diagnostic and surgical techniques

8/3/2019 Diagnostic and Surgical Techniques

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30 Surv Ophthalmol 45 (1) JulyAugust 2000

SCHOLL AND ZRENNER

Since Karpe

62

introduced the electroretinogram(ERG) as a routine assessment technique in ophthal-mology, many new stimulation and recording tech-niques have provided answers to pathophysiologicaland clinical questions. Basic research gave insightinto the physiology and pathophysiology of the

sources and components of the electrical signals thatcan be recorded at the cornea in normal subjectsand in patients with retinal disorders, respectively.Many studies of retinal electrophysiology refer to he-reditary retinal disorders. In retinitis pigmentosa(RP), ERG changes usually precede ophthalmoscop-ically visible fundus disease in all genetic patterns,and ERG abnormalities are the main criterion forthe diagnosis of many hereditary retinal disorders.

Considering the wealth of information, we will notprovide a comprehensive review of electrophysiolog-ical findings in acquired retinal disorders. Rather,we will cover only a selection of the investigationalwork that has been done in recent years. The basisfor our selection is 1) research work related to com-mon retinal disorders, such as glaucoma or diabeticretinopathy; 2) lesser known topics, such as hepaticretinopathy and photochemical damage to the ret-ina; and (3) studies that have been very recentlypublished. We further restricted our selection ofelectrophysiology to electroretinography and elec-tro-oculography. In a short paragraph at the end ofeach section, the conclusions for clinical applicationare summarized. Because in most geographic loca-tions, the very recent techniques, such as the multi-focal ERG or the cone type specific (S-. M- andL-cone) ERGs, are not available, we restricted theconclusions to the ERG measures that are includedin the standard of the International Society of Clini-cal Electrophysiology of Vision (ISCEV).

83,84

Several aspects of acquired disorders will not bediscussed, such as ocular trauma and opaque media(for a review, see Harding

49

), retinal detachment,

63

foreign metallic bodies in the eye,

69,104,114

and circula-tory deficiencies (for a review, see Johnson

58

).

Effect of Age onElectrophysiologic Measurements

STANDARD ERG

Age is associated with a measurable decrement inthe amplitude of the b-wave. Peterson

93

noted a lin-ear reduction with age of the b-wave amplitude fromabout the age of 10 years, with the exception of women in the age group 4049 years in whom ahighly significant increase in the b-potential can bemeasured. Birch and Anderson recorded full-fieldERGs in 269 normal subjects, including 10 normal

infants tested within 1 week of birth and 30 healthy

preterm infants tested at 4 months adjusted age.

12

Rapid development of the rod response is evidentduring the first 4 months of life, with a greater thantenfold increase in peak-to-peak amplitude. Between4 months and adulthood, there is a further triplingof rod amplitude. Cone responses show a similar,

but less dramatic, growth in amplitude betweenbirth and age 4 months. Adult cone amplitudes areless than double those at age 4 months. For both rodand cone responses, amplitudes show a gradual de-cline with age up to 55 years, and a rapid declinethereafter. Best-fit exponential functions show thatthe age at which amplitude drops to one half that ofthe young adult level (ages 15 to 24 years) is 69 yearsfor the rod response and 70 years for the cone re-sponse (Fig. 1).

Reduced amplitudes may reflect a general reduc-tion in average retinal activity in older subjects. Thiscould be related to the senile changes that havebeen found to occur both in the outer and inner lay-ers of the retina

40

(for review, see Weale

123

). In an ef-fort to provide further insight into the causes of am-plitude reduction with age, Birch and Andersonobtained rod retinal illuminance vs amplitude func-tions.

12

They found log k, an index of sensitivity, tobe only modestly decreased with age consistent withonly modest decreases in photopigment optical den-sity.

32,67

Thus, reduced sensitivity can account foronly a small reduction in amplitude. A much largercontribution comes from the decline in V

max

. Maxi-mum amplitude varies with the number of func-tional b-wave generators.

13,126

Bipolar or Mller celldeath in the aging retina

29

could account for muchof the decline in amplitude.

12

It cannot be ruled out,however, that subtle preretinal media changes (e.g., yellowing of the lens with age) could also accountfor a decrease in amplitude as the consequence oftheir filter effects and the reduction of the amountof light reaching the retinal photoreceptors.

The effects of age on ERG timing are controver-sial. Weleber reported similar age-related reductionsin ERG amplitude, but not in photopic and scotopicimplicit times,

125

whereas Iijima found mild to mod-

erate age dependency in both amplitudes and tim-ing.

52

In the study of Birch and Anderson, implicittimes were significantly correlated with age for therod response, the maximal response, the single-flashcone response, and the 30-Hz flicker response.

12

Inour clinic, we found age-related reductions in ampli-tude and prolongations of implicit times for nearlyall responses of the ISCEV standard protocol.

53,54

Forthe rod response, the mean amplitude in the agegroup beyond 65 years is about 93% of the mean am-plitude in the age group between 6 and 19 years, forthe maximal response 95% and for the cone re-

sponse 72%.


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ELECTROPHYSIOLOGY IN THE INVESTIGATION OF ACQUIRED RETINAL DISORDERS

31

PATTERN ERG (PERG)

ERG measurements to periodic stimuli revealedthat age-related changes in the visual system are notuniform across the spatio-temporal spectrum, butare greater at specific spatial and temporal frequen-cies. For the pattern ERG (PERG) Porciatti and co-workers tested the effect of spatial and temporal fre-quency.

96

They found systematically lower amplitudesfor older subjects than for younger ones, but therewas no systematic tendency for selective reduction inamplitude in the high, middle, or low spatial fre-quency regions. There was only a slight age effect ontemporal frequency, that is, the amplitudes of theolder subjects were relatively more depressed at thehigher temporal frequencies. Their phase data sug-gest that there is little, if any, age-related latency dif-ference in the PERG.

When considering amplitude and phase data indifferent age groups, one has to consider the differ-ent retinal illuminance, for example, the possiblerole of senile miosis. The effect of retinal illumi-nance on neural latency has long been known as thecause of the well known Pulfrich effect.

98

The mag-nitude of the latency measured by psychophysicalmeans is about 20 msec/log-unit,

100

similar to whatPorciatti and coworkers observed.

96

Trick examinedage-related alterations in retinal function, measur-ing PERGs and VEPs.

118

She found that the observedPERG alterations cannot be completely explained by

the reduction in retinal illumination associated with

senile miosis, but reflects age-related neurophysio-logic changes. The most significant age-related dif-ferences in PERG amplitude were obtained whenlarge checks were used. This suggests that slight dif-ferences in visual acuity or retinal image quality be-

tween younger and older subjects can not accountfor the reductions in PERG amplitude.

ELECTRO-OCULOGRAM (EOG)

The age effects on EOG parameters are controver-sial. Some authors report significant correlations ofEOG parameters with age,

1,3,76

whereas others denysuch changes.

28,129

In most studies, the slow oscilla-tions and light peaktodark trough ratios(L/D,Arden index) are usually reported. Little is knownabout the fast oscillations. In a study in our clinic,

age was not correlated with the L/D ratio, but thequotient of the fast oscillation was significantly cor-related with age (r

0.32, P

0.005).

33

However, Weleber, who routinely measured the fast oscilla-tions, did not find any significant correlations withage for all EOG parameters.

125

CONCLUSIONS FOR CLINICAL APPLICATION

It is generally recommended that each laboratoryestablish a range of normal values for each electro-physiologic response. Because of the effect of age, itis crucial that the population of normal subjects

comprises subjects of different ages.

Fig. 1. Left: Variation of log ERG amplitude with age. Rod peak-to-peak amplitudes for subjects aged 5 years and older.Solid curve is best-fit exponential with half amplitude at age 69 years, right. Right: Cone peak-to-peak amplitudes to 30-Hzflicker for subjects aged 5 years and older. Solid curve is best-fit exponential with half amplitude at age 70 years. Open circlesindicate female; solid circles indicate male. (Reprinted from Birch DG, Anderson JL12 with permission ofArch of Ophthalmol.)


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SCHOLL AND ZRENNER

Diabetic Retinopathy

Diabetic retinopathy affects the retinal blood ves-sels that develop in the complex metabolic milieu ofsystemic diabetes mellitus. The primary pathophysio-logic process affects the permeability of the bloodvessels because of a metabolic derangement. Retinal

arterioles and capillaries close, and this leads to reti-nal ischemia and cell death (nonproliferative dia-betic retinopathy [NPDR]). In proliferative diabeticretinopathy (PDR), there are secondary changes, in-cluding retinal edema and fibrovascular prolifera-tion leading to ERG abnormalities.

15

However, it isalso possible that abnormalities in retinal metabo-lism secondary to diabetes could cause retinal dys-function without a microvascular basis for the ERGchanges

60

(for a recent review, see Tzekov andArden

120

).

STANDARD ERG A- AND B-WAVES

Studies on the parameters of the standard ERG indiabetic retinopathy remain equivocal. Juen and Kie-selbach could reveal significant different ERG valuesfor several ERG parameters in diabetics with and without retinopathy.

60

Holopigian and coworkersalso found several ERG parameters to be abnormalin early diabetic retinopathy.

51

However, Jenkins andCartwright reported normal or even supernormalamplitudes in the flash ERG of patients with early di-abetic retinopathy.

57

Nevertheless, the standard ERG can be of clinical

value in diabetic retinopathy, as was shown byBresnick and coworkers. They developed an elec-troretinographic protocol for diabetic retinopathy,which contains scotopic b-wave amplitude (and tim-ing), oscillatory potential (OP) amplitude (and tim-ing), and 30-Hz flicker timing.

15

They were able toshow that in diabetic retinopathy, the reduction ofamplitudes and the delay of peak implicit times inthe ERG are related to the severity of retinopathy.

18,20

PATTERN ERG

Arden and coworkers

4

recorded PERGs and OPs

from the eyes of diabetic patients with various de-grees of milder retinopathy. They found reducedamplitudes only in the presence of cotton-wool spotsand angiographic evidence of capillary nonperfu-sion. Their scatter of results in the OPs was larger, sothey suggested that PERG provides more reliabledata than OPs. On the other hand, Wanger and Pers-son could not find any flash ERG or PERG changesthat would distinguish between the presence or ab-sence of retinopathy in diabetic patients.

122

Also inthe study of Jenkins and Cartwright,

57

the PERG am-plitudes of patients with early diabetic retinopathy

were within normal limits.

OSCILLATORY POTENTIALS

Reductions in the amplitudes of OPs have beenreported in diabetic retinopathy,

17,18,60

although Wanger and Persson

122

could not find any suchchanges. In studies by Bresnick and coworkers,

16,17,19

the amplitude of the OPs predicted the progression

of eyes with NPDR or mild PDR to severe PDR. Ab-normal OP amplitudes indicate a high risk of devel-oping proliferative diabetic retinopathy and are cor-related with the rate of progression of diabeticretinopathy.

16,17,19

However, the clinician has to con-sider that OPs have a high intra- and interindividualvariability.

4,71

There is evidence that individual OPs have differentneural generators. For example, individual OPs havedifferent retinal depth profiles, with the earlier OPsarising more proximally within the retina than thelater ones.

121

Holopigian and coworkers

51

examined

the amplitudes of the individual OP wavelets. Their re-sults did not show selective changes in OP amplitude,but did show a uniform reduction for all OPs. Fromthese results and from their results concerning thestandard ERG changes, which have been mentionedabove, they suggest that additional retinal sites mustbe affected in early diabetic retinopathy.

Shirao and Kawasaki

108

point out that in early dia-betic retinopathy a prolongation of the peak latencyof the OPs can be diagnosed much earlier than a re-duction of the OP amplitude. The natural course ofdiabetes is an incipient prolongation of the peak la-

tency, which is followed by the reduction of ampli-tude and prolongation of the interpeak intervals(Fig. 2). Both the prolongation of the peak latencyand the reduction of amplitude of the OPs canquantitatively represent the diabetes-induced retinaldysfunction.

They investigated the OP abnormalities in Strep-tozotocin-induced diabetic rats and found that thepeak latency of the second OP (OP2) began to beprotracted as early as 2 weeks after diabetogenesis.From the rapidity of the OP changes in experimen-tal diabetes in the absence of retinal vascular dys-function, they concluded that the prolongation ofthe OP peak latency at the preretinopathy stage maynot be attributable to diabetic angiopathy, butrather to certain neuronal alterations.

S-CONE ERG

Greenstein and coworkers

45

reported that diabetesdecreases the sensitivity of the S-cone pathway moreselectively than RP or open-angle glaucoma, suggest-ing that the S-cone pathway is more vulnerable to hy-poxia than L- or M-cone pathways. Yamamoto andcoworkers

127

used the method of Gouras and

MacKay

43

in diabetic patients with and without retin-


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33

opathy. They found that both retinopathic and non-retinopathic diabetes reduce the amplitudes of theb-waves of the S-cone ERG and decrease its sensitiv-ity significantly. On the other hand, the L- andM-cone amplitudes were not decreased in eitherstage of diabetes.

ERG RECORDINGS OF THE FOVEAL CONES

Weiner and coworkers

124

examined patients withNPDR, with and without clinically significant macu-lar edema (CSME). They could show that slowing

and decreased amplitudes of the foveal cone re-sponses are significantly associated with the pres-ence of CSME in eyes with NPDR. Early changes inthe foveal ERG may, therefore, indicate developingCSME and could be a potential tool for early detec-tion of significant diabetic maculopathy, before lossof central vision has occurred.

MULTIFOCAL ERG

An important feature of beginning diabetic retin-opathy is its focal nature. Standard ERG recordingtechniques measure an overall response of the ret-

ina. Therefore, small areas of retinal dysfunction

may go undetected in the recording of the overallretinal response, because when large stimuli areused, small abnormalities will not affect responsesevoked from a retina that is predominantly normal.For simultaneous ERG testing of multiple small reti-nal areas, Sutter and Tran

113

developed the VisualEvoked Response Imaging System (VERIS), whichallows a fast, objective evaluation of retinal function,using a multifocal technique. Palmowski andcoworkers

90

explored the efficacy of the multifocalERG in detecting and localizing dysfunctional reti-

nal areas in diabetes. They found reduced overallamplitudes and delayed latencies in the first-orderresponse component in patients with NPDR, but notin diabetics without retinopathy. Because the first-order response components arise predominantly inthe outer retina, there is obviously some impairmentof outer retinal function in diabetes. The second-order response component apparently has substan-tial contributions from the inner retina. Since dia-betic retinopathy is presumably a disease that affectsthe inner retina more, the second-order responsecomponent should be more suitable for detecting

early disturbances. Amplitudes of the second-order

Fig. 2. Mean (M) and standard deviation (SD) of (A) the peak latency of the first OP peak and (B) the summed ampli-tude of the OPs (O1O4) in normal subjects, diabetic eyes at pre-retinopathy stage and at overt retinopathy stage. Stage 0:no funduscopic or angiographic abnormality; Stage A I: funduscopic microaneurysms only; Stage A II: Stage A I plus atleast one of dot hemorrhages or hard exudates; Stage B I: at least one of large soft exudates, small but multiple exudatesor superficial flame-shaped retinal hemorrhages, plus angiographically confirmed non-perfusion area(s) or dye leakage;Stage B II: Stage B I plus diffuse retinal edema or marked venous dilatation. beThe shaded areas indicate the normal range(M 2 SD in the control subjects). Open circles and vertical bars indicate M and 1 SD, respectively. *P 0.05; **P 0.01;***P 0.001. (Reprinted from Shirao Y, Kawasaki K108 with permission ofProg Retin Eye Res.)


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SCHOLL AND ZRENNER

response component were indeed significantly re-duced in diabetic patients with or without retinopa-thy. Looking at the waveforms, Palmowski andcoworkers observed a difference between the nor-mal subjects and the diabetic patients. This featureoccurs at about 40 msec and was markedly reduced

in amplitude even in the patients with no clinicallyapparent retinopathy (Fig. 3). They increased thebase interval from 13 msec to 26 msec and foundthat the feature is reduced or absent both in patientswith retinopathy and without. They concluded thatthe feature disappears because of a change in the dy-namics of adaptive mechanisms.

EOG RESPONSES TO NONPHOTIC STIMULI

FROM RPE

It has been electrophysiologically shown that theRPE is more susceptible to mild hypoxia than arethe retinal neurons.

78

Diabetic retinal pigment epi-

theliopathy presumably occurs because of hypoxicconditions caused by diabetes. But the time coursesand the L/D ratios of the conventional EOG do notessentially differ among the stages of retinopathy.The L/D ratio reflects not only the function of theRPE, but depends also on photoreceptor integrity

and physical arrangement between the photorecep-tors and the RPE.For selectively testing the function of the RPE,

Yonemura and Kawasaki

128

developed three kinds ofnon-photic EOG responses as novel function testsfor the RPE: 1) responses to an increase in sodiumbicarbonite concentration; 2) responses to an ele-vated osmolarity due to an addition of fructose; and3) responses to the addition of Diamox. Shirao andKawasaki

108

measured the time course of the EOG innormal control subjects and diabetics at variousstages of retinopathy after injection of bicarbonate.The mean amplitude of the bicarbonate response

Fig. 3.

First slice of the second-order response component with astimulus base interval of 13.33msec. A: Areas of approximatelyequal eccentricities whose responses,having similar waveforms, were aver-aged to achieve a better signal-to-noise ratio. B:Response average, de-rived from rings shown in A in acontrol subject, in a diabetic patient without retinopathy, and in a dia-betic patient with retinopathy. A fea-ture found in control subjects at alatency of 40 msec is marked ingray. It was greatly reduced or ab-sent throughout the retina in non-proliferative diabetic retinopathy.(Reprinted from Palmowski AM etal

90

with permission ofInvest Oph-thalmol Vis Sci

.)


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35

was significantly reduced in diabetics as early as thepreretinopathy stage, and it progressively deterio-rated as the retinopathy stage advanced (Fig. 4).

Pathologic function of the RPE apparently takesplace very early in diabetes and can be detected onlywith non-photic stimuli as the bicarbonate response.


To monitor the effects of diabetic retinopathy on

retinal function, standard scotopic and photopicERG measures can be used, as they are related to theseverity of retinopathy. The most sensitive indica-tors, however, are the OPs. Abnormal OPs indicate a

high risk of developing proliferative diabetic retin-opathy. For the OPs, both amplitude and timingshould be taken into account.

Primary Open-Angle Glaucoma (POAG)

Glaucoma primarily affects retinal ganglion cells.

Whether or not there is also loss from other innerretinal cells such as amacrine cells is still under de-bate. Since inner retinal layers are morphologicallydestroyed by the disease, studies on the human ERGin glaucoma have concentrated on the cells locatedmore proximally in the retina, which also contributeto the measurable potentials at the cornea. ThePERG generally is viewed as the major signal reflect-ing ganglion cell activity, because it depends on theintegrity of those cells

80

(for a review, see Berningerand Arden9 and Zrenner130). It allows distinction be-tween retinal/macular dysfunctions (P50 compo-nent) and optic nerve head disease (N95 compo-nent).50 Inner retinal contributions to the flash ERGhave been thought mainly to originate from ama-crine cells, such as the OPs.64,89 Another inner reti-nal contribution to the dark-adapted flash ERG, anegative-going potential called the scotopic thresh-old response (STR), also has been ascribed to ama-crine cells.86,111

SCOTOPIC FLASH-ERG

Korth and coworkers examined dark-adaptedflash-evoked ERG components in glaucoma pa-

tients.70

They elicited small scotopic PII responses,using near-threshold intensities that were far belowthe standard flash intensity used for conventionalERG testing. Secondly, they elicited the STR. The

Fig. 4. Averaged time courses of the bicarbonate re-sponse in control subjects () and in diabetics (, Stage0; , Stage A I; , Stage A II; , Stage B I). Shaded areaindicates the normal range. (Reprinted from Shirao Y, Ka-wasaki K108 with permission ofProg Retin Eye Res.)

Fig. 5. Amplitude histograms of the STR (A) and scotopic PII (B) for the glaucoma patients and the normal controls.

(Reprinted from Korth M et al70 with permission ofInvest Ophthalmol Vis Sci.)


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36 Surv Ophthalmol 45 (1) JulyAugust 2000 SCHOLL AND ZRENNER

scotopic PII amplitudes were significantly reducedin the glaucoma patients compared with the controlgroup. The STR maximum amplitude is apparentlynot strongly affected by glaucoma (Fig. 5).

The peak time of both the PII and the STR werenot significantly delayed. The preserved STR sug-

gests that structures responsible for its generationare less damaged in glaucoma than the structures re-sponsible for scotopic PII. Frishman and coworkersfound that a sensitive, negative-going ERG compo-nent was abolished or greatly reduced in macaquemonkey eyes with experimental glaucoma.38 Therewas no consistent reduction of other wave forms ofthe scotopic ERG. So both studies found glaucoma-induced changes in scotopic ERG components, butthey found different components to be affected. Theconclusion to be drawn is that inner retinal neuronscontribute to the scotopic ERG, but the relative bal-ance of these components may vary appreciablyacross species.

PATTERN ERG

Bach and coworkers could show that the PERGcan reveal ganglion cell damage that is not detectedby conventional perimetry;8 the PERG amplitude re-ductions in glaucoma were very much dependent oncheck size.7 They could also show that the PERG am-plitude parallels the morphometric measure of com-puterized disk analysis.6

A case example132 demonstrates that the PERG is amuch better indicator of the damage caused by

POAG than the flash-ERG parameters of the ISCEV-standard. Patient SG (64-year-old female) hadPOAG in both eyes for 4 years. Several days beforethe electrophysiologic recordings, her intraocularpressures were 38 mm Hg in the right eye and 28mm Hg in the left. Argon laser trabeculoplasty andbeta-blocker therapy reduced the pressure to about

23 mm Hg in both eyes. Visual acuity was 6/18 in theright eye and 6/12 in the left. As shown in Fig. 6A,the PERG was reduced in both eyes. In contrast,cone responses (Fig. 6B) and rod responses (Fig.6C) elicited by Ganzfeld stimuli were not affected.

Pfeiffer and coworkers performed a longitudinal

prospective study in patients with high-risk ocularhypertension.94 Initially, 17 eyes had a normal PERGand 17 eyes had a pathologic PERG. Within the ob-servation period (maximally, 31 months), 5 of 29eyes developed visual field loss, that is, conversionfrom ocular hypertension to glaucoma. All five eyeshad a pathologic PERG during the first visit. Of theeyes that had a normal PERG on the first visit, nonedeveloped visual field defects. From their data theycalculated a sensitivity of 100% for the prediction ofthe conversion of a patient from ocular hyperten-sion to glaucoma with a specificity of 71%.


Since the PERG at least partly reflects ganglioncell activity, it is the electrophysiologic measure ofchoice for functional testing of glaucoma. ThePERG, which is a prognostic tool, should be helpfulfor the decision to treat or not to treat patients withocular hypertension.

Toxic Conditions

There are a substantial number of toxic agentsthat affect the retina (for a review, see Grant andSchuman44 and Zrenner131). Some prominent toxic

agents whose effect can be shown by electrophysio-logic means are chloroquine or hydroxychloro-quine,34 phenothiazines,82 and vigabatrin.5,25,72 Inthis section, two examples are chosen: 1) hepatic ret-inopathy (as an example of an endogenous toxicity)and lead intoxication (as an example for an exoge-nous toxicity).

Fig. 6. PERG (A), cone-ERG (B), and rod-ERG (C) of a 64-year-old female patient (SG) who had primary open-angle

glaucoma since the age of 4 in both eyes. (Reprinted from Zrenner E et al132

with permission ofDoc Ophthalmol.)


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ELECTROPHYSIOLOGY IN THE INVESTIGATION OF ACQUIRED RETINAL DISORDERS 37

HEPATIC RETINOPATHY

Hepatic encephalopathy is a syndrome that is asso-ciated with hepatic failure. As a consequence of por-tal systemic shunts or impaired hepatocellularextraction, potentially neuroactive nitrogenous me-tabolites accumulate in the peripheral blood plasma.

Of the many substances that have been implicated inthe pathogenesis of hepatic encephalopathy, ammo-nia is thought to be a key factor.22,22 Because ammo-nia is directly toxic to cultured astrocytes,87,88 it willaffect Mller cells within the retina. Impaired Mllercell function will influence the generation of ERGpotentials.

Eckstein and coworkers31 evaluated the retinalfunction of 11 patients who suffered from variousstages of hepatic encephalopathy. Patients were vita-min Asubstituted and classified into two groups de-pending on their stage of hepatic encephalopathy

according to the criteria of Pappas and Jones91

:group I included patients with stages 01 disease,and group II included stages 23. Group I patientsshowed normal scotopic b-waves, whereas group IIpatients showed significantly decreased amplitudesand increased implicit times. A-wave amplitudeswere almost within normal limits for the group I pa-tients and a-wave latencies were only slightly ele- vated. Group II patients showed significantly re-duced a-wave amplitudes and increased latencies.Similar results were obtained under photopic condi-tions. B-wave amplitudes were only slightly reduced

in group I, but significantly reduced in group II. Im-plicit times were significantly increased only ingroup II patients. The most sensitive indicator of ret-inal dysfunction caused by hepatic failure was theOP2. Amplitudes were reduced to about 95% of thecontrols in group I patients, but significantly re-duced in group II patients. Implicit times were sig-nificantly increased in both groups.

CHRONIC EXPOSURE TO LEAD

Anorganic lead is a major environmental pollut-ant with a world production of 3.5 million tons andan annual release via gasoline of 300,000 tons peryear. If lead is taken up in the early developmentalstages of life, its effects on brain functions are lon-glasting and persist even after cessation of expo-sure.47 Acute or subacute lead toxicity depends onthe blood levels. With high blood levels ( 90 g/100 ml blood), encephalopathy, papilledema, andabdominal symptoms are present. Medium bloodlevels (3060 g/100 ml blood) lead to a reductionof the rod-ERG amplitude and a disturbance of he-moglobine synthesis. Subtoxic blood levels ( 30g/100 ml blood) during childhood can result indevelopmental retardation and reduction of the in-

telligence quotient.

Ophthalmologic symptoms occur in only about12% of all exposed persons. They comprise formsof optic neuritis possibly with papilledema, variablereduction of visual acuity that does not correlatewith papilledema, central scotoma (rarely ring scot-oma) of the visual field, palsy of the ocular muscles,

disturbance of dark and light adaptation,37

and colorvision defects.In the following case example, subject AM had

been working in a printing office and was exposed tolead through inhalation. Symptoms occurred 10years after exposure, with an increasing loss of visualacuity in both eyes. Lead blood level was 20 g/100ml blood at the time of presentation. Visual acuitywas 2/20 in the right eye and 4/20 in the left. Visualfield testing revealed a central scotoma in both eyes.Nagel anomaloscope testing revealed deuteranopia.Other clinical examinations, such as funduscopy, im-aging by computed tomography (CT), and visualevoked potentials (VEP), did not reveal any patho-logic signs. In the ERG, there was a reduction of am-plitude and an increase of implicit times of the b-wave.Both features are more prominent for the rod andS-cone ERG (Fig. 7A) than for the L-cone ERG (Fig.7B), which was more or less normal.


The ERG is a sensitive and objective tool for de-tecting toxic effects on the retina. In the case re-ported above, the diagnosis of lead-related toxicityof the retina was made based mainly on the electro-physiologic deficits. In lead toxicity, it is very impor-tant to draw this conclusion because there is a thera-peutic consequence. Lead toxicity can be treatedwith dimercaprol, calcium EDTA, or penicillamine.

Inflammatory Conditions

Various inflammatory conditions of the choroidand the retina affect the ERG to an extent that tendsto correlate with apparent fundus abnormalities.Thus, patients with minimal to moderate fundus in-volvement from such conditions as syphilis or othertypes of chorioretinitis of unknown etiology in initialstages usually have either normal or only moderatelysubnormal ERG amplitudes. Both the a- and theb-wave are affected and the implicit times are nor-mal.10 In diffuse, generally chronic inflammatorystates of the retina, the EOG L/D ratio is subnormal,its degree of abnormality generally correlating withthe extent of clinically apparent disease and itsnoted effect on the ERG.35 Patients with local formsof inflammatory disease of the fundus, includingtoxoplasmosis and histoplasmosis, generally shownormal Ganzfeld ERG responses. Local inflamma-tory disease also does not affect the EOG.

Inflammatory disorders of the choroid and the


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retina that lead to pigmentary degenerative changestypically have less marked ERG abnormalities thantrue RP. Thus, the ERG is useful in establishing a di-agnosis, which can be difficult by fundus appearancealone. In posterior uveitis, the ERG is subnormal butusually not extinguished, as would be the case in RPwith comparable fundus changes. Another feature isthe unilateral involvement or the substantial differ-

ence in amplitude reduction in posterior uveitis,which contrasts the symmetric involvement in RP.

CENTRAL SEROUS CHORIORETINOPATHY

The pathogenesis of idiopathic central serouschorioretinopathy is still incompletely understood.Ophthalmoscopic findings showing an accumula-tion of serous fluid in the subretinal space suggestdisturbance of the photoreceptors in the macula. Inpatients with idiopathic central serous chorioretin-opathy, Miyake and coworkers85 recently recorded a-and b-waves, as well as OPs, in the macular region,

using focal stimuli. They found reduced a-wave,

b-wave, and OPs, as well as prolonged implicit timesfor these ERG responses. Since the photoreceptorssubstantially contribute to the a-wave, their findingsupports the presence of dysfunctional photorecep-tors in this disease. Surprisingly, the b-wave and OPshad deteriorated even more severely than the a-wave(Fig. 8). Apparently, the functional disturbance oc-curs not only in the photoreceptors, but also, and

probably more severely, in the middle and inner ret-inal layers, as the b-wave and the OPs reflect activityof these layers. They suggest that their results cannotbe explained by receptor disorientation (Stiles-Craw-ford effect) or disturbance of photopigment regen-eration. They reexamined patients 25 months afterthe macular detachment and visual acuity resolved.They found that the a- and b-wave had recovered al-most to normal control levels. But the OPs remainedsmaller in the affected eye than in the fellow eye(Fig. 9). They conclude that the uncomplete recov-ery of the OPs indicates some subclinical abnormal-

ity in the middle and inner retinal layers.

Fig. 7. Top: Scotopic ERG responses to white and blue stimuli in a subject (AM) with chronic exposure to lead per inha-

lation. B-wave amplitudes are significantly reduced (left) and b-wave latency is significantly prolonged (right). Bottom:Photopic ERG responses to red light flashes. B-wave amplitudes are subnormal but within normal limits. B-wave latenciesare subnormal in the right eye and significantly increased in the left eye for lower flash intensities (right). For higher flashintensities, b-wave latencies are significantly increased in both eyes.


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If the focal ERG of Miyake and coworkers revealsobvious electrophysiologic damage to the outer andinner layers of the retina, the multifocal ERG alsoshould be promising. In a case study in our clinic, a22-year-old woman suffered from idiopathic central

serous chorioretinopathy 9 months prior to clinicaltesting in our department. Visual acuity was 20/20.Fluorescein angiography revealed a central blockingand two small defects of the RPE. In the multifocalERG, the foveal response was moderately reducedand the parafoveal responses were markedly re-duced. There was also a region with reduced ampli-tudes between the fovea and the blind spot, whichwas in good agreement with the perimetric results(Fig. 10). Asymmetric or focal impairment of the ret-ina due to idiopathic central serous chorioretinopa-thy can be well demonstrated by multifocal ERG

techniques.

UNCOMMON INFLAMMATORY DISORDERS WITH

MARKED ERG ABNORMALITIES

In some presumed inflammatory disorders, func-tional impairment of the retina is more apparent by re-ductions in ERG amplitudes than might have been an-ticipated from the extent of clinically apparent disease.Two such examples are birdshot chorioretinopathy101

and the multiple evanescent white-dot syndrome(MEWDS).56 There are marked abnormalities in thescotopic and photopic ERG in both birdshotchorioretinopathy39,61,97 and MEWDS.110


In global inflammatory disease, the ERG will paral-lel the funduscopically visible fundus changes. TheERG can be helpful in distinguishing chorioretinitis

from hereditary retinal degenerations (e.g., RP).

Fig. 8. Local macular ERGs in five representative patients with idiopathic central serous chorioretinopathy. The stimulusspot was 10 in diameter. Two different time constants (T.C.), 0.03 and 0.003 seconds, were used simultaneously. As com-pared with the normal fellow eyes (Right), the affected eyes (Left) show reduced amplitudes, particularly in the b-wavesand OPs, and delayed implicit times. (Reprinted from Miyake Y et al85 with permission of the Am J Ophthalmol.)


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There are uncommon disorders (birdshot chorioret-inopathy, MEWDS), in which the ERG is unexpectedlyabnormal. Detection of local inflammatory disease(e.g., idiopathic central serous chorioretinopathy) by

the ERG requires local measurements (focal ERG,multifocal ERG).

Cancer

CHOROIDAL MELANOMA

Malignant melanoma of the choroid is one of thefew primary eye diseases that is life threatening. Re-cent reviews are given by Shields107 and Foulds.36 Thesensitivity of the RPE and its transepithelial potentialto influences of the chemical milieu of the choroidand the outer retina make the transepithelial poten-

tial a likely indicator of nearby tumors. Whether the

malignant melanoma originates in the choroid or inthe RPE itself may make little difference in the re-sponsiveness of the transepithelial potential. A re-duction in the EOG L/D ratio in patients with malig-

nant melanoma was first reported by Ponte andLauricella95 and Bohar and Farkas.14 Subsequently,larger samples of patients were investigated, for exam-ple, 22 patients by Jones,59 54 patients by Staman,112

and 30 patients by Markoff.81 These studies all agreedthat the presence of malignant melanoma resulted inlarge reductions in the EOG L/D ratio, whether ornot retinal detachment was present and regardless ofthe size of the melanoma.27

CANCER-ASSOCIATED RETINOPATHY

Cancer-associated retinopathy (CAR) occurs most

often in association with small cell carcinoma of the

Fig. 9. Local macular ERGs in five patients in the convalescant stage of idiopathic central serous chorioretinopathy. Thecase numbers correspond to those used in Fig. 8. A- and b-waves in the affected eyes show nearly the same amplitudes asthose in the normal fellow eyes. The amplitudes of the OPs, however, are smaller than those in the normal fellow eyes.(Reprinted from Miyake Y et al85 with permission of the Am J Ophthalmol.)


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lung,116 but also with other types of neoplasia66,117

(for review, see Thirkill115). Vision abnormalities arefrequently the first sign of illness, which prompts thepatient to seek medical help. Complaints of flashinglights, loss of color vision, and night blindness arethe most common early signs leading to subsequentclinical examinations and tests that identify the

causal cancer. The underlying mechanism involves

inhibition of photoreceptor function with subse-quent decay probably caused by an immune responseto retinal-specific proteins.115 CAR is characterized byclinical, histopathologic, and electrophysiologic evi-dence of degeneration and loss of both rod and conephotoreceptors, with ERG a-waves and b-waves re-duced markedly in amplitude.55,103 However, by

means of the scotopic and photopic ERG, another

Fig. 10. Perimetric and multifocalERG results of the left eye of a 22- year-old woman with idiopathic cen-tral serous chorioretinopathy. (n)Static perimetric results (Tbingen Automated Perimeter 30). (o) Tracearray of 61 first-order kernel ERG waves from the same eye. (p) Re-sponse density plot of the same eyecalculated as scalar product. (Re-printed from Kretschmann U et al75

with permission of Klin Monatsbl Au-genheilkd.)


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type of dysfunction was found that selectively causescone dysfunction leaving the rods unaffected.24,79

MELANOMA-ASSOCIATED RETINOPATHY

Retinal dysfunction associated with malignantmelanoma (MAR), which is similar to that observed

in congenital stationary night blindness (CSNB), wasfirst described by Ripps and coworkers.99 Becausethe patient received vincristine chemotherapy, it wasreasonable to assume that vincristine contributed tothe development of the retinal dysfunctions. How-ever, the findings could be reproduced in patientswith cutaneous malignant melanoma who had notreceived vincristine chemotherapy.11,65

Alexander and coworkers reported a patient withmelanoma who had ERG changes similar to thoseobserved in the patients with CSNB, suggesting acommon underlying defect.2 The dark-adapted rodERG responses showed a selective reduction in theamplitude of the b-wave and an absence of OPs com-pared with the normal response. Both the a-waveamplitude and the a-wave implicit time were normal.The light-adapted cone ERG responses showed a se-lective reduction in b-wave amplitude and a diminu-ation of the OPs compared with the normal re-sponse. A-wave amplitude and a-wave implicit time were normal. To separate ON-components fromOFF-components, the investigators administeredlonger flash durations. They obtained a severely re-duced initial positive ON-component of the cone-ERG from their patient; the later positive compo-nent, representing a response to flash offset, wassimilar in both the patient and a representative nor-mal subject (Fig. 11).

As we know from the experiments of Bush andSieving with selective blockade of either the ON- orthe OFF-pathway, the depolarizing bipolar cells(DBCs) drive the ON-pathway and the hyperpolariz-ing bipolar cells (HBCs) drive the OFF-pathway.21

The DBCs appear to be the only type of bipolar cellthat subserves the mammalian rod pathway.26,106 Aselective reduction in the ON-response componentcould be explained by a postsynaptic defect in the

DBCs, which could cause such defects. The same siteof defect is suspected in CSNB.109


The EOG might be useful in the diagnosis of chor-oidal melanoma. The association of cancer withcompromised retinal function highlights the impor-tance of searching for occult malignancies in pa-tients with acquired visual problems and abnormalelectroretinographic findings who have no other oc-ular explanation for their symptoms. It can be diffi-cult to differentiate cancer-associated retinal dys-

function from the effects of chemotherapy.

Vitamin A Deficiency

ERG AMPLITUDE DECREASE DUE TO REDUCED

RETINOL BLOOD LEVELS

Any condition that interferes with ingestion, ab-sorption, storage, or transport of vitamin A (e.g., di-etary deficiency, liver disease, intestinal malabsorp-tion caused by abetalipoproteinemia42) can lead to adeficiency in target tissues. As soon as the bloodlevel of retinol falls, the level of rod visual pigment(rhodopsin) also falls, and reciprocally, the visualthreshold rises, thus leading to night blindness.30

Electroretinographic findings show reduced rod andcone responses with normal implicit times,92 withthe rod ERG affected before the cone ERG.41 Afterstarting vitamin A supplementation there is a com-

plete recovery in the electroretinographic findings.92

Fig. 11. ERG responses (UIC) to flashes of a constant lu-minance (3.7 log cd/m2) but of different durations in a

melanoma patient (thick tracings) and a representativenormal subject (thin tracings). Responses of the two subjects are positioned vertically such that they coincide attime of flash onset. Flash durations in milliseconds are in-dicated at the right of each pair of waveforms. Responseswere obtained against a rod-desensitizing adapting field of2.1 log cd/m2. (Reprinted from Alexander KR et al2 withpermission ofInvest Ophthalmol Vis Sci.)


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In a study of chronic alcohol-abusive patients withliver cirrhosis, a reduction of ERG amplitudes wasobserved without an increase of latencies. This wasmainly ascribed to vitamin A deficiency and was re-versed within 1 month by vitamin A substitution.102

DEFECTIVE RETINOL-BINDING

PROTEIN SYNTHESIS

Most of the bodys retinol is stored in the liver inesterized form. The release from the hepatocytes re-quires the association of retinol with retinol bindingprotein (RBP). Seeliger and coworkers report thephenotype of two sisters with a compound heterozy-gous mutation in the gene for serum RBP.105 Bothexhibited extinguished rod ERGs with either normalor reduced cone ERGs. Since acne was the onlysymptom besides night vision problems, the mark-edly abnormal ERG led to the diagnosis.


The rod ERG is indicated when any form of vita-min A deficiency is suspected. The effect of treat-ment (e.g., vitamin A supplementation) on retinalfunction can be monitored by the (scotopic) ERG.

Photochemical Damage

It is generally accepted that there are three differ-ent mechanisms of light damage.46 When the light is very intense, in the order of terawatts per square

centimeter, it will cause an acoustic shock wave inthe retina. This so-called mechanical damage can becaused only by very strong lasers, such as the YAG la-ser, which is commonly used in ophthalmology.Lower intensities, down to about 10 watts per squarecentimeter, cause thermal damage, in which the

temperature of the retina rises to the point at whichproteins denaturate and the tissue cannot properlyfunction. At lower intensities, photochemical dam-ages can occur. Damage assessed by means of fun-duscopy and densitometry is most extensive 2 daysafter light exposure.74 The intensity of transition be-tween thermal and photochemical damages de-pends on several factors, the most important onesbeing the wavelength of the light and the size of theexposed area. The transition between thermal andphotochemical damage is often not sharp, however,since photochemical damages are enhanced by tem-perature rises. In photochemical damage, the light isabsorbed by a pigment, which starts a chain of chem-ical reactions presumably through radicals eventu-ally leading to breakdown of retinal structures.73

PHOTOCHEMICAL DAMAGE TO DIFFERENT

PHOTORECEPTOR TYPES

Kremers employed the intraretinal (local) ERG toestablish the threshold for changes in the ERGshortly after exposure to intense white lights inmacaque monkeys.73 With use of the local ERG, it was possible to limit the damage to small retinalpatches, and with the use of selective chromatic ad-

aptation and dark adaptation it was possible to assess

Fig. 12. Response amplitudes as a function of stimulus in-tensities for S-cone a- and b-waves (stimulus wavelength450 nm) and for L-Mcone a- and b-waves (550 nm). Re-sponse amplitudes were measured before () and after(") a 600 sec, 87 W/cm2 exposure. The exposure de-creased only the S-cone response amplitudes. (Reprinted

from Kremers J73 with permission.)

Fig. 13. Relative response decrease (dR (Rpre Rpost) /Rpre) of the different photoreceptor systems as function ofthe cumulative exposure time to exposures of 87 W/cm2.The data originate from the same experiment describedin Fig. 12. All systems show decreasing responses when ex-posure time increases. ERG responses of the S-cones weremost vulnerable to the exposures, followed by those of therods. The L- and M-cones were least vulnerable. (Re-

printed from Kremers J73 with permission.)


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the relative vulnerability of different photoreceptorsystems. The amplitude decrease was about 20% forthe S-cones and virtually zero for the L-Mcones(Fig. 12).

Kremers also studied ERG responses after severalexposures. Fig. 13 shows the response amplitude de-

crease as a function of the cumulative exposuretime. After the first exposure of 200 seconds, theS-cone system showed considerably reduced re-sponses (60%); the amplitudes of the rod responseswere also reduced (35%) and the L-Mcone systemshowed a marginal reduction of 20%. After an addi-tional exposure of 400 seconds, cone and rod re-sponses were further reduced, but L-Mcone re-sponses were back to baseline level. With additionalexposures, further reduction in S-cone and rod re-sponses occurred. Until after the fourth exposure,S-cone responses were no longer recordable. L-Mcone response also showed a tendency to be re-duced, but these systems did not reach the reduc-tion criterion.

Several aspects of the ERG changes resemble thepsychophysical observations made by Kitahara andcoworkers,68 including the ERG changes directly af-ter exposure to bright white light, the vulnerabilityof the S-cones, and the total reversibility after lim-ited exposure time, but only partial recovery afterextended exposures. These early ERG changes arepossibly the electrophysiologic equivalent of psycho-physical detectable disturbances which occur di-rectly after exposure to bright light.23,48,119

CONSEQUENCES FOR OPHTHALMIC SURGERY:

PHOTOCHEMICAL DAMAGE BY THE

OPERATING MICROSCOPE

Lessel and coworkers77 performed an electrophysi-ologic study on a series of 30 patients 6 months aftercataract surgery. In 15 patients, extracapsular extrac-tion (ECCE) was performed with light intensitiesduring surgery of 3.47.3 milliwatts per square centi-meter. Fifteen patients underwent intracapsular(ICCE), during which the light intensities were substan-tially lower (0.83.7 microwatts per square centimeter).Significantly reduced amplitudes of the photopic ERGb-waves and significantly reduced L/D ratios of theEOG were found in the ECCE-group, whereas there wasno such change in the ICCE-group. These findings indi-cate light-induced damage by the operating micro-scope, which is probably caused by reduced number offunctioning cones and a deterioration of the RPE.

Summary

We have presented a brief review of electrophysio-logic findings in acquired retinal disorders, includ-

ing diabetic retinopathy, glaucoma, inflammation,

vitamin A deficiency, cancer, photochemical dam-age, hepatic retinopathy, and damage caused bychronic lead exposure. Information obtained byadministration of ERG and EOG can assist in theevaluation of disorders at presentation and in thefollow-up during and after treatment. We conclude

our discussion of each entity with a section on theclinical usefulness of testing in that disorder.

Method of Literature Search

The literature search was performed using the Sil- ver Platter MEDLINE database from 1966 to 1999.Primary search terms were electrophysiology OR elec-troretinography OR electroretinogram ORERG OR elec-trooculography OR electro-oculography OR electrooculo-gram OR electro-oculogram OREOG in combinationwith the subheadings agingAND retin*, diabeticORdiabetesAND retinopathy, glaucoma, lead, hepaticAND

retinopathy, chorioretinitis, cancerAND retinopathy, vita-minAND retin*, light and damage. Major current jour-nals in ophthalmology, vision research, and neuro-science were used for additional information. Thereferences contained in these articles were also re-viewed and were selected if they included importantelectrophysiologic findings. English abstracts fromnon-English and non-German articles were used.Materials from current conferences and symposia onelectrophysiology of vision were also used. Twobooks covered a broad range of the discussed topics:Principles and Practice of Clinical Electrophysiology of Vi-

sion (Heckenlively JR, Arden GB, eds) and Electro- physiological Testing in Disorders of the Retina, OpticNerve, and Visual Pathway(Fishman GA and Sokol S,eds.). Given the broad scope of the topic, however,from the initial set of citations, the references usedas sources for this review were chosen for inclusionor exclusion based on primary focus of the report onelectrophysiological (patho-) mechanisms, clinicalrelevance and originality.

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The authors thank J. Kremers for discussion, G. Drasch for thecontribution concerning lead toxicity, and R. Hofer for technicalassistance.

This work was supported by fortne-Grant 707-0-0 (Tbingen,Germany) to HS.

The authors have no commercial or proprietary interest in anyproduct or concept discussed in this article.

Reprint address: Dr H. P. N. Scholl, Department of Pathophysi-ology of Vision and Neuro-Ophthalmology, University Eye Hospi-tal, Schleichstrasse 12-16, 72076 Tbingen, Germany. E-mail:[email protected]

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