthalmoI1968;66:

164. Berson EL: Nutrition

Hurler's

RR:

of patients

Row; 1977;2:739-824.

162. Azizi

macular

studies

Choroidal Diseases. Hagerstown,

209-214.

tiformis:

GW, Hobson

electroretinographic

131

P, Jacobson

analysis of 3 genes in pacongenital

118:538-543.

amaurosis.

Arch

132

The Electroretinogram

182. Sohocki

MM,

Bowne

SJ, Sullivan

LS, et al:

192. Birch DG, Anderson

Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amautosis. Nat

in cone-rod

Genet 2000;24:79-83.

2288-2299.

183. Marlhens

F, Bareil C, Griffoin

193. Krauss HR, Heckenlively changes in cone-rod

cause Leber's

amautosis.

NatGenet

1997;17:139-141.

H, Fishman

with autosomal Leber

recessive

congenital

194. Heckenlively

SA, et

Telangiectasia

gene in patients

retinitis

amautosis,

pigmentosa

or

Proc Natl Acad Sri

Leber's

guanylate

congenital

cyclase gene mutations

amaurosis.

Nat Genet 1996:14:

sociated with

in the CRX Leber

homeobox

congenital

gene as-

amautosis.

Nat

Genet 1998;18:311-312. 187. Sohocki

MM,

Sullivan

LS, Mintz-Hittner

HA, et al: A range of clinical ated with

mutations

phenotypes

in CRX,

transcription-factor

associ-

a photoreceptor

gene. Am J Hum Genet 1998;

63:1307-1315. 188. Swaroop A, Wang QL, Wu W, et al: Leber congenital

amaurosis

mutation retinal

(R90W)

transcription

of photoreceptor

caused bya homozygous

in the homeodomain

for the involvement

189. Stockton

factor CRX: of CRX function.

DW, Lewis

on chromosome

phenotype.

direct

RA, Abboud

EB, et

congenital

amautosis

14q24. Hum Genet 1998;103:

subtypes

GA, Alexander

of cone-rod

KR, et al:

dysttophy.

Arch

191. Yagasaki K, Jacobson SG: Cone-rod diversity

FW, et al: ocular

concentric

annular

Am J OphthalmoI1974;78:

198. van den Biesen PR, Deutman

AF, Pinckers

A]: Evolution

annular

of benign

ular dystrophy.

concentric

Am J Ophthalmol1985;

199. Miyake

Y, Shiroyama

NA, Horiguchi

al: Bull's-eye

maculopathy

and negative

retinogram.

M, et electrQ-

Retina 1989;9:210-215.

200. Madsen brothers.

mac-

100:73-78.

PH: Total achromatopsia

in two

Acta OphthalmoI1967;45:587-593. M: What is it that confines

in a

color? Invest Ophthalmol1974;

13:648-674. 202. Kohl S, Marx T, Giddings gene encoding toreceptor

I, et al: Total

is caused by mutations the a-subunit

cGMP-gated

in the

of the cone pho-

cation channel.

Nat

Genet 1998;19:257-259. 203. Pokorny

], Smith

Classification

of complete

somal recessive

VC, Pinckers

A], et al:

and incomplete

achromatopsia.

auto-

Graefes Arch Clin

Exp OphthalmoI1982;2i9:121-130.

OphthalmoI1993;111:781-788. phy: phenotypic

, Fitzke dystrophy:

384-396.

evidence

Hum Mol Genet 1999;

degenera-

Soc 1987;85:438--470.

AF: Benign

dystrophy.

world without

in the development

de-

Arch OphthalmoI1995;113:195-201.

201. Alpern

328-333. 190. Szlyk JP, Fishman

]R: RP cone-rod

19q cone-rod

colourblindness

at: A novel locus for Leber

testing.

Chromosome

macular

in cone-rod

Arch OphthalmoI1981;99:1983-1991.

of the

8:299-30.1.

Clinical

generations.

197. Deutman CL, Wang QL, Chen S, et al: De

novo mutations

Arch Oph-

DA, Rosales TO:

196. Evans K, Duvall- Young] in

461-464. 186. Freund

]R, Martin

tion. Trans Am Ophthalmol

I, Rozet JM, Calvos P, et al: Reti-

nal-specific

]R: Visual field

degenerations.

and optic atrophy

195. Heckenlively

USA 1998;95:3088-3093. 185. Perrault

to retini-

Vis Sci 1990;31:

thalmoI1982;100:1784-1790.

GA, Grover

in the RPE65

Invest Ophthalmol

congenital

in RPE65

al: Mutations

tis pigmentosa.

Rod visual fields

comparisons

JM, et al:

Mutations

184. Morimura

]L:

degeneration:

by retinal

dystro-

function

Arch OphthalmoI1989;107:701-708.

204. Gouras P, MacKay

C], Lewis

cone electroretinogram

isolated

achromat.

In: Drum

B, Verriest

Vision Deficiencies. Dordrecht: R9-91.

AL: The

blue

in a sex-Iinked G, eds: Color

Kluwer;

1989;9:

133

References

205. Spivey

BE, Pearlroan

]T, Burian

HM:

Elec-

rroretinographic findings (including flicker) in carriers of congenital X-Iinked achromatopsia. Doc OphthalmoI1964;18:367-375. 206. Krill

AE: Congenital

In: Krill

AE, Archer

defects.

DB, eds: Kril15 Hereditary MD:

& Row; 1977;2:369-370.

207. Pagon RA, Chatrian Carrier

detection

GE, Hammer RD, et al:

MA, Maguire

A, et

in carriers of blue cone

Am J Ophthalmol1986;

], Davenport

et al: Molecular

genetics

102:

monochromacy.

], Maumenee

heterogeneity

chromats.

IH,

blue cone

IH, Zrenner

R, Kakuk

lateral macular macy (BCM)

troretinogram.

stationary

night

blindness

Am J Ophthalmol1990;

elec-

109:44-48.

night

region

gene. Mol Vis

activity

blindness.

of the retina in

Invest Ophthalmol

1966;5:497-507.

Tp, Hahn

LB, Reboul

T, et al: Mis-

in the gene encoding

unit of rod transducin congenital stationary 1996; 13:358-360.

in the Nougaret night

T, Haim

dominant

blindness.

M, Piczenik

stationary

rediscovered.

the IX subform of Nat Genet

Y, et al:

night-blindness:

Acta Ophthalmol

1991;69:694-702. 222. Sandberg

MA, Pawlyk

and cone function tionary

night

BS, Dan ], et al: Rod

in the Nougaret

blindness.

form of sta-

Arch Ophthalmol1998;

116:867-872.

212. Ikeda

H, Ripps H: The electroretinogram

of the cone-roonochromat.

223. Fran<;:ois ], Verriest

Arch Ophthalmol1966;

75:.';13-517.

congenital

with myopia

GF, Thompson stationary

and nystagmus

complaints

of nyctalopia.

Strabismus

1988;25:33-36.

214. Heckenlively

night without

J Paediatr

optic atrophy night

stationary

O,tJhthalmoI1971;

Ophthalmologica

A, et al: in Nouga-

1956;132:244-257.

HS:

224. Dryja

TP, Berson EL, Rao VR, et al: Het-

erozygous

missense

clinical

gene as a cause of congenital

Ophthalmol

DA, Rosenbauro oscillatory

and dysplasia

blindness.

AE, Martin

G, de Rouck

in hemeralopia

blindness

po-

in congeni-

Am J Ophthalmol

1983;96:526-534. in congenital

visual functions

blindness.

mutation

in the rhodopsin stationary

night

Nat Genet 1993;4:280-283.

225. Gal A, Orth U, Baehr W, et al: Heterozy-

]R, Martin

Loss of electroretinographic

tal stationary

[The

ret's disorder.]

213. Price M], ]udisch X-Iinked

Doc

with an electronegative

and the electrical

congenital

a large family

1999;5:13.

215. Krill

fundus

Autosomal

in blue cone monochro-

and part of the red pigment

tentials,

and normal

221. Rosenberg

loss of the locus control

nyctalopia.

KG, Carr RE, Siegel IM: Autosomal

mono-

LE, Coats CL, et al: Bi-

atrophy with

VC, Seiple WH, et

in congenital

congenital

E, et al:

among blue-cone

Am J Hum Genet 1993;53:987-1000.

211. Ayyagari

AL:

218. Noble

220. Dryja

Science 1989;245:831-838.

210. Nathans Genetic

CM, Maumenee of human

with my-

OphthalmoI1987;65:307-318.

sense mutation

209. Nathans

nyctalopia

219. Carr RE, Ripps H, Siegel IM, et al: Rho-

254-261.

(LCR)

al: Cone function

dopsin

al: Electroretinograms monochromatism.

recessive cone

by electroretinography.

208. Berson EL, Sandberg

KF, Berson EL: Cone elec-

in con~enital

opia. Am J OphthalmoI1974;78:127-136.

dominant

in an X-Iinked

dysfunction syndrome ClinRes 1981;29:116A.

DA, Arbel

troretinograms

217. Siegel IM, Greenstein

color vision

Retinal and Choroidal Diseases. Hagerstown, Harper

216. Hill

D: Photopic night

10:625-636.

abnormalities

blindness.

Invest

gous missense

mutation

in the rod cGMP

phos-

phodiesterase f3-subunit gene in autosomal dominant stationary night blindness. Nat Genet 1994; 7:64-68.

134

The Electroretinogram

226. Peachey

NS, Fishman

al: A form of congenital ness with

apparent

defect

tion. Invest Ophthalmol 227. al-Jandal

blind-

of rod phototransduc-

Vis Sci 1990;31:237-246.

within

the rhodopsin

causing autosomal

stationary

PE, et

night

N, Farrar GJ, Kiang AS, et al: A

novel mutation 94-Ile)

GA, Kilbride

stationary

night

dominant

blindness.

gene (Thrcongenital

Hum Mutat

1999;13:

Y, Horiguchi

ERG-tlicker

M, Ota I, et al: Char-

anomaly

stationary

Ophthalmol

Vis Sci 1987;11:1816-1823.

229. Kmiyama

night

blindness.

M, Yamamoto

Undetectable

congenital

230. Bech-Hansen

stationary

K, et al:

cium-channel incomplete

Springer-Verlag;

Comparison

X-Iinked

231. Strom TM,

congenital

congenital

heterogeneity

stationary

night

Y, Kawase Y: Reduced

of oscillatory

potentials

recessive

in female

congenital

AH, Sailri JC, Jacobson SG, et al: Auagainst retinal

bipolar

Ophthalmol

cells in cuta-

retinopathy.

Invest

Vis Sci 1993;34:91-100.

240. Miyake

Y, Yagasaki K, Horiguchi

types of conJpn J Ophthal-

station-

stationary

in photopic

M, et al:

and incomplete blindness.

electroretino-

mol 1987;31:81-87. 241. Fishman al: Acquired

GA, Alexander unilateral

with a negative

night

KR, Milam blindness

electroretinogram

AH, et

associated

waveform.

MA,

Ophthalmology

in

242. Kelsey JH, Arden

GB: Acquired

loss of dark adaptation.

Br J OphthalmoI1971;55:

blindness.

1996;103:96-104. unilateral

38-43.

Am J Hum Genet 1998;62:865-875. 233. Miyake

mela-

night

gene mu-

KM, Pearce WG, Musarella

malignant

Vis Sci 1992;33:477-483.

genital

Nat Genet 1998; 19:260-263.

for genetic

cutaneous

gram in complete

ary night

et al: Evidence

with

noma. Invest Ophthalmol

NS,

night

X-linked

232. Boycott

blindness

GA, Peachey

in paraneoplastic

On- and off- responses

G, Apfelstedt-Sylla congenital

che-

cause

tated in incomplete blindness.

KR, Fishman

neous melanoma-associated

stationary

calcium-channel

NS,et al:

electroretino-

before and after vincristine

response defect

toantibodies

in a cal-

SR,

Doc OphthalmoI1993;84:231-235.

239. Milam

1998;19:264-267.

Nyakatura

E, et al: An L-type

N, Peachey

of cone-mediated

motherapy.

b-wave

gene in Xp11.23

JB, Hilfer

Biology of the Eye:

1984:171-204.

237. Yee W, Bhoopalam

blind-

MJ, Maybaum

mutations

O:l-subunit

NatGenet

night 7-639.

NT, Naylor

TA, et al: Loss-of-function

blindness.

In: Scheffield

in hereditary

Heredity and Visual Development. New York:

night

S, Nitta

ness. Br J OphthalmoI1996;80:63

X-Iinked

disorders.

eds: Cell and Developmental

et al: 'On'

Invest

S cone electroretinogram

in complete

X-Iinked

retinal

L III: The

basis of visual dysfunction

238. Alexander

in incomplete

congenital

blindness.

cellular

grams obtained

75-81. 228. Miyake acteristic

236. Ripps H, Siegel IM, Mehaffey

amplitude

stationary

243. Ayaki M, Oguchi eral night

carriers of night

Am J OphthalmoI1984;98:208-215.

blindness

Y, Matsuhashi with

normal

M: Unilat-

fundus.

Am J

OphthalmoI1984;98:630-632. 244. Franceschetti

A, Fran~ois J, Babel J: [Here-

234. Ripps H, Carr RE, Siegel IM, et al: Func-

ditary Chorioretinal

Degenerations: Tapeto-Retinal

tional abnormalities

Degenerations.] Paris: Masson et Cie; 1963;2:

blindness.

in vincristine-induced

Invest Ophthalmol

night

Vis Sci 1984;25:

1205-1250.

787-794.

245. Miyake

235. Berson EL, blindness

with

Lessell malignant

thalmoI1988;106:307-311.

S: Paraneoplastic melanoma.

night

Am J Oph-

Y, Horiguchi

Electrophysiological Oguchi's

M, Suzuki

findings

S, et al:

in patients

with

disease. Jpn J OphthalmoI1996;40:

511-519. 246. Carr RE, Gouras P: Oguchi's OphthalmoI1965;73:646-656.

disease. Arch

135

References

247. Nakazawa

M, Wada Y, Fuchs S, et al: Ogu-

chi disease: phenotypic tients with

characteristics

the frequent

the arrestin

1147deIA

of pa-

clinical,

mutation

in

gene. Retina 1997;17:17-22.

248. Kubota

Y: The oscillatory

ERG in Oguchi's

of the

disease. Doc Ophtha!mo! Proc

H: Rhodopsin

in Oguchi's

kinetics

and

disease. Invest Oph-

tions. Am J Ophthalmol196

250. Fuchs S, Nakazawa

M, Tamai M, et al: A

1-base pair deletion

262. Franceschetti eration

A: [On tapeto-retinal

in childhood.]

In: Sautter

in the arrestin

cause of Oguchi

disease in

Enke

263. Fishman

GA: Fundus

264. Armstrong

]D,

kinase gene in the

term follow-up

of Stargardt's

flavimaculatus.

Ophthalmology

in the rhodopsin

Oguchi

form of stationary

night

blindness.

Nat

Genet 1997;15:175-178.

265. Fishman

252. Carr RE, Ripps H: Visual pigment

kinetics

and adaptation

Doc

in fundus

Ophtha!mo! ProcSer

albipunctatus.

1974;9:193-199. Defining

fundus

Symposium,

1976. Doc Oph-

tha!mo! Proc Ser 1977; 13:227-234. 254. Carr RE: Congenital

ited retinal

Meyer

nightblind-

D, Xu S, et al: Long-

inherited

GA: Electroretinography

macular

et al: Retinal in fundus

dystrophies.

pigment

AC, Eernardino

flavimaculatus:

a light

cal study of the fundus

lesions, the physiologic

deficit,

A metabolism.

268. Fish G, Grey R, Sehmi

and the vitamin

a cliniDoc Oph-

choroid

tha!mo!1977;43:277-302. 256. Yamamoto Mutations

H, Simon A, Eriksson

and fundus

cause delayed

albipunctatus.

nonprogressive

S, Larget-Piet

A gene for Stargardt's

disease (fundus

Nat Genet 1999;22:

nightblindness

with fleck

retina.

13:384-386.

F, Setogawa T, Tamai A: ERG of nightblindness

fleck retina. Jpn J Ophtha!mo!1966;

with

D, et al: flavimacu-

latus) maps to the short arm of chromosome

F, Tamai A, Kurimoto

270. Gerber

S, Rozet ]M,

Eonneau

1.

D, et al: A

gene for late-onset

fundus

macular

maps to chromosome

dystrophy

flavimaculattis

271. Allikmets

R, Singh N, Sun H, et al: A pho-

toreceptor cell-specific ATP-binding gene (AECR) is mutated in recessive

S, et al:

macular

retina. Am J O/Jhtha!mo!1972:73:673-685.

with 1p13.

Am J Hum Genet 1995;56:396-399.

1O(suppl):

301-316.

Fleck

Br J

OphthalmoI1981;65:359-363.

dark adaptation

F: A very rare cause of congenital

new cases of congenital

259. Kandori

KS, et al: The dark dystrophies.

Nat Genet 1993;5:308~311.

Jpn J Ophtha!mo!1959; 258. Kandori

retinal

1980;87:

269. Kapran ], Gerber

188-191. 257. Kandori

and electron

study. Ophthalmology

in posterior

VE ]r,

abnormalities

11-cis retinol

in the gene encoding

dehydrogenase

U, et al:

and

Retina 1985;5:

epithelial

microscopic 1189-1200.

albipunctatus:

and inher-

Doc OphthalmoI1985;60:

172-178.

ness. Trans Am Ophtha!mo! Soc 1974;72:448-487. Fundus

1998;105:448-457.

107-119.

255. Marmor

MF:

disease and fundus

GA: Electrophysiology

267. Eagle RC ]r, Lucier

stationary

a

Arch OphthalmoI1976;94:

disorders.

266. Fishman albipuncta-

Stuttgart:

flavimaculatus:

KC, Berson EL, et al:

S, Sippel

Defects

degen-

H, ed: [Droel-

Verlag; 1963:107-120.

251. Yamamoto

tus. 14th ISCERG

macu-

ed: Neuro-ophthal-

mology Update. New York: Masson Publishers;

Japanese. Nat Genet 1995;10:360-362.

MF:

progressive

In: Smith ]L,

clinical classification. 2061-2067.

253. Marmor

observa-

7 ;64:3-23.

GA: Hereditary

lar dystrophies.

flavimaculatus:

opment and Progress in Ophthalmology.]

tha!mo!1967;6:42&--436. homozygous

AE: Fundus

and histopathologic

1977:73-89.

249. Carr RE, Ripps

gene is a frequent

EA, Krill

functional

261. Fishman

potentials

Ser 1974;10:317-324.

rod adaptation

260. Klien

dystrophy.

transporter Stargardt

Nat Genet 1997;15:236-246.

136

The Electroretinogram

272. Sun H, Nathans

J: Stargardt's

calized to the disc membrane segments.

ABCR

of retinal

is lo-

rod outer

LL,

the ABCR

Rabin AR, Molday

transporter

disease, is expressed toreceptor

implicated

AS: ABCR,

in both cone and rod phoVis Sci 2000;

274. Stone EM, Nichols features

progressive

BE, Kimura

of a Stargardt-like

macular

dystrophy

age to chromosome

AE, et al: dominant

with genetic

6q. Arch Ophthalmol1994;

macular

(VMD).

technical

problems

tients. Doc Ophthalmol

lies with

G: The

in recording

Proc Ser 1982;31 :73-79.

AF: Electro-oculography

vitelliform

DC-

from pa-

dystrophy

in fami-

of the fovea: de-

of the carrier state. Arch Ophthalmol1969;

81:305-316. K, Bither

PP, Park R, et al: A domi-

macular

to chromosome

13q34. Arch OphthalmoI1994;112:

dystrophy

locus maps

759-764. 276. Batricks

ME: Vitelliform

ing in normal

fundi.

lesions develop-

Am J OphthalmoI1977;83:

324-327.

286. Weingeist topathology

TA, Kobrin

]L, Watzke

of Best's macular

RC: His-

dystrophy.

Arch

OphthalmoI1982;100:1108-1114. 287. O'Gorman S, Flaherty WA, Fishman al: Histopathologic

findings

macular

Arch Ophthalmol1988;

dystrophy.

GA, et

in Best's vitelliform 106:

1261-1268.

277. Mohler

CW, Fine SL: Long-term

tion of patients

with

Best's vitelliform

evalua-

288. Lotery

dystrophy.

Allelic

A], Munier

KR, et al:

Invest Ophthalmol

variation

1981 ;88:688-692.

278. Fishman

GA, Baca W, Alexander

Visual acuity in patients with Best vitelliform macular dystrophy. Ophthalmology 1993; 100:

289. Petrukhin

1665-1670.

macular

279. Miller

SA, Bresnick

roidal neovascular form macular

GH, Chandra

membrane

dystrophy.

SR: Cho-

in Best's vitelli-

Am J Ophthalmol1976;

KG, Scher BM, Catr RE: Polymor-

phous presentations subretinal atrophy.

in vitelliform

macular

neovascularization

dys-

and central

Br J OphthalmoI1978;62:

WF, Robertson

DM,

Duboff

SM:

Hereditary vitelliform macular degeneration: variable fundus findings within a single pedigree. Arch OphthalmoI1977;95:979-983.

macular

degeneration.

M], Bakall

B, et al:

of the gene responsible

dystrophy.

for Best

Nat Genet 1998;19:241-247.

290. Hsieh RC, Fine BS, Lyons ]S: Pattern trophies of the retinal pigment epithelium. OphthalmoI1977;95:429-435. 291. Marmor MF, Byers B: Pattern the pigment

epithelium.

dysArch

dystrophy

of

Am J Ophthalmol1977;

84:32-44. 292. Marmor

MF: Pattern

dystrophies.

In:

Heckenlively ]R, Arden GB, eds: Principles and Practice of Clinical Electrophysiology of Vision.

561-570. 281. Maloney

GA, et al:

gene in Best

Vis Sci 2000;41:1291-1296. K, Koisti

Identification

82:252-255. 280. Noble

FL, Fishman

in the VMD2

disease and age-related

Ophthalmology

choroidal

Acta Oph-

ERG c-wave

degeneration

284. Rover ], Hut tel M, Shaubele

tection

nant Stargardt's

trophy:

L, et al:

dystrophy.

SE, Skoog KO: The

285. Deutman link-

112:765-772. 275. Zhang

G, Regenbogen

macular

Acta OphthalmoI1980;58:659-666. ERG:

41 (suppl): 144. Clinical

283. Nilsson in vitelliform

in Stargardt

cells. Invest Ophthalmol

Best's vitelliform

thalmoI1986;175:1-31.

Nat Genet 1997;17:15-16.

273. Molday

282. Godel V, Chaine

St Louis:

Mosby-Year

293. Deutman

Book;

1991:700-704.

AF, van Blommestein

]D,

Henkes HE, et al: Butterfly-shaped pigment dystrophy of the fovea. Arch Ophthalmol1970; 83:558-569. 294. O'Donnell Autosomal pigment 680-683.

FE, Schatz H, Reid P, et al:

dominant epithelium.

dystrophy

of the retinal

Arch OphthalmoI1979;97:

137

References

295. Ayazi S, Fa~an R: Pattern pi~ment

epithelium.

dystrophy

of the

Retina 1981;1:287-289.

296. Sjogren

H: Dystrophia

pigmentosae

retinae.

reticularis

307. Frank

Acta OphthalmoI1950;28:

308. Fetkenhour al: Central

A retinal

RP, Oosterhuis

]A, Delleman

lesion resembling

reticularis

laminae

Winkelman

Sjogren's

pigmentosae

]E, Crone

Excerpta

Medica;

K: [Fundus

pulveru-

Graefes Arch Clin Ophthalmol1969;

Carolina's

dominant

et a!: Butterfly-shaped

VC, Vandenburgh

pigment

fovea caused by a point

dystrophy

mutation

in codon

K,

I, Walsh ]B, Henkind

form macular

dystrophy

epithelial

dystrophy:

North

Carolina

macular

areolar pigment

V, Gurney dystrophy

epithelial

313. Rohrschneider

Br J Ophthal-

dystrophy:

function

phy. Retina 1998;18:453-459.

of the retinal

pigment

Ophthalmology

1982;89:1400-1406.

302. Fishman

GA, Woolf

al: Reticular

epithelium.

MB, Goldberg

tapeto-retinal

dystrophy:

ble late stage of Sjogren's

reticular

MF, et as a possi-

dystrophy.

in maternally GEDIAM

of macular

inherited

Group.

M, Vialettes pattern

diabetes

Ophthalmology

B,

WH, Wadsworth

Hereditary

macular

aciduria.

6. Genomics 1992;13;681-685.

macular

dystrophy

mapping

316. Rabb M, Mullen

1999;106:

in a Belizean

degeneration

]B ]r:

Carolina

Clinical

Am J OphthalmoI1971;1:224-230.

Carolina

macular

dystrophy

G, et al: (MCDR1)

in

Texas. Retina 1998;18:448-452. 306. Reichel

MB, Kelse!l

notype

of a British

trophy

family

linked

North

RE, Fan ], et al: PheCarolina

to chromosome

OphthalmoI1998;82:1162-1168.

macular

dys-

6q. Br J

L, Yelchits

macular family

317. Pauleikhoff

and amino-

(MCDR1):

to 6q14-q16.2.

a review Ophthalmic

Genet 1993; 14: 143-150.

North

]A, Sidbury

is assigned to chro-

315. Small KW, Weber ] , Roses A, et al: North

and deafness.

305. Sma!l KW, Garcia CA, Ga!lardo North

dystrophy

Am J Ophthalmol1998;

304. Lefler

dystro-

Roses A, et al: North

mosome

Paediatr

1821-1827.

macular

macular

Carolina

dystrophy

in a German

Carolina

and retined

P, Virally-Monod

et al: Prevalence

Carolina

314. Small KW, Weber ]L,

Br J OphthalmoI1976;60:35-40. 303. Massin

with North

A, Kruse

testing

pedigree

one family,

110:51 5-518.

K, Blankenagel

FE, et al: Macular

301. Watzke

RC, Folk ]C, Lang RM: Pattern

N, et al: and central

one disease. Arch Ophthalmol1992;

mol 1982;66: 170-173.

dystrophy

WC: North foveal dystro-

is it? Br J Ophthalmol199f,

312. Small KW, Hermsen

and butterfly-shaped

a continuum?

dystro-

75:401-406.

167

P: Vitelli-

macular

1989;96:1747-1754.

], McLean

of the

of the RDS gene. Nat Genet 1993;3:202-207. 300. Gutman

Carolina

progressive

phy: how progressive BE, Sheffield

areolar

Ophthalmologica

Ophthalmology

311. Small KW, Killian

178:

176-182. 299. Nichols

G], et

dystrophy.

GF: Central

dystrophy.

310. Small KW: North phy, revisited.

298. Slezak H, Hommer

N, Dobbie

epithelial

VM, ]udisch

pi~ment epithelial 1984; 189:69-72.

1970;2:40-45.

lentus.]

CL, Gurney

areolar pigment

309. Hermsen

In:

RA, eds: Perspectives in

Ophthalmology. Amsterdam:

R],

foveal dystro-

Am J OphthalmoI1976;81:745-753.

]W:

dystrophia

retinae.

III MB, Williams

progressive

phy. Am J OphthalmoI1974;78:903-916.

laminae

279-295. 297. Mesker

HR, Landers

et al: A new dominant

dystrophy

S, et al: A phenotype

maps to MCDR11ocus. 125:502-508.

D, Sauer CG, Muller

and genetic

evidence

dominant

North

a German

family. Am J OphthalmoI1997;124:

412-415.

Carolina

CR, et al:

for autosomal

macular

dystrophy

in

138

TheElectroretinogram

318. Small KW, Puech B, Mullen Catolina

macular

dystrophy

maps to the MCDR11ocus. 319. Douglas sive bifocal

M,

L, et al: Notth

phenotype

in France

Mol Vis 1997;3:1.

Waheed

atrophy:

Progressive

a rare familial

332. Noble

cone dysfunction.

1988;106:557-560.

742-751.

333. Pinckers

calization

RE, Godley

BF, Evans K, et al: Lo-

of the gene for progressive

chorioretinal

atrophy

(PBCRA)

bifocal

to chromosome

6q. Hum Mol Cenet 1995;4:1653-1656. 321. Krill

AE, Deutman

degenerations:

macular Am J Oph-

thalmoI1972;73:352-369.

A, Deutman

sive cone degeneration,

RD: Progres-

dominantly

inherited.

Arch OphthalmoI1968;80:77-83.

with dominant

DW:

inheritance.

334. Krill

AF, Fishman

AE, Deutman

cone degenerations.

335. Kellner

photopic

dystrophy,

nyctalopia,

scotopic 1976;

A: X-Iinked

progressive

cone dys-

Proc Ser 1982;33:399-403.

IR, Weleber

recessive cone dystrophy entity

with

sheen:

Mizuo-Naka-

Arch Ophthalmol1986;

eration:

MP, Moore

AT: The cone dys-

339. Rosenberg

clinical

P, Foerster

MH:

and electrophysiologi-

b-waves.

and delayed

MH,

U, Foerster

b-waves

in progressive

tended

classification.

cone dystrophies:

an ex-

Cer J OphthalmoI1993;2:

170-177. 330. Noble golden

tapetal

S, Carr RE: The

sheen reflex

in retinal

Am J OphthalmoI1989;107:211-217.

disease.

SE: Retinal

cone

rod ERG type: five

AY, Halevy

DA, et al:

dystrophy

with

rod electroretinogram

Kellner

U, Wessing A:

and supernormal

dark-adapted

in the electroretinogram.

Graefes Arch

Clin Exp OphthalmoI1990;228:116-119. 342. O'Donnell sheen macular

KG, Margolis

degen-

Vis Res 1996;36:889-901.

341. Foerster

329. Kellner function

retinal

pigmentosa.

Vis Sci 1990;31:2283-2287. T, Simonsen

DC, Cideciyan

Cone dystrophy

of dys-

human retinitis

Sites of disease action in a retinal

Cer J OphthalmoI1992;1:105-109. Pattern

with

Rod

cyclic guano-

new cases. Acta OphthalmoI1993;71:246-255.

cal findings.

MH:

Br J Ophthal-

S, Berson EL:

of supernormal

supernormal

U, Kleine-Hartlage

Cone dystrophies:

GA: Supernormal

in an elevated

comparison

340. Hood

Eye 1998; 12:553-565.

328. Kellner

MA, Miller

sine monophosphate-type

dysfunction 104:

rod re-

Arch Oph-

78.

Invest Ophthalmol

RG: X-Iinked

with tapetal-Iike

1322-1328.

trophies.

Br J

CJ: Cone

degeneration.

KR, Fishman

electroretinograms

trophy. Doc Ophthalmol

MacKay

and supernormal

ERG in cone dystrophy.

338. Sandberg

Ophthalmologica

173:81-101.

327. Simunovic

Cone dystrophies

thalmoI1983;101:718-724.

gressive cone dystrophies.

mura phenomenon.

MH:

electroretinogram.

336. Gouras P, Eggers HM,

mol 1984;68:69-

recognized

M: The

Doc OphthalmoI1973;35:

U, Foerster

with negative

324. Fran9ois I, de Rouck A, de Laey II: Pro-

a newly

cone

1977;174:145-150.

337. Alexander

Am J OphthalmoI1974;77:293-303.

326. Heckenlively

AF: Peripheral

disease. Ophthalmologica

sponses: a new retinal

IT, Owen WG, Brounley

325. Pinckers

Am J Ophthalmol

OphthalmoI1993;77:404-409.

322. Berson EL, Gouras P, Gunkel

Cone dystrophy

1987;

1-80.

AF: Dominant

the cone dystrophies.

323. Pearlman

YC, et al:

Ophthalmology

KG, Siegel IM, Carr RE: Progressive

peripheral

disease of the eyes. Br J OphthalmoI1968;52:

320. Kelsell

KG, Greenstein

cone dystrophy.

94:1401-1409.

I, Wyse CT: Progres-

chorio-retinal

331. Ripps H, Noble

FE Jr, Welch dystrophy:

inant maculopathy.

RB: Fenestrated

a new autosomal

dom-

Arch OphthalmoI1979;97:

1292-1296. 343. O'Donnell sheen macular 98:57.).

FE Jr, Welch dystrophy.

RB: Fenestrated

Arch Ophthalmol1980;

139

References

344. Slagsvold dystrophy:

IE: Fenestrated

a new autosomal

sheen macular

dominant

maculopa-

macular

MI,

Mets MB: Fenestrated

dystrophy.

sheen

Arch OphthalmoI1984;102:

dystrophy.

PA: Fenestrated

sheen

347. Polk TD, ial internal

Am J OphthalmoI1991;112:

Gass ID,

limiting

sheen retinal

Green WR, et al: Famil-

membrane

dystrophy.

dystrophy:

a new

Arch Ophthalmol1997;

348. Simell

0, Takki

and gyrate atrophy

K: Raised plasma-ornithine of the choroid

of ornithine

gyrate atrophy.

C, et al: Expression

aminotransferase

Invest Ophthalmol

gene in

Vis Sci 1988;7:

diet. i Clin

0, Sipila I: Gy-

and retina:

in juvenile

the ocular

patients

despite

normal

or near normal

plasma ornithine

tration.

Ophthalmology

1987;94: 1428-1433.

358. Berson E, Hanson

AH III,

Rosner B, et al:

A two year trial of low protein, B6 for patients

concen-

low arginine

diets

with gyrate atrophy.

Birth Defects 1982;18:209-218. L: [A case of choroideremia.]

360. Sieving

1871;2:191.

PA, Niffenegger

Electroretinographic grees with

lH,

findings

choroideremia.

Berson EL:

in selected

pedi-

Am i Ophthalmol

1986;101:361-367.

1001-1005. 350. Mitchell

GA, Brody

least two mutant transferase

LC, Sipila I, et al: At

alleles of ornithine

cause gyrate atrophy

and retina in Finns.

o-amino-

of the choroid

Proc Natl Acad Sci USA 1989;

361. Nussbaum

RL, Lewis

Choroideremia

is linked

ment length

polymorphism

Ami

351. McClatchey et al: Splicing transferase

AI, Kaufman

defect

(OAT)

DL,

Berson EL,

at the ornithine

352. Weleber

RG, Kennaway

B6 in management

of choroid

NG, Buist NR: of gyrate atrophy

rate atrophy

MI, Caruso RC, Valle D: Gy-

of the choroid

of ornithine

and retina:

slows retinal

long-term

degenera-

RG, Kennaway

NG: Clinical

of vitamin

B6 for gyrate atrophy

and retina.

Ophthalmology

with

and low-protein,

trial

of the choroid

1981 ;88:316-324.

355. Berson EL, Shih VE, Sullivan in patients

PL: Ocular

gyrate atrophy low-arginine

thalmology 1981;88:311-315.

Xq13-q24.

with

to

1985;92:800-806.

FP, van de Pol Dl, van Kerkhoff

LP, et al: Cloning patients

R: Map-

diseases: provisional

of the locus for choroideremia Ophthalmology

of a gene that is rearranged

choroideremia.

364. Merry

DE, lanne

of a candidate

in

Nature 1990;347:

on pyri-

diets. Oph-

PA, Landers

lE: Isolation

gene for choroideremia.

Proc Natl

A cad Sci USA 1992;89:2135-2139. 365. Seabra MC, Brown

tion. Arch OphthalmoI1991;109:1539-1548. 354. Weleber

frag-

at Xq13-21.

674-677.

and retina. Lancet 1978;2:1213.

353. Kaiser-Kupfer

lG, et al:

RL, Ferrell

ophthalmic

363. Cremers

Hnm Genet 1990;47:790-794.

DXYS1

RA, Nussbaum

ping X-linked assignment

amino-

locus in gyrate atrophy. Am J

RA, Lesko

to the restriction

Hum Genet 1985;37:473-481.

362. Lewis

86:197-201.

reduction

K, Simell

of the choroid

Naturwissenschaften

349. Inana G, Hotta Y, Zintz

amino

of hyperorni-

an arginine-deficient

359. Mauthner

and retina.

Lancet 1973;1:1031-1033.

Vitamin

rate atrophy

or vitamin

115:878-885.

doxine

with

disease progresses

1-7.

findings

thinemia

SW, et al: Gy-

and retina:

and correction

357. Vannas-Sulonen

346. Sneed SR, Sieving

defect

of the choroid

Invest 1980;65:371-378.

855-856.

macular

rate atrophy

acid metabolism

thy. Acta OphthalmoI1981;59:683-688. 345. Daily

356. Valle D. Walser M, Brusilow

nal degeneration

MS, Goldstein

in choroideremia:

rab geranylgeranyl

transferase.

lL:

Reti-

deficiency

Science 1993;259:

377-381. 366. Fran<;ois l, de Rouck A: Electrophysiological studies

in Groenblad-Strandberg

Doc Ophthalmol

syndrome.

Proc Ser 1980;23: 19-25.

of

140

The Electroretinogram

367. Kellner X-Iinked

U, Briimmer

congenital

S, Foerster

retinoschisis.

MH,

Clin Exp OphthalmoI1990;228:432-437 368. de long PT, Zrenner Mizuo

phenomenon

pathogenesis

in X-Iinked

fundus

Y, Terasaki

reflex

with X-Iinked

juvenile

Arch

H: Golden hyaloid

retinoschisis

T, Katsumi

0, Hirose

physiological

similarities

between

recessive

retinoschisis.

in a patient

371. Sieving

PA, Bingham

381. Noble

KG, Carr RE, Siegel IM: Familial

T: Electro-

dystrophy.

two eyes with

382. Fishman

Doc Ophthalmol

EL, Kemp I, et al:

retinoschisis

mutation

associated

with a rod-cone

Am J OphthalmoI1978;85:551-55

Diagnostic

GA, Iampol

features

electroretinogram

with

preservation

scotopic

383. Hirose

from XLRS1

hereditary

of the

LM,

b-wave. Am J Oph-

ings in X-Iinked

syn-

GA, Derlacki

Dl, et

and electroretinographic

find-

juvenile

retinoschisis.

Arch Oph-

I, Merin

Press; 1988:85-104. 385. Brown

DM,

Graemiger

linkage

RA, Hergersberg

sive vitreoretinopathy

386. Stickler

374. Yanoff M, Kertesz LE: Histopathology

Rahn E, Zimmerman

of juvenile

WA: Pathology

retinoschisis.

retinoschisis.

ju-

Arch OphthalmoI1972;88:

(COL2A1) drome

et al: Positional

cloning juvenile

A, Wameke-Wittstock

NN,

Ala-Kokko

L, Knowlton

R,

in a family

388. Brown

al: Procollagen

the Stickler

DM,

of the photoreceptor

A, et al: Mu-

gene cause abnormalities as well as inner responses

of the ERG. Doc OphthalmoI1999;98:153-173.

syn-

Proc Natl A cad

Nichols

BE, Weingeist

II gene mutation

drome. Arch Ophthalmol1992; K, George N, Moore

RG,

II gene

Sci USA 1991;88:6624-6627.

retinoschisis.

Nat Genet

with

(arthro-ophthalmopathy).

of the gene associated

1997;17:164-170. tations of the XLRS1

5q13-14.

FI, et al:

et al: Stop codon in the procollagen

131-138. 376. Sauer CG, Gehrig

GB, Belau PG, Farrell

387. Ahmad of hereditary

to chromosome

Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc 1965;40:433-455.

Arch OphthalmoI1968;79:49-53. 375. Manschot

M,

of Wagner disease and ero-

Arch OphthalmoI1995;113:671-675.

436-441.

vitreoreti-

DA, ed: Retinal

Dystrophies and Degenerations. New York: Raven

et a!: Genetic Arch OphthalmoI1970;84:

and retinal

S: Hereditary

In: Newsome

retinal

degenerations.

CL: Wagner's

degeneration

373. Carr RE, Siegel IM: The vitreo-tapeto-

377. Bradshaw

MF:

Arch OphthalmoI1973;89:176-185.

384. Schulman

thalmoI1987;105:513-516.

with X-Iinked

Goldberg

T, Lee KY, Schepens

nal degenerations.

NS, Fishman

al: Psychophysical

venile

7.

of the Favre-Goldmann

vitreoretinar

detachment.

thalmoI1999;128:179-184. 372. Peachey

Br J

drome. Br J OphthalmoI1976;60:345-353.

X-Iinked

Arg213Trp

juvenile

foveal retinoschisis.

OphthalmoI1989;73:470-473

Retina 1999;

1985;60:149-161.

Juvenile

reti-

Doc Ophthalmol

K, Hara S: Autosomal

without

foveal retinoschisis

370. Tanino

M: Familial

patients.

1987;65:393-400.

tapetal-Iike

retinoschisis.

CL, et al:

Arch Ophthalmol

I, Matsuhashi

in female

380. Yamaguchi

19:84-86.

X-Iinked

379. Shimazaki noschisis

retinoschisis:

phenomenon.

and posterior

RA, Lee GB, Martonyi

foveal retinoschisis.

1977;95:1190-1196. GI, et al:

OphthalmoI1991;109:1104-1108. 369. Miyake

378. Lewis Familial

.

E, van Meel

of the Mizuo

et al:

Graefes Arch

389. Bennett Autosomal

neovascular

tory vitreoretinopathy. 1125-1135. 390. Stone EM,

Kimura

syn-

110: 1589-1593.

SR, Folk IC, Kimura dominant

TA, et

in Stickler

AE, et al: inflamma-

Ophthalmology

1990;97:

AE, Folk IC, et al: Ge-

netic linkage

of autosomal

inflammatory

vitreoretinopathy

dominant

neovascular

to chromosome

11q13. Hum Mol Cenet 1992;1:685-689.

References

391. Kaufman Autosomal

SI, Goldberg

dominant

MR, Orth DH,

et al:

404. Van Nouhuys reoretinopathy

vitreoretinochoroidopathy.

tal disorders

392. Blair NP, Goldberg

thalmoI1982;54:

dominant

(ADVlRC).

MF, Fishman

in autosomal

choroidopathy.

MF:

dominant

etal:

110:

MF, Lee FL, Tso MO, et al: His-

topathologic

study of autosomal

retinochoroidopathy: tary dystrophy

dominant

peripheral

annular

vitreopigmen-

of the retina. Ophthalmology

1989;

96:1736-1746. El, Payne IW: Autosomal

nant vitreoretinochoroidopathy:

domi-

report of the

third family. Arch OphthalmoI1993;111:194-196. 396. Roider I, Fritsch somal dominant

E, Hoerauf

Retina

1997; 17:294-299. 397. Criswick

VG, Schepens

CL: Familial

exu-

Am J Ophthalmol1969;

68:578-594. exudative

Trans Am Ophthalmol

vitreoreti-

Soc 1995;93:

et al: Familial

A, Paysse EA, Coats DK,

exudative

persistent

vitreoretinopathy

hyperplastic

primary

mimvitreous.

Am J OphthalmoI1999;127:469-471.

AE: Birdshot

T, Katsumi

function

0, Pruett

in birdshot

409. Gass JD: Vitiliginous

410. Aaberg TM:

Diffuse

patch choroidopathy Carmel,

Fluorescein

California,

411. Fuerst

nopathy.

Am J Ophthalmol1992;

401. MUller Mapping

B, Orth

linkage

U, Van Nouhuys

of the autosomal

vitreoretinopathy

114: 14.'5-148.

dominant

locus (EVR1)

Macula

October

DJ, Tessler

analysis in four families.

402. Laqua nopathy.

exudative

vitreoreti-

213:121-133.

tosomal

EL, Norris

dominant

IL,

exudative

Cleasby

GW: Au-

vitreoretinopathy.

Arch OphthalmoI1983;101:1532-1535.

GA, et al:

Arch Ophthalmol

HA, de Rouck

retinopathy.

studies

A, de Laey JJ, et al: in birdshot

Am J Ophthalmol1988;

413. Kaplan

HJ, Aaberg TM:

chorio-

106:430-436.

Birdshot

retinocho-

roidopathy.

Am J OphthalmoI1980;90:773-782.

414. Godel

V, Batuch

E, Lazar M: Late develop-

415. Priem

in birdshot

Am J Ophthalmol1989;21

HA, Oosterhuis

JA: Birdshot

tion. Br J OphthalmoI1988;72:646-659.

Graefes Arch Clin Exp Ophthalmol1980;

403. Feldman

Fishman

retinochoroidopathy.

1984;102:214-219.

clinical

characteristics

416. Baarsma GS, Kijlstra Association HLA-A29

H: Familial

1979.

HH,

exudative

20:317-319.

at

Symposium,

retinopathy:

Genomics 1994;

salmon

Presented

CE, et al:

by multipoint

Arch

inflammatory

choroidopathy.

vitreoreti-

retinochoroidopa-

syndrome.

linked

exudative

RC, et al:

chorioretinitis.

ment of chorioretinallesions

familial

retino-

;99: 1778-1787.

400. Plager DA, Orgel lK, Ellis FD, et al: Xrecessive

pars

Am J OphthalmoI1980;89:

Electrophysiologic

399. Chang-Godinich

WH,

changes in chronic

thy. Acta OphthalmoI1991;69:327-337.

412. Priem

473-521.

icking

31-45. 408. Hirose

Birdshot

398. Benson WE: Familial nopathy.

choroidopathy.

International

dative vitreoretinopathy.

as-

Am J OphthalmoI1981;91:505-512.

Ophthalmol1981

H, et al: Auto-

vitreoretinochoroidopathy.

M: Temporal Arch Ophthalmol

Ram say RC, Knobloch

407. Ryan SJ, Maumenee

Retinal

395. Traboulsi

HL,

Electrophysiologic

planitis.

1563-1567. 394. Goldberg

retina. Doc Oph-

1969;81:207-214. 406. Cantrill

vitreoretino-

vit-

1-414.

pects of the electroretinogram.

Electro-ocu-

Arch Ophthalmol1992;

of the peripheral

405. Berson EL, Gouras P, Hoff

Br J OphthalmoI1984;68:2-9.

393. Han DP, Lewandowski lography

GA, et al:

vitreoretinochoroidopathy

exudative

and other vascular developmen-

Arch OphthalmoI1982;100:272-278.

Autosomal

CE: Dominant

141

267-269.

of birdshot antigen.

retino:49-52. chorio-

and evolu-

A, Oosterhuis

JA, et al:

retinochoroidopathy

Doc Ophthalmol1986;61

and :

142

The ElectroretinogT;

417. Nussenblatt Birdshot

RB, Mittal

KK, Ryan S, et al:

retinochoroidopathy

HLA-A29

antigen

ro retinal

S-antigen.

associated

and immune

with

responsiveness

Am J OphthalmoI1982;94:

tracted

Glaser JS, Gass JD, et al: Pro-

enlargement

ple evanescent

of the blind

white

spot in multi-

dot syndrome.

Arch Oph-

thalmoI1989;107:194-198. blind

MP, Shults WT, et al: spot enlargement:

trum of disease. Ophthalmology 420. Kiillillel

evanescent

with acute blind thalmol1989;

white-dot

spot enlargement.

HS, et al: syndrome

Am J Oph-

107 :425-426.

421. Fletcher

WA, Iilles

Acute idiopathic blind

a spec-

1991;98:497-502.

AS, Folk JC, Thompson

The multiple

blind

spot syndrome

RK, Goodman

D, et al:

spot enlargement:

a big

without

optic disc edema.

of bilateral

ML,

Lesser

acute idiopathic

blind

ment. J Clin Neuroophthalmol1992; 423. Jaillpol Multiple

LM,

Sieving

evanescent

course

spot enlarge12: 173-177.

PA, Pugh D, et al:

white

dot syndrome,

Arch OphthalmoI1984;102:671-674.

424. Sieving

PA, Fishman

Multiple

evanescent

electrophysiology retinal

pigment

GA, Jaillpol

white

LM,

dot syndrome,

of the phororeceprors epithelial

et al: II:

during

disease. Arch Ophthal-

mol 1984;102:675-679. 425. Gass JD: Acute

zonal occult outer retinopa-

426. Gass JD, Stern C: Acute as a variant

outer retinopathy.

13:79-97.

histoplasmosis.

Arch OphthalmoI1984;102:

annular

outer

of acute zonal occult

Am J Ophthalmol1995;

427. Jacobson SG, Morales dysfunction

cult outer retinopathy. 1187-1198.

that mimics

ocular

1776-1784. 430. Morgan

CM, Schatz H: Recurrent Ophthalmology

431. Khorram Blind

KD, Jampol

spot enlargement

multifocal

multifo-

1986;93:1138-1147.

LM,

Rosenberg

MA:

as a manifestation

choroiditis.

of

Arch OphthalmoI1991;109:

1403-1407. 432. Adachi [The

E, Chiba Y, Kanaizuka

electroretinogram

in uveitis

D, et al: studies

time of each wave.] Nippon

on Ganka

Gakkai Zasshi 1970;74:1557-1560. 433. Cruz RD, Adachi-Usami electroretinograms potentials

in Behget's

OphthalmoI1990;34:

visually

Y: Flash evoked

disease. Jpn J

142-148.

434. Hatt M, Niemeyer in connection

E, Kakisu

and pattern

with

G: [Electroretinography

Behget's

435. Verity

disease.]

Graefes

DH, Vaughan

RW, Madanat

W, et al:

is associated

with oc-

Factor V Leiden

mutation

ular involvement

in Behget disease. Am J Oph-

thalmol1999;

128:352-356.

436. Peachey

NS, Charles

Electroretinographic

HC, Lee CM, et al:

findings

437. Krill

AE, Diamond

in sickle cell reti-

119:

DS, Sun XK, et al: in acute zonal oc-

Ophthalmology

1995; 102:

M: The

electroretino-

artery disease. Arch Ophthalmo{

1962;68:42-51. 438. Ulrich

WD,

Ulrich

CH, K1istner R, et al:

ERG and EGG in carotid ease. Doc Ophthalmol

of retinal

choroiditis

a syndrome

gram in carotid

330-334.

Pattern

RF, Gass JD: Multifocal

nopathy. Arch OphthalmoI1987;105:934-938.

thy. J Clin Neuroophthalmol1993;

retinopathy

Am J

Arch Clin Exp OphthalmoI1976;198:113-120.

I: clin

ical findings.

uveitis.

and pan uveitis:

cortical

RL: Prolonged

W: A new chorioreti-

with anterior

OphthalmoI1973;76:758-762.

the implicit

Arch OphthalmoI1988;106:44-49. 422. Cooper

RA, Dorsch

associated

cal choroiditis.

419. Singh K, de Frank Acute idiopathic

nopathy

429. Dreyer

147-158. 418. Hammed LM,

428. Nozik

439. Johnson sensitivity

artery occlusion

dis-

Proc Ser 1980;23:49-55.

MA, Marcus

S, Elman

MJ: ERG

loss in venous stasis retinopathy.

Invest Ophthalmol 440. Henkes

Vis Sci 1987;28:319.

HE: Electroretinography

tory disturbances

in circula-

of the retina: electroretinogram

in cases of occlusion of the central retinal artery or one of its branches. Arch Ophthalmol1954;5 1: 42-53.

References

441. Karpe G, Uchermann troretinogram, culatory

VII:

A: The clinical

the electroretinogram

disturbances

elec-

452. Henkes

in cir-

nographic

of the retina. Acta Ophthal-

mol 1955;33:493-516. 442. Flower

troretinographic

KR: Elec-

chan~es and choroidal

in a case of central

HE, van der Kam IP: Electroreti-

studies

retinal

defects

artery occlusion.

Am

in general

in arteriosclerosis. 453. Eichler

RW, Speros P, Kenyon

tentials

retinopathy.

454. Muller

W, Gaub I, Spit tel U, et al: Oscilla-

Doc Ophthalmol ProcSer

in retinal

vascular

disease. Doc Ophthal-

in cases of systemic

455. Bernstein

HN:

hypertension.

1984;40:167-171.

Chloroquine

ocular toxicity.

Surv OphthalmoI1967;12:415-447.

444. Ponte F: ERG and vascular disturbances.

456. Finbloom

as,

In: Franl;ois

J, ed: The Clinical

al: Comparison

of hydtoxychlotoquine

retinography.

Symposium

Value of Electro-

in Ghent,

1966. Basel:

S Karger AG; 1968:300-311. 445. Johnson

MA, Marcus

Neovascularization

S, Elman retinal

findings.

457. Rynes RI: Ophthalmologic

vein occlu-

term hydtoxychloroquine

Arch Ophthal-

T, McMeel

in the prognosis

retinal

JW: Electro-

and classification

vein occlusion.

Arch Ophthalmol

1983;101:232-235.

rubeosis

implicit

S, Bauer B: Cone

time as an early predictor

in central

retinal

vein occlusion.

of Am

J OphthalmoI1998;125:247-249. 448. Kaye SB, Harding raphy in unilateral as a predictor

retinal

of rubeosis

vein occlusion

iridis. Arch Ophthalmol

1988; 106:353-356. 449. Johnson graphic

findings

acute central

TJ: Electroretino-

in iris neovascularization

retinal

vein occlusion.

due to

Arch Ophthal-

mol 1993;111:806-814. MA, Hood

transduction

is affected

associated

with

DC: Rod photoreceptor in central

retinal

vein

iris neovascularization.

J Opt Soc Am 1996;13:572-576. 451. Breton

ME, Quinn

Electroretinogram as predictors occlusion 1343-1352.

toxt

at presentation

in central

Ophthalmology

retinal 1989;96:

vein

safety oflong-

sulfate

treatment.

Livesey

SI, Richards

for hydroxychlotoquine

459. Mavrikakis chlotoquine

M, Papazoglou toxicity

IM, et

retinal

tox-

S, Sfikakis

PP,

in long term hydroxy-

treatment.

Ann Rheum Dis 1996;

55:187-189. 460. Krill

AE, Potts AM, Iohanson

retinopathy:

between graphic

investigation

dark adaptation findings

CE: Chloroof discrepancy

and electtoretino-

in advanced

stages. Am J Oph-

thalmoI1971;71:530-543. A, Sandberg

Hydroxychlotoquine

MA, Gaudio

retinopathy.

AR, et al:

Am J Ophthal-

mol 1991;112:528-534. 462. Henkind findings.

P, Carr RE, Siegel IM: Early chlo-

retinography:

clinical

463. Adlakha Electrodiagnosis 267-284.

and functional

Arch OphthalmoI1964;71:157-165. a, Crews SI, Shearer AC, et al: in drug-induced

the eye. Trans Ophthalmol

GE, Keene SS, et al:

parameters

of rubeosis

patients.

of retinal

is it necessary? Eye 1990;4:572-576.

roquine

450. Johnson occlusion

icity:

461. Weiner

MA, McPhee

co,

al: Screening

quine

SP: Early electroretinog-

central

OA, et and chlo-

Am J Med 1983;75:35-39.

et al: Retinal

447. Larsson J, Andreasson b-wave

use and the development

458. Morsman

446. Sabates R, Hirose

K, Newsome

MJ, et al:

mo11988; 106:348-352.

of central

roquine

Silver

city. J RheumatoI1985;12:692-694.

in central

sion: electroretinographic

retinography

po-

Doc Oph-

thalmol Proc Ser 1984;40:161-165.

443. Eichler findings

and

I, Stave I, Bohm I: Oscillatory

in hypertensive

tory potentials

mol 1980;23:57-61.

hypertension

Angiology 1954;5:49-58.

J OphthalmoI1977;83:451-459. J, Stave J: Electroretinographic

143

disorders

Soc UK 1967;87:

of

144

The Electroretinogram

464. Sassaman FW, Cassidy JT, Alpern troretinography

in patients

sue diseases treated Am J Ophthalmol 465. Siddall

with

M: Elec-

connective

tis-

hydroxychloroquine.

and thioridazine.

Can J

effects of phenothiazines

of retinal

on

degeneration

on Non-steroid

W: [On the

after application

In: Smith JL, ed: Neuro-ophthalmology

blyopia:

1980:109-118.

731-734.

470. Potts AM: Uveal pigment

and phenothia-

482. Frani;ois

Trans Am Ophthalmol

Soc 1962;

FH: Thioridazine

nopathy. Arch Ophthalmol 472. Meredith Progressive

TA, Aaberg TM,

Arch Ophthalmol

474. Marmor pro~ressive?

reti-

Willerson

WD:

after receiving

thi-

1978;96: 1172-1176.

A: An ophthalmoscopic

under treatment

Ophthalmol

pigmentary

1973;90:251-255.

chorioretinopathy

473. Appelbaum patients

with

study of

thioridazine.

Arch

MF:

Is thioridazine

Relationship

JB, Hillery

poisoning.

M, Fenton

follow-up

J, de Rouck

and optic evaluation

M: Two

in quinine

A, Cambie

in quinine

am-

1987;65:

E: Retinal

poisoning.

483. Bacon P, Spalton

DJ, Smith

from quinine

Br J Ophthalmol

Ann

retinopathy

of pigmentary

Br J Ophthalmol

changes

1990;74:

739-742. BH, Lipkowitz

retinopathy.

476. Goar EL, Fletcher following

J: Nummular

Retina 1984;4:253-256. MC: Toxic chorioreti-

the use of NP-207 .Am J Oph-

thalmol1957;44:603-608.

toxicity.

SE: Blindness 1988;72:

219-224. 484. Stelmach

MZ,

O'Day

J: Partly

visual failure

with

J Ophthalmol

1992;20:57-64.

485. McKellar

MJ, Hidajat

physiological

methanol

toxicity:

features.

reversible

toxicity.

Aust NZ

RR, Elder clinical

MJ: Acute

and electro-

Aust NZ J Ophthalmol

1997;25:225-230. 486. Hayreh al: Methyl

475. Kozy D, Doft

nopathy

FC: Electro-

1973;90:307-309.

ocular methanol

1963;69:578-580.

to visual function.

thioridazine

Blodi

OphthalmoI1972;4:177-185.

60:517-552. 471. Davidorf

oridazine.

HM,

a case report. Arch Ophthalmol

New York: Masson Publishers;

zine compounds.

retinal

Am J Ophthal-

changes in acute quinine

year electrophysiology

Focus.

Canada,

reduced

deposits.

480. Cibis GW, Burian

481. Moloney

hydrochloride

SymCom-

moI1968;66:825-835.

469. Fishman

chorioretinopathy.

of ex-

of the Second Laurentian

and corneal

retinogram

in psychiatry.]

GA: Thioridazine

summary

International

479. Burns CA: Indomethacin,

Arch Ophthalmol

toxic pigmentary

1972;73:

Anti-inflammatory

Proceedings

Klin Monatsbl Augenheilkd 1963;143:743-749.

(Mellaril)

NO: Five-year

with indomethacin.

sensitivity,

1970;28:16-69.

of high doses of phenothiazine

GH, Canta LR: Indo-

Am J Ophthalmol

Rheumatology Conference, Quebec, 1966. Excetpta Medica 1968;49:53.

retinopathy.]

468. Busch Kcr, Busch G, Lehmann question

perience posium

Ned Tijdschr Geneeskd 1966; 110: 1687.

the eye. Doc Ophthalmol

HE, van Lith

retinopathy.

pounds.

PP: [Phenothiazine

467. Boet DJ: Toxic

methacin

478. Rothermich

toxic changes associated

1966; 1: 190-198.

466. Alkemade

477. Henkes 846-856.

1970;70:515-523.

JR: Ocular

with chlorpromazine Ophthalmol

with

MS, Hayreh alcohol

SS, Baumbach

poisoning,

III:

GL, et

ocular toxicity.

Arch OphthalmoI1977;95:1851-1858. 487. Baumbach

GL, Cancilla

G, et al: Methyl

alcohol

PA, Martin-Amat

poisoning,

tions of the morphological

IV: alterna-

findings

and optic nerve. Arch Ophthalmol

of the retina 1977;95:

1859-1865. 488. Murray Methanol

TG,

Burton

poisoning:

rural and functional

TC,

a rodent evidence

ment. Arch Ophthalmol

Rajani C, et al: model

with struc-

for retinal

1991;109:1012-1016.

involve-

145

References

489. Ports AM, Proglin on the visual toxicity

J, Farkas I, et al: Studies of methanol.

Am J Ophthol-

mol 1955;40:76-83. AD: The electroretinogram

methyl

alcohol

poisoning

in

in human

be-

ings. Am J OphtholmoI1962;54:34-53. 491. Peyman traocular

of gentamicin:

ES, et al: In-

Arch OphtholmoI1974;92:42-47.

492. Palimeris

G, Moschos

mental

findings.

Doc Ophtholmol

502. Krauss GL, Johnson tion: electroretinogram

experi-

Proc Ser 1978;

493. Mochizuki

M, Kawasaki

of antibiotics:

electroretinogram.

K, et

evaluation

by

Doc OphtholmoI1988;69:

195-202.

toxicity

PS, Digre

associated

KB, Creel DJ: Retinal

with occupational

to the fish anesthetic

MS-222.

nogram from cisplatin

toxicity.

N, Fioravanti

cisplatin

Holopigian

tered carmustine.

and intravenously

arthritis:

K, ad-

adminis-

Am J OphtholmoI1992;113:

toxicity

per ptomoted

DJ, WangJM,

508. Oavies SC, Marcus

tion of the prostate.

Wong KC: Transient

with transurethral

resec-

Arch OphtholmoI1987;105:

JO, Polkinghorne

of patients

thin and carotene: ophthalmological

taking

P,

canthaxan-

an electroretinographic

and

survey. Hum ToxicoI1989;8:

439-450.

RE, Hungerford

des-

Lancet 1983;2:181-184.

509. Lakhanpal

V, Schocket

thy. Ophthalmology

SS, Jiji R: Oefetox-

toxic retinal

and presumed

pigmen-

optic neutopa-

1984;91:443-451.

510. Olivieri

NF, Buncic

and auditory

neurotoxicity

subcutaneous

JL, et

intravenous

R, Chew

E, et al: Visual

in patients

defetoxamine

infusions.

receiving N Engl J

Med 1986;314:869-873.

499. Harnois

C, Samson J, Malenfant

Canthaxanthin

retinopathy:

reversibility.

anatomic

M, et al:

511. Borgna-Pignatti

and func-

AM: Visual loss in patient

Arch OphtholmoI1989;107:

538-540. 500. Eke T, Talbot

JF, Lawden

sistent visual field constriction Vigabatrin.

of cop-

damage? Br J Oph-

of high-dose

tary degeneration GB, Oluwole

P;et al: Ocular

an example

amine(Oesferal)-induced

1537-1539.

et al: Monitoring

J, et al: Cere-

by desfetrioxa-

thalmoI1989;73:42-47.

497. Creel

associated

S,

of desfetrioxa-

P, Lunec induced

auto-oxidative

fetrioxamine.

tional

usefulness

of desfetrioxamine:

al: Ocular toxicity

498. Arden

A, Sancasciani

storage of iron and anaemia in

435-438.

blindness

1999;

mine. Q J Med 1985;56:345-355.

Doc Ophtholmol

caused by intra-arterially

SG, et

visual loss ia

Ophthalmology

507. Pall H, Blake OR, Winyard

et al: Maculopathy

Neurology

L, Coupland

Vigabatrin.

bral and ocular toxicity

electroreti-

MJ, Seiple WH,

M, drug,

mine. Br Med J 1984;289:961-962.

1993;84:237-246. 496. Kupersmich ministered

I, Miintyjiirvi

and asymptomatic

506. Blake OR, Winyard

MF: Negative-type

find-

antiepileptic

visual field defects.

et al: Increased rheumatoid

exposure

Am J Ophtholmol

1997;124:843-844. 495. Marmor

and ophthalmologic

H, Racette

patients taking 106:1792-1798. 505. Giordano

494. Bernstein

NR: Viga-

1999;53:922-926. at: Symptomatic

K, Torisaki

MA, Miller

a gabaergic

causes concentric

504. Oaneshvar

toxicity

with

cone system dysfunc-

R, Nousiainen

15:45-52.

al: Retinal

retinal

et al: Vigabatrin,

E,

of gentamicin:

with pe-

associated

Arch OphthalmoI1998;116:817-819.

503. Kiifviiiinen

M, Chimonidou

injection

visual field contraction

Vigabatrin.

U, et al: Elec-

of a patient

ings. Neurology 1998;50:614-618.

toxic effects

and clearance.

et al: Intravicreal

evaluation

batrin-associated

GA, May DR, Ericson

injection

K. Pung T, Kellner

trophysiologic ripheral

490. Ruedemann chronic

501. Ruether

MC: Severe perassociated

Br Med J 1997;314:180-181.

with

neous desfetrioxamine.

C, De Stefano

P, Btoglia

on high-dose

subcuta-

Lancet 1984;1:681.

146

TheElectroretinogram

512. Rubinstein

M, Dupont

Ocular toxicity

P, Doppee

of desferrioxamine.

IP, et al:

Lancet 1985;

524. Weleber

Ra,

al: Abnormal

retinal

isotretinoin

1:817-818. 513. Marciani

MG, Cianciulli

Toxic effects of high-dose ment in patients physiological

with

P, Stefani

deferoxamine

iron overload:

study of cerebral

tion. Haematologica 514. Marmor

N, et al: treat-

an electro-

and visual func-

1991;76:131-134. (Viagra)

Surv OphthalmoI1999;44:

therapy

fenretinide,

526. Fazio aT,

phy with

Lancet 1999;353:375.

al: Short time influences

T, Meschi

of sildenafil

Invest Ophthalmol

M, et

on visual

Vis Sci 1999;40(suppl):

766.

blindness

RP: Electroretinography

and other vitamin

in night

thalmol

bined with

spots of the fundus

night blindness

mura's syndrome).

com-

and xerosis (Uye-

]R, Martin

Doc Ophthalmol

Ra, Miyake

negative

open-

Y: Familial

optic atro-

electroretinograms.

Arch Oph-

1992; 110:640-645. A: Electroretinograph-

ical study of the hypoplasia

of the optic nerve.

1976;172:308--330.

529. Sprague ]B, Wilson in bilateral

WB: Electrophysiologic

optic nerve hypoplasia.

Ophthalmol

1981 ;99: 1028-1029.

530. Fuller

Do,

Bright-flash

Knighton

Arch

RW, Machemer

electroretinography

R:

for the evaluaAm J Ophthal-

mol 1975;80:214-223.

519. Dowling

IE: Night

blindness,

tion, and the electroretinogram.

dark adapta-

Am J Ophthalmol

531. Abrams guished

OW, Knighton

bright-flash

RW: Falsely

electroretinogram:

1960;50:875-889.

ciation

520. Genest A: Vitamin

Ophthalmol1982;100:1427-1429.

gram in humans.

A and the electroretino-

In: Fran~ois I, ed: The Clinical

Value of Electroretinography.

Symposium

in Ghent,

1966. Basel: S Karger AG; 1968:250-259. 521. Sandberg

MA, Rosen IB, Berson EL: Cone

and rod function

in vitamin

alcoholism

A deficiency

and in retinitis

with

pigmentosa.

with dense vitreous

532. Mandelbaum Nonrecordable

533. Tzekov

R, Arden

gram in diabetic

troretinogram

in a case of vitamin

malabsorption.

A deficiency

due to

Br J OphthalmoI1983;67:37-42.

523. Rushton

WA: Rod/cone

regeneration.

J Physiol (Lond)

rivalry

in pigment

1968;198:219-236.

in vitreous

1982;89:73-75.

OB: The electroretino-

retinopathy.

Surv Ophthalmol

1999;44:53-60. 534. Chung

D, Haim T, et al: Night

Arch

S, Ober RR, Ogden TE: electroretinogram

Ophthalmology

522. Perlman

I, Barzilai

extinits asso-

hemorrhage.

hemorrhage.

Am J OphthalmoI1977:84:658-665.

vision

aA,

1986;63:45-54.

tion of eyes with opaque vitreous.

Am J OphthalmoI1959;48:

101-103.

chronic

with

Arch Ophthalmol

in advanced

528. Fran~ois ], de Rouck

findings

A deficiencies.

Arch OphthalmoI1955;54:841-849. 518. Fuchs A: White

associated

retinoid.

Heckenlively

Ophthalmologica

517. Dhanda

function

et al: The electroretinogram

527. Weleber

function.

MI, Peck OL, Caruso RC,

retinal

a synthetic

side-effects

U, Gockeln

et

with

for acne. Arch Ophthalmol

525. Kaiser-Kupfer et al: Abnormal

515. Vobig MA, Klotz T, Staak M, et al: Retinal

516. Kretschmann

]M,

associated

1986;104:831-837.

angle glaucoma.

153-162.

of sildenafil.

ST, Hanifin

function

1986;104:69-70.

MF, Kessler R: Sildenafil

and ophthalmology.

aenman

NH,

Kim SH, Kwak MS: The elec-

sensitivity

in patients

betes. Korean J Ophthalmol 535. Bresnick

with

dia-

1993;7:43-47.

OH: Electroretinography

and

color vision

in diabetes

mellitus.

Cunha-Vaz

]0,

a, et al, eds: Microvascu-

Fedele

lar and Neurological Padova: Livina

Complications

Press; 1987: 17-33.

In: Crepaldi of Diabetes.

a,

147

References

536. Yonemura

D, Kawasaki

Early deterioration human

K, Okumua

in the temporal

electroretinogram

T, et al:

aspect of the

in diabetes

mellitus.

Folia Ophthalmol Jpn 1977;28:379-388. 537. Yonemura

D, Kawasaki

tachment

logical study on activities

of neuronal

in man with reference

to its clinical

elements

application.

and non-

Jpn J Ophthalmol1977;

22:195-213. GH, Palta M: Temporal

of the electroretinogram

in diabetic

aspects retinopathy.

Arch OphthalmoI1987;105:660-664. 539. Bresnick

relation

to severity

nopathy. Arch Ophthalmol1987; 540. Bresnick

potential

of diabetic 105:929-933.

GH, Palta M: Predicting

sion to severe proliferative

reti-

diabetic

progres-

retinopathy.

Arch OphthalmoI1987;105:810-814. 541. Bresnick

GH, Korth

K, Groo A, et al: Elec-

report. Arch OphthalmoI1984;102:1307-1311. 542. Deneault ERG's

LG, Kozak WM,

in streptozotocin-diabetic insulin

regimens.

TS:

rats under dif-

Doc Ophthalmol

Proc Ser

1980;23:67-76. T, O'Connor

PR: ERG and EOG

pre and post photocoagulation.

Doc

Ophthalmol Proc Ser 1972;2: 17-23. 544. Wepman

as a prognostic

J, et al: The aid in retinal

Arch OphthalmoI1958;59:515-520.

551. Schmoger

E: [The

of electroretinograms

prognostic

significance

in conjunction

with

on the electroretinogram

dark adaptation

in diabetic

thalmol ProcSer

1977;13:139-147.

TE,

electroretinogram tion in diabetic

335-343. 552. Fran~ois J, de Rouck

A: [Electroretinogra:-

phy in myopia

detachment

myopia.]

and retinal

caused by

Acta OphthalmoI1955;33:131-155.

553. Cibis PA, Becker silicone

B, Okun

in retinal

E, et al: The use

detachment

surgery.

Arch OphthalmoI1963;68:590-599. 554. Frumar

KD, Gregor ZJ, Carter

Electrophysiological

RM, et al:

responses after vitrectomy

tamponade.

Trans Ophthalmol

Soc UK 1985;104:129-132. 555. Foerster

MH,

and its influence

Esser J, Laqua

H: Silicone

on electrophysiologic

and

retinopathy.

Callahan

influence

oil

findings.

A, Lessel MR, Gnad H, et al: The of intravitreously

Doc Oph-

after peripheral

FT: The

retinal

abla-

Am J Ophthalmol

injected

potentials

557. Meredith

TA, Lindsey

et al: Electroretinographic

silicone

following

558. Declercq

SS, Meredith

Experimental

siderosis

oil injection.

PC, Rosenthal

in the rabbit:

between

electroretinography

559. Doslak of silicone

oil on the electroretinogram.

547. Franchi

Ophthalmol

Vis Sci 1988;29:1881-1884.

An electrophysiological in diabetic

L, et al:

study on panretinal retinopathy.

atr Syst OphthalmoI1987;10:64-67

.

pho-

Metab Pedi-

MJ: A theoretical

AR:

correlation

and histopathology.

nography following extensive photocoagulation. Arch OphthalmoI1975;93:591-598. M, Scoccianti

HF, vit-

Br J OphthalmoI1985;69:254-260.

Arch OphthalmoI1977;95:1051-1058.

A, Cordella

oil

DT, Edelhauser studies

1976;81:397-402. RN: Visual fields and electroreti-

silicone

of the eye.

Doc OphthalmoI1986;62:41-46.

recto my and intraocular

F, Riekhof

retinopathy.

556. Thaler

546. Frank

tocoagulation

retinal

Klin Monatsbl Augenheilkd 1957;131:

on electrophysiological

B, Sokol S, Price J: The effects of

photocoagulation

545. Ogden

electroretinogram

Am J OphthalmoI1985;99:201-206.

543. Lawwill in diabetes

550. Jacobson JH, Basar D, Carroll

and intraocular

Denowski

in de-

566-576.

of liquid

troretinographic oscillatory potentials predict progression of diabetic retinopathy: preliminary

ferent

I: The electroretinogram

detachment.]

GH, Palta M: Oscillatory

amplitudes:

electroretinog-

of the retina. Arch OphthalmoI1957;57:

detachment.

538. Bresnick

I: Clinical

of the retina. Acta Ophthal-

mol 1969;47:633-641. 549. Rendahl

K: Electrophysio-

neuronal

retinal

548. Karpe G, Rendahl raphy in detachment

study of the effect Invest

148

The Electroretinogram

560. Wirth

A: ERG and endocrine

In: Fran~ois ], ed: The Clinical nography. Symposium

571. Burian

disorders.

Value of Electroreti-

in Ghent,

dystrophy.

1966. Basel:

S Karger AG; 1968:260-266. 561. Pearlman graphic

]T, Burian

findings

HM:

in thyroid

Electroretino-

dysfunction.

Am J

A, Tota G: Electroretinogram

adrenal cortical

function.

In: Schmoger

Advances in Electrophysiology Visual System. Proceedings Symposium.

Leipzig:

and E, ed:

and Pathology of the of the 6th ISCERG

Thieme;

1968:347-350.

Burns CA: Electroretinography in patients

Am J Ophthalmol

G, Marconcini

ERG variations

in myotonic

ert's). Doc Ophthalmol

C, Perossini

M:

(Stein-

Proc Ser 1980;23:133-136.

B, Michiels

myotonic

myotonic

dystrophy

I: Retinal

tions, electroretinographic with

with

1966;61: 1044-1054.

572. Cavallacci

573. Stanescu

OphthalmoI1964;58:216-226. 562. Wirth

HM,

and dark adaptation

degenera-

aspects in patients

dystrophy.

Doc Ophthalmol

Proc

Ser 1977;13:257-262. 574. Creel Dl, Crandall tion of minimal

AS, Ziter

expression

FA: Identifica-

of myotonic

dystro-

563. Zimmerman T], Dawson WW, Fitzgerald CR: Electroretinographic changes in normal

phy using electroretinography. Electroencephalogr Clin Neurophysiol 1985;61 :229-235.

eyes during

575. Stewart

administration

of prednisone.

Ann

564. Negi A, Honda costeroids

Y, Kawano

S: Why do corti-

increase the ERG amplitude?

perimental

study in rabbits.

An ex-

Doc Ophthalmol

Proc

Ser 1980;23:79-85. Y, Kawano

gluco- and mineralocorticoid Nippon

S: [Effects

of

and ACTH

on rab-

Ganka Gakkai Zasshi 1980;84:

304-310. M, Tota G: The effects of aldos-

terone on the c-wave of the rabbit.

Doc Ophthal-

mol Proc Ser 1980;23:87-90. 567. Wirth

icine. Ophthalmologica

al: Hepatic

in general

med-

AK, Reichenbach

retinopathia:

A, ]acobi

P, et

changes in retinal

func-

569. Ellis C], Allen Electroretinographic Parkinson's

TG,

CD, et al: in idiopathic

ME,

Harley

basis of myotonic

pansion of a trinucleotide 3' end of a transcript member.

dystrophy:

(CTG)

encoding

HG, et ex-

repeat at the

a protein

Cell 1992;68:799-808.

kinase

Dl, et al: on the

Invest Ophthalmol

Vis

Sci 1993;34:3646-3652. 577. Fitzgerald et al: Retinal

KM, Cibis

GW, Giambrone

signal transmission

dystrophy:

evidence

SA,

in Duchenne for dysfunction

the photoreceptor/depolarizing

bipolar

in

cell path-

way. J Clin Invest 1994;93:2425-2430. DM,

al: Dystrophin

Bulman

for normal

579. Pillers Oregon

DE, Weleber

expression

troretinography.

function

as defined

Seltzer WK, Powell

581. Shanske

in

pigmentosa,

and complete

heart

1958;60:280-289.

S, Moraes CT, Lombes tissue distribution

deletions

in

phenotype

1993; 111: 1558-1563.

ophthalmoplegia,

block. Arch Ophthalmol

BR, et al:

electroretinogram

580. Kearns TP, Sayre GP: Retinitis

DNA

retina is by elec-

Nat Genet 1993;4:82-86.

DM,

Xp21. Arch Ophthalmol

Widespread

RG, et

in the human

eye disease: consistent

external

Clin Vis Sci 1987;1:347-355.

570. Brook ]D, McCurrach al: Molecular

Marsden

abnormalities

disease and the effect of levodopa

administration.

family

KM, Harris

gene mutations

Negative-configuration

tion. Vis Res 1997;37:1699-1706.

Doc Ophthalmol

The effects of dystrophin

required

1979;178:273-288.

Visual electrophys-

576. Cibis GW, Fitzgerald

578. Pillers

A: Electroretinogram

568. Eckstein

ML:

congenita.

Proc Ser 1972;2:5-16.

muscular

566. Perossini

Rubin

ERG in mice and humans.

565. Negi A, Honda bits' ERG.]

HL,

iology of myotonia

OphthalmoI1973;5:757-765.

in Kearns-Sayre

A, et al:

of mitochondrial syndrome.

Neurology 1990;40:24-28. 582. Isashiki Retinal

Y, Nakagawa

manifestations

associated with

M, Ohba N, et al:

in mitochondrial

mitochondrial

DNA

Acta Ophthalmol Scand 1998;76:6-13.

diseases

mutation.

References

583. Lowes

M: Chronic

ophthalmoplegia,

progressive

pigmentary

heart block (Kearns-Sayre

594. Jaben S, Flynn

external

retinopathy,

syndrome):

JT: Neuronal

cinosis (Batten-Yogt's

and

report of

Neuro-ophthalmology

Update. New York: Masson

Publishers;

584. Bastiaensen

595. Pinckers

A, Bolmers

lipofuscinosis

(E.R.G.

LA, Notermans

further

evidence

of a genuine

with uncommon

features.

SL, Ramaekers

or Kearns disease: entity

in a case

Ophthalmologica

Y, Awaya S, et al: Early reti-

in mitochondrial

mitochondrial

DNA

586. Mullie

MA, Harding

The

manifestations

retinal

Retina 1994;

myopathy:

AE, Petty

RK, et al:

of mitochondrial

KP, Kohlschutter findings

in heterozygotes.

597. Isolation

pigmentary

TR, YanoffM:

retinopathy

a light and electron

study. Ophthalmology

The

1988;226:516-521.

BW, Weiner

atrophies:

599. Harding

of Kearns-Sayre microscopic

drome:

with special reference Nippon

sification

Batten

Disease

LP: The olivopon-

a review. Medicine 1970;

AE: The clinical

cerebellar

of ocular

in Kearns-Sayre

syn-

to the new stage

Ganka Gakkai Zasshi 1989;

93:329-338.

worth.'

features

of the late onset autosomal

and clas-

dominant

ataxias: a study of 11 families

ing descendants

Y, Awaya S: [Studies

and visual functions

Brain

600. Drack Progression lar atrophy

of'the

Drew

family

includ-

of Wal-

1982;105:1-28.

AY, Traboulsi

El, Maumenee

of retinopathy with

retinal

IH:

in olivopontocerebel-

degeneration.

Arch Oph-

thalmoI1992;110:712-713.

589. Holt II, Cooper IM, Morgan-Hughes et al: Deletions of muscle mitochondrial

IA, DNA.

601. To KW, Adamian vopontocerebe!lar

Lancet 1988;1:1462. 590. Moraes CT, DiMauro Mitochondrial

DNA

S, Zeviani

deletions

ternal ophthalmoplegia

M, et al:

in progressive

and Kearns-Sayre

ex-

syn-

M, Jakobiec

atrophy

investigation.

1993;100:15-23.

Ophthalmology

602. Traboulsi

El, Maumenee

al: Olivopontocerebe!lar study. Arch Ophthalmol

ceroid lipofuscinosis.

IR, Arden

GB, eds: Principles

and Practice of Clinical Electrophysiology Mosby-Year

592. Weleber

Book;

RG: The

disorders:

593. Bateman

1991:786-792.

dystrophic

IB, Philippart

of the Hagberg-Santavuori thalmoI1986;102:262-271.

in neu-

Eye 1998;12:580-590. M: Ocular syndrome.

603. Bjork

a clinical

features Am J Oph-

U, Waldenstein

in hereditary

degeneration

be!lar ataxia mapping Genet 1995;10:89-93.

retinal

de-

1988;106:801-806. L: Reti-

ataxia. J Neurol

1956;19:186-193.

604. Gouw LG, Kaplan Retinal

with

and ocular histopathologic

A, Lindholm

nal degeneration

Neurosurg Psychiatry

retina in mul-

the electroretinogram

ronal ceroid lipofuscinoses.

of Vision.

IH, Green WR, et

atrophy

591. Gottlob,

I: Neuronal

degenera-

and histopathologic

generation:

In: Heckenlively

FA, et al: Oli-

with retinal

tion: an electroretinographic

drome. N Engl J Med 1989;320:1293-1299.

tisystem

ceroid

Graefes Arch Clin

of a novel gene underlying

tocerebellar

1982;89:1433-1440.

fundus

St Louis:

A, et al:

of neuronal

49:227-241.

587. Eagle RC Ir, Hedges

classification.]

lipofuscinosis

598. Konigsmark

1985; 103: 1825-1830.

588. Ota I, Miyake

ceroid

Ann Ocul

disease, CLN3. International Batten Consortium. Cell 1995;82:949-957.

a study of 22 cases. Arch Ophthalmol

syndrome:

D: Neuronal

et E.O.G.).

I, Leipert

Exp Ophthalmol

myopathy

deletion.

14:270-276.

atypical

596. Gottlob

Electrophysiological

nal involvement with

1977:299-317.

( Paris} 1974;207:523-.)29.

1982;

184:40-50. 585. Ota Y, Miyake

lipofus-

disease). In: Smith JL, ed:

a case. Acta OphthalmoI1975;53:610-619.

CH, et al: Kearns syndrome

ceroid

149

CD, Haines

characterizes to chromosome

JH, et al: a spinocere3p. Nat

150

The Electroretinogram

605. David

G, Abbas N, Stevanin

ing of the SCA7 gene reveals a highly CAG repeat expansion.

unstable

disease: neurophysiologic

sual impairments.

Neurology 1998;51:962-967.

F, Richard

after growth

618. Spritz cutaneous

vi-

treatment.

M, Mahon

metallosis:

support

mechanism

for an oxidative

in the human

PB:

R, Miller

deficiency.

intraocular

metallic

follow-up

in experimental

study after removal

of intraocular

Proc Ser 1982;31 :

receiving

long-term

Heckenlively lR, for taurine in pa-

parenteral

B, lurklies

crystalline

624. Bagolini

a

B, Ioli-Spada

nal degeneration

for-

G: Bietti's

with marginal

625. Fran<;ois 1, de Laey 11: Bietti's

613. Prijot

fundus

I, Marechol-Courtois

C:

In: Fran~ois J,

1968:440-443.

albinos.

M: A new form

A: The electroretinogram

Vis Res 1978;18:1465-1466.

PS: Crystalline

1981 ;92:640-646.

lively

lR, Arden

GB, eds: Principles and Practice

of Clinical Electrophysiology

Am J OphthalmoI1974;77:837-844. F, Wirth

O'Connor

627. Weleber RG, Wilson Dl: Bietti's crystalline dystrophy of the cornea and retina. In: Hecken-

Arch OphthalmoI1963;69:32-38.

616. Tomei

WM,

retinopathy (Bietti's tapetoretinal degeneration without corneal dystrophy). Am J Ophthalmol

614. Krill AE, Lee GB: The electroretinogram in albinos and carriers of the ocular albino trait.

of albinism.

crystalline

Ann OphthalmoI1978;10:

709-716. 626. Mauldin

ed: The Clinical Value of Electroretinography. Symposium in Ghent, 1966. Basel: S Karger AG;

615. Bergsma DR, Kaiser-Kupfer

dystrophy.

tapetOreti-

corneal dystro-

69-72. and myopia.

U, et al:

of the retina and

phy. Am J OphthalmoI1968;65:53-60.

E, Colmant

nutrition.

C, Schmidt

dystrophy

eign body. Doc Ophthalmol Proc Ser 1978; 15:

Electroretinography

DA,

and taurine

cornea. Retina 1999;19:168-171.

PC:

siderosis:

Doc Ophthalmol

623. lurklies Bietti's

Electrophysiology

lR, Martin

dysfunction

N Engl J Med 1985;312:142-146.

bodies. Acta

OphthalmoI1969(suppI100):3-63. 612. Declercq SS, Phillip CA, Meredith

retinal

622. Geggel HS, Ament ME, et al: Nutritional requirement

quantiDoc

in eyes with

foreign

defi-

199-207.

E, et al:

tients

retained

HS, Heckenlively

et al: Human

eye. Ophthalmologica

OphthalmoI1991;76:231-240. 611. Knave B: Electroretinography

and re-

in cats fed casein, I: taurine

621. Geggel

(free radical)

B, Merksamer

induced

in cats. Am J Pathol

ciency. Invest OphthalmoI1976;15:47-52.

and

A long term follow up of ocular siderosis: tative assessment of the electroretinogram.

of oculo-

Hum Mol Genet 1994;3:

1975;78:505-524. 620. Schmidt SY, Berson EL, Hayes KC: Retinal

1988; 196:204-209. 610. Schechner

1989;96:1778-1785.

degeneration

degeneration

Good P, Gross K: Electrophysiology

GA: Elec-

oculocutane-

genetics

study of nutritionally

versed retinal

Ocular siderosis. Eye 1993;7:419-425. ::3.

Ophthalmology RA: Molecular

albinism.

structural

disease

Lancet 1991;

GJ, Johnston

in human

1469-1475.

338:191. 608. Hope-Ross

NS, Fishman

findings

619. Hayes KC, Rabin AR, Berson EL: An ultra-

P: Early electroretino-

in Creutzfeldt-Jakob

hormone

ous albinism.

P, et al:

Creutzfeldt-Jakob

gram alterations

troretinographic

Nat Genet 1997; 17:65-70.

606. De Seze J, Hache JC, Vermersch

607. Renault

617. Wack MA, Peachey

G, et al: Clon-

of

Mosby-Year

Book;

628. Richards et al: Autosomal Ophthalmology

of Vision. St Louis:

1991:683-691.

BW, Brodstein dominant

DE, Nussbaum crystalline

1991;98:658-665.

11,

dystrophy

References

629. Miyauchi E: A family strating

0, Murayama

with

crystalline

an autosomal

K, Adachi-Usami retinopathy

dominant

640. Jacobson

demon-

inheritance

pat-

tern. Retina 1999;19:573-574. 630. Wilson Bietti's

Dl, Weleber

crystalline

correlative

CE. Tipping

triad to diagnose

paraneoplastic

nopathy.

Ann NeuroI1990;28:

162-167.

641. Keltner

RG, Klein

dystrophy:

ML,

et al:

a clinicopathologic

study. Arch OphthalmoI1989;107:

JL, Thirkill

Management

AH: Clinical

retinopathy.

aspects: paraneoplastic

In: Djamgoz

MB, Archer

SN, Val-

lerga S, eds: Neurobiology and Clinical Aspects of the Outer Retina. London:

Chapman

& Hall;

1995:

461-471.

associated

CE, Roth AM, Keltner retinopathy.

lL:

reti-

of cancer-associ-

Arch OphthalmoI1992;110:

Y, Mehta

Cancer-

Arch Ophthalmol1987;

105:

372-375.

MC,

Electrophysiological retinopathy.

Katsumi

findings

0, et al:

in paraneoplastic

Graefes Arch Clin Exp Ophthalmol

1992;230:324-328. 643. Marmor

MF, Jacobson SG, Foerster

et al: Diagnostic

632. Thirkill

SJ:

CE, Tyler NK, et al:

and monitoring

ated retinopathy.

642. Matsui

631. Milam

DM.

48-53.

213-221.

clinical

drome with night enhanced

findings

blindness,

MH,

of a new syn-

maculopathy,

S cone sensitivity.

an~

Am J Ophthalmol

1990;110:124-134.

633. Thirkill

CE: Cancer associated

the CAR syndrome.

retinopathy:

Neuro-Ophthalmology

1994;

14:297-323.

644. Fishman trophy

MD,

Recoverin,

but not visinin,

the human

retina identified

ated retinopathy.

Haley

TL,

et al:

is an autoantigen

in

with a cancer-associ-

Invest Ophthalmol

Vis Sci 1993;

34:81-90.

with

NS: Rod-cone

under photopic

Ophthalmology

1989;96:913-918.

645.)acobson

SG, Marmor

SWS (blue) identified

conditions.

MF, Kemp

cone hypersensitivity retinal

dys-

a rod system electroreti-

degeneration.

CM, et al:

in a newly Invest Ophthalmol

Vis Sci 1990;31 :827 -838.

635. Adamus

G, Guy l, Schmied

lL,

of anti-recoverin

autoantibodies

ated retinopathy.

Invest Ophthalmol

et al: Role

in cancer-associVis Sci 1993;

34:2626-2633.

646. Jacobson SG, Roman AJ, Roman

MI, et al:

Relatively

in the

enhanced

Goldmann-Favre

S cone function

syndrome.

Am J Ophthalmol

1991;111:446-453.

636. Whitcup

SM, Vistica

BP, Milam

Recoverin-associated

retinopathy:

and immunologically

distinctive

AH, et al:

a clinically disease. Am J

G, Aptsiauri

enolase antibodies

N, Guy l, et al: Anti-

in cancer associated

thy. Invest Ophthalmol

647. Hood

DC, Cideciyan

Enhanced

S cone syndrome:

normally

retinopa-

Vis Sci 1993;34(suppl

4):

1485. 638. Sawyer RA, Selhorst lB, Zimmerman caused by photoreceptor

as a remote

LE, degen-

effect of cancer. Am J Oph-

thalmoI1976;81:606-613. lL,

evidence

for an ab-

of S cones. Vis Res 1995;

648. Haider

NE, Jacobson SG, Cideciyan

al: Mutation

of a nuclear

causes enhanced retinal

et al: Blindness

large number

AY, Roman AJ, et al:

35:1473-1481.

OphthalmoI1998;126:230-237. 637. Adamus

639. Keltner

GA, Peachey

associated

nogram obtained

634. Polans AS, Burton

eration

Thirkill

A clinical

151

Roth AM, Chang RS: Photore-

ceptor degeneration: possible autoimmune order. Arch OphthalmoI1983;101:564-569.

dis-

receptor

S cone syndrome,

AY, e~

gene, NR2E3, a disorder

of

cell fate. NatGenet2000;24:127-131.

649. Skalka

HW: Hereditary

nous retinochoroidal 1979;87:286-291.

pigmented

parave-

atrophy. Am J Ophthalmol

152

The Electroretinogram

650. Traboulsi pigmented

El, Maumenee

paravenous

Arch Ophtha!mo! 651. Noble

662. Hirose

IH: Hereditary

chorioretinal

ance and retinal

1986; 104; 1636-1640.

KG: Hereditary

venous chorioretinal

pigmented

functions.

para-

1989;108:365-369. retinochoroidal

expression

in monozygotic

discordant

twins. Arch Ophtha!-

664. Haustrate paravenous

IR, Kokame

retinochoroidal

FM, Oosterhuis

GT: Pigmented

atrophy. Doc Ophtha!-

665. Iohansen Pigmented

entity?

MD:

667. Yamaguchi

& Row, 1977;2:625-636.

Ophtha!mo!

radiata. Br J

1937;21:645-648.

656. Foxman Rubeola

Retino-choroiditis

SG, Heckenlively

retinopathy

IR, Sinclair

and pigmented

SH:

paravenous

Doc Ophthalmol

flammatory

T:

atrophy.

MI: Pigmented

atrophy:

a nosologic

1988;70:185-193.

K, Hara S, Tanifuji

pigmented

Y, et al: In-

paravenous

roidal atrophy.

Br J Ophthalmol

668. Hayasaka

S, Shibasaki

Pigmented

C, Autzen

1988;66:474-477.

retinochoroidal

tary Retina! and Choroida! Diseases. Hagerstown,

(PPRA).

chorioretinal

654. Krill AE: Incomplete tions. In Krill AE, Archer

paravenous

IA: Pigmented

I, Lund-Andersen

paravenous

666. Klop K, Van Schooneveld

rod-cone degeneraDB, eds: Kri!!s Heredi-

P: ERG and

1986;63:209-237.

Acta Ophthalmol

Harper

1979;

retinochoroidal

atrophy

mo! Proc Ser 1984;40:235-241.

655. Brown TH:

appear-

1986;62:25-29.

retinochoroidal

Doc Ophthalmol

mo! 1991;109:1408-1410. 653. Heckenlively

A, Heilig

paravenous

atrophy. Doc Ophthalmol

WB Ir: Pigmented atrophy:

parave-

fundus

Ann Ophthalmol

663. Lessel MR, Thaler EOG in progressive

paravenous

Y: Pigmentary

degeneration:

11:709-718.

atrophy. Am J Ophtha!mo!

652. Small KW, Anderson

paravenous

T, Miyake

nous chorioretinal

atrophy.

paravenous

retinocho-

1989;73:463-467.

H, Noda S, et al:

retinochotoidal

atrophy

1985;

in a 68-year-old

99:605-606.

177-180.

657. Chisholm IA, Dudgeon I: Pigmented venous retino-choroidal atrophy: helicoid

pararetino-

669. Young WO, Small KW: Pigmented

parave-

nous retinochoroidal

with

retinochoroidal

choroidal

atrophy. Am J Ophtha!mo!

atrophy.

Br J Ophtha!mo!

optic disc drusen.

1973;57:

KG, Carr RE: Pigmented

chorioretinal

paravenous

atrophy. Am J Ophtha!mo!

1983;96:

(PPRCA)

Ophthalmic Paediatr

Genet

670. Parafita mented

M, Diaz A, Torrijos

paravenous

IG, et al: Pig-

retinochoroidal

atrophy.

Optom VisSci 1993;70:75-78.

338-344. 659. Takei

atrophy

1991;23:

1993; 14:23-27.

584-587. 658. Noble

man. Ann Ophthalmol

Y, Harada M, Mizuno

paravenous

retinochoroidal

K: Pigmented

atrophy. Jpn J Oph-

tha!mo! 1977;21:311-317.

SUGGESTEDREADINGS

660. Noble

KG, Carr RE: Peripapillary

tary retinal

degeneration.

pigmen-

Am J Ophtha!mo!

1978;

86:65-75. 661. Pearlman

IT, Kamin

al: Pigmented

paravenous

phy. Am J Ophtha!mo!

DF, Kopelow retinochoroidal

1975;80:630-635.

SM, et atro-

Armington

JC: The Electroretinogram.

Academic

Press; 1974.

Armington

JC, Johnson

New York:

EP, Riggs LA: The

topic a-wave in the electrical man retina. J Physiol (Lond)

sco-

response of the hu1952;118:289-298.

Armington

JC, Schwab GJ: Electroretinogram

nyctalopia.

Arch Ophthalmol

Auerbach

E, Burian

HM:

1954;52:725-733. Studies

topic-scotopic

relationships

troretinogram.

Am J Ophthalmol

on the pho-

in the human

elec-

1955;40:42-60.

in

Suggested Readings

Berson EL: Hereditary fication

retinal

with the full-field

In: Lawwill Hague:

diseases: classi-

electroretinogram.

Dr W Junk BY Publishers.

Doc Ophthal-

1977;13:149-171.

Birch DG: Clinical

electroretinography.

Ophthal-

Dystrophies. Norwalk,

Century-Crofts; Bresnick lively

JR, Arden

retinopathy.

Brunette

of Vision. St Louis:

1991:619-635.

JR: Clinical

foundations.

In: Hecken-

GB, eds: Principles and Practice

Book;

electroretinography,

1:

Can J OphthalmoI1982;17:143-149.

Burns CA: Ocular effects of indomethacin: lamp and electroretinographic

Duane

TD,

retinal

ed: Clinical

phia: JB Lippincott

(ERG)

slit

study.

of several retinal

Ophthalmology.

In:

Electrophysiologic

aspects

diseases. Am J Ophthalmol1964;

58:95-107. Visual Electrodiagnostic

ing: A Practical

Guide for the Clinician.

MD:

& Wilkins;

Williams

GE, Lettich

I: a standardized

PL, et al: Com-

electroretinography, Am J EEG

1echnol

1980:20;57-77. Deutman

AF: The Hereditary

Dystrophies of the

Posterior Pole of the Eye. Springfield, C Thomas;

Fujina

Little,

T, Hamasaki

the retinal

Galloway

Dl: The effect

of occluding

circulation

of monkeys.

on the elec-

J Physiol (Lond)

NR: Early receptor

potential

1965;

in the

eye. Br J OphthalmoI1967;51:261-264.

Galloway

NR: Ophthalmic Electrodiagnosis. WB Saunders

Phila-

Co; 1975.

EB, Berson EL: Rod and cone contrito the human

early receptor

potential.

Vis Res 1970;10:207-218. Heckenlively

JR: Retinitis Pigmentosa. Philadel-

phia: JB Lippincott Henkes

HE:

Co; 1988.

[Phenothiazine

Hood DC, Birch

retinopathy.]

Ned

and rod receptor

MA:

Belknap

Hood DC, Birch DG: A computational the amplitude the human

and implicit

ERG.

diseases: electroretinogram gram findings.

In: Peyman

retinal

1980;2:857-904.

Philadelphia:

of

Vis Neurosci 1992;8:107-126. Spring-

DW, Caruso RC, et al: Atten-

effects of diazepam

gram of normal

humans.

on the electroretino-

Retina 1989;9:216-225.

Press; 1987:

and choroidal

and electro-oculoGA, Sanders DR,

MF, eds: Principles and Practice of

Ophthalmology.

model

time of the b-wave of

Jacobson JH: Clinical Electroretinography. field, IL: Charles C Thomas; 1961.

Knighton GA: Hereditary

function.

Vis Sci 1990;31:2070-2081.

Jaffe MJ, Hommer

JE: The Retina: An Approachable Part of Cambridge,

DG: The a-wave of the human

electroretinogram

RW, Blankenship

logical evaluation

Goldberg

& Co; 1969.

IL: Charles

1971.

164-186. Fishman

Responses of the Visual Brown

and choroidal

troretinogram 180:837-845.

uating the Brain.

SJ, ed: Electrical

Invest Ophthalmol

E, Nelson

method.

1est-

Baltimore,

1982.

puter assisted quantitative

Dowling

1966. Basel: S Karger AG;

Tijdschr Geneeskd 1966;110:789-790.

Carr RE, Siegel IM:

Chatrian

Fricker

butions

Philadel-

in

In: Fran-

Value of Electroretinography.

in Ghent,

Goldstein

degenerations.

blindness.

1968:451-4 72.

delphia:

Co; 1976;vol 3, chap 24.

Carr RE, Siegel IM:

of congenital

~ois J, ed: The Clinical

human

Invest OphthalmoI1966;5:325. Carr RE: Primary

Fran~ois J, de Rouck A: Electroretinography

System. Boston:

Electrophysiology

Mosby-Year

CT: Appleton-

1982.

GH: Diabetic

of Clinical

of Retinal and

IL: Charles

1974.

Symposium

MA, Garcia CA: Manual

Choroidal

C Thomas;

the diagnosis

mol Clin North Am 1989;2:469-497. Bloome

A, Fran~ois J, Babel J: Chorioreti-

nal Heredodegenerations. Springfield,

T, ed: ERG, VER and Psychophysics.

mol ProcSer

Franceschetti

153

WB Saunders

Co;

IntOphthalmolClin

GW: Electrophysio-

of eyes with opaque 1980;20:1-19.

media.

154

TheElectroretinogram

Krill AE: Clinical

elecrroretinography.

In: Hughes

Pepperberg

DR, Birch DG, Hofmann

WR, ed: Year Book of Ophthalmology. Chicago:

Recovery

Year Book Medical

tion inferred

Krill

Publishers;

1959-1960:5-27.

clinical

applications.

and electro-

Ponte F: Electroretinographic

AE: Hereditary

normal

normal

D, Kriss A: The infant fundi,

with

but an ab-

MF, Lurie

M: Light-induced

responses of the retinal KM, Marmor

Epithelium.

pigment

electrical

epithelium.

In:

MF, eds: The Retinal Pigment

Cambridge,

MA: Harvard

University

S, Auerbach

E: The central

eral retina in macular ment as reflected

and periph-

degenerations:

E: Retinitis

EA, Frishman

Heckenlively

Mosby-Year

Noble

KG: Pathology

dystrophies. Okun

Pedriel

Book;

of Vision. St

macular

I: ERG and retinal

detachment.

In:

Value of Electroreti-

in Ghent,

1966. Basel:

S Karger AG; 1968:435:--439. blindness

revisited:

Invest Ophthalmol

from man

Vis Sci 1982;23:

in Ghent,

the dark-

Doc Ophthalmol

PU, Stout ]T: Birdshot

Value 1966.

retino-

In: Schachat AP, Murphy Mosby-Year

RP, eds:

Book;

1994:2:1677-1685. RH: Monitoring

photoreceptors

Ophthalmol

and essential

Symposium

choroidopathy.

communications

and pigment

cells: effects of "mild"

71.

I, ed: The Clinical

Basel: S Karger AG; 1968:384-392.

L]: Dissecting

electroretinogram.

Ryan S], Dugel

tween

H: Chloroquine

Arch OphthalmoI1963;69:59-

In: Fran9ois

Co; 1972:187-206.

Fran~ois ], ed: The Clinical

Steinberg

Sem OphthalmoI1987;2:110-129.

of Electroretinography.

Rendahl

CY Mosby

Retina. 2nd ed. St Louis:

1991:101-111.

of the hereditary

G: Electroretinogram

hemeralopia.

measurements.

1998-1999;95:187-215.

In:

GB, eds: Principles and

E, Gouras P, Bernstein

retinopathy.

tion. St Louis:

adapted

Practice of Clinical Electrophysiology Louis:

of

In: Potts AM, ed: The Assessment of Visual Func-

Robson ]G, Frishman

pigmentosa.

LI: The b-wave.

IR, Arden

of the 4th Symposium 1965. Jpn J Ophthaln:lol

588-609.

Surv OphthalmoI1976;20:303-346. Newman

of the

In: Naka-

1966; 10(suppl):282-285.

to molecules.

by the electroretinogram.

S, Auerbach

in Hakone,

Ripps H: Night

involve-

Arch OphthalmoI1970;84:710-718. Merin

ISCERG

nography. Symposium

Press; 1979:226-244. Merin

Pathways. Proceedings

Potts AM: Electrophysiological

ERG. Surv OphthalmoI1989;34:173-186.

Marmor Zinn

Row; 1972;1:227-295.

appearing

evaluation

degenerations.

jima A, ed: Retinal Degenerations, ERG, and Optic

Retinal and Choroidal Dis-

SR, Taylor

nystagmus,

alpha-wave

J Opt Soc Am 1996; 13:586-600.

sectoral tapeto-retinal

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.

Basel: S Karger AG; 1968:273-289. 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:

Retinal Dystrophies and Degenerations. New York: Raven Press; 1988:21-69. 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

~

""

J

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

The Electro-Oculogram

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

The Electro-Oculogram

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

The Electro-Oculogram

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

The Electro-Oculogram

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 a19°noticed 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

The Electro-Oculogram

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:

on the light

of the cat. Invest

Vis Sci 1983;24:37-46.

9. Marmor

MF, Donovan

WJ, Gaba DM:

Effects

of hypoxia

and hyperoxia

on the human

standing

potential.

Doc OphthalmoI1985;60:347-352.

10. Linsenmeier

RA, Steinberg

poxia alters K+ homeostasis lial cell membrane Invest Ophthalmol 11. Missotten

hy-

responses

epithe-

in the cat retina.

Vis Sci 1984;25(suppl):289.

L, Goethals

the standing

RH: Mild

and pigment

potential

M: Timolol

reduces

of the eye. Ophthalmic Res

1977;9:321-323. 12. Marmor

MF, Zrenner

E: Standard

for clinical

electro-oculography. International Society for Clinical Electrophysiology of Vision. Arch OphthalmoI1993;11:601-604.

REFERENCES

13. Arden 1. Marg E: Development

of electro-oculography.

Arch OphthalmoI1951;45:169-185.

of the human

2. Riggs LA: Electroretinography night

blindness.

oculography conditions

in cases of

Am J OphthalmoI1954;38:70-78.

3. Fran~ois ], Verriest

G, de Rouck

as a functional of the fundus,

A: Electro-

test in pathological I: first results. Br J

oculography

in fundus

G, de Rouck pathology.

A: ElectroBr J Ophthal-

the standing

eye and the bleaching

of visual purple.

in pigmentary

14. De Groot SG, Gebhard termined

by adapting

JW: Pupil

luminance.

RG, Eisner

physiological

studies.

A: Retinal

In: Newsome

K, Yamamoto

degenerations

of

tions. Folia

S, Yonemura

approach epithelium.]

D:

to clinical test for Nippon Ganka

1977;81:1303-1312. D, Kawasaki

HE,

Hochgesand

of the electro-oculogram.

potential

and its clinical

EGG values of young

and

DA, ed:

P: Empirical

of the

applica-

Ophthalmol Jpn 1978;29:408-416.

model

Doc Ophthalmol1973;

subjects.

S: Normal

Doc Ophthalmol

Proc Ser 1977; 13:93-97. 18. Hansen

K, Tanabe ], et al:

of the standing

eye to acetazolamide

function

Retinal Dystrophies and Degenerations. New York:

6. Kawasaki

Susceptibility

size as de-

1952;42:492-495.

34:229-241.

7. Yonemura

1962;

J Opt Soc Am

17. Jones RM, Stevens TS, Gould

GakkaiZasshi

and regen-

J Physiol (Lond)

the retina. Arch OphthalmoI1962;68:369-389.

[Electrophysiological the retinal pigment

on

potential

161:205-226.

16. Kolder

GB, Fojas MR: Electrophysiological

abnormalities

between

Raven Press; 1988:21-69.

mol 1956;40:305-312. 5. Arden

eration

15. Weleber

OphthalmoI1956;40:108-112. 4. Fran~ois ], Verriest

GB, Kelsey JH: Some observations

the relationship

tentials

RM, Fulton

in human

AB: Corneoretinal

infants.

Doc Ophthalmol

poProc

Ser 1983;37:81-86. 19. Trimble

JL, Ernest JT, Newell

oculography

in infants.

FW: Electro-

Invest Ophthalmol

Vis Sci

ER, Linsenmeier

RA:

1977;16:668-670. 20. Steinberg The cellular

RH, Griff origin

of the light peak. Doc Oph-

thalmol Proc Ser 1983;37:1-11.

171

References

21. Thaler

A, Heilig

retinopathy:

P, Lessel MR: Ischemic

reduced

amplitUdes

light-peak

32. Wakabayashi

and dark-trough

in electrooculography.

In: Lawwill

K, Yonemura

Electrophysiological T,

dystrophy

and retinal

ed: ERG, VER and Psychophysics. 14th ISCERG

dystrophy.

Ophthalmic Paediatr

Symposium.

13-17.

Hague:

Doc Ophthalmol 22. Hofmann selectively

Dr W Junk BV Publishers.

Proc Ser 1977;13:119-121. H, Niemeyer

the EOG-Iight

G: Calcium

33. Kawasaki blocks

peak. Doc Ophthalmol

23. Griff

ER, Linsenmeier

The cellular

origin

RA, Steinberg

RH:

of the fast oscillation.

Doc

Ophthalmol Proc Ser 1983;37:13-20. 24. Kolder

H, Brecher

the corneoretinal

potential

of

in man. Arch Ophthal-

mol 1966;75:232-237. 25. Kolder enlively

JR, Arden

GB, eds: Principles and Prac-

tice of Clinical Electrophysiology Mosby-Year 26. Thaler

Book;

Heilig

P, et al: The

intensity

influ-

and adaptation

and peak latency.

time

Ophthalmic Res

1982;14:210-214. dure for the simultaneous slow EOG oscillations.

D: A clinical recording

proce-

of fast and

Int OphthalmoI1981;3:

P, Scheiber

phase of the EOG-oscillation

V: The

initial

in ischemic

reti-

Doc Ophthalmol Proc Ser 1978;15:

Mosby-Year

Book;

BA, Krill

clinical

AE: Fundus

GA: Fundus

classification.

RG: Fast and slow oscillations

the electro-oculogram phy and retinitis

in Best's macular

pigmentosa.

of

dystro-

Arch Ophthalmol

1989;107:530-537. 30. Yonemura

36. Fishman

D, Kawasaki

juvenile

K, Wakabayashi

for Stargardt's retinoschisis.

K, et

disease and

Doc Ophthalmol

Proc Ser 1983;37: 115-120. 31. Yonemura

D, Kawasaki

al: New approach sis of flecked

flavimaculatUs:

to electro-physiological

retinal

syndrome.

Proc Ser 1982:31:165-175.

a

Arch OphthalmoI1976;94:

testing

in fundus

flavimacu-

latUs. Arch OphthalmoI1979;97:1896-1898. 37. Fran9ois

I, de Rouck

Electro-oculography

A, Fernandez-Sasso

in vitelliform

D:

degeneration

of the macula. Arch OphthalmoI1967;77:726-733.

Electroretinography

A, Fernandez-Sasso

D:

and electro-oculography

diseases of the posterior

in

pole of the eye. Bibl

troretinogram Doc Ophthalmol

form macular

RC, Hirose

in 'vitelliform'

K, et analy-

Doc Ophthalmol

T: The elec-

macular

lesions.

Proc Ser 1983;37:93-103.

LI, Metz

HS, Woodward

and fluorescein degeneration.

F: Elec-

stUdies in vitelliArch Ophthalmol

1972;87:636-641. 41. Cross HE, Bard L: Electro-oculography dystrophy.

in

Am J Ophthalmol1974;

77:46-50. 42. Godel V, Chaine Best's vitelliform

G, Regenbogen

macular

thalmoI1986(suppl);175:1-31. K, Wakabayashi

observa-

GA, Young RS, Schall SP, et al:

Best's macular

al: EOG application

flavimaculatus:

2061-2067.

trophysiologic

29. Weleber

of Vision. St

1991:163-166.

clinical, functional and histopathologic tions. Am J OphthalmoI1967;64:3-23.

40. Schwartz

151-153.

X-Iinked

Louis:

39. Sabates R, Pruett A, Heilig

K: Non-

OphthalmoI1969;80:132-163.

179-189. 28. Thaler

pattern

GB, eds: Principles and

38. Fran9ois I, de Rouck

27. de Rouck A, Kayembe

nopathy.

IR, Arden

Electro-oculogram

of the electro-oculogram:

ence of stimulus on amplitUde

of Vision. St Louis:

1991:301-313.

AR, Lessel MR,

fast oscillation

In: Heck-

epithelial

Genet 1983;3:

K, Tanabe I, Wakabayashi

35. Fishman

HE: Electro-oculography.

pigment

Practice of Clinical Electrophysiology

34. Klien

GA: Fast oscillations

K:

photic standing potential responses: hyperosmolarity, bicarbonate, and Diamox responses. In: Heckenlively

1985;60:361-368.

D, Kawasaki

analysis of Best's macular

dystrophy.

L, et al: Acta Oph-

172

The Electro-Oculogram

43. Deutman

AF: Electro-oculography

lies with vitelliform tection

dystrophy

in fami-

of the fovea: de-

of the carrier state. Arch Ophthalmol1969;

81:305-316.

Ophthalmologica

macular

degeneration

lar pigment

epithelial

dystrophy.

foveomacuAm J Ophthal-

mol 1980;89:680-691. 46. Fishman

S, Rabb MF, et al:

macular

degeneration.

MF: Pattern

]R, Arden

dystrophies.

In: Heck-

GB, eds: Principles and Prac-

Year Book;

ofVision.

St Louis:

1991 :700-704.

HE, et al: Butterfly-shaped

]D,

pigment

Henkes

dystrophy

of the fovea. Arch OphthalmoI1970;83:558-569. MF, Byers B: Pattern

the pigment

epithelium.

dystrophy

of

Am J Ophthalmol1977;

of the retinal

pigment

epithelium.

57. Krill

51. Kingham Reticular

]D,

Fenzl

dystrophy

thelium:

a clinical

RE, Willerson

of the retinal

D, et al:

pigment

and electrophysiologic

of three generations.

epistudy

Arch OphthalmoI1978;96:

P, Archer

A patterned

macular

and atrophic

D, Maumenee dystrophy

IH, et al:

with yellow

changes. Br J Ophthalmol

53. Ayazi S, F agan R: Pattern epithelium.

54. O'Donnell Autosomal

with both

honeycomb

Nat Genet 1999;22: 199-202.

AE, Klien

BA: Flecked

retina syn-

GA, Carrasco C, Fishman

electro-oculogram

in diffuse

M: The

(familial)

drusen.

59. Sunness IS, Massof RW: Focal electro-oculogram in age-related

macular

degeneration.

Am J

Optom Physio! Opt 1986;63:7-11. MacDonald

nie NM:

Fundus

capillary

glomerulonephritis

MK,

McKech-

changes in (type II) mesangiosimulating

drusen:

report. Br J Ophtha!mo!1989;

73:297-302. 61. Duvall- Young I, Short CD, Raines MF, et al: changes in mesangiocapillary

lonephritis

type II: clinical

giographic

findings.

glomeru-

and fluorescein

an-

Br J Ophtha!mo!1989;73:

62. Leys A, Vanrenterghem et al: Fundus

glomerulonephritis graphic

Y, Van Damme

B,

changes in membranoproliferative type II: a fluorescein

study of 23 patients.

angio-

Graefes Arch C!in

63. Leys A, Michielsen retinal

neovascular

chronic

B, Leys M, et al: Sub-

membranes

membranoproliferative

associated

with

glometuloneph-

ritis type II. Graefes Arch C!in Exp Ophtha!mo!

1980;64:127-134. pigment

and Doyne

Exp Ophtha!mo!1991;229:406-410.

1177-1184. 52. Cortin

FL, et al: A

associated

900-906.

Arch OphthalmoI1977;95:429-435.

680-683.

dystrophy.

Fundus RC, Fine BS, Lyons ]S: Patterned

dystrophies

pigment

Leventinese

histopathological

84:32-44.

plaques

retinal

AI, Munier

mutation

60. Duvall-YoungI,

AF, van Blommestein

49. Marmor

Lotery

single EFEMP1

Arch Ophtha!mo!1976;94:231-233.

tice of Clinical Electrophysiology

48. Deutman

Arch Oph-

tha!mo!1983;101:1198-1203.

58. Fishman

Arch

OphthalmoI1977;95:73-76. 47. Marmor

GH: Butterfly-shaped

in four generations.

drome. Arch Ophtha!mo!1965;74:496-508.

GA, Trimble

Pseudovitelliform

50. Hsieh

IG, Bresnick

dystrophy

Malattia

1971; 163:312-324.

45. Vine AK, Schatz H: Adult-onset

Mosby-

macular

56. Stone EM,

44. Fran9ois ]: Vitelliform

enlively

55. Prensky

dystrophy

of the

Retina 1981;1:287-289.

FE, Schatz H, Reid P, et al:

dominant epithelium.

dystrophy

of the retinal

Arch OphthalmoI1979;97:

1990;228:499-504. 64. Michielsen Fundus

B, Leys A, Van Damme

changes in chronic

tive glomerulonephritis

B, et al:

membranoprolifera-

type II. Doc Ophtha!mo!

1990-1991;76:219-229. 65. Ulbig

MR,

Riordan-Eva

P, Holz FG, et al:

Membranoproliferative glometulonephritis type II associated with central serous retinopathy. Am J Ophtha!mo!1993;116:410-413.

a

173

References

66. O'Brien

C, Ouvall- Young J, Brown

Electrophysiology glomerulonephritis normalities.

with

associated

fundus

ab-

Br J OphthalmoI1993;77:778-780.

67. Ohdo S, Hirayama tion of ectodermal macular

M, et al:

of type II mesangiocapillary

K, Terawaki

dysplasia,

dystrophy:

T: Associa-

ectrodactyly,

the EEM

and

syndrome.

J Med

Genet 1983;20:52-57. 68. Albrectsen syndactyly

and retinal

IB: Hypotrichosis,

degeneration

in two sib-

lin~s. Acta Derm Venereol1956; 1:96-101.

Association

of ectodermal

and macular report).

M, Yanashima

1963;70:629139. 79. Whitcup 8M, Butler Retinal

toxicity

children

dideoxyinosine.

dystrophy:

dysplasia, EEM

ectrodactyly

syndrome

Ophthalmic PaediatrGenet

(case

1989;10:

8M, Butler

inosine.

New Engl J Med 1992;326:1226-1227.

treated

with dideoxy-

BY, 8hay LE, Wyvill

pilot study of sequential

KM, et al: A

therapy

with

zidovu-

dine plus acyclovir, dideoxyinosine, and dideoxycytidine in patients with severe human imvirus infection.

J Infect Dis 1993;

168:810-817. 82. Whitcup

et al: A clinicopathologic

M: The

mol 1994;112:1594-1598.

in early retinitis

thalmol1964;

pigmentosa.

72: 104-110.

AE, Oeutman

cone degenerations.

AF, Fishman

Doc OphthalmoI1973;35:

AE: The electroretinographic

trooculographic

findings

and elec-

in patients

with

lar lesions. Trans Am Acad Ophthalmol

macu-

Otolaryngol

73. Yolker-Oieben

HJ, van Lith

with X-chromosomal

of a family

recessive

myopia.

In: Oodt

E, Pearlman

ISCERG

Symposium. Hague:

nyctalopia

and

T, eds: 11 th

Proc Ser 1974;4:

rod adaptation

in Oguchi's

kinetics

and

disease. Invest Oph-

thalmoI1967;6:426-436. 75. Miyake

toxicity

of desferrioxamine:

85. Davies al: Ocular

M, Suzuki

findings

S, et al:

in patients

with

disease. Jpn J OphthalmoI1996;40:

8C, Marcus toxicity

B: The electro-oculogram

ders of the retinal

circulation.

in disor-

Am J Ophthalmol

1966;61:505-508. 77. Pinckers

A, Broekhuyse arthritis.

RM: The

P, et al: Ocular of cop-

damage? Br J Oph-

EOG in

Acta OphthalmoI1983;61:

RE, Hungerford

of high-dose

V, 8chocket

des-

thy. Ophthalmology

HE:

pigmen-

optic neuropa-

1984;91:443-451.

and experimental

Doc Ophthalmol

88, Jiji R: Deferoxtoxic retinal

and presumed

87. Jackson J, Kolder

88. Kolder

JL, et

intravenous

Lancet 1983;2:181-184.

HE,

Homer

LD,

et al:

optic nerve transection.

Proc Ser 1983;37:35-40. Electro-oculography.

logica 1974;169:127-140.

511-519. 76. Ashworth

J, et al: Cereby desferriox-

an example

auto-oxidative

86. Lakhanpal

EOG

Y, Horiguchi

Electrophysiological

rheumatoid

84. Pall H, Blake DR, Winyard

tary degeneration

74. Carr RE, Ripps H: Rhodopsin

Arch Ophthal-

amine. Q J Med 1985;56:345-355.

amine(Desferal)-induced

169-177.

Oguchi's

P, Lunec induced

ferrioxamine.

Or W Junk BY

Doc Ophthalmol

with didanosine.

bral and ocular toxicity

RB,

of the retinalle-

thalmoI1989;73:42-47.

GH, Went

et al: Electro-ophthalmology

K, Nussenblatt

report

83. Blake DR, Winyard

per promoted

1966;70:1063-1083.

Publishers.

8M, Dastgheib

sions associated

1-80.

831-837.

KM, Pizzo PA, et al:

lesions in children

Arch Oph-

LN,

with 2',3'-

Retinal

studies

72. Krill

Caruso R, et al:

immunodeficiency

treated

70. Gouras P, Carr RE: Electrophysiological

71. Krill

in chloro-

Am J OphthalmoI1992;113:1-7.

munodeficiency

287-292.

EOG

Arch Ophthalmol

KM,

in human

virus-infected

81. Nguyen

K, Kato K, et al:

RD: The

and other retinopathies.

80. Whitcup

B, Svendsen

69. Hayakawa

78. Gouras P, Gunkel quine

Ophthalmo-

174

The Electro-Oculogram

89. Thaler fluence

A, Lessel MR, Gnad H, et al: The

of intravitreously

electrophysiological

injected

potentials

silicone

in-

oil on

OphthalmoI1986;62:41-46. 90. Foerster

MH,

and its influence

Arden

Esser J, Laqua

H: Silicone

on electrophysiologic

oil

findings.

beticus:

HE, Houtsmuller

an evaluation

AJ: Fundus

dia-

of the preretinopathic

stage. Am J OphthalmoI1965;60:662-670. 92. Good P, Gross K: Electrophysiology allosis: support mechanism

for an oxidative

in the human

and met-

fluence

V, et al: The

in-

on the EOG. Doc Ophthalmol

between

malignant

M: On the lack of corre-

ERG and EOG

melanoma

alterations

of the choroid.

Visual Electrodiagnostic

ing: A Practical

Guide for the Clinician.

MD:

& Wilkins;

Williams

Fishman

in

In: Law-

retinal

In: Peyman

thalmology. Philadelphia:

WB Saunders

S] , ed: Electrical

System. Boston: Galloway

Little,

Responses of the Visual Brown

Dr W Junk BV

Proc Ser 1977;13:

87-92.

Philadelphia:

WB Saunders

EOG

and choroidal

mas. Invest Ophthalmol 96. Jones RM, Klein

CR, Dawson malignant

WW, et melano-

Vis Sci 1979;18(suppl):121. R, De Venecia G, et al: Ab-

normal

electro-oculograms

lignant

melanoma

from eyes with

of the choroid.

a '11a-

Invest Ophthal-

mol Vis Sci 1981;20:276-279. 97. Markoff

J, Shaken

electro-oculogram

In: Fran<;:ois ],

Value of Electroretinography.

Kelsey ]H: Variations oculogram. Krill

E, Shields J, et al: The

in presumed

choroidal

mela-

G, Huber

C, eds:

Techniques in Clinical Electrophysiology 19th ISCERG

Symposium.

BV Publishers.

Doc Ophthalmol

Hague:

of Vision. Dr W Junk

Proc Ser 1982;31 :

clinical

mol 1970;9:600-61 Krill

in the normal

and electro-

applications.

Invest Ophthal-

7.

AE: Electroretinogram. DB, eds: Krills

Choroidal

electro-

Br J OphthalmoI1967;51:44-49.

AE: The electroretinogram

oculogram:

Archer,

nomas and nevi. In: Niemeyer

105.

ed: The Clinical

Co; 1975.

of the electro-oculo-

Basel: S Karger AG; 1968:66-73.

95. Staman JA, Fitzgerald al: The

& Co; 1969.

NR: Ophthalmic Electrodiagnosis.

gram to the electroretinogram.

Hague:

Co; 1980;

2:857-904.

ISCERG

Doc Ophthalmol

GA, Sanders DR,

MF, eds: Principles and Practice ofOph-

Gouras P: Relationships

Symposium.

and choroidal

and electro-oculo-

will T, ed: ERG, VER and Psychophysics. 14th Publishers.

1est-

Baltimore,

1982.

GA: Hereditary

F ricker

Proc Ser 1974; 10:325-328.

lation

Carr RE, Siegel IM:

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.

Am J OphthalmoI1985;99:201-206. 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: Retinal Dystrophies and Degenerations. New York: Raven Press; 1988:21-69. 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

5

3.2

0.66

38

4

42

4.8

0.43

22

5

5

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

5

3.2

2.88

21

15

5

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.

Redrawn with permission of Kluwer Academic Publishers from Birch DG, Fish GE: Focal coneelectroretinograms: aging and macular disease.Doc OphthalmoI1988:69: 211-220.

182

The Focal and Multifocal

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

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(A) Forfull-field

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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

A

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tient with retinitis pigmentosa and severefield constriction. (A) Individual from

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fied Humphrey threshold program. Number at each point is log of ratio of patient:r threshold to mean

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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.

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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

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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

The Focal and Multifocal

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.

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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

The Focal and Multifocal

Electroretinogram

REFERENCES SUMMARY 1. Osterberg

The focal ERG evolved

because of the in-

sensitivity of the conventional (full-field) ERG to disease limited to the macula. Al-

G: Topography

and cones in the human 1935(suppI6);13:11-96. 2. Curcio

CA. Sloan KR. Kalina RE, et al: Human

though it is theoretically possible to conduct multiple independent focal ERG tests

photoreceptor

from regions across the retina, constraints imposed by recording lens tolerance and testing time effectively limit measurements to the fovea and parafovea. Thus, the focal ERG is most useful as an objective measure

3. BiersdorfWR,

of foveal function. There is an emerging consensus that the focal ERG response is abnormal in eyes with <20/40 vision due to macular disease. Conversely, a normal focal

5. Seiple WH,

ERG in conjunction with poor visual acuity suggests a disease site proximal to the pho-

gram as a clinical

toreceptors. The multi focal ERG incorporates

7. Nagata M, Honda

state-

of-the-art stimulus and recording technology with powerful analysis algorithms. At the simplest level, the multifocal ERG provides an objective equivalent to the visual

of the layer of rods

retina. Acta Ophthalmol

topography.

J Comp Neuro11990;

292:497-523. Diller

gram in macular

DA: Local electroretino-

degeneration.

Am J Ophthalmol

1969;68:296-303. 4. BiersdorfWR: ERG.

Temporal

CurrEyeRes

ating macular

Siegel IM, Carr RE, et al: Evalufunction

Invest Ophthalmol 6. Arden

factors in the foveal

1981-1982;1:717-722.

using the focal ERG.

Vis Sci 1986;27:1123-1130.

GB, Banks JL: Foveal electroretinotest. Br J Ophthalmol1966;

50:740.

macular

Y: The

macular

local electroretinograms

retina and their clinical

and para-

of the human

application.

In: Arden

Press; 1972:309-322.

field by simultaneously assessing approximately 100 retinal locations. The ultimate power of the procedure, however, lies in the

8. Hirose

T, Miyake

recording

of electroretinogram

fact that the local responses contain components from all levels of the retina. The

observation.

9. Jacobson JH, Kawasaki

K, Hirose

evolving capability of the analysis routines to separate photoreceptor from ganglion cell components is leading to an increasingly sensitive diagnostic test and a potentially powerful toot for evaluating treatment

human

and occipital

efficacy.

G,

ed: The Visual System: Neurophysiology, Biophysics, and Their Clinical Applications. New York: Plenum

evoked

response:

Y, Hara A: Simultaneous under

direct

Arch OphthalmoI1977;95:1205-1208.

electroretinogram

in response

to focal illumination

I nvest Ophthalmol1969; 10. Miyake amblyopia:

and visual

focal stimulation

T: The potential

of the retina.

106:348-35 7.

Y, Awaya S: Stimulus deprivation simultaneous recording of local mac-

ular electroretinogram

and visual evoked

re-

sponse. Arch OphthalmoI1984;102:998-1003. 11. Sandberg channel

MA, Ariel M: A hand-held,

stimulator-ophthalmoscope.

thalmoI1977;95:1881-1882.

two-

Arch Oph-

194

TheFocal and Multijocal Electroretinogram

34. Kawabata

H, Adachi-Usam

electroretinogram

44. Jacobson SG, Marmor

E: Multifocal

in myopia.

SWS (blue)

Invest Ophthalmol

Vis Sci 1997;38:2844-2851.

identified

35. Hood DC, Holopigian

K, Greenstein

Vis Sci 1990;31:827-838.

Assessment

of local retinal

function

with retinitis

pigmentosa

ERG technique.

ed: Noninvasive Washington,

Enhanced

for measuring

in-

MW, Kretschmann

UH, Apfelstedt-

time topography

focal electroretinograms.

of multi-

Invest Ophthalmol

Vis Sci

MA,

Effron

MH,

cone electroretinograms Ophthalmol

Berson EL:

in dominant

with reduced

Focal

penetrance.

U, Seeliger

electroretinography

with Stargardt's

macular

40. Piao CH, Kondo

dystrophy.

M, Tanikawa

electroretinogram

in occult

trophy. Invest Ophthalmol 41. Kretschmann

K,

distribution

U, Apfelstedt-

electroretinography

in

Am J Ophthalmo/1998;125:

drome with night

blindness,

S cone sensitivity.

perimetry

GR, Green WR: correlated

in human

49. Sutter

with

eyes with glau-

EE, Bearse MA Jr: The optic nerve of the human

AM,

et al: Mapping

of retinal

macular

retinopathy

dys-

K, et

in diseases

et

maculopathy,

and

Am J Ophthalmol

Vis Res

EE, Bearse MA Jr,

function

nogram. Invest Ophthalmol

in diabetic electroreti-

Vis Sci 1997;38:

2586-2596. 51. Fortune

B, Schneck

ME, Adams AJ: Multidelays reveal local retinal

in early diabetic

Ophthalmol

Invest

LJ, Viswanathan

al: Evidence

for a ganglion

the primate

electroretinogram

TTX

retinopathy.

Vis Sci 1999;40:2638-2651.

52. Hood DC, Frishman

of a new syn-

ERG.

using the multifocal

dysfunction

mul-

MH,

Sutter

focal electroretinogram

detachment.

MF, Jacobson SG, Foerster findings

cell atrophy

50. Palmowski

Doc OphthalmoI1997-1998;94:239-252.

clinical

HA, Dunkelberger

ganglion

A, et al: Mul-

by multifocal

in retinal

48. Quigley

1999;39:419-436.

Vis Res 1998;38:3817-3828.

electroretinogram

1990;110:124-134.

pigmentosa.

Br J Ophthal-

42. Sasoh M, Yoshida S, Kuze M, et al: The

enhanced

retinitis

head component

MW, Ruether

pole determined

electroretinography.

al: Diagnostic

M, Kretschmann

in patients

Vis Sci 2000;41:513-517.

U, Seeliger

al: Spatial cone activity

43. Marmor

Vis Sci 1999;

coma. Am J Ophthalmo/1989;107:453-464.

mol 1998;82:267-275.

tifocal

in enhanced

Invest Ophthalmol

Sylla E, et al: Multifocal

automated

Invest

MW, Ruether

et al: Multifocal

of the posterior

47. Seeliger

Retinal

retinitis

Vis Sci 1978;17:1096-1101.

39. Kretschmann

tifocal

EE, et al: Topog-

214-226.

1998;39:718-723.

pigmentosa

for an ab-

of S cones. Vis Res 1995;

40:1866-1873.

Sylla E, et al: Implicit

38. Sandberg

AJ, et al:

evidence

MF, Tan F, Sutter

S cone syndrome.

of America;

1997;11:33-41. 37. Seeliger

AV, Roman

raphy of cone electrophysiology

Assessment of the Visual System. Society

Invest Ophthalmol

35:1473-1481. 46. Marmor

ERG records. In: Yager D,

DC: Optical

large number

CM, er al:

in a newly

degeneration.

S cone syndrome:

normally

Vis Res 1998;38:163-179.

multifocal

retinal

45. Hood DC, Cideciyan

in patients

using the multi-focal

36. Hood D, Li L: A technique dividual

V, et al:

MF, Kemp

cone hypersensitivity

on the multifocal

S, et

cell contribution (ERG):

ERG

to

effects of

in macaque.

Vis

Neurosci 1999;16:411-416. 53. Hood

DC, Greenstein

al: Identifying the human

V, Frishman

inner retinal multifocal

L, et

contributions

ERG.

to

Vis Res 1999;39:

2285-2291. 54. Hood

DC, Greenstein

al: An attempt

to detect

the inner retina with nhhth/lfmol

VC, Holopigian glaucomatous

the multifocal

Vi.\",'i'ci 2000:41:1570-1579.

K, et

damage to ERG. Invest

Suggested Readings

SUGGESTEDREADINGS Arden

GB, Bankes JL: Foveal

as a clinical

electroretinogram

test. Br J OphthalmoI1966;50:740.

Bankes JL: The foveal electroretinogram. Trans Ophthalmol Birch DG: Clinical Fuller

DG, Birch

Soc UK 1967;87:249-262. electroretinography.

Function for the Clinician. Saunders

In:

DG, eds: Assessment of Visual Philadelphia:

WB

Co; 1989:469-497.

Fish GE, Birch DG: The

focal electroretinogram

in the clinical

assessment

of macular

Ophthalmology

1989;96:109-114.

Heckenlively

JR, Arden

disease.

GB, eds: Principles

and Practice of Clinical Electrophysiology St Louis:

Mosby-Year

Book;

Hood DC, Greenstein Identifying human

V, Frishman

inner retinal

multifocal

ERG.

of Vision.

1991. L, et al:

contributions

to the

Vis Res 1999;39:

2285-2291. Hood

DC, Seiple W, Holopigian

parison of the components full-field

ERGs.

Sandberg

K, et al: A com-

of the multifocal

and

Vis Neurosci 1997;14:533-544.

MA, Jacobson SG, Berson EL: Foveal

cone electroretinograms and juvenile

macular

in retinitis

pigmentosa

degeneration.

Am J Oph-

thalmoI1979;88:702-707. Sutter

EE, Bearse MAJr:

component 419-436.

of the human

The optic nerve head ERG.

Vis Res 1999;39:

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

ThePattern Electroretinogram

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

and Its Determinants

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

ThePattern Electroretinogram

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

and Its Determinants

205

4 05

> 6 "'

~O -0. E <

-2

-4 0

50

rime (ms)

100 Time (ms)

B 4

4 OD

as

2

~

~ 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.

0

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

ThePattern Electroretinogram

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,1°following 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

ThePattern Electroretinogram

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

A

Scotopic rod

Maximal

Photopic

5001 400 300 200 100 11

~ 0) "0 .E "0. E <

0

100

0

50

c 500 400 300 200 100 0

100

~ 0) "0 .E -0. E <

150 100 50 0

a

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)

O

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

ThePattern Electroretinogram

A Scotopic

Maximal

rod

PERG

~ 0> -0 .E "6. E <1:

0

100

150

400

100 200 50

0

100

100

50

100

c 150

400

100

[

200 50 o o

Figure 4-7 ERG findings

0

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)

0

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

D

Clinical

211

Applications

Figure 4-7 (D,E) Although maculas show no significant visible abnormality,

PERG

demonstrates marked central retinal dysfunction.

E

212

ThePattern Electroretinogram

A

3o-Hzflicker

Scotopic rod

0

Photopic 150

100

1001

2

50

5q

0

n

0

100

50

O -2 -4

0

150

150

100

100

50

50

50

O

100

0

0 0

100

PERG

4

150

50

0

50

c 150 100 50 0

o

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

ThePattern Electroretinogram

A ~

Scotopic

Maximal

rod

Photopic

400

-;;;-0

300

.~ -0. E <1:

200 100

0

100 B

::;;:

400

';j;' "0

300

~ -0. E <1:

200 100

0

a

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

D

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.

E

216

ThePattern Electroretinogram

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

ThePattern Electroretinogram

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

A

Pattern YEP

Flash VEP

PERG

-J\ 1-

B

c

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

D

Clinical

Applications

223

Figure 4-13 (D.E) Fundi of both patients show global disc pallor:

E

224

ThePattern Electroretinogram

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

ThePattern Electroretinogram

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.

REFERENCES 1. Corbett sessment

MC, Shilling of clinical

wich Grading trodiagnostic

JS, Holder

investigations:

GE: The asthe Green-

System and its application testing

in ophthalmology.

to elecEye 1995;

9(sup,pI):59-64. 2. Marmor

MF, Holder

Guidelines

for basic pattern

recommendations for Clinical

GE, Porciatti

V, et al:

electroretinography:

by the International

Electrophysiology

Society

ofVision.

OphthalmoI1995-1996;91

:291-298.

3. Riggs LA, Johnson

LP, Schick AM:

responses of the human pattern.

eye to moving

Doc

Electrical stimulus

Science 1964;144:567-568.

4. Lawwill

T: The

for clinical

evaluation

bar-pattern

electroretinogram

of the central

OphthalmoI1974;78:121-126.

retina. Am J

228

ThePattern Electroretinogram

5. Dawson proved

WW, Trick

electrode

Ophtholmol 6. Arden

GL, Litzkow

CA: Im-

for electroretinography.

16. Porciatti

Invest

Vis Sci 1979; 18:988-991.

GB, Carter

foil electrode:

quency

extending

the horizons

Invest Ophtholmol

17. Korth

Vis Sci

trast transfer

C: [Localizing

in the visual pathway

by simultaneous

of retinal

responses.]

and cortical

recording

Berl Dtsch Oph-

D, Drasdo on the latency

309-313.

A: Electroretinographic gratings

before and after

of the optic nerve. Science 1981 ;211 :

GE: The pattern

anterior

visual pathway

tionship

to the pattern

personal

clinical

review

electroretinogram

dysfunction

in

potential:

The uniform

S, Frishman

LJ, Robson JG:

field and pattern

with e~perimental ing activity.

ERG in macaques

glaucoma:

removal

Invest Ophtholmol

of spik-

Vis Sci 2000;41:

2797-2810. 11. Holder dysfunction.

of abnormal

in anterior

pattern

visual pathway

Br J OphtholmoI1987;71:166-171.

12. Berninger

T, Schuurmans

of the pattern

ERG across temporal

frequency.

tic of the pattern

RP, Berninger

responses

Doc OphtholmoI1985;59: 14. Bach M, Holder the pattern

in man and cat.

size tuning a reappraisal.

21. Aylward

on

Graefes Arch Clin Exp Oph-

GW, Billson

V, Billson

FA: The

wide-angle pattern electroretinogram: relation between pattern electroretinogram amplitude area using large stimuli.

Doc Oph-

thalmoI1989;73:275-283. 22. Sakaue H, Katsumi recordings:

pattern

0, Mehta

reversal

M, et al: Si-

ERG and VER

effect of stimulus

scotoma. Invest Ophthalmol

field and central

Vis Sci 1990;31 :

A, Wildber~er

electroretinogram,

pattern-

J Neurophysiol1984;

H, Torok

visual evoked functions

OphthalmoI1995;90:229-245.

Doc

24. Hawlina

M, Konec

B: Pattern

potential

in maculopathy.

of

loop electrode

193-202.

15. Hess RF, Baker CL Jr: Human electroretinogram.

depends

thalmoI1999;237:93-99.

psychophysical

187-197.

GE: Check

OphtholmoI1996-1997;92:

.11:939-951.

frequency.

23. Junghardt

T: Luminance

recorded

electroretinogram:

characteris-

electroretinogram

506-511.

Doc OphtholmoI1985;61:17-25. 13. Schuurmans

M, et al:

on simultaneous

20. Zapf HR, Bach M: The contrast

multaneous

RP: Spatial tuning

0, Mehta

contrast

of

Vis Res 1989;29:

steady-state pattern reversal electroretinogram and visual evoked response. Ophthalmic Res

and stimulus G E: Significance

electroretinography

and contrast

S, Katsumi

of stimulus

temporal

10. Viswanathan

evoked

a

of 743 eyes. Eye 1997;11:

924-934.

and amplitude

1992;24:110-118.

and its rela-

visual evoked

Vis Sci 1985;

N: The effect of stim-

electroretinogram.

19. Tetsuka Effect

953-955. 9. Holder

Invest Ophthalmol

ulus contrast

8. Maffei

responses to alternating

0: Spatial con-

of the pattern-evoked

18. Thompson the pattern

section

functions

26:303-308.

lesions

tho/mol Gesomte 1980;77:409-417. L, Fiorentini

and early glau-

M, Rix R, Sembritzki

electroretinogram.

A, Teping

S, et al: Pattern of spatial fre-

in ocular hypertension

for clinical

1979;18:421-426. 7. Groneberg

B, Brunori

as a function

coma. Doc OphthalmoI1987;65:349-355.

RM, Hogg C, et al: A gold

electroretino,graphy.

V, Falsini

electroretinogram

and Doc

B: New noncorneal

for clinical

HK-

electroretinography.

Doc OphthalmoI1992;8i:253-259. 25. Otto T, Bach M: [Reproducibility tern electroretino~ram.]

of the pat-

Ophthalmologe

1997;94:

217-221. 26. Holder

GE: Recording

troretinogram J Electrophysiol

with

the pattern

the Arden

elec-

gold foil electrode.

Technol1988; 14: 183-190.

References

27. Thompson method

retinography. 315-319. 28. Arden

39. Korth

fibre in electro-

evoked

GE: Gold foil

a two centre study of electrode

relia-

Doc OphthalmoI1994;86:275-284. TA: The

pattern

gram and its contamination.

40. Trick

LR: Age-related

function.

Doc Ophtha!mo!1987;65:35-43.

of the human

KH: Pattern

electrode

42. Muir

site, stimu-

Ius mode and check size. Electroencephalogr NeurophysioI1989;74:

Clin

11-18.

31. Odom IV, Holder

GE, Fenghali

electroretinogram

IG, et al:

intrasession

a two centre comparison.

alterations

in retinal

I, Drance

SM, et al:

optic nerve. Am J Ophtha!mo!1984;

IA, Barlow

ance of the pattern

Clin Vis Sci 1992;7:

HL,

Morrison

ID:

electroretinogram

lnvarievoked

by

psychophysically equivalent stimuli in human ageing. J Physio! (Lond) 1996;497:825-835. 43. Tomoda

reliability:

H, Celesia

GG, Brigell

The effects of age on steady-state troretinograms

263-282.

MG, et a!: pattern

arid visual evoked

elec-

potentials.

Doc

Ophtha!mo!1991;77:201-211.

32. Froehlich

I, Kaufman

of pattern

Electroencephalogr

Dl: Improving

electroretinogram

the re-

recording.

Clin NeurophysioI1992;84:

44. Porciatti

V, Burr DC, Morrone

MC, et al:

The effects of aging on the pattern retinogram

394-399.

and visual evoked

electro-

potential

in hu-

mans. Vis Res 1992;32:1199-1209.

33. Arden

GB, Vaegan, Hogg CR: Clinical

experimental

evidence

that the pattern

troretinogram

(PERG)

is generated

proximal

retinal

retinogram

and

elec-

in more

K, Snow I, Seiple W, et al:-Vari-

of the pattern

electroretinogram.

Doc Oph-

tha!mo!1988;70:103-115.

layers than the focal electro-

(FERG).

45. Holopigian ability

46. Prager TC,

Ann NY A cad Sci 1982;388:

580-607.

Fea AM, Sponsel WE, et al: The

gold foil electrode

in pattern

electroretinography.

Doc Ophtha!mo!1994;86:267-274.

34. Adachi-Usami size and defocusing

E, Kuroda

N, Kakisu

Y: Check

effects on equipotential

maps of pattern-evoked

electroretinograms.

Doc

OphthalmoI1987;65:367-375. 35. Leipert

KP, Gottlob

electroretinoand de-

focus. Doc OphthalmoI1987;67:335-346. GE, Huber

on pattern

and flash ERG and pattern

MI: The effects of miosis visual

Doc Ophthalmol Proc Ser 1984;

40:109-116.

and intraindividual

pattern

electroretinogram.

R, et al: Repro-

variability

of the

Ger J Ophtha!mo!

48. Maffei ERG

L, Fiorentini

in the monkey

A, Bisti S, et al: Pattern

after section of the optic

49. Sherman

I: Simultaneous

pattern-reversal

electroretinograms and visual evoked potentials in diseases of the macula and optic nerve. Ann NY A cad Sci 1982;388:214-226.

37. Fiorentini

A, Trimarchi

properties

and visual evoked

C: Development

of pattern potentials

of

electroretinogram in infants.

Vis Res

1992;32:1609-1621. 38. Celesia

PC, Walter P, Brunner

ducibility

nerve. Exp Brain Res 1985;59:423-425.

36. Holder

potentials.

47. Iacobi

1994;3:216-219. I: Pattern

gram: effects of miosis, accommodation,

temporal

and glau-

Ophtha!mo!1987;84:

97:760-766.

effects of reference

evoked

eyes.] Foltschr

The effect of age on the nerve fiber population

Clin Vis Sci 1986;

30. Tan CB, King PI, Chiappa

liability

F, et al: [Pattern-

in normal

41. Balaszi AG, Rootman

electroretino-

1:185-190.

Pattern

B, Horn

385-387.

GB, Hogg CR, Holder

29. Berninger

ERG:

M, Storck

electroretinograms

comarous

Ophthalmic Physiol Opt 1987;7:

electrodes: bility.

DA, Drasdo N: An improved

for using the DTL

GG, Cone S, Kaufman

D: Effects

electroretinogram

visual evoked

Electroencephalogr

NeurophysioI1986;64:24.

IM,

ERG in man following

section

O'Connor

and Clin

PS, Young RS, et al: surgical re-

of the optic nerve. Invest Ophtha!mo!

Sci 1987;28:492-499.

of age and sex on pattern potentials.

50. Harrison The pattern

Vis

ThePattern Electroretinogram

230

51. Blondeau Pattem

P, Lamarche

J, Lafond

electroretinogram

tion in pigeons. 52. Tobimatsu

G, et al:

62. Salzman I, Seiple W, Carr R, et al: Electro-

and optic nerve sec-

CUlT Eye Res 1987;6:747-756. S, Celesia GG, Cone SB, et al:

Electroretinograms to checkerboard pattern reversal in cats: physiological characteristics and effect of retrograde

degeneration

cells. Electroencephalogr

of ganglion

Clin Neurophysiol1989;

ences between

of cat and pri-

GL, Wintermeyer

7-768. and

TH,

Coupland

electroretinogram

pattern

retinal

Boston:

Butter-

GB: Electrophysiological

between

disorders.

retinal

dis-

and optic nerve

Doc OphthalmoI1988;68:247-255.

66. Holder

GE, Votruba

(DOA)

M, Carter AC, et al:

findings

linking

in dominant

to the OPAl

3q 28-qter.

optic

locus on

Doc Ophthalmol1998-

1999;95;217-228.

FC, Ringo JL, Spekreijse origin

for

In: Barber C, Blum

1987:221-224.

chromosome

1983;10:256-260.

luminance

of the pattern

dysfunction.

T, eds: Evoked Potentials III. worths;

atrophy

in optic nerve demyelination.

CanJ NeurolSci 56. Riemslag

SG: The

:S 135.

GE: Abnormalities

Electrophysiological

55. Kirkham

ERG abnormalities

disease. Electroencepha-

logr Clin Neurophysiol1985;61

crimination

23:774-779.

of the pattern

in man. J Physiol (Lond)

H, et al:

electro-

67. Groneberg

A: Simultaneously

nal and cortical

1985;363:

board stimuli.

191-209.

potentials

recorded

elicited

Doc Ophthalmol

reti-

by checker-

Proc Ser 1980;23:

,

255-262.

57. van den Berg TJ, Boltjes electroretinogram

B, Spekreijse

H:

68. Arden

can be more than the

sum of local luminance

responses. Doc Ophthal-

mol 1988;69:307-314.

A comparison

OA, Arden

of pattern

layer thickness

GB:

ERG amplitudes in different

and

zones of the

OA, Orasdo N: Computation

the luminance

and pattern

components

electroretinogram.

of

of the

Doc Ophthalmol

PA, Steinberg

RH: Proximal

to the intraretinal

D: Pattern

potentials

ERGs

in maculopathies

and and

Vis Sci

1985;26:726-735.

patients tentials

GE: Pattern

with

delayed

electroretinography pattern

due to distal anterior

function.

visual evoked visual pathway

J Neurol Neurosurg Psychiatry

in podys-

1989;52:

retinal

8-Hz pattern

71. Gunduz contrast

K, Arden

sensitivity

GB: Changes

associated

in colour

with operating

ERG of cat. J NeurophysioI1987;57:104-120.

argon lasers. Br J OphthalmoI1989;73:241-246.

61. Baker CL Jr, Hess RR, Olsen BT, et al: Cur-

72. Holder

rent source density

(PERG)

in an integrated

pathway

diagnosis.

linear components

dis-

1364-1368.

1987;66:233-244.

contribution

A: Pattern

in macular

optic nerve diseases. Invest Ophthalmol

70. Holder

59. Thompson

60. Sieving

RM, Macfarlan

electroretinograms

ease. Br J OphthalmoI1984;68:878-884.

visual evoked

retina. Clin VisSci 1990;5:415-420.

bar pattern

GB, Carter

and Ganzfeld

69. Celesia GG, Kaufman

58. Orasdo N, Thompson nuclear

GE: Pattern

visual pathway

65. Ryan S, Arden

OH: Spatial

temporal frequency tuning of pattern-reversal retinal potentials. Invest Ophthalmol Vis Sci 1982;

Pattern

in

anterior

ERG in optic nerve lesions: changes specific

E, et al: Oiffer-

electroretinograms

mate. J NeurophysioI1986;56:74

retinogram

63. Holder

proximal

53. Hess RF, Baker CL, Zrenner

The

mac-

64. Holder

73:341-352.

54. Trick

physiological assessment of aphakic cystoid ular oedema. Br J OphthalmoI1986;70:819-824.

analysis of linear and nonof the primate

gram. J Physiol (Lond)

electroretino-

1988;407:155-176.

73. Dodt

GE: Pattern

electroretinography approach

to visual

Prog Ret Eye Res. In press.

E: The electrical

man eye to patterned

response of the hu-

stimuli:

clinical

tions. Doc O/)hthalmoI1987:65:271~286.

observa-

231

References

74. Hawlina

M, Iarc M, Popovix

ERG is preserved low-up

in retinitis

P: Pattern

pigmentosa:

study. Electroencephalogr

a fol-

Clin Neurophysiol

86. Arden

GB, Hamilton

al: Pattern

electroretinograms

when background

rates to a preproliferative

75. Ruether

screening

K, Kellner

U: Inner

retinal

retinal

dystrophies.

func-

Acta Anat

87. Coupland

76. Downes

ures in diabetic

SM, Fitzke

phenotype

FW, Holder

of an autosomal

cone-rod

dystrophy

mutation

in RetGC-1.

GE, et al:

and pattern

caused by an ARG838CYS Vis Sci

1999;40:S722.

of oscillatory

electroretinogram

retinopathy.

88. Jenkins nogram

TC,

Cartwright

in minimal

JP: The electroreti-

diabetic

retinopathy.

SM, Bessant DA, et al:

89. Prager TC, Garcia CA, Mincher

cyclase activator

1A

The pattern

electroretinogram

(GUCA1A)

in an autosomal

cone dys-

J Ophthalmol

1990; 109:279-284.

pedigree

mapping

dominant

to a new locus on chro-

6p21.1. Hum Mol Genet 1998;7:273-277. MP, Mitchell

Electroretinographic

KW, McDonnell

findings

S:

in macular

79. Lois N, Holder

dystro-

logical findings

GE, Perd AC: Electrophysio-

in Stargardt-fundus

tus. Electroencephalogr 80. Lois N, Holder

GE, Fitzke

trafamilial

of phenotype

variation

tlavimacula-

Clin Neurophysiol.

dystrophy-fundus

In press.

FW, et al: In-

91. Nesher

R, Trick

retinogram

in retinal

comparison

Doc Ophthalmol

graphic

MR, Arden sensitivity findings

81. Stavrou

P, Good PA, Misson

thalmol

findings

in Stargardt's-fundus

82. Allikmets

toreceptor cell-specific ATP-binding gene (ABCR) is mutated in recessive macular

dystrophy.

83. Sun H, Nathans

Nat Genet 1997; 15:236-246. I: Stargardt's

ized to the disc membrane segments.

ABCR

of retinal

is local-

rod outer

Azarian

sights into the function and etiology

from the phenotype

of Stargardt's

in phodisease

knockout

mice.

Cell 1999;98: 13-23. 85. Downes Clinical trophy:

SM, Fitzke

features similar

FW, Holder

GE, et al:

of codon 172 RDS macular phenotype

in 12 families.

OphthalmoI1999;117:1373-1383.

AM: Color

electroretino-

after diode and argon laser phoretinopathy.

Am J Oph-

1994; 117:583-588. MB, Spalton

Dl,

Holder

serous retinopathy

lupus erythematosus.

G: Visual in systemic

Br J Ophthalmol

1993;77:

607-609. 94. Birch DG, Anderson Pattern-reversal

JL, Fish GE, et al:

electroretinographic

in untreated

eyes with

membranes.

Invest Ophthalmol

95. Smith

SM, et al: In-

of Rim protein

in ABCR

GB, Hamilton

subfoveal

acuity neovascular

Vis Sci 1992;33:

2097-2104.

Nat Genet 1997;17:15-16.

84. Weng I, Mata NL, toreceptors

transporter Stargardt

of visual

1991;77:225-235.

and pattern

loss from central

R, Singh N, Sun H, et al: A pho-

of the pattern

in diabetic

93. Eckstein

disease. Eye 1998; 12:953-958.

electro-

and optic nerve disease: a

dysfunction.

tocoagulation

tlavimaculatus

function

patients.

GL: The pattern

quantitative

Vis Sci 1999;40:2668-2675.

trophysiological

B, et al: Evi-

of macular

ERG in type I diabetic

Ophthalmol

GP, et al: Elec-

dys-

Am J

A~

Diabetes Care 1990;13:412-418.

contrast

Invest

CA, et al:

in diabetes.

S, Di Leo MA, Falsini

dence for early impairment

92. Ulbig

in Stargardt

tlavimaculatus.

90. Caputo with pattern

phy. Doc OphthalmoI1996-1997;92:325-339.

macular

Br J

OphthalmoI1990;74:681-684.

in guanylate

78. Clarke

meas-

Doc Ophthalmol

77. Payne AM, Downes

mosome

use as a

1986;70:330-335.

A mutation trophy

deterio-

1987;66:207-218.

dominant

Invest Ophthalmol

retinopathy

SG: A comparison

potential

J, et

abnormal

stage: possible

test. Br J Ophthalmol

(Basel) 1998;162:169-177. Ocular

become

diabetic

1998;1001(suppl):46. tion in hereditary

AM, Wilson-Holt

Evoked

RG, Brimlow

responses

GM, Lea SJ, et al:

in patients

holes. Doc Ophthalmol

with

macular

1990;75:135-144.

232

ThePattern Electroretinogram

96. Falsini Macular

B, Minnella

A, Buzzonetti

electroretinograms

tern stimulation

to flicker

in lamellar

macular

L, et al:

107. Fiorentini

and pat-

The ERG

holes. Doc

patients

OphthalmoI1992;79:99-108.

pathway.

97. Murray

490-493.

DC, Stavrou

P, Good PA, et al: Elec-

troretinographic

findings

chromic

Eye 1997;11:102-108.

cyclitis.

in Fuchs'

hetero-

98. Persson HE, Wan~er P: Pattern troretinograms

and visual evoked

tials in multiple

reversal elecpoten-

sclerosis. Br J Ophthalmol1984;

troretinogram

V, von Berger GP: Pattern and visual evoked

optic nerve disease: early diagnosis sis. Doc Ophthalmol

tern electroretinogram

J Neurol Neurosurg Psychiatry PJ, van Lith

The pattern-elicited nal responses

and progno-

V, et al: Pat-

in multiple

neuritis.

11: retiOphthalmo-

TH,

electroretinogram

Coupland

Can J Neurol Sci 1983;10:256-260.

~ram in patients

Y: The pattern

with

electroretino-

electroretinogram

disease. Ophthalmology

electroretinogram

a combined

psychophysical

UO. Porciatti

sclerosis.

S]: The pat-

in optic neuritis: and electrophysio-

1986; 109:469-490.

V, Sartucci

F: Retinal

to chromatic

and cortical

evoked

responses

specific

losses in both eyes of patients

111. Falsini Macular

B, Bardocci

dysfunction

contrast

stimuli: with

mul-

optic neuritis.

A, Porciatti

in multiple

vealed by steady-state

Brain

flicker

V, et al:

sclerosis re-

and pattern

ERGs.

Clin NeurophysioI1992;82:

112. Porciatti

V: Non-Iinearities

ERG evoked

by pattern

their variation

dysfunction.

in the focal

and uniform-field in retinal

Invest Ophthalmol

stim-

and optic nerve Vis Sci 1987;28:

1306-1313.

OphthalmoI1986;62:53-59. The pattern

and multiple

tern evoked

ulation:

optic nerve disease. Doc

104. Seiple W, Price MJ, Kupersmith

C, et al:

53-59.

SG: The pattern

in optic nerve demyelination.

103. Ota I, Miyake

in glaucoma

I, Harnois

and visual-evoked

Am J OphthalmoI1983;96:72-83.

Electroencephalogr

logica 1986;192:217-219. 102. Kirkham

electroretinograrns

potentials

in

visual

1996;119:723-740.

1984;47:879-883.

electroretinogram,

gratings

Vis Sci 1981;21:

tiple sclerosis and unilateral

sclerosis.

GH, van der Poel H:

in retrobulbar

Invest Ophthalmol

logical study. Brain

in

Proc Ser 1984;40: 117-126.

100. Serra G, Carreras M, Tugnoli

101. Ringens

elec-

potential

M. et al:

with diseases of the peripheral

109. Plant GT, Hess RF, Thomas

68:760-764. 99. Porciatti

L. Pirchio

108. Bobak P, Bodis- Wollner Pattern

cortical

A. Maffei

in response to alternating

U3.

M, et al:

Berninger

retinograms

in optic nerve

TA, Heider

W: Pattern

in optic neuritis

stage and after remission.

1983;90:1127-1132.

during

electro-

the acute

Graefes Arch Clin Exp

OphthalmoI1990;228:410-414. 105. Holder

GE: The

incidence

of abnormal

pat-

tern electroretinography

in optic nerve demyeli-

nation. Electroencephalogr

Clin Neurophysiol1991;

pressive

106. Holder the evaluation

GE: Pattern

electroretinography

of ~Iaucoma

In: Heckenlively

in

and in optic nerve JR, Arden

GB, eds:

Principles and Practice of Clinical Electrophysiology ofVision. 549-556.

St Louis:

Mosby-Year

Book;

1991:

a, Wray SH, Lorance

An analysis of the pathophysiology development

78:18-26.

function.

114. Kaufmann

of treatment

R, et al:

and the

strategies

for com-

optic nerve lesions using pattern

troretinogram

and visual evoked

Neurology 1986;36(suppl 115. Kaufman The pattern

elec-

potential.

1):232.

Dl, Lorance

RW, Woods M, et al:

electroretinogram:

study in acute optic neuropathy.

a long-term Neurology 1988;

38:1767-1774. U6.

Ruther

K, Ehlich

P, Philipp

nostic value of the pattern cases of tumors

affecting

A, et al: Prog-

electroretinogram the optic pathway.

Graefes Arch Clin Exp OphthalmoI1998;236: 259-263.

in

References

117. Parmar DN, Prognostic

Sofat A, Bowman

value of the pattern

gram in chiasmal

compression.

127. Papst N. Bopp M. Schnaudigel

R, et al:

electroretino-

electroretinogram

Br J Ophthalmol

potentials

2000;84:1024-1026. F, Di Bartolo

et al: Standardized automated Graves'

echography,

neuropathy.

E, Lepri

pattern

and visual-evoked perimetry

Lith

electro-

potential

119. Papst N, Bopp M, Wundrack mal dominant

infantile

or descending

degeneration?]

coma? Ophthalmologica

of

1998;212

EM:

optic atrophy:

[Autosoascending

Klin Monatsbl Au-

TA, Iaeger W, Krastel

and colour perimetry

optic atrophy.

H: Electro-

in dominant

in-

Br J OphthalmoI1991;75:

M, Fitzke

features

21 pedigrees

FW, Holder

in affected

with dominant 116:351-358.

122. Mauguiere

F, Holder

Evoked

potentials:

yield of evoked

I, Binnie Clinical

GE, Luxon

abnormal

C, Cooper

and di-

In: Osselton

Butterworth-

visual evoked

and pattern

in drusen-associated

optic

Arch OphthalmoI1992;110:75-81.

ritis: a case report with visual evoked

potentials.

J Clin NeuroophthalmoI1991;11:45-49. 125. Quigley

HA, Addicks

tients

with chronic

quantitative visual field ropathy,

correlation defect

glaucoma, ischemic

neu-

and toxic neuropathy.

Ophthalmol

glaucoma.

Vis Sci 1983;24:749-753.

K: [Negative

ERG and its suppression

Nippon Ganka Gakkai Zasshi 1986;

132. Weinstein

GW, Arden

al: The

electroretinogram

pattern

ular hypertension

GB, Hitchings

and glaucoma.

RA, et

(PERG)

in oc-

Arch Ophthalmol

1988; 106:923-928. 133. Graham PA: The definition

fields:

of pre-glaucoma:

stUdy. Trans Ophthalmol

MF: Ocular

a ten-year

Soc UK

pressure and visual

follow-up

study. Arch Ophthal-

mol 1969;81:25-40. 135. Perkins ES: The Bedford glaucoma survey: long term follow-up of borderline cases. Br J OphthalmoI1973;57:179-185. 136. Walker

WM:

Ocular

hypertension:

follow-

1963 to 1974. Trans Ophthal-

137. Jensen JE: Glaucoma follow-up

Invest

screening:

of ocular normotensives.

a 16-year

Acta Ophthal-

mol 1984;62:203-209.

hypertension:

126. Wanger P, Persson HE: Pattern-reversal in unilateral

T, Kawasaki

pattern

90:882-887.

138. Lundberg

Arch OphthalmoI1982;100:135-146.

electroretinograms

in glaucoma.]

Doc Ophthalmol

.

mol Soc UK 1974;94:525-534.

III:

of nerve fiber loss and

in glaucoma,

papilledema,

glaucoma.

Proc Ser 1984;40:101-107

Up of 109 cases from

EM, Green WR:

nerve damage in human

KW: Simultaneous

recordin~ of the pattern electroretinogram an1 visual evoked cortical potential in a group of pa-

134. Armaly

124. Song HS, Wray SH: Bee sting optic neu-

Optic

130. Howe JW, Mitchell

1969;88:153-165.

DE, et al:

potential

visual field

Doc OphthalmoI1986;61:335-341.

a prospective

1995:431-481.

electroretinogram neuropathy.

et al:

R, et al, eds: A Manualof

123. Scholl GB, Song HS, Winkler pattern

LM,

waveforms

potentials.

Neurophysiology. Oxford:

Heinemann;

from

optic atrophy. Arch

Ophthalmol1998;

agnostic

GE, et al:

individuals

FC, de Vos GW,

ERG and glaucomatous

wave in human

Clinical

The

defects.

of glau-

1986:192:171-175.

131. Ohta H, Tamura

49-.12. 121. Votruba

S, van

electroretino-

129. van den Berg TJ, Riemslag

genheilkd 1985;187:101-104.

fantile

PJ, Vijfvinkel-Bruinenga

GH: The pattern-elicited

ct al: Pattern

120. Berninger

cortical

Graefes Arch Clin Exp

gram, I: a tool in the early detection

and

in the early diagnosis Ophthalmologica

128. Ringens

A,

(suppl1):101-103.

physiology

in glaucoma.

OE: Pattern

evoked

OphthalmoI1984;222:29-33.

118. Genovesi-Ebert retinography

and visually

233

L, Wetrell a prospective

study. Acta Ophthalmo{

K, Linnar

E: Ocular

20-year follow-up

1987;65:705-708.

234

The Pattern Electroretinogram

139. Bach M, Speidel-Fiaux troretinogram

A: Pattern

in glaucoma

elec-

149. Bomer TG, Meyer

and ocular hyperten-

sion. Doc Ophthalmo/1989;73:173-181.

nerve-head

140. Pfeiffer

terim

retinogram

N, Bach M: The pattern-electroin glaucoma

and ocular hypertension:

a cross-sectional

and longitudinal

Ophthalmo/1992;

1:35-40.

141. Pfeiffer

B, Bach M: Predictive

electroretinogram

risk ocular hypertension.

in high-

Invest Ophthalmol

Vis

Sci 1993;34:1710-1715. 142. Neoh patients

M, et al: Pattern

and automated

with glaucoma

perimetry

in

and ocular hypertension.

Br J Ophthalmo/1994;78:359-362. 143. Bach M, Sulimma lation of the pattern

F, Gerling

J: Little

electroretinogram

and visual field measures

corre-

(PERG)

in early glaucoma.

Doc

Ophthalmo/1997-1998;94:253-263. E, Arden

et al: The pattern

electroretinogram

and ocular hypertension.

GB, O'Sullivan

F,

in glaucoma

Br J Ophthalmo/1992;

76:387-394.

1996;5:26-30. 150. Martus

GL,

al: Pattern

reversal electroretinogram

Bickler-Bluth

M, Cooper

in ocular hypertension:

DG, et

151. Halliday Delayed

AM, McDonald

sual evoked

M, Horn F, Jonas J: Utility

color pattern-electroretinogram

sclerosis. BrMedJ

of the

(PERG)

in glau-

P, Chadwick

responses in the diagnosis

management

of patients

sclerosis. Brain

The

RA, Fitzke

and psychophysics

and glaucoma:

ent pathomechanisms

evidence

suspected

evoked

of the anterior

in compression

visual pathways.

Brain

1976;99:

357-374.

pression

GE: The effects of chiasmal

on the pattern

com-

potential.

Clin NeurophysioI1978;45:

156. Lennerstrand potentials

visual evoked

G: Delayed in retinal

visual evoked

disease. Acta Oph-

thalmoI1982;60:497-504. 157. Holder evoked

GE, Chesterton

potential

in Harada's

]R: The visual disease. Neuro-

1984;4:43-45.

in ocular

al: Combined

for differ-

the visual system in central

Eye

of multiple

E, Kriss A, et al:

potential

158. Papakostopoulos

in early glaucoma.

CD: and

1975;98:261-282.

F, et al:

1994;8:516-520.

D, Hart CD, Cooper

electrophysiological

Electroencephalogr

R, et

assessment

of

serous retinopathy.

Clin NeurophysioI1984;59:

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 response

correlation

risk factors. Curr Eye Res 1988;7:

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

with glaucoma

in-

results after 2.5 years. Ger J Ophthalmol

154. Halliday

144. O'Donaghue

abnormalities

optic

analysis in ocular hypertension:

tis. Lancet 1972;1:982-985.

C, Kaye SB, Brown

electroretinogram

Bach M, et al: Pat-

and computerized

variate sensory model

N, Tillmon

value of the pattern

study. Ger J

]H,

tern electroretinogram

GB, O'Sullivan

F, et al:

and peripheral

in ocular hypertension

comparison

and correlation

Br J Ophthalmo/1995;79:326-331.

colour and

of results.

159. Bass S], Sherman Visual evoked

Invest Ophthalmol 160. Thompson Pupillary

], Bodis-Wollner

potentials

in macular

I, et al:

disease.

Vis Sci 1985;26:1071-1074. HS, Watzke

dysfunction

RC, Weinstein

in macular

]M:

disease. Trans

Am Ophthalmol Soc 1980;78:311-317.

Suggested Readings

161. Folk JC, Thompson sual function nopathy.

in central

serous reti.

Arch OphthalmoI1984;102:1299-1302.

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.

SUGGESTEDREADINGS 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 thalmol.

is generated

and exelectro-

M, Holder

GE, et al: Standard

electroretinography.

Doc Oph-

In press.

Baker CL ]r, Hess RF, Olsen BT, et al: Current source density components

analysis of linear and non-linear

of the primate

J Physiol(Lond} Heckenlively

]R, Arden

Practice of Clinical Louis:

electroretinogram.

1988;407:155-176.

Mosby-

GB, eds: Principles and

Electrophysiology

Year Book;

Hess RF, Baker CL ]r: Human electroretinogram. Holder

GE: The

of Vision. St

1991 :549-556. pattern-evoked

J Neurophysiol1984;51 pattern

anterior

visual pathway

tionship

to the pattern

personal

clinical

electroretinogram dysfunction

visual evoked

review

:939-951. in

and its relapotential:

a

of 743 eyes. Eye 1997;11:

924-934. Holder

GE: Significance

electroretinography dysfunction. Maffei

953-955

pattern

visual pathway

Br J OphthalmoI1987;71:166-171.

L, Fiorentini

sponses to alternating section

of abnormal

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 Visual Evoked Potential

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

A

The Visual Evoked Potential

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.

B

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

c

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.

Redrawn with permission of Kluwer Academic Publishers 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

The Visual Evoked Potential

B

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.~

t

:

:r-

III 1

111111II

2 3 456

1

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

The Visual Evoked Potential

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

Use of the VEP in Adults

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

The Visual Evoked Potential

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 a18°found 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

Use of the VEP in Adults

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

A

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

The Visual Evoked Potential

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 a19°reported 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-

Use of the VEP in Adults

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

The Visual Evoked Potential

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

Use of the VEP in Adults

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

The Visual Evoked Potential

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

A

from the left eye were normal. In this case, a positive finding of a recordable pattern

B

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

Use of the VEP in Adults

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

The Visual Evoked Potential

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

Use of the VEP in Adults

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

The Visual Evoked Potential

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.

The Visual Evoked Potential

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.

A

5-5-2 Childhood Amblyopia and Binocular Function

B 1 !,V

O/LV ll:[~~~ I

~~,

- ~

I

I

I

I

0.5

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.2°s 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

A

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.2°9 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

B

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

The Visual Evoked Potential

sual cortex.22,23 The technique

provides

a

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 a123°reported 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

The Visual Evoked Potential

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

The Visual Evoked Potential

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

The Visual Evoked Potential

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-

Doc OphthalmoI1998;95:

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

1961;159:302-221. of

map. Arch Ophthalmol

1991;109:816-824.

evoked

of dipole

to source identification potentials.

localization

of human

Ann NY A cad Sci 1982;388:

139-155.

Striate cortical

CE, Tenke

CE, Givre

contribution

pattern-reversal

monkey.

Vis Res 1991;31:1143-1157. MG, Marchese function

flash visual evoked

SI, et al:

to the surface-

recorded

amplitude

potentials.

VEP in the alert

AL: The

of simultaneously potential

gram. Clin Vis Sci 1993;8:41-46.

and pattern-

Vis Res 1995;35:

S, Tomoda

potentials

motion.

in humans:

and achromatic

to visual

stimulation

gratings

with

and apparent

J Neurol Sci 1995;134:73-82.

16. Brosnahan OKN,

H, Kato M: Parvocel-

contributions

D, Norcia

perceptual

AM, Schor CM, et al:

and VEP direction

17. Regan D: Speedy assessment in amblyopia

by the evoked

Ophthalmologica assessment

of visual acuity

potential

method.

1977;175:159-164. P, Levi

of visual function:

sweep technique potential.

biases in

Vis Res 1998;38:2833-2840.

18. Tyler CW, Apkarian

8. Schroeder

9. Brigell

evoked

strabismus.

7. Wood CC: Application

H, et al: Con-

of motion-onset

Iular and magnocellular chromatic

striate cortex: a revi-

the classic Holmes

govpOten-

197-205. 15. Tobimatsu

cortex in

J Physiol (Lond)

the visual field

rep-

W: The representa-

monkeys.

cortical

Z, Kuba M, Spekreijse

trast dependence

1931;54:470-479.

PM, Whitteridge

tion of the visual field on the cerebral

methods

14. Kubova

reversal evoked

G: A contribution

Zuidema

tials. Vis Res 1994;34:1541-1547.

patient:

1992;7:65-78. 4. Holmes

stimu.

in man. Vis Res

erns the shape of motion-evoked

3. Brigell

sionof

eye to moving

Science 1964;144:567.

13. Bach M, Ullrich

1-14.

I, eds: Fron-

EP, Schick AM: Electri-

of the human

Ius patterns.

and recording

of visual physiol-

1986:15-27.

Vis Res 1996;36:3567-3572.

of stimulus

LH:

in VEP

tiers of Clinical Neuroscience: Evoked Potentials.

of Vision.

lines for calibration

selection

ogy. In: Cracco RQ, Bodis-Wollner New York: ARLiss;

Electrophysiology

MF, Mylin

of stimulus

DM,

for the pattern

Invest Ophthalmol

et al: Rapid

an electronic visual evoked

Vis Sci 1979;18:

703-713. Iuminancerecorded

and electroretino-

19. Nelson Lock-in

JI, Seiple WH,

techniques

evoked

potential.

Kupersmith

MJ, et al:

for the swept stimulus J Clin NeurophysioI1984;1:

409-436. 20. Gottlob acuity

I, Fendick

measurements

visual-evoked-cortical cal application disorders. 27:40-47.

MG, Guo S, et al: Visual by swept spatial frequency potentials

in children

(VECPs):

clini-

with various visual

J Pediatr Ophthalmol

Strabismus

1990;

269

References

21. Riddell

PM, Ladenheim

B, Mast J,et al:

Comparison

of measures of visual acuity

fants: Teller

acuity cards and sweep visual

evoked

potentials.

32. Sokol S: Problems

in in-

evoked

Optom Vis Sci 1997;74:

LW, Levi

chophysical

studies

normal

OM:

Binocular

of binocular

and stereoblind

beats: psy-

interaction

humans.

in

Vis Res 1989;

potential.

23. Stevens JL, Berman

JL, Schmeisser

al: Oichoptic

beat visual evoked

luminance

ET, et

of binocularity

dren. J Pediatr Ophthalmol Strabismus

po-

in chil-

1994;31 :

368-373.

MR, White

and check size on visually

tical potentials.

function

EE: A deterministic

linear systems analysis. eds: Nonlinear

approach

to non-

In: Pincer RB, Nabet

Vision. Cleveland:

B,

CRC Press;

CT: Effects

patterns:

of retinal

cortical effect

responses

Kupersmith

The assessment

of evoked

using real-time

MJ, Nelson potential retrieval.

36. Thompson

CR, Harding

potential

in patients

R, Coldran

Hz flash visual evoked

potentials

Science and Medicine. New York: Elsevier;

cataract extraction

fovea.

Vis Res 1968;8:135-147. 27. Oken

poral variability

KH, Gill E: Normal

tem-

of the P100. Electroencephalogr

Clin NeurophysioI1987;68:153-156. 28. Sokol S, Hansen Evoked

potential

and preferential in pediatric

tivity

potential

in glaucoma

Spekreijse

looking

esti-

patients.

latency

A, et al: Pat-

and contrast

sensiIn:

PA, eds: Electrophysiology

and Pathology of the Visual Pathways. Hague: W Junk BV Publishers.

Or

Doc Ophthalmol Proc Ser

1981;27:79-86. 30. Sokol S, Moskowitz

A, Towle

lated changes in the latency potential:

influence

31. Sokol S, Moskowitz on the peak latency tential.

VL: Age-re-

of the visual evoked

of check size. Electroen-

cephalogr Clin Neurophysiol1981

J, Bass S, et al: Pre-sur-

of post-surgical

in cataract patients: ses of test measures.

statistical

analy-

Clin VisSci 1991;6:191-207.

GF: Evaluation

opaque media.

visual function

multivariate

of ocular trauma,

In: Heckenlively

JR, Arden

GB,

eds: Principles and Practice of Clinical ElectrophysiMosby-Year

Book;

1991:

567-572.

and ocular hypertension.

H, Apkarian

post-

1987;66:291-299.

ology of Vision. St Louis:

1983;90:552-562.

29. Sokol S, Oomar A, Moskowitz tern evoked

A, et al:

JT, et al: 10predict

visual acuity. Doc Ophthalmol

38. Davis ET, Sherman

39. Harding

VC, Moskowitz

mates of visual acuity Ophthalmology

Proc Ser 1978;15:193-201.

gical prediction

BS, Chiappa

Invest Op~

GF: The visual

Evoked Potentials and Evoked Magnetic Fields in

HG: Cortical

JI, et al:

contrast

with cataracts.

37. Odom JY, Hobson

of the human

as a

thalmol Vis Sci 1984;25:627-631.

Doc Ophthalmol

to stimulation

to

1365-1376.

1992:171-220.

responses

cor-

Vis Res 1970; 10:

25. Regan O: Human Brain Electrophysiology:

26. OeVoe RC, Ripps H, Vaughan

evoked

of check-size

eccentricity.

35. Seiple WH,

evoked

1989.

of contour

Vis Res 1968;8:701-711.

MR: Evoked

thresholds

24. Sutter

in the visual

Ann iVY A cad Sci 1982;388:

sharpness

checkerboard

in the assessment

control

of pattern

33. Harter

34. Harter

29:27-35.

tentials

of stimulus

of peak latency

657-661.

702-707. 22. Baitch

measurement

A: Effect

Vis Res 1981;21:1279-1286.

of retinal evoked

GW:

ally evoked

potential.

blur po-

Clinical "'

aspects

of the

Trans Am Ophthalmol

visu-

Soc

1977;85:627-673. 41. Fuller

DG, Hut ton WL:

Presurgical Evalua-

tion of Eyes with Opaque Media. New York: Grune & Stratton;

1982.

42. Rinkoff

J, de Juan E, Landers

YEP: useful

in management

hemorrhage.

Invest Ophthalmol

26(suppl):322.

;51 :559-562.

of the pattern

40. Weinstein

M, et al: Flash

of diabetic

vitreous

Vis Sci 1985;

270

The Visual Evoked Potential

43. Scherfig

E, Edmund

Flash visual evoked factor for vitreous Ophthalmology

J, Tinning

potential

53. Kubova

S, et al:

tion-onset

as a prognostic

operations

in diabetic

the diagnosis

eyes.

al: Combined

D, Hart CD, Cooper

electrophysiological

the visual system in central

of glaucoma.

54. Quigley

R, et

assessment

of

serous retinopathy.

HA, Dunkelberger

mology 1988;95:357-363.

77-80.

55. Morgan

Visual function

in central

56. Graham a review

evoked

J, Bass SJ, Noble

potential

choroidopathy.

(VEP)

KG, et al: Visual

delays in central

Invest Ophthalmol

serous

Vis Sci 1986;27:

214-221. matching

J, Diddie

and Stiles-Crawford

serous choroidopathy.

in central

investigating

glaucoma.

Anomalous

pigment

Optic

lationships

and receptor

JM, Birch DG, et al:

epithelial

photoreceptor

orientation.

re-

Invest Oph-

thalmol Vis Sci 1980; 19:956-966. MB, Spalton

loss from central

AM, McDonald

DJ, Holder

G: Visual

in systemic

Br J OphthalmoI1993;77:

607-609.

59. Brigell tentials:

Yee RD, Hepler

of the visual evoked

lar holes: comparison

RS, et al: Al-

potential

by macu-

with optic neuritis.

Graefes

Arch Clin Exp OphthalmoI1987;225:123-128. 51. Shimada

Y, Adachi-Usami

How are macular evoked

MG, Celesia

In: Barber C, Celesia

E, Murayama

changes reflected cortical

VL, Moskowitz

M, et al:

potentials?

K:

B, Matyszak

sions. Brain 61. Trapp

transection

management

rate. Invest Ophthalmol

Vis Sci

et al:

sclerosis le-

I, Ransohoff

RM, et al:

sclerosis. N Engl J Med 1998;338:278-285.

responses

and ocular

Esiri MM,

in the lesions of multiple

P, Chadwick

potential

MK,

England.

1997;120:393-399. BD, Peterson

Visual evoked

effects of check size, field size

I, et al,

Evoked

damage in acute multiple

Acta Ophthal-

A, Sokol S, et al: The in glaucoma

GG, Hashimoto

Potentials Symposium. Nottingham, Amsterdam: Elsevier; 1999:95-102.

Axonal

po-

and basic sciences.

Neuroscience: Evoked Potentials and

62. Asselman

hypertension:

1983;24:175-183.

Brigell

GG: Visual evoked

in pattern

visual evoked and stimulation

I: De-

study. Neurology

Magnetic Fields. Sixth International

Axonal

mol Scand 1997;75:277-280. 52. Towle

Dl,

a prospective

advances in clinical

60. Ferguson LN,

WI, Mushin

response in optic neuritis.

GG, Kaufman

neuritis:

eds: Functional

serous retinopathy

lupus erythematosus.

50. Johnson

to

Aust NZ J Ophthalmol

1990;40:919-923.

CR, Enoch

49. Eckstein

A: Electrophysiology: and applications

1998;26:71-85. 57. Halliday

58. Celesia

Mod Probl Ophthalmol

1978; 19:284-295. 48. Fitzgerald

visually

SL, Klistorner

Lancet 1972;1:982-985.

KR: Color

effect

cell death in glaucoma:

of signal origins

layed visual evoked

47. Smith VC, Pokorny

teration

IE: Selective

875-879.

se-

Arch OphthalmoI1984;102:

1299-1302. 46. Sherman

GR, Green WR:

does it really occur? Br J OphthalmoI1994;78:

HS, Han DP, et al:

abnormalities

rous retinopathy.

improve

Doc Ophthalmol

Chronic human glaucoma causing selectively greater loss of large optic nerve fibers. Ophthal-

Electroencephalogr Clin NeurophysioI1984;59:

45. Folk JC, Thompson

I, et al: Mo-

potentials

1996-1997;92:211-221.

1984;91:1475-1479.

44. Papkostopoulos

Z, Kuba M, Hrochova visual evoked

of patients

sclerosis. Brain 63. Chiappa evoked

DW, Marsden

DC:

in the diagnosis

and

suspected

of multiple

1975;98:261-282.

KH, Hill

potentials:

RA: Pattern-shift

interpretation.

visual

In: Chiappa

KH, ed: Evoked Potentials in Clinical Medicine. 3rd ed. Philadelphia:

Lippincott-Raven;

1997:

95-165. 64. Ormerod

IE, Miller

al: The role of NMR of multiple

DH,

imaging

McDQnald

sclerosis and isolated

lesions. Brain

1987;110:

WI, et

in the assessment neurological

1579-1616.

References

65. Miller

DH,

Newton

et al: Magnetic

MR, Van der Poel JC,

resonance

nerve in optic neuritis.

imaging

of the optic

Neurology 1988;38:

175-179.

Detection

of hidden

rosis: a comparison

CM, de Rouck AF, et al:

visual loss in multiple of pattern-reversal

potentials

and contrast

scle-

visual

sensitivity.

dystrophies

of children.

MJ, Logan

potential

WI, Mushin

J: De-

UK 1973;93:315-324. 68. Chiappa

pattern

localization

shift visual,

and short latency

using brainstem

somatosensory.

In:

Thompson RA, Green JR, eds: New Perspectives in Cerebral Localization. New York: Raven Press; 1982:63-114. 69. Waxman

sa:

pathophysiology

Membranes, of multiple

myelin,

and the

sclerosis. N Engl J

Med 1982;306:1529-1533. 70. Waxman

sa:

in leuko-

Can J Neurol sa 1988;

in spinal cord

sclerosis: what can we do

functional

potentials

recovery? J Neurotrauma

1992;9(suppl1):S105-117.

in leukodystrophies.

sa:

causes and mechanisms

of clinical

and functional

In: Koetsier

recovery.

Demyelination:

myelinating Diseases. Handbook rology, Series 3. Amsterdam:

digitalis

S, Osaka H, et al: Effect

on conduction

dysfunction

JC, ed: De-

of Clinical

Neu-

Merzbacher

disease. J Neural Sci 1996; 141 :49-53.

78. Mamoli

B, Graf M, Toifl

potentials

in a family

K: EEG,

with adrenoleucodystrophy.

NeuraphysiaI1979;47:411-419.

79. Tobimatsu

S, Fukui

modality

evoked

R, Kato M, et al: Multi-

potentials

in patients

ers with adrenoleukodystrophy eloneuropathy.

Electraencephalagr

physiaI1985;62:

18-24.

80. Kaplan

pathophysiology

et al: The

of acute optic neuritis:

of the gadolinium

and electrophysiological

an asso-

leakage with clinical deficits.

and carri-

and adrenomyClin Neura-

PW, Kruse B, Tusa RJ, et al: Visual in adrenomyeloneuropa-

thy. Ann Neural 1995;37:550-552. 81. Kaplan

PW, Tusa RJ, Shankroff

sual evoked

potentials

J, et al: Vi-

in adrenoleukodystrophy:

trioleate

and Lorenzo

82. Troncoso evoked

J, Mancall

oil. \

EL, Schatz NJ: Visual

responses in pernicious

anemia. Arch

Neural 1979;36:168-169. I, Korczy/l

AD: Dissociated

sensory loss and visual evoked DH,

velocity Electr~

encephalagrClin

83. Bodis-Wollner a, Miller

pattern-

and nerve conduction

1985;47:

29-47. 72. Youl BD, Turano

of

in Pelizaeus-

Ann Neural 1993;34:169-174.

abnormality

Elsevier;

Electra-

encephalagr Clin NeuraphysiaI1982;54:39-48.

a trial with glycerol

71. Kocsis JD, Waxman

WE, et al:

visual and somatosensory

system abnormalities

Demyelination

and multiple

to enhance

ciation

WJ:

studies

ON, Garg BP, DeMyer

Brain stem auditory,

evoked

KH: Physiologic

responses:

auditory

76. Markand

77. Nezu A, Kimura

AM, McDonald

layed pattern-evoked responses in optic neuritis in relation to visual acuity. Trans Ophthalmol Soc

injury

evoked

evoked

Doc

OphthalmoI1991;77:255-264. 67. Halliday

evoked

LJ, Taylor

Multimodal 15:26-31.

66. Leys MJ, Candaele

evoked

75. De Meirleir

271

Brain

1991;114:

patient

potentials

in a

anemia. Mt Sinai J Med

1980;47:579-582. 84. Krumholz Evoked

2437-2450.

with pernicious

A, Weiss HD,

responses

in vitamin

Goldstein

PJ, et al:

B-12 deficiency.

Ann Neural 1981;9:407-409. 73. Fulgente

T, Thomas

Are VEP abnormalities dependent

on plaque

physiopathology and multiple-lead

A, Lobefalo

L, et al:

in optic neuritis

(ON)

size? A reappraisal

of the

of ON based on improved recordings.

MRI

ltal J Neurol Sci

1996;17:43-54. 74. Thorpe netisation

JW, Barker aJ, Jones SJ, et al: Magtransfer

ratios and transverse

sation decay curves in optic neuritis: with clinical

findings

magneti-

correlation

and electrophysiology.

J Neurol Neurosurg Psychiatry

1995;59:487-492.

85. Clifford-Jones DN:

Chronic

imental

RE, McDonald

WI, Landon

optic nerve compression:

study. Brain

1985;108:241-262.

an exper-

272

The Visual Evoked Potential

86. Halliday

AM,

pattern-evoked anterior

Halliday

potential

E, Kriss A, et al: The in compression

visual pathways.

Brain

1976;99:357-374.

87. Trobe ID, Glaser IS, LaFlamme roid optic neuropathy:

clinical

ale for management.

of the

P: Dysthy-

profile

andration-

value of visual evoked of Graves'

M, et al: The

potentials

in optic neu-

disease. J Endocrinol

Invest

89. Tsaloumas

MD,

Flash and pattern

Good PA, Burdon

visual evoked

and monitoring

neuropathy.

MA, et al:

potentials

of dysthyroid

in the

optic

90. Salvi M, Spaggiari

E, Neri

study of visual evoked fies asymptomatic J Clin Endocrinol

in patients

ophthalmopathy

identi-

optic nerve involvement.

potentials

W, Gjerris

F, et al:

in pseudotumor

AM, Mushin

cere-

I: The visual evoked

in neuroophthalmology.

Int Ophthalmol

Clin 1980;20:155-183. 93. Falsini

C, Porciatti

electroretinograms in idiopathic

sion. Ophthalmologica

V, et al:

and visual evoked intracranial

hyperten-

1992;205: 194-203.

94. Ischemic Optic Neuropathy Decompression Trial Research Group: Optic nerve decompression surgery for nonarteritic optic neuropathy (NAION) may be harmful.

anterior ischemic is not effective and

J Am Med Assoc 1995;273:

98. Tandon

DA, Thakar

Trans-ethmoidal

M: in the

optic nerve lesions

A, Mahapatra

AK, et al:

optic nerve decompression.

99. Fuller

DG, Hut ton WL:

operative

vision

PD, Mastaglia

ischaemic

FL, Carroll

optic neuropathy:

WM:

a correla-

tive clinical

and visual evoked

potential

study of

18 patients.

J Neurol Neurosurg Psychiatry 1986;

Prediction

in eyes with

of post-

severe trauma.

Retina 1990;10(suppl1):S20-34. C, Walsh JC, McLeod

potentials

in the detection

optic toxic effects secondary

JG: Visual of subclinical

to ethambutol.

Arch Neurol 1983;40:645-648. A, Sandramouli

ethambutol

102. Woung

S, Verma L, et al:

toxicity:

J Clin Neuroophthalmol

is it reversible?

1993;13:15-17.

LC, Jou JR, Liaw

SL: Visual func-

tion in recovered

ethambutol

J Ocul Pharmacol

Ther 1995;11:411-419.

103. Maiese

K, Walker

toxicity.

optic neuropathy.

RW, Gargan R, et al:

cisplatin-associated

optic and otic

Arch Neurol 1992;49:83-86.

104. Triantafyllou

N, Fisfis M, Sideris G, et al:

Neurophysiological

and neuro-otological

study

of homozygous beta-thalassemia under longterm desferrioxamine (DFO) treatment. Acta Neurol Scand 1991 ;83:306-308. 105. Marciani

MG, Cianciulli

Toxic effects of high-dose physiological

49:128-135.

potentials

trauma. J Craniomaxillofac

ment in patients

625-632. 95. Thompson

E, Ehrenfeld

of suspected

Intra-arterial

B, Tamburrelli

potentials

and is-

clinical

Surg 1996;24:1-11.

Ocular

bri. Arch NeuroI1985;42:150-153.

Anterior

CP, Altenmuller

The use of flash visual evoked

101. Kumar

Metab 1997;82: 1027-1030.

91. Sorensen PS, Trojaborg

92. Halliday

neuritis

overlapping

Arch OphthalmoI1991;109:1668-1672.

97. Cornelius

evoked

F, et al: The

potentials

with thyroid-associated

Pattern

profiles.

100. Yiannikas

Eye 1994;8:638-645.

Visual evoked

S: Optic

Clin OtolaryngoI1994;19:98-104.

1992;15:821-826.

potential

Lessell

optic neuropathy:

due to craniofacial

1199-1209.

diagnosis

chemic

early diagnosis

Arch OphthalmoI1978;96:

88. Setala K, Raitta C, Valimaki ropathy

96. Rizzo JF III,

with iron overload:

study of cerebral

tion. Haematologica 106. Miller

P, Stefani

treat-

an electro-

and visual func-

1991;76:131-134.

NR: Walsh and Hoyts Clinical Neuro-

Ophthalmology. 4th ed. Baltimore: Wilkins;

N, et al:

deferoxamine

Williams

&

1995;4:4394-4538.

107. Conrad

B, Benecke

sual evoked

potentials

R, Musers

H, et al: Vi-

in neurosyphilis.

J Neurol

Neurosurg Psychiatry 1983;46:23-27. 108. Streletz Visual evoked

LJ, Chambers potentials

1981;31:1545-1549.

RA, Bae SH, et al:

in sarcoidosis.

Neurology

273

References

109. Gott PS, Kumar

V, Kadakia

cance of multimodality malities

in sarcoidosis.

LungDis

I, et al: signifi-

evoked

potential

121. Nikoskelainen

abnor-

Sarcoidosis Vasc Diffuse

Nervous

A, Iantti

122. Kerrison V, Korpela

system involvement

erythematosus,

Sjogren

M, et al:

in systemic

syndrome

ophthalmic

lupus

and sclero-

JB, Maumenee genetics.

111. lragui

drial myopathies,

VI, Kalmijn

potentials tomatic

I, Plummer

in HIV retinal

infection:

evidence

and postretinal

absence of infectious

Dl, et al:

and visual evoked

retinopathy.

in the

Neurology

Borrelia clinical

SP, Krause A, Muller

infection:

unilateral

manifestation.]

A: [Acute

papillitis

Ophthalmologe

124. Ohtsuka

impair-

Y, Amano

R, Oka E, et al: Myo-

with ragged-red

fibers:

a clinical

125. Sartucci Evoked

1997;94:

with

F, Rossi B, Tognoni

potentials

G, et al:

in the evaluation

mitochondrial

myopathy.

of patients

Eur Neuro11993;

33:428-435.

113. Selbst RG, Selhorst Parainfectious following

IB, Harbison

optic neuritis:

varicella.

childhood.

IW, et al:

report and review

optic atrophies

phy with

CV, Lund

dominant

families.

A: Hereditary

transmission:

evoked optic atro-

three Danish

LB, Glaser IS: Dominant

phy: the clinical

profile.

optic atro-

Arch OphthalmoI1979;97:

1680-1686.

physical

optic atrophy.

potential

findings

Trans Ophthalmol

in

Soc

C, Schramm

flash-evoked

visual potentials

erative

monitoring

Neurosurgery

tion during

hereditary

associated

optic neuropathy.

with

Science

1988;242:1427-1430. 119. Carroll neuropathy:

WM,

Mastaglia

tial study of affected

FL: Leber's

and visual evoked and asymptomatic

bers ofa six generation

GF, Bland JD, Smith monitoring

tentials

SS, Laljee

family.

IR, Mastaglia

optic neuropathy:

response

VH: Visual

HC, Horrocks

of intra-operative

during

gery (FESS)

functional

JM, et al:

visual evoked

endoscopic

po-

sinus sur-

under general anaesthesia.

Brain

optic

131. Jones NS: Visual evoked scopic and anterior

mem1979;102:

J Laryngol

J Laryn-

studies

members

FL, Howe IW, et clinical

and visual

in asymptomatic of a 4-generation

Br J OphthalmoI1980;64:751-757.

and family.

ventral

potentials

skull base surgery:

in endo. a review.

OtoI1997;111:513-516.

132. Yokoyama

T, Sugiyama

al: Visual evoked

symptomatic

funCtion?

of optic nerve func-

poten-

559-580.

al: Leber's

of visual pathway

goIOtoI1996;110:31-36.

a clinical

120. Livingstone

R: Are

useful for intraop-

1990;53:890-895. Monitoring

mutation

J, Fahlbusch

surgery. J Neurol Neurosurg Psychiatry

118. Wallace

DNA

of

1987;21:709-715.

potential

130. Hussain

Mitochondrial

monitoring

308-326.

UK 1979;99:96-102. DC, Singh G, Lot MT, et al:

M:

Ann NY A cad Sci 1982;388:

128. Cedzich

evoked

GF, Crews SI, Pitts SM: Psycho-

and visual evoked

hereditary

PA: Intraoperative

potentials.

129. Harding

117. Harding

P, Nunemacher neurophysiological

J Clin NeurophysioI1995;12:97-109.

127. Raudzens

Acta OphthalmoI1950;28:437-468.

116. Kline

RS, Raudzens

of intraoperative

monitoring.

in

J Genet Hum 1966;15:312-321.

115. Lodberg

126. Fisher Efficacy

Arch NeuroI1983;40:347-350.

114. Iaeger W: Hereditary

evoked

L, et al:

mitochon-

I: electrophysiologic

clonus epilepsy

as isolated

591-594.

Leber's

with

and electrophysiologic follow-up study on two sibling cases. J Child NeuroI1993;8:366-372.

1996;47:1452-1456. 112. Pradella

R, Loffredo

in patients

ments. Doc OphthalmoI1995;89:211-218.

of asymp-

impairment

IH: Neuro-

CUlT Opin Ophthalmol

G, DeMarco

Visual dysfunction

electroretinograms

AR, optic

1997;8:35-40. 123. Ambrosio

derma. Acta Neurol Scand 1993;88:299-308.

Pattern

hereditary

atrophy. Arch OphthalmoI1977;95:969-978.

1997;14:159-164.

110. Hietaharju

E, Sogg RL, Rosenthal

et al: The early phase in Leber

pallidotomy

potential

K, Nishizawa guidance

in Parkinson's

rol Med Chir 1997;37:257-263.

S, et

for posterodisease. Neu-

274

The Visual Evoked Potential

133. Tobimatsu

S, Shima F, Ishido

K, et al: Vi-

sual evoked

potentials

in the vicinity

tract during

stereotactic

pallidotomy.

cephalogrClin

tern visual evoked

Electroen-

ous acuity

NeurophysioI1997;104:274-279.

134. Hinton Optic

143. Bobak P, Khanna

of the optic

teration

nerve degeneration

in Alzheimer's

dis-

CA, Drucker

cells in Alzheimer's

DN:

145. Tan CT, Murray

Retinal

liberate

ganglion

disease and aging. Ann Neu-

ro/1993;33:248-257. 136. Wright

flash and pattern

alteration

GF, Orwin

indicator

NM,

147. Morgan

137. Coburn

KL, Ashford

MA:

Voluntary

selective

sponses. Ophthalmology

potentials

in dementia:

delay of flash P2 in probable ease. J Neuropsychiatry

Alzheimer's

dis-

of pattern

WS: Psychophysiology

149. Towle

VL, Sutcliffe

A, Growdon

functional

JH, et al: Retinocalcarine

in Alzhei-

nent of the visual evoked

and electrophysiological

electrophysiological Alzheimer's

disease. Electroencephalogr

U, Gambarelli

al: Different

susceptibilities

in

Clin Neu-

D, Farnarier

G, et

of the geniculate

visual pathways

to human

disease: a combined

physiological-neuropathological

neuro-

study. Electro-

encephalogr Clin NeurophysioI1991;78:413-423. 141. Carroll incidence

WM,

Kriss A, Baraitser

evoked

M, et al: The

and nature of visual pathway

ment in Friedreich's potential

ataxia: clinical

involve-

and visual

study of 22 patients.

Brain

1980;103:413-434. 142. Perretti tosomal

cerebellar

modal electrophysiological son between

B, et al: Au-

ataxia type I: multistudy and compari-

SCA1 and SCA2 patients.

Sci 1996; 142:45-53.

pattern

with

the P300 compo-

potential.

Arch Oph-

reversal

Barrett

G, Halliday

visual evoked in one half field

AM:

potential

to

and its signifi-

cance for the analysis of visual field

defects.

151. Blumhardt al: The

LD,

Barrett

effect of field

G, Halliday

AM,

size on the pattern

J Neurol

et

reversal

VEP. Clin Vis Sci 1989;4:27-40. 152. Holder

GE: Pattern

visual evoked

in patients

with posteriorly

situated

pying

lesions. Doc OphthalmoI1985;59:

153. Brigell

M, Rubboli

pole model.

121-128.

G, Celesia

GG: Identifi-

activated

by hemifield

cation of the hemisphere visual stimulation

potential

space-occu-

using a single equivalent

Electroencephalogr

di-

Clin Neurophysiol

1993;87:291-299.

A, Santoro L, Lanzillo

dominant

of P300.

Br J OphthalmoI1977;61:454-461.

140. Aguglia

and extrageniculate

LD,

The asymmetrical

rophysioI1993;87:9:;-104.

Creutzfeldt-Jakob

re-

103:4 7 -50.

150. Blumhardt M, et al: An

study of visual processing

et al:

E, Sokol S: Diagnosing

visual deficits

thalmol1985;

study. Arch NeuroI1992;49:93-101. GG, Villa AE, Brigell

IM,

visual evoked

1985;92: 1356-1362.

138. Rizzo JF III, Cronin-Golomb

139. Celesia

alter-

Psychol BnII1981;89:506-540.

431-435.

mer's disease: a clinical

C: Voluntary

Ann NeuroI1982;12:

RK, N ugent B, Harrison

alteration

148. Pritchard

Clin Neurosci 1991;3:

function

potential.

1984;47:518-523.

496-497.

Doc OphthalmoI1986;62:89-96.

Visual evoked

Sawyers D, et al: De-

potentials?

of dementia.

JW, Moreno

al-

Ann Neurol

of the visual evoked

KH, Yiannikas

ation of evoked

A: The

VEP as a diagnostic

CM: Voluntary

potentials.

J Neural Neurosurg Psychiatry 146. Chiappa

CE, Harding

I, Epstein

of visual evoked

1982;12:475-478.

ease. N Engl J Med 1986;315:485-487. 135. Curcio

I, et al: Pat-

in cases of ambigu-

loss. Doc OphthalmoI1993;85:185-192.

144. Baumgarrner

DR, Sadun AA, Blanks JC, et al:

P, Goodwin

potentials

154. Brecelj

I: Electrodiagnostics

compressive

of chiasmal

lesions. Int J PsychophysioI1994;16:

263-272. 155. Flanagan

IG, Harding

visual evoked

potentials

GF: Multi-channel

in early compressive

lesions of the chiasm. Doc OphthalmoI1988;69: 271-281.

275

Reference~

156. Haimovic

IC, Pedley

TA: Hemi-field

pat-

terI1 reversal visual evoked

potentials,

of the chiasm and posterior

visual pathways.

Electroencephalogr

II: lesions

Clin NeurophysioI1982;54:

al: Evoked

CG, AminoffMJ,

potentials

field defects

Kennard

in the evaluation

due to chiasmal

C, et

of visual

or retrochiasmal

158. Guillery

RW, Okoro

visual pathways

AN, Witkop

CJ Jr: Ab-

in the brain of a human

albino. Brain Res 1975;96:373-377. 159. Creel DJ, Summers anomalies Paediatr

associated

albinism.

Genet 1990;11:193-200.

160. Apkarian

in congenital

try in albinism: thalmolVis

nystagmus,

a comparison

VEP asymme-

study. Invest Oph-

Sci 1991;32:2653-2661.

161. Celesia

GG, Meredith

try, visual evoked spectrum

J: VEP pro-

Electroencephalogr 16-30.

hemianopsia.

hemianesthesia,

ML,

et al:

ID, Conte

syndrome.

MM,

potentials

Multichannel

D, Mecacci

L: Pat-

potentials

in patients

Brain

Cogn 1995;27:

M, Bernardi

visual evoked

graine. Electroencephalogr

L, et al: Viand normals:

in transient

potentials

G, et al: in mi-

S, Kussmaul

CL, Munte

Clin Neurophysiol1995;

processing

defect.

Neuropsychologia

1996;34:

172. Brecelj pattern

I, Strucl M, Raic V: Simultaneous

electroretinogram rec9rdings

and visual evoked

in dyslexic

children.

E, Ridder

WH

Ill,

Dudeck

of a magnocellular

grams and visual evoked

Vis Res 1996;36:

1047-1053.

Visual association tern-evoked

I, Atkin

A, Raab E, et al:

cortex and vision

occipital

potential

in man: pat-

in a blind

Visual function

CR, Kuroiwa

Y, et al:

of the extrageniculocalcarine to cortical

Visual evoked

in migraine.

pattern-reversal 1998;121:233-241.

during

stimulation

of "cortical

177. Abraham

FA, Melamed

tic value of visual evoked

AP, De Pasqua V, et al:

potentials

long periods

in migraine.

Brain

sys-

blindness.

potentials

blindness"

in chil-

dren. Arch Neuro/1979;6:126-129.

1997;17:742-747.

166. Afra J, Cecchini

boy.

Science 1977;198:629-631.

in the evaluation

reversal electroretinopotentials

K, et

defectde-

176. Frank Y, Torres F: Visual evoked of pattern

Doc

Arch Neuro/ 1980;37:704-706.

K, Osawa M, Iwata M: Simultane-

ous recording

TF, et al:

Developmental dyslexia: passive visual stimulation provides no evidence for a magnocellular

tem in man: relationship

96:1-5. 165. Shibata

or steady-

Vis Neurosci 1993; 10:939-946:-

175. Celesia GG, Archer M, Sabbadini

Burton

in dyslexics

to find a difference

state responses.

basis of

Neurol Clin 1993; 11 :

pends on the type of dyslexia.

Neurology

17-35. 164. Tagliati

Cephalalgia

170. Victor

174. Bodis-Wollner

tern reversal visual evoked hemineglect

dyslexia.

al: The presence

and spatial ne-

potentials.

MP, Spinelli

for 2

dyslexia.

Ophthalmo/1997-1998;94:355-364.

1991;41:1918-1922. 163. Viggiano

AM: Neuroanatomic

developmental 161-173.

173. Borsting P, Rusconi

glect: a study with evoked

in developmental

169. Galaburda

potential

Clin NeurophysioI1983;56:

162. Vallar G, Sandroni Hemianopia,

K: Perime-

and visual evoked

array in homonymous

FW,

evidence

1123-1127.

JT, Pluff

potentials

and anatomical

defect

171. Iohannes

P, Shallo-Hoffmann

read-

Proc Natl A cad Sci USA 1991;88:7943-7947.

failure

Ophthalmic

L, et al: A with

MS, Rosen GD, Drislane

magnocellular

sual evoked

CG, King RA: Visual

with

in children

N Engl J Med 1993;328:989-996.

168. Livingstone

lesions. Neurology 1982;32:986-991.

with

S, Garzia RP, Turner

visual pathway

et al: Physiological

157. Maitland

jections

defective

ing disability.

121-131.

normal

167. Lehmkuhle

blindness of

following

E, Levy

potentials

S: Prognosin occipital

basilar artery occlusion.

Neurophysio/1975;38:126-135.

Appl

276

The Visual Evoked Potential

178. Duchowny

MS, Weiss IP, Majlessi

Visual evoked blindness

responses

after head trauma

longitudinal

H, et al:

in childhood

and meningitis:

24:933-940. CS, Nickel

mological

examination

mental

BL, Billson

in infants:

time of pattern an index of matura-

Vis Res 1979;19:747-755.

190. Sokol S: Infant

visual development:

potential

Ann NY Acad Sci 1982;388:

estimates.

develop-

191. Moskowitz

aspects. Surv OphthalmoI1982;26:

A, Sokol S: Developmental

changes in the human

visual system as reflected

177-189.

by the latency

180. Abramov

troencephalogr Clin NeurophysioI1983;56:

I, Gordon

J, Hendrickson

The retina of the newborn

human

A, et al:

infant.

Science

1982;217:265-267. 181. Yuodelis

C, Hendrickson

and quantitative during

182. Magoon myelin

EH,

fovea

of

human

lateral geniculate

to a critical

and VEP)

Vis Res 1986;26:195-219.

assessment.

period

development nucleus:

France TD,

and young children.

Strabismus

study. Arch Ophthalmol

Postnatal

P: The use of a sys-

to electrodiagnostic

evoked

of the

MC,

Fiorentini

potentials

to luminance

K, Teller

sensitivity

VEP. Vis Res 1997;37:2057-2072.

idence for synapse elimination

196. Hansen

185. Hubel

Neurosci Lett 1982;33:247-252. DH, Wiesel

of ocular dominance

TN,

in monkey

of chromatic in infancy

striate

197. Braddick Cortical

278:377-409.

288:363-365. AB, Friedman

VEP development

SL, Weiss IP, et al:

in infancy

hood: a longitudinal

and early child-

study. Electroencephalogr

S, Casaer P: Stepwise

VEP latencies

and the process of myelination

the human

visual pathway.

decrease in in

Brain Dev 1997; 19:

.147-551.

stimuli

S, Towle

of human

27 weeks conceptual atrics 1997;28:318-323.

VL, Cakmur

visual evoked

R, et al: potentials:

age to 2 years. Neuropedi-

AB: The VEP threshin dark-adapted

0, Atkinson

binocularity

infants.

J, Julesz B, et al:

in infants.

Nature 1980;

B: FPL

of fusion,

and stereoacuity

stereopsis

and VEP measures in normal

Vis Res 1996;36:1321-1327.

199. Makrides

M, Neumann

Are long-chain

polyunsaturated

sential nutrients

in infancy?

M, Simmer

K, et al:

fatty acids es-

Lancet 1995;345:

1463-1468. 200. Birch EE, Hoffman

188. Kos-Pietro Maturation

the sweep

198. Birch E, Petrig infants.

Clin ElectrophysioI1980;49:476-489. 187. Tsuneishi

contrast

as tested with

Vis Neurosci 1995;12:223-228.

cortex. Philos Trans R Soc Lond B Bioi Sci 1977;

186. Ballet

DY: The devel-

and achromatic

RM, Fulton

olds for full-field

Lev ay S: Plasticity

columns

of visual

and colour con-

Vis Res 1996;36:3141-3155.

195. Kelly JP, Borchert

184. Huttenlocher PR, de Courten C, Garey LJ, et al: Synaptogenesis in human visual cortex: evdevelopment.

in

A, Burr DC: De-

opment

normal

deficits

properties

1977; 198:836-838.

during

Bousch GA:

J Pediatr Ophthalmol

of the temporal

trast in infants.

relationship

for the visual system. Science

(ERG

1996;33:298-'302.

194. Morrone velopment

TL:

H, Apkarian

1-15.

tem analysis approach

infants

1981;99:655-659. 183. Hickey

192. Spekreijse

reversal VEP. Elec-

A sweep VEP test for color vision

optic nerve and tract: a light

microscopic

of the pattern

193. Ver Hoeve IN,

Vis Res 1986;26:847-855. Robb RM: Development

in human

and electron

A: A qualitative

analysis of the human

development.

evoked

514-525.

FA: Ophthal-

of the infant:

potentials

tion of spatial vision.

a

study of six cases. Neurology 1974;

179. Hoyt

189. Sokol S, Jones K: Implicit evoked

cortical

DR, Uauy R, et al: Vi-

sual acuity and the essentiality hexaenoic acid and arachidonic of term infants. 201. Dobson human havioural

Pediatr Res 1998;44:201-209.

V, Teller

infants:

of docosaacid in the diet

DY: Visual acuity

a review

and comparison

and electrophysiological

Res 1978:18:1233-1238.

in of be-

studies.

Vis

References

202. McCulloch Visual evoked following

DL,

Taylor

potentials

perinatal

L], Whyte

HE:

214. Odom JV. Hoyt

and visual prognosis

asphyxia.

ral deprivation

Arch Ophthalmol

tential

203. Mackie

RT, MeCulloch

1412-1416.

visual acuity

in multiply

DL:

Assessment

handicapped

of

children.

215. Hoyt

204. Bane MC, Birch EE: VEP acuity, FPL

acu-

potential

ity and visual behavior

chil-

dren. J Pediatr Ophthalmol

impaired

Strabismus

1992;29:

R, Hoyt

205. Hubel

tal monocular

Wiesel TN:

Binocular

interac-

reared with arti-

217. Gelbart

206. Sherman

SM, Spear PD: Organization

Long-term

sual pathways

in normal

ofvi-

deprived

SS, Hoyt CS, Jastrzebski visual results in bilateral

207. Kratz KE, Spear PD: Effects

of visual depri-

on responses of striate cortex

competition

neurons

in the cat.

J Comp NeuroI1976;170:141-151. 208. Levi vision

DM:

and amblyopia.

CUlT Opin Ophthalmol

B: Visually

responses of amblyopes

210. Sokol S, Shaterian potential

sual function.

evoked

to a spatially

cortical

alternating

ET: The pattern

in amblyopia

evoked ofvi-

], Stockbridge

DH,

visual maturation.

222. Uemura

Specialists

Medical

Books;

cies in amblyopia.

evoked

potentiallaten-

infants.

Br J OphthalmoI1983;67:

their use in pediatric ed: Electrophysiology

visually

ophthalmology. Little,

In: Sokol S,

225. Lambert

&

Clin 1980;31 :251-268.

LM ]r, Sokol S: Changes

fixation

1983;67:127-130.

Brown

patterns

in the treatment

and the visually of esotropia

evoked

with am-

O!JhthalmoloQ'V 1980:87:1273-1281.

0: Visual Genet

in low-birthweight

electrophysiological

14:425-435.

GB, Marg E: Delayed

in infancy.

Br J Ophthalmol

SR, Kriss A, Taylor

visual maturation: 1989;96:524-529.

in the bi-

responses

CS, Jastrzebski

potentials:

and Psychophysics: Their Use in

Ophthalmic Diagnosis. Boston: Co. I nt Ophthalmol

evoked

in

K, Iwase K, Hara K: Maturation

visual maturation

212. Sokol S: Pattern

Y, Katsumi

Dt'V Med Child Neuro11972;

224. Hoyt

310-314.

vi-

studies

delay. Ophthalmic Paediatr

of visual evoked

211. Sokol S: Abnormal

AR: Dissociated

electrodiagnostic

Y, Oguchi

developmental

223. Watanabe

Symposia

1976:59-67.

Fielder

NeuroI1980;22:327-335.

Miami:

blvooia.

ocular

who are "slow to see." Dt'V Med Child

1981;1:49-58.

nocular

of congenital

RS: Delayed

sual development: infants

as an index

In: More S, Mein

221. MelIor

L, eds: Orthoptics: Past, Present and Future.

potential

I,

cataract. Br J

JW J r, Sokol S: The visual-evoked

in the diagnosis

220. Illingworth

Invest OphthalmoI1973;12:936-939.

213. Wilcox

H, Russell-Eggitt

in unilateral

Arch Dis Child 1961;36:407-409.

209. Sokol S, Bloom

cortical

DA, MoIler

motor apraxia. Am J OphthalmoI1982;93:700-703.

of binocular

1994;5:3-10.

stimulus.

GB, etal: congenital

OphthalmoI1996;80:794-798. 219. Gittinger potential

Pathophysiology

;

cataracts. Am J OphthalmoI1982;93:615-621.

et al: Visual acuity

in binocular

surgery for congeni-

cataracts. Am J Ophthalmol1981

218. Thompson

and alterations

CS, Marg E, et al: Good vi-

after neonatal

cats. Physiol Rev 1982;62:738-855.

vation

evoked

91:559-565.

ficial squint. J NeurophysioI1965;28:1041-1059.

and visually

visually

Arch Ophthalmol1984;

102:58-61. 216. Beller sua! function

DH,

po-

GB, Marg E: Ambly-

esotropia:

measurements.

202-209.

tions in striate cortex of kittens

on vi-

evoked

Arch OphthalmoI1981;99:

CS, Jastrzebski

opia and congenital

of natu-

eye patching

and children:

measurements.

Br J OphthalmoI1995;79:290-296.

of visually

CS, Marg E: Effect

and unilateral

sual acuity of infants

1991:109:229-233.

277

a longitudinal assessment.

D: Delayed clinical

and

Ophthalmology

278

The Visual Evoked Potential

226. Granet

DB, Hertle

The visual-evoked

RW, Quinn

response

tral visual impairment.

GE, et al:

in infants

with cen-

MP, Mitchell

KW, Gibson

M: The

Nagata T, Yoshikawa

Electroencephalogram the primate

Am J Ophthalmol1993;

116:437-443. 227. Clarke

236. Ochikubo,

and evoked

Y, et al: potentials

Electro-

encephologr Clin ElectrophysioI1993;88:397

--407.

237. E hIe A, Sklar F: Visual evoked infants

pairment

238. Sklar FH, E hIe AL, Clark WK: Visual

in infancy.

Eye 1997;11:398-402.

M, McCulloch

D, Rother

C, et al:

with

hydrocephalus.

potentials

prognostic value of flash visual evoked potentials in the assessment of non-ocular visual im-

228. Borchert

evoked

potentials:

monitor

patients

Neurosurgery

poplasia. Am J OphthalmoI1995;120:605-612.

239. York DH,

229. Liu GT, Malloy

Relationship

P, Needle

in neurofibromatosis

sual evoked

potentials.

M, et al: Optic type 1: role of vi-

Pediatr Neuro11995;

12:

230. North gliomas

K, Cochineas

C, Tang E, et al: Optic

in neurofibromatosis

sual evoked

potentials.

type 1: role of vi-

Pediatr Neuro11994;

10:

231. Taylor

MJ, Murphy

nostic reliability evoked

Pulliam between

and intracranial

WJ, Whyte

of somatosensory

potentials

of asphyxiated

HE: Prog-

potentials,

term infants.

Dev Med Child NeuroI1992;34:507-515. 232. Majnemer tials as predictors

size in hydrocephalus.

233. Ekert

rodevelopmental

the evaluation

inten-

243. Wright

NK, Whyte

outcome

HE, et al:

for prediction in preterm

D: Event-related of high-risk

infants.

Recording

KW, Eriksen pattern

under chloral of neuinfants.

gene therapy

protocol.

KJ, Shors TJ, et al:

visual evoked

hydrate

and mental

1984;14:283-286.

sedation.

potentials Arch Ophtholmol

1986;104:718-721. 244. Burde

RM: Discussion:

tion of pattern

visually

voluntary

evoked

alterna-

responses.

Oph-

tholmology 1985;92: 1362-1363. potentials

in

Ann NY A cad

,')ci 1982;388:557-571. 235. Pike MG, Wong PK, Bencivenga

SUGGESTEDREADINGS R, et al:

Electrophysiologic studies, computed tomography, and neurologic outcome in acute bacterial meningitis.

RJ: Canavan

RP, et

in hydrocephalus:

Neurosurgery

in neonatal

potentials

and ventricular

to head size, shunting

development.

of outcome

Bioi Neonate 1997;71:148-155. 234. Kurtzberg

potentials

Science 1996;272:1085.

PG, Keenan

Visual evoked

DD: Visual evoked

pressure

AN, Sclabassi RJ, Hirsch

al: Visual evoked

242. Levine

Pediatr NeuroI1996;14:189-195.

JG, et al:

potentials

321-329.

poten-

of the literature.

to

Doc OphtholmoI1987;66:

B: Evoked

review

MW, Rosenfeld visual evoked

SG, Cochrane

A, Rosenblatt

sive care unit survivors:

technique hydrocephalus.

pressure. J Neurosurg 1981;55:

intracranial

relationship

and visual

shunted

909-916.

241. Guthkelch

117-123.

a noninvasive with

1979;4:529-534.

240. Coupland

89-90.

in

Neurology 1979;29:

1541-1544.

Clinical assessment, optic disk measurements, and visual-evoked 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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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"

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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

A

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 constant-intensity 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

retinochoroidopathy,

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

c

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

D

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

E

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 Ethyl-m-aminobenzoic

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

retinochoroidopathy, 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,

retinochoroidopathy,

Graves disease, YEP in, 250 Guanosine

disorders

in Tay-Sachs

Histoplasmosis ERG in, 75

72

3

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

M

PERG

5

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.

See also specific type

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

Membranoproliferative 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

O

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

N

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,

1

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

1

of ERG,

See also Pattern

nerve head, drusen of, PERG

85, 86, 89!

18, 19!

retinoschisis,

component,

in, 168

Optic

105-106

75, 77!

p

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

with constant-intensity

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)

retinochoroidopathy, 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

retinochoroidopathy,

in Oguchi

station.

blindness

S-cone

fundus

response

component,

(STR),

PERG

6

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,

See also specific type

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

u

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,

v

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

3

YEP, 240-241

in children, Traumatic

ERG

in ERG, 266,267

optic neuropathies,

253

value of, in pediatric

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

A

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

See also specific type

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

value of, in pediatric

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