IX PRINCIPLES OF CLINICAL TESTING AND EVALUATION OF VISUAL DYSFUNCTION FROM DEVELOPMENTAL, TOXIC, AND ACQUIRED CAUSES

N electrophysiological and psychophysical measurements allow an assessment of the health of every segment of the visual system from retinal pigment epithelium (RPE) to the visual cortex. An understanding of each test and their interrelationships assists the diagnosis of a number of diseases.19 This is facilitated by the layered nature of the visual system and the assignment of electrical potentials from specific tests to particular cell layers.

Because most evoked responses stimulate the entire retina, regional loss of function might not be noticeable in the test results. By adjusting stimulus conditions and techniques of recording, a representation of the sequence of events along the visual pathway can be recognized, and the cone and rod systems can be measured separately. If the stimulus has an abrupt onset (as is usual), the delay between stimulus and response indicates additional signs of dysfunction that are not elicitable by other methods (e.g., psychophysics).

An understanding of the neuronal response order (from photoreceptor to visual cortex) and the interrelationships of the responses is important, since an abnormality at a lower level will usually give an abnormal response farther along the sequence chain, and misleading interpretations can be made if abnormal test results are inappropriately taken out of context. For instance, an abnormal visual evoked cortical potential (VECP) might be found in a number of retinal dystrophies and could be misinterpreted if an electroretinogram (ERG) is not performed to confirm that the defect is retinal, not in the optic pathway. Therefore, after taking an initial history from the patient, the tests to be performed on the patient should be ordered in such a manner as to maximize the success in diagnosing the level of dysfunction. For instance, if the patient has an abnormal ERG, then a VECP is seldom necessary. In practice, this approach must also be modified to maximize patient flow; in some clinics, tests are scheduled on different days, and patients who require further tests are recalled. In other cases, a VECP will be done before the ERG because the latter requires pupillary dilation and the patient cannot be recalled.

While the retina is composed of a complex neuronal matrix with both vertical and horizontal components, it is possible to detect abnormalities of the rods and cones, the photoreceptor layer generally, the middle retina, and the gan-

glion cell layer (table 49.1). If the central retina is reasonably healthy, then the VECP can detect abnormalities in the conduction of retina-generated signals to the visual cortex.

A directed approach to visual system evaluation is especially important for disorders that either have specific sites that have been shown to be abnormal on histopathology of the suspected disease or are believed to be abnormal on the basis of clinical appearance or other tests. For example, the ERG is well suited to evaluate generalized photoreceptor disease such as retinitis pigmentosa (RP) because the response is a mass one that is initiated by photoreceptors. Widespread photoreceptor dysfunction and loss are early features of RP. Best’s macular dystrophy, on the other hand, presumably has a diffusely abnormal RPE, with inclusions of lipofuscin on histopathology but normal photoreceptors (except in regions of RPE loss or scarring). Therefore, it is not surprising that the ERG is normal in Best’s dystrophy but the electro-oculogram (EOG), which tests potentials generated by the RPE, is abnormal.

While table 49.1 is helpful in forming a perspective on how the various tests can be used to evaluate cellular layers or “minisystems” in the visual system, it is useful, despite the risk of redundancy, to tabulate each test with the information that can be expected from doing it. These are presented in table 49.2.

The retinal pigment epithelium

The two main tests for evaluating the RPE are the EOG and the c-wave of the direct-coupled electroretinogram (DCERG) (see chapter 42). The EOG electrodes, placed on the inner and outer canthi of each eye, measure the standing potential of the pigment epithelium as the pigment fixates regularly between two points 30 degrees apart. This standing potential normally fluctuates but decreases with dark adaptation; subsequent light adaptation causes a large slow oscillation increase. The maximum value measured during light adaptation divided by the smallest dark-adapted value represents the Arden light peak/dark trough ratio, which is widely used to assess RPE function.

In certain disorders, the slow oscillations of the EOG can be abnormal to varying degrees, while the ERG is invariably

normal or near normal. Examples of such diseases would include Best’s vitelliform macular dystrophy, Stargardt’s disease or fundus flavimaculatus, dominant drusen, and pattern dystrophy of the RPE. Of interest, the fast oscillations of the EOG are preserved in Best’s macular dystrophy, even at a time when the slow oscillation is markedly abnormal.18

In other disorders, such as cone dystrophy, the EOG is normal, but the ERG is abnormal. In some forms of cone dysfunction, the standing potential of the eye may be subnormal even though the light-induced slow rise of this potential is of a normal absolute value. This results in a light- to-dark ratio for the slow oscillation that is greater than normal. Supernormal EOG light-to-dark ratios have been reported in X-linked cone dystrophy and cone dysfunction secondary to digoxin retinal toxicity.19,21

In certain subtypes of RP, the slow oscillations of the EOG may be relatively preserved. For example, type I RP, which is associated with early diffuse severe rod dysfunction, is usually associated with an abnormal EOG slow oscillation early in the disease.18 On the other hand, type II RP, which is associated with regional loss of rod and cone function (often a cone-rod loss pattern) is more likely to have preservation of the EOG slow oscillation. Of importance with

regard to the site of pathology, the fast oscillations of the EOG appear abnormal earlier than do the slow oscillations of the EOG in some forms of RP.18

The large c-wave that is found with d.c. ERG testing correlates highly with the EOG Arden ratio when measured concurrently in patients in a number of different diseases.16 Current techniques for measuring the c-wave are difficult to employ in the clinical setting, so the test is not widely used, even though it is a good measure of RPE function.

The early receptor potential

The early receptor potential (ERP) is evoked by an intense stimulus flash. It occurs with no detectable latency and precedes the a-wave. The initial corneal positive R1 has been correlated with the conversion of lumirhodopsin to metarhodopsin I.15 The following negative R2 corresponds with the conversion of metarhodopsin I to metarhodopsin II.6 The corneal voltage results from charge displacement across the outer limb membrane due to changes in the conformation of visual pigment. Capacitative current then flows from (or to) the inner limb. Cones contribute disproportionately to the ERP, since more of their pigment is present in the true surface membrane. In humans, Goldstein and

Berson found that of the total ERP amplitude, 60% to 80% was generated by cones and 20% to 40% by rods.10 To record the ERP, investigators have used a lens filled with saline solution coupled to the electrode in a side arm that is covered with black tape to eliminate the photovoltaic artifact that occurs.4 Because there is no neural amplification, flashes that elicit measurable ERPs bleach a considerable proportion of the pigment in the retina, and the interstimulus intervals should be at least several minutes. The ERP has been tested in a number of retinal dystrophies, and while delays have not been found, amplitude reduction has been observed that corresponds to a decrease in the quantity of visual pigment. Several types of RP have shown quicker regeneration time than normal.3 The clinical usefulness of the ERP is limited, since the test has not been shown to be diagnostic of any particular disease and can be performed only in a limited number of research centers. A more extensive discussion of this topic can be found in chapter 40.

Electroretinogram

A number of studies5 have been performed that correlate the mass ERG response to intracellular and intercellular retinal recordings, and there is general agreement that the a-wave is generated by the receptor layer and the b-wave is generated by Müller cells as a sequela to bipolar cell activity. While there is a temptation to think simplistically about origins of the ERG responses, various studies suggest complicated interactions involving inhibitory and excitatory cells affecting the receptor-bipolar-ganglion cell junctions and cell bodies.

Electroretinographic waveform changes characteristic of disease

There are several changes in waveform that, when present, greatly help in arriving at a diagnosis. These include a loss of oscillatory potentials, a negative response, that is, a large a-wave and reduced b-wave (table 49.3), the combination of a very abnormal photopic ERG with a normal rod ERG, and a highly abnormal cone and rod ERG. Specific loss of oscillatory potentials has been notably associated with X- linked and autosomal-recessive congenital stationary night blindness, vascular ischemia, and occasional cases of cone dysfunction and retinotoxicity, for example, to ethambutol. The negative waveform, seen under test conditions of dark adaptation when a bright flash stimulus is used, is a wellformed negative a-wave and a b-wave that may reach the isoelectric point. Negative a-waves are most commonly seen in cases of juvenile retinoschisis and congenital stationary night blindness, but other disorders are in the differential diagnosis and are presented in table 49.3. Historically, the term negative waveform has been applied to the scotopic bright-

flash ERG, but many disorders can produce such a waveform in the photopic ERG as well.

Various degrees of negativity may be found. Thus, in some cases of retinoschisis and congenital night blindness, the b- wave is entirely absent, and the ERG consists of a PIII only. There is considerable amplification at the photoreceptorbipolar synapse, so small photoreceptor responses produce large b-waves, and the latter “saturate” for flashes of intensity that are sufficient to evoke a measurable a-wave. The isolated PIII response is thus only seen with bright flashes under scotopic conditions.

Inferences about the site of pathological lesions can be made by considering at what level the dysfunction appears to occur and by comparing various tests of different levels. Thus, in juvenile retinoschisis, the patient typically has a large a-wave and a poor b-wave, which suggests that the dysfunction lies after the photoreceptor layer. Likewise, in congenital stationary night blindness, which also has a large negative wave (see tables 49.3 and 49.4), the rod ERG varies from very small to nonrecordable, while the dark-adapted bright-flash ERG has a large a-wave and a poor b-wave, again suggesting a problem in the rod system distal to the rod photoreceptor. Miyake covers the distinguishing features of the various forms of CSNB in chapter 74. A poor cone response (either flicker or photopic ERG) in the face of a full visual field and good response is typically seen in cone degenerations or dystrophies.

A comparison of tests is often useful in localizing the level of the visual system that is primarily affected. Table 49.4 lists multiple examples of this phenomena. An abnormal EOG and a normal ERG suggest RPE dysfunction, such as in Best’s disease. A normal ERG with an abnormal VECP (assuming macular function is present) strongly suggests an optic neuropathy or retrochiasmal problem. An abnormal pattern ERG in the face of a normal VECP and flash ERG suggests ganglion cell dysfunction, as might be seen in early glaucoma, and also occurs in conditions such as Stargardt’s disease before visual acuity is noticeably depressed.

Interpretation of the VECP and ERG may help to differentiate primary optic atrophy from optic atrophy secondary to retinal degeneration, but occasionally, this comparison can be difficult in situations such as long-standing advanced glaucoma, in which results of both tests may be abnormal. Also, some disorders, such as dominantly inherited optic atrophy, may have mildly abnormal ERGs as well as abnormal VECPs. Nevertheless, the combination of VECP and ERG is very useful to determine the site of pathology, especially in blond fundi in the face of subnormal visual acuity.

For a limited number of indications, the combination of VECP and pattern ERG (PERG) is extremely helpful. Disorders that produce dysfunction of ganglion cells but good acuity, such as early glaucoma, are most likely to produce

abnormalities of the PERG with lesser defects of normal VECPs. This results from the fact that relatively few intact macular fibers are needed to produce an intact VECP, whereas current studies suggest that ganglion cell responses to the PERG may be abnormal early in the course of the disease.

Additional information about the RPE/receptor disease can be obtained by performing both EOGs and ERGs on the same patient. In some disorders, both results will be abnormal. In advanced and late stages of RP, both the ERG and the slow oscillation of the EOG will be markedly abnormal. However, in very early RP, the fast oscillations of the EOG may be more abnormal than the slow oscillation.

A distinctive pattern of abnormality that stands alone in electrophysiology is the abnormal misrouting of temporal retinostriate projections as detected by the VECP in oculocutaneous and ocular forms of albinism.1 Testing must include measurements of cortical potentials over both the right and left occipital regions to obtain the required information. For reasons that are at present unclear, temporal

retinal fibers that should pass to the ipsilateral visual cortex decussate in the chiasm in albinos to project the opposite visual cortex. Thus, patients with albinism show a deficiency of ipsilateral or uncrossed responses. This pattern of abnormal retinocortical visual representation is so characteristic of all types of albinism that it is included in the operational definition as to which disorders should be called albinism and which represent only a variable hypopigmentation state from other causes.

The best stimulus to elicit VECR, for detecting asymmetry of retinocortical projections appears to be the onset/ disappearance of large patterns against a homogeneous gray field of equal mean luminance rather than flashes or pattern reversal.7 The best way of demonstrating the abnormal cortical projections is an examination for asymmetry of the left-minus-right occipital VECP signals as stimulated through the right and left eyes. This avoids problems with interpretation of hemispheric differences related to ocular dominance or individual differences in cortical topography.

Alternately, monocular VECP testing with bilateral occipital recording may demonstrate disproportionate uncrossed nerve fibers characteristic of all types of albinism.

Correlation of test results with clinical findings

There is often a misconception that individual electrophysiological tests are always diagnostic and can be interpreted in isolation without other tests and often without regard to the ocular findings. Where there are some characteristic electrophysiological tests for specific disease states, the vast majority of patients need a combination of tests selected to properly arrive at a diagnosis. A few patients will present

who have extensive testing but for whom a diagnosis is not found. To better define these patients, serial testing needs to be performed, often over years, in a search for diagnostic changes or for progression or stability in the disease; this allows for sensible counseling as well as placing the patient in a diagnostic category. Most patients accept the necessity to do serial testing if the rationale for evaluating the possibility of progression is explained.

Table 49.4 gives examples of ERG patterns that, when correlated with the clinical findings, are diagnostic of specific diseases or disorders. It is also important to correlate the clinical findings with the electrophysiological and psychophysical data; otherwise, a patient’s condition might be

misinterpreted. More frequently, the opposite occurs; that is, incorrect diagnoses are made because electrophysiological testing is not employed and clinical signs or symptoms suggesting a dystrophic or visual pathway disease are misinterpreted or neglected. Classic examples of conditions that are difficult to detect clinically but easy to diagnose electrophysiologically are RP sine pigmento, cone dystrophies with or without macular involvement, congenital stationary night blindness, Best’s macular dystrophy, optic neuropathies without disk pallor, and hysterical amblyopia.

Kinetic visual fields correlating with the ERG and retinal findings often give a definitive answer as to the type of problem that a patient has; this is particularly relevant in cases of cone-rod dysfunction (with or without a bull’s-eye macular lesion) in which the photopic b-wave is proportionately more affected than the rod signal but both are abnormal.

Patients with the cone-rod ERG pattern dysfunction may have a variety of problems, including a progressive disorder similar to RP, a cone degeneration with a subnormal rod response, occasionally juvenile retinoschisis (although the negative wave is present), advanced fundus flavimaculatus with severe macular loss, and cone-rod dystrophy.11,12

A proportion of cone-rod dystrophies in which the cone ERG is disproportionately depressed follow a course similar to typical RP (rod-cone degeneration) and exhibit, at some stage, alterations of the peripheral visual field, often with a ring scotoma. Others progress clinically with a pattern of change like that in cone degeneration or dysfunction and have (until very late in the condition) full peripheral visual fields and no ring scotomas but may have central scotomas. One of the more useful aspects of serial visual field testing of many patients with retinal dystrophies, particularly RP, is to reassure the patient that the condition is not progressing rapidly. Anxiety levels are usually high in these patients, and annual fields showing little change reinforce the concept that the patient has a chronic disease and that sudden blindness is very unlikely. A patient who is demonstrating rapid change should be carefully evaluated for the possibility of cystoid macular edema, hyperthyroidism, uveitis, serious systemic disease, and drug (or, rarely, light) toxicity. Occasional patients with RP will demonstrate reversible visual loss during episodes of viral or bacterial systemic or respirator infections. A few patients will complain of visual loss during pregnancy, but in most patients, this appears to be temporary.13

Dark-adaptation testing has traditionally been performed by measuring the threshold of vision after a preadapting bleaching with bright light. This must be done to standardize the test. Most laboratories use the Goldmann-Weekers dark adaptometer and a nonstandarized technique to determine the white light threshold of perception to a small light presented 10 degrees eccentrically. In normals, the threshold-time relationship is biphasic. If the preadapta-

tion bleaches more than 50% of the rhodopsin, the scotopic system will take 10 minutes or more to become more sensitive than the photopic system. Therefore, after a rapid initial dark adaptation of 1–3 minutes, “cone” thresholds determine sensitivity until the cone-rod break, after which rods develop around 3.5 log unit greater sensitivity. More sophisticated dark adaptometers are automated and test various points in the peripheral retina; they employ red and bluegreen test objects so that the relative sensitivities of the scotopic and photopic systems can be determined at various times during dark adaptation.9,14

In a number of patients with various types of retinal dystrophy, patients will relate a history of night blindness such that there are expectations, when psychophysical testing is done to measure rod sensitivity, that it should be very abnormal. Frequently, there is little correlation between final rod thresholds after 40 minutes of dark adaptation and the subjective complaint. Many patients with RP feel that their night vision is “fine,” since it has not changed from childhood. It is useful to take measurements from at least two or three different retinal areas and take care to avoid known scotomas found on visual field testing. Patients with type I RP will typically have at least 3.5 log units of elevation of the final rod threshold, while patients with type II RP often have 2.5 log units or less. Patients with type II can have more severe loss in more advanced stages in which the visual field is less than 10 degrees.

REFERENCES

1.Apkarian P, Reits D, Spekreijse H, van Dorp D: A decisive electrophysiological test for human albinism. Electroencephalogr Clin Neurophysiol 1983; 55:513–531.

2.Apkarian P, Spekreijse H, van Swaay E, van Schooneveld

M:Visual evoked potentials in Prader-Willi syndrome. Doc Ophthalmol 1989; 71:355–368.

3.Berson EL: Electrical phenomena in the retina. In Moses RA, Hart WM (eds): Adler’s Physiology of the Eye. St. Louis, CV Mosby, 1987, pp 541–542.

4.Berson EL, Goldstein EB: Recovery of the human early receptor potential in dominantly inherited retinitis pigmentosa. Arch Ophthalmol 1970; 83:412.

5.Brown KT: The electroretinogram: Its components and their origins. Vision Res 1968; 8:633–677.

6.Cone RA: Early receptor potential: Photoreversible charge displacement in rhodopsin. Science 1967; 155:1128.

7.Creel D, Spekreijse H, Reits D: Evoked potentials in albinos: Efficacy of pattern stimuli in detecting misrouted optic fibers.

Electroencephalogr Clin Neurophysiol 1981; 52:595–603.

8.Enoch JM, Fitzgerald CR, Campos EC: Quantitative Layer-by- Layer Perimetry: An Extended Analysis. New York, Grune & Stratton, 1981.

9.Ernst W, Faulkner DJ, Hogg CR, Powell DJ, Arden GB, Vaegan: An automated static perimeter/adaptometer using light emitting diodes. Br J Ophthalmol 1983; 67:431–442.

10.Goldstein EG, Berson EL: Rod and cone contributions to the early human receptor potential. Vision Res 1970; 10:207.

11.Heckenlively JR: Cone-rod dystrophy. Ophthalmology 1986; 93: 1450–1451.

12.Heckenlively JR, Martin DA, Rosales TR: Telangiectasia and optic atrophy in cone-rod degenerations. Arch Ophthalmol 1981; 99:1983–1991.

13.Heckenlively JR, Yoser SL, Friedman LH, Oversier JJ: Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol 1988; 105:504–511.

14.Jacobson SG, Voigt WJ, Parel JM, Ets-G I, Apáthy PP, Nghiem-Phu L, Myers SW, Patella VM: Automated lightand dark-adapted perimetry for evaluating retinitis pigmentosa. Ophthalmology 1986; 93:1604–1611.

15.Pak WL: Some properties of the early electrical response in the vertebrate retina. Cold Spring Harbor Symp Quant Biol 1965; 30:493.

16.Röver J, Bach M: C-wave versus electrooculogram in diseases of the retinal pigment epithelium. Doc Ophthalmol 1987; 65: 385–392.

17.van Lith GHM: The macular function in the ERG. Doc Ophthalmol Proc Ser 1976; 10:405–415.

18.Weleber RG: Fast and slow oscillations of the EOG in Best’s macular dystrophy and retinitis pigmentosa. Arch Ophthalmol 1989; 107:530–537.

19.Weleber RG, Eisner A: Retinal function and physiological studies. In Newsome DA (ed): Retinal Dystrophies and Degenerations. New York, Raven Press, 1988, pp 21–69.

20.Weleber RG, Pillers DM, Hanna CE, Magenis RE, Buist NRM: Åland Island eye disease (Forsius-Ericksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness. Arch Ophthalmol 1989; 107:1170–1179.

21.Weleber RG, Shults WT: Dioxin retinal toxicity: Clinical and electrophysiologic evaluation of cone dysfunction syndrome. Arch Ophthalmol 1981; 99:1568–1572.

T the electroretinogram (ERG) has long been reported to be reduced in highly myopic eyes. The first report of ERG changes in myopia is usually attributed to Karpe,8 who reported abnormal ERGs in four eyes with high myopia. Several early reports on the ERG in myopia showed that ERG amplitudes were generally within normal limits up to 8 diopters of correction provided that there were no degenerative alterations in the retina but were abnormal with more severe myopia and associated retinopathy.1,4,5,7 There was also some evidence in the early literature suggesting that photopic responses were affected earlier, and possibly to a greater degree, than scotopic responses,1,2 although this observation has not been replicated in subsequent studies. With the development of more sophisticated and sensitive recording techniques, ERG abnormalities have been observed with less severe myopia.

Myopia is generally associated with change in eye shape resulting from elongation of the optic axis. Several studies have shown that ERG amplitudes are inversely proportional to axial length.15,16,21 Pallin15 demonstrated a significant negative correlation between ERG b-wave amplitude and the length of the optic axis, which was measured with ultrasonography. This study also demonstrated a high positive correlation between refractive error and the length of the optic axis (figure 50.1), with b-wave amplitudes higher in hyperopic and emmetropic eyes than in myopic eyes. Sex differences in ERG amplitudes have also been attributed to gender differences in average axial lengths.15 The dependency of ERG amplitudes on axial length was confirmed in subsequent studies,16,21 although the shape of the posterior segment, rather than the size and axial length alone, appeared to be the critical determinant of the saturated amplitude in a study reported by Chen et al.3

Some studies have reported selective losses in the b-wave of the electroretinogram in myopia, a finding that would imply differential effects on signal transmission from the photoreceptors to the proximal retina. However, deficits at the level of the b-wave seem to be more common in patients with high myopia who also have chorioretinal degeneration, atrophy, and thinning of the posterior sclera.2,17 Perlman et al.16 reported that all myopes demonstrate subnormal amplitudes but a normal waveform morphology, defined by a normal ratio between a- and b-wave amplitudes. However,

the characterization of ERG responses in hypermetropic eyes in the Perlman et al.16 study was more complicated. While all myopic eyes had a- to b-wave amplitude ratios that were within normal limits despite generalized amplitude reductions, hypermetropic eyes had a- to b-wave amplitude ratios that were either subnormal, normal, or hypernormal. For example, the group of patients with subnormal a- to b- wave amplitude ratios was characterized by a relatively large a-wave and a subnormal b-wave, whereas the reverse applied to the group with hypernormal a- to b-wave amplitude ratios. These findings in the hypermetropic eyes were consistent with variable effects on the transmission of signals from the outer retina. However, no definite relationship was found between axial length of the eye and the a- to b-wave amplitude ratios, although there was an inverse relationship between axial length and the amplitude of the dark-adapted ERG evoked by a dim stimulus within each group. Westall et al.21 did not show a selective loss of b-wave amplitude across a broad range of refractive error in patients who were carefully screened to exclude pathological defects.

Previous studies have reported a selective loss of shortwavelength cone (S-cone) spectral sensitivity and reduced cortical evoked potentials to short-wavelength light in myopia.10,11 To investigate the retinal contribution to the S-cone deficits that had previously been documented, Yamamoto et al.22 recorded cone-mediated ERGs to different chromatic stimuli in myopic and normal eyes to elicit short-wavelength-sensitive (S-), and mixed long- (L) and middle- (M) wavelength-sensitive responses. The S-cone and L,M-cone b-wave amplitudes decreased progressively with increasing myopia and were significantly lower in high myopia compared with emmetropic eyes. The S-cone and the L- and M-cone ERGs were almost equally affected in the myopic eye, with S-cone function decreasing at a slightly slower rate compared to L,M-cone ERGs as refractive error increased. These results suggest that the reduction of S-cone sensitivity may originate from inner retinal or higher-order changes that would not be reflected in the conventional ERG.

Westall et al.21 performed an elegant study investigating the relationship between axial length, refractive error, and ERG responses. The extensive ERG protocol that was used included stimuli that conformed to the standards set forth by

F 50.1 The relationship between refractive error (in diopters of correction) and the length of the optic axis measured with ultrasonography. (Data from Pallin O.15)

the International Society for Clinical Electrophysiology of Vision, which was the first study to have done this. ERGs from 60 subjects were recorded with varying degrees of myopia but without evidence of myopic retinopathy. The study revealed a significant difference between subjects with high myopia and subjects with small refractive error for Vmax, the maximum saturated amplitude, the b-wave of the cone response, and the summed dark-adapted oscillatory potentials. A linear reduction in the logarithmic transform of the ERG amplitude with increasing axial length was demonstrated (figure 50.2). However, there were no differences in the implicit time of peak components, in the ratio of b- to a-wave amplitude derived from the maximal response, and in the semisaturation intensity estimated from the Naka-Rushton fit to the rod intensity series. In addition, they show relatively larger attenuation of later than earlier photopic oscillatory potentials, which suggests anomalies in pathways beyond the photoreceptors, possibly in the OFFbipolar cell pathway in eyes with progressively greater myopia.

The finding of reduced ERG amplitudes in myopia using conventional full-field stimulation has also been reported when only the macula or adjacent regions are tested. Ishkawa et al.6 examined the relationship between the amplitude of the photopic ERG recorded from the macula (focal ERG) and the degree of myopia. The amplitudes of the a- and b-waves of the focal ERG were significantly smaller than those of normal eyes, and the amplitudes were inversely proportional to the degree of myopia. The abnormal amplitude was interpreted by the authors to suggest a reduction in the number of macular cones that were contributing to the signal. More recently, Kawabata and Adachi-Usami9 investigated local retinal function in patients with various degrees of myopia who had undergone multifocal electroretinography (mERG). In the mERG recording tech-

F 50.2 ERG amplitude plotted against axial length. The y- axis shows the log ERG amplitude and the x-axis the axial length of the eye. Crosses represent individual data points. Regression lines (thick lines) and inner and outer ranges (thin lines) represent the expected value (from regression) plus and minus two standard deviations. Regression equations and R2 values are shown for Vmax (A), b-wave amplitude of the cone response (B), and the sum of the dark-adapted oscillatory amplitudes (C). (Data from Westall CA, Dhaliwal HS, Panton CM, et al.21)

nique, small areas of the retina are stimulated simultaneously and local contributions to a massed electrical potential are extracted from a continuously recorded ERG (see chapter 17). The technique permits the mapping of the topography of local retinal function. Again, amplitudes were reduced as refractive error increased, the rate of change being slower for N1, the first negative peak of the mERG waveform, than for P1, the first positive peak. The latencies of N1 and P1 were also delayed, but the rates of change were more similar for each component in comparison to the amplitude parameter. What was particularly interesting about this study is the selective loss of function in more peripheral retinal regions in the myopic groups, as evidenced by the more rapid loss of local amplitudes in the parafoveal

F 50.3 A, Multifocal electroretinographic topographies (three-dimensional view). The response densities (nV/degree2) decreased in all measured retinal fields as the refractive errors increased. B, Summed responses from 103 individual hexagons. N1 and P1 amplitudes of the summed response decreased as the refractive error increased. Both L1 and L2 latencies for high myopia were significantly delayed in comparison to those of emmetropia/low

areas (figure 50.3). This finding suggests that peripheral cones may be more sensitive to changes in eye shape produced by myopia, perhaps related to a more rapid change in the density of cones in these areas.

Implicit time of ERGs are generally within normal limits with high myopia. Perlman et al.16 reported normal implicit times for both darkand light-adapted responses. Lemagne et al.13 also reported normal implicit times for rod-mediated responses to a single flash after 20 minutes of dark adaptation. Cone ERG implicit times to white flashes have been reported to be normal in patients with refractive errors ranging from -5.0 to -10 diopters,12 and cone ERGs to chromatic stimuli have also been reported to be within normal limits.22 In a group of patients with gyrate atrophy and high myopia, implicit times were normal or mildly elongated,20 and in a complete form of congenital stationary night blindness, implicit times have been reported to be within normal limits in patients with a mean of -8.0 diopters of myopia.14 Ishikawa et al.6 also reported normal implicit time of macular focal ERGs in eyes showing only tigroid fundus, but those associated with posterior staphyloma involving the macula were significantly delayed. Kawabata and Adachi-Usami9 reported mildly delayed latencies for the

myopia. C, Summed responses from six concentric rings centered on the macula. Response amplitudes were suppressed to a greater degree in the more peripheral rings in high myopia. D, Summed responses over four quadrants (superior-nasal, superior-temporal, inferior-nasal, and inferior-temporal regions). (Data from Kawabata H, Adachi-Usami E.9)

mERG recordings in myopia. However, Westall et al.21 reported no significant difference in implicit times for a broad range of ERG stimuli and refractive errors.

The cause of the changes in ERG amplitudes with refractive error is not well understood. Increased ocular resistance due to the elongated eyeball in myopia was thought to be the major cause of decreased ERG amplitudes.15 Pallin15 argued that the current passing from the retina to the surface of the eye passes through highly resistant conductors consisting of both intraocular and extraocular tissues and that the density of these conducting tissues increases with axial length. Lemagne et al.13 designed a specially built system that allowed simultaneous recording of both the ERG and the resistance between the active and reference electrodes used for recording the ERG. The authors reported that ERG amplitudes were negatively correlated with the resistance measurements. However, there was broad variability in resistance measurements that was not correlated with refractive error, and the correlation between the resistance and amplitude measurements was relatively weak. Furthermore, resistance was measured between the electrode on the eye and a reference electrode on the midline of the forehead, which would not have allowed a specific test of resistance of

ocular tissue. Whether the correlation between resistance and ERG amplitude holds when the active and reference electrodes are both positioned on the eye, and the relationship of the resistance measurements to axial length, has yet to be determined.

Chen et al.3 dismiss the resistance argument as an explanation of reduced amplitudes because ocular current would be expected to increase with resistance, and according to these authors, a lower, not higher, resistance would be needed to explain the reduced ERG amplitudes in myopia. In contrast, Chen et al.3 tested between two alternative hypotheses about the mechanism of reduced ERG amplitudes in myopia. One hypothesis, called the stretched retina hypothesis, predicted a reduced retinal sensitivity but a normal saturated amplitude because there would be fewer receptors per unit area of retina and more space between receptors as a result of the elongated eye. Thus, as a result of the reduced ability of photoreceptors to capture photons, higher intensities of light would be required to elicit a threshold response (sensitivity), but the saturated amplitude (responsivity) would be unaltered provided that sufficient light is provided. An alternative hypothesis in which function but not retinal spacing varies, predicted reduced saturated amplitudes and normal sensitivity. They reported significant reductions in the saturated amplitude with progressively higher degrees of myopia but normal retinal sensitivity. Thus, the data were consistent with the decreased cell responsivity hypothesis rather than the enlargement of the eye with wider spacing of retinal elements. In addition, the shape of the posterior segment, which was characterized with magnetic resonance images, rather than the size and axial length alone appeared to be the critical determinant of the saturated amplitude. It is not yet understood why retinal cells in myopia would have a lower responsivity. The finding of normal sensitivity and reduced saturated amplitudes has recently been confirmed.21

Optical factors have also been implicated as playing a role in the reduction of ERG amplitudes in myopia. Assuming a similar stimulus intensity and pupil size, retinal illuminance may be lower in the myopic eye compared to the normal eye. Retinal illuminance refers to the density of light falling on a unit area of retina, and with an elongated eye, light is spread over a wider area, thereby decreasing retinal illuminance. If the myopic eye functioned to shift the intensityresponse curve so that a given light intensity is less effective, then retinal illuminance could be adjusted to equate amplitudes. The sensitivity but not the saturated amplitude of the myopic retina would be expected to be altered. However, several studies have demonstrated that saturated b-wave amplitudes are lower for the myopic eye,3,9,21 ruling out the possibility that reduced retinal illuminance is the explanation for the reduced ERG amplitudes.

To summarize, ERG amplitudes are negatively correlated with refractive errors that are caused by elongation of

the optic axis, with generally subnormal amplitudes for the highly myopic eye without pathological changes. This finding applies to both rodand cone-mediated vision. Parafoveal and peripheral cone-mediated responses may be affected to a greater degree than more central regions, possibly related to the differences in the packing density of cones, and the deficits are slightly greater for the L- and M- cones compared to S-cones, possibly related to the greater number of L- and M-cones. Implicit timing of the peak components of the ERG are generally reported to be normal regardless of refractive state and with normal appearing fundi. The cause of the reduced amplitudes in myopia is not well understood. Differences in electrical and optical factors and loss of photoreceptor density have been implicated as the cause of the reduced ERG amplitudes in myopia.

REFERENCES

1.Aladjov S, Denev V, Penov G, Todorov S: The influence of galvanic current on the electroretinogram of the myopic eye. In Francois J (ed): The Clinical Value of Electroretinography: XXth International Congress of Ophthalmology. Basel/New York, Karger, 1966, pp 444–450.

2.Blach RK, Barrie J, Kolb H: Electrical activity of the eye in high myopia. Br J Ophthal 1966; 50:629–641.

3.Chen JF, Elsner AE, Burns SA, Hansen RM, Lou PL, Kwong KK, et al: The effect of eye shape on retinal responses. Clin Vis Sci 1992; 7:520–530.

4.Franceschetti A, Dieterle P, Schwartz A: Skotopisches elektroretinogram bei myopie mit und ohne vongenitaler hemeralopie: Symposium Luhacovice. Acta Fac Med Univ Brunensis 1960; 4:247–253.

5.Francois J, De Rouck A: L’electroretinographie dans la myopie et les decollements myopigenes de la retine. Bull Soc Belge Ophthal 1954; 107:323–331.

6.Ishikawa M, Miyake Y, Shiroyama N: Focal macular electroretinogram in high myopia. Nippon Ganka Gakkai Zasshi 1990; 94:1040–1047.

7.Jayle GE, Boyer RL: In Electroretinographia, 1960, pp 263–272.

8.Karpe G: Basis of clinical electroretinography. Acta Ophthalmol 1945; 24 (suppl):5–118.

9.Kawabata H, Adachi-Usami E: Multifocal electroretinogram in myopia. Invest Ophthalmol Vis Sci 1997; 38:2844–2851.

10.Kawabata H, Murayama K, Kakisu Y, Adachi-Usami E: Bluecone spectral sensitivity in eyes with high myopia as estimated by the flash VECP. Folia Ophthalmol Jpn 1995; 46:535–539.

11.Koike A, Tokoro T: Spectral sensitivities in high myopic eyes.

J Jpn Ophthalmol Soc 1986; 90:556–560.

12.Lachapelle P, Little JM, Polomeno RC: The photopic electroretinogram in congenital stationary night blindness with myopia. Invest Ophthalmol Vis Sci 1983; 24:442–450.

13.Lemagne JM, Gagne S, Cortin P: Resistance in clinical electroretinography: Its role in amplitude variability. Can J Ophthalmol 1982; 17:67–69.

14.Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T: Congenital stationary night blindness with negative electroretinogram: A new classification. Arch Ophthalmol 1986; 104:1013–1020.

15.Pallin O: The influence of the axial length of the eye on the size of the recorded b-wave potential in the clinical single-flash electroretinogram. Acta Ophthalmol 1969; 101 (suppl):1–57.

16.Perlman I, Meyer E, Haim T, Zonis S: Retinal function in high refractive error assessed electroretinographically. Br J Ophthalmol 1984; 68:79–84.

17.Ponte F: Boll Oculist 1962; 41:739–746.

18.Prijot E, Colmant I, Marechal-Courtois C: Electroretinography and myopia. In Francois J (ed): The Clinical Value of Electroretinography: XXth International Congress of Ophthalmology.

Basel/New York, Karger, 1966, pp 440–443.

19.Uchida A: Studies of electrical activities of the eye in high myopia. Nippon Ganka Gakkai Zasshi 1977; 81(9):1328–1350.

20.Weleber RG, Kennaway NG: Gyrate atrophy of the choroid and retina. In Heckenlively JR (ed): Retinitis Pigmentosa. Lippincott, Philadelphia, 1988, pp 198–220.

21.Westall CA, Dhaliwal HS, Panton CM, Sigesmun D, Levin AV, Nischal KK, Heon E: Values of electroretinogram responses according to axial length. Doc Ophthalmol 2001; 102:115– 130.

22.Yamamoto S, Nitta K, Kamiyama M: Cone electroretinogram to chromatic stimuli in myopic eyes. Vision Res 1997; 37:2157– 2159.

.

S visual loss is commonly encountered in routine clinical practice and often presents a challenge to the ophthalmologist. The main role of electrophysiology is to provide objective evidence of normal retinal and/or intracranial visual pathway function in the presence of subjective reports that suggest otherwise. In some patients, it is not possible to distinguish between malingering and hysteria; in others, there is little doubt. A clinical review of functional visual loss has addressed the diagnostic distinctions.20 The term nonorganic visual loss is preferred, particularly if volitional aspects are uncertain.

It was commented in the first edition of this volume that although the clinical value of electrophysiology in the diagnosis of nonorganic visual loss was widely accepted, there were relatively few reports in the literature.15 That remains the case. The first report appears to be that of Potts and Nagaya,25 who reported that patients with hysterical amblyopia had normal foveal visual evoked potentials (VEP) to a 0.06-degree flashing red stimulus, whereas patients with strabismic amblyopia showed diminished or absent responses. The use of diffuse flash stimulation was also described by Arden’s group,1 and those authors cautioned against the unequivocal acceptance of electrophysiological criteria, citing one case of almost certain hysterical amblyopia in which scotopic flash VEP (FVEP) anomalies were observed. It is the case, however, that functional overlay superimposed on underlying organic dysfunction may be encountered. Subsequent reports, though mostly anecdotal, confirmed the finding of normal FVEPs in nonorganic visual loss.2,3,11,22 The use of the FVEP in assisting disclose the nonorganic basis of suspect symptoms following trauma was also described.21

However, although the use of a luminance stimulus may be satisfactory in the evaluation of hysterical total blindness, which is not usually difficult to ascertain clinically, a contrast stimulus is necessary to evaluate less severe reported deficits. Halliday19 first described the use of the pattern-reversal VEP (PVEP) in hysterical visual loss, reporting normal, symmetrical PVEPs in both eyes of patients despite markedly asymmetrical visual acuity. The technique was thought to be most useful in unilateral visual loss in which the good eye acts as a control. It was also stressed that a normal PVEP, although

strongly suggestive of nonorganic visual loss, does not preclude the existence of some organic disease.

The early studies using flashed-pattern VEPs12,13,26 found that the maximum response amplitude occurred with check sizes of 10–30 minutes of arc. Later studies with pattern reversal came to similar conclusions for small fields but further suggested an interrelationship between check size and field size.8,23,24 Small checks and fields are better for foveal stimulation, large checks and large fields for more peripheral retina.

The clinical management of patients with nonorganic visual loss would be facilitated if a simple relationship between VEP measurements and visual acuity existed that enabled an objective assessment of acuity. Unfortunately, most scaling methods that use pattern reversal perform relatively poorly as predictors of acuity,7 although Halliday and McDonald10 suggested that a well-formed pattern-reversal VEP is incompatible with a visual acuity of ~6/36 or worse. Despite the problems, attempts to assess acuity objectively in patients who are suspected of nonorganic visual loss have been made. Wildberger32 reported the findings in two groups of patients: 17 “malingerers” (mostly schoolgirls) with no signs of an organic lesion and 10 patients (accident or disease) with signs but marked overlay. The findings in the patients were compared with those obtained in normal subjects to the same four check sizes in relation to insertion of graded orthoptic filters intended to reduce the acuity. The VEPs were easily able to detect malingering in the second group of patients, in whom acuities were usually claimed to be markedly reduced, but were not sensitive in the first group with milder claimed reductions. The VEP was assessed with the offset amplitude of the P100 component (P100–N135); in this author’s laboratories, the onset amplitude of the pattern-reversal VEP (N75–P100) seems more sensitive. It is probably advisable routinely to measure both parameters. A recent publication33 reported the use of pattern-reversal VEP in 72 patients with functional visual loss, suggesting that the discrepancy between acuity estimated by VEP and the best performed visual acuity was less than three lines on a Snellen chart in 88% of patients.

The use of pattern-onset stimulation, rather than pattern reversal, was previously described to yield improved results

(G. B. Arden, personal communication; see also Holder15). This has been confirmed in the authors’ laboratories (V. McBain, et al., unpublished data). It is recognized that the pattern-onset or appearance VEP (PaVEP) is more susceptible to blur than is the pattern-reversal VEP. This enables a more direct relationship to be established between visual acuity and the presence or absence of a response to small check sizes of varying contrast. In addition, the spatiotemporal tuning function of the PaVEP is simpler and correlates closely with contrast sensitivity,17,19,24 and the responses are often of larger amplitude than in reversal VEPs.24 Furthermore, if a short (e.g., 40ms) appearance time is used, it is difficult for the patient to defocus the pattern voluntarily.18 PaVEP results are generally superior to those obtained with reversal when the patient is deliberately trying to influence the results.

Technical factors in the recording of patients who are suspected of hysteria or malingering are of paramount importance but receive little attention. The patient may fail to fixate, may attempt to defocus, may attempt prolonged eye closure during blinking, and so on. PVEP changes have been reported under such conditions.5,28,29 Direct observation of the patient, with the patient aware of such monitoring, will often result in improved compliance (figure 51.1). Careful observation of both the raw electroencephalographic (EEG) input and the developing average is advisable; the appearance of an alpha rhythm in the ongoing EEG may indicate

a failure in concentration. Equally, a tendency for the P100 component to broaden or increase in latency in the acquired average suggests that accommodation or fixation is unsatisfactory. Verbal commands to the patient to concentrate and attend to the fixation mark (or the center of the screen if perception of the fixation mark is denied) may be beneficial. If all perception is denied with one eye, fixation can be obtained by using the better eye, and an instruction to “try to keep your eyes still” will surprisingly often produce good results following occlusion of this eye and prompt commencement of stimulation. It may be necessary to stop averaging after fewer sweeps than usual to prevent waveform deterioration. A tendency for the P100 component to sharpen and remain of stable or slightly reducing latency during acquisition of the average only occurs with good patient compliance; observation of a broadening of the peak and/or increase in P100 latency suggests poor patient compliance and demands intervention by the recordist. A subjective report of stimulus perception should be obtained from the patient in all cases. Marked discrepancies between the subjective reports and the objective electrophysiological findings can be useful in alerting the examiner to nonorganic visual loss, particularly if marked interocular perceptual asymmetries are unaccompanied by VEP asymmetries.

It is advisable to record the PERG. The PERG P50 component is very susceptible to deterioration with poor compliance, and a normal PERG can only be obtained with

F 51.1 VEP and PERG findings in a 32-year-old female with reduced right visual acuity following trauma. Litigation was pending. Left eye findings (6/5) are normal. Ophthalmic examina-

tion was normal. Right eye PVEP was normal when the patient was aware that she was under direct observation [RE(o)] but delayed when she thought that she was unobserved [RE(u)].

satisfactory fixation, accommodation, and so on. Factors that affect the PERG are described elsewhere in this volume (see chapter 22). Equally, cases of mild maculopathy, with an unequivocally abnormal PERG, may sometimes have a PVEP within the normal range (Holder, unpublished observations); a normal PVEP should not therefore be presumed to preclude mild macular dysfunction. Rover and Bach27 report the use of simultaneous recording of the PERG and PVEP to reveal malingering. Their patients complained of marked acuity loss, but only a few representative cases were discussed, and no quantitative patient data were presented. In particular, no mention was made as to whether their cases were bilateral or unilateral. A normal PERG and PVEP indicated malingering; a normal PERG and an abnormal PVEP indicated a “lesion of the visual pathway”; and an abnormal PERG and an abnormal PVEP indicated blurred image, poor cooperation, or retinal dysfunction.

Simultaneous PERG and PVEP can be particularly useful in unilateral cases; PVEP interpretation in a patient who is deliberately attempting to influence the results can be substantially improved by knowledge of the retinal response

simultaneously recorded to the same stimulus. Binocular registration of the PERG, with the “good” eye enabling fixation, will usually reveal whether the PERG from the “bad” eye is abnormal or not (see figure 51.1). Significant macular dysfunction is excluded if the PERG from the bad eye is normal with binocular stimulation. If there is a unilateral PERG abnormality in the bad eye, the nature of the abnormality will indicate either ganglion cell/optic nerve or more distal dysfunction depending on whether the N95 or P50 component of the PERG is affected16 (see chapter 22).

Routine ERG should also be performed; ERGs can be markedly abnormal in retinal dysfunction with no or minimal fundus abnormality but constricted visual fields, and field loss is often a feature of nonorganic visual loss. PERG and PVEP findings may be normal in such conditions if the maculae are spared. However, because normal PVEPs may be found in patients with cortical blindness, particular care should be taken before making the diagnosis of nonorganic visual loss if the symptoms suggest possible cortical dysfunction. Celesia’s group6 studied a 72-year-old woman with bilateral destruction of area 17 and attributed the

F 51.2 Electrophysiological findings in a 43-year-old female with a one-month history of sudden painless visual loss in the right eye. Ophthalmic examination was normal. The patient had a mother and sister who had previously had optic neuritis as part of multiple sclerosis, and it was suspected that the visual loss was

nonorganic. The PVEPs from both right and left eyes are delayed; the lack of relative afferent pupillary defect presumably relating to the subclinical demyelination in the asymptomatic left optic nerve. Note the mild relative N95 reduction in the PERG from the right eye compared with the left.

presence of normal VEPs to conduction in extrageniculocalcarine pathways. Bodis-Wollner et a1.4 reported normal VEPs in a 6-year-old boy with destruction of areas 18 and 19 but preservation of area 17. Similarly, retrochiasmal lesions may not give a PVEP abnormality even with a demonstrable field defect (see chapter 78). Evaluation of the P300 component may circumvent such problems.30

To conclude, electrodiagnostic testing is invaluable in the detection or confirmation of nonorganic visual loss, particularly if it is unilateral, so one eye can be judged against the other. Although the reader is reminded of the warning of Halliday9 that normal electrophysiology does not preclude the presence of some underlying organic disease, the demonstration of normal electrophysiology can be reassuring, both for the clinician and, if the patient is a child, for concerned parents. Particular caution must be exercised if there is a possibility of cortical dysfunction. The most challenging patients are probably those with functional overlay superimposed on genuine underlying organic dysfunction. It is essential that an accurate history is taken and comprehensive ophthalmic and neurological examination performed; particular techniques for revealing functional deficit have been described in full elsewhere.31 Electrophysiological examination is always advisable if there is any doubt. The objective nature of electrodiagnostic testing may not only demonstrate normal visual pathway function in patients whose symptoms suggest otherwise, but also reveal the presence of organic dysfunction in a patient with a presumed diagnosis of nonorganic visual loss (figure 51.2).

REFERENCES

1.Adams WL, Arden GB, Behrman J: Responses of human visual cortex following excitation of peripheral rods: Some applications in the clinical diagnosis of functional and organic visual defects. Br J Ophthalmol 1969; 53:439–452.

2.Beck EC, Dustman RE, Lewis EG: The use of the averaged evoked potential in the evaluation of central nervous system disorders. Int J Neurol 1975; 9:211–232.

3.Berman MS, Levi DM: Hysterical amblyopia: Electrodiagnostic and clinical evaluation. Am J Optom Physiol Opt 1975; 52:267–274.

4.Bodis-Wollner I, Atkin A, Raab E, et al: Visual association cortex and vision in man: Pattern evoked occipital potentials in a blind boy. Science 1977; 198:629–631.

5.Bumgarten J, Epstein CM: Voluntary alteration of visual evoked potentials. Ann Neurol 1982; 12:475–478.

6.Celesia GG, Archer CR, Kuroiwa Y, et al: Visual function of the extrageniculocalcarine system in man: Relationship to cortical blindness. Arch Neurol 1980; 37:704–706.

7.Chan H, Odom TV, Coldren L, et al: Acuity estimates by visually evoked potentials is affected by scaling. Doc Ophthalmol 1986; 62:107–117.

8.Erwin CW: Pattern reversal evoked potentials. Am J Electroencephalogr Technol 1981; 20:161–184.

9.Halliday AM: Evoked responses in organic and functional sensory loss. In Fessard A, LeLord G (eds): Activities Evoquees et

Leur Conditionnement Chez L’Homme Normal et en Pathologie Mentale.

Paris, Institut National de la Sante et de la Recherche Medicale, 1973, pp 189–212.

10.Halliday AM, McDonald WI: Visual evoked potentials. In Stalberg E, Young RR (eds): Neurology 1: Clinical Neurophysiology.

London, Butterworths, 1981, pp 228–258.

11.Harding GFA: The visual evoked response. Adv Ophthalmol 1974; 28:2–28.

12.Harter MR, White CT: Effects of contour sharpness and check size on visually evoked cortical potentials. Vision Res 1968; 8:701–711.

13.Harter MR, White CT: Evoked cortical responses to checkerboard patterns: Effect of check size as a function of visual acuity. Electroencephalogr Clin Neurophysiol 1970; 28:48–

14.Holder GE: Significance of abnormal pattern electroretinography in anterior visual pathway dysfunction. Br J Ophthalmol 1987; 71:166–171.

15.Holder GE: Electrodiagnostic testing in malingering and hysteria. In Heckenlively JR, Arden GB (eds): Principles and Practice of Clinical Electrophysiology of Vision. St. Louis, Mosby Year Book, 1991, pp 573–577.

16.Holder GE: The pattern electroretinogram and an integrated approach to visual pathway diagnosis. Prog Ret Eye Res 2001; 20:531–561.

17.Howe JW, Mitchell KW: The objective assessment of contrast sensitivity by electrophysiological means. Br J Ophthalmol 1984; 68:626–638.

18.Howe JW, Mitchell KW, Robson C: Electrophysiological assessment of visual acuity. Trans Ophthalmol Soc UK 1981; 101:105–108.

19.Jetzel J, Parry N: Minimising the effects of spatial nonlinearities on VEP estimation of resolution limit. ARVO Abstracts 2001; 42:4584.

20.Kathol RG, Cox TA, Corbett JJ, et al: Functional visual loss:

1.A true psychiatric disorder? Psychol Med 1983; 13:307–

21.Kooi KA, Yamada T, Marshall RE: Binocular and monocular visual evoked potential in the differential diagnosis of psychogenic and disease related disorders. Int J Neurol 1975; 9:272–286.

22.Lazurus GM: A clinical application of the visual evoked potential in the diagnosis of ophthalmic and neuroophthalmic pathology: Organic and functional lesions. Am Optom Assoc 1974; 45:1056–1063.

23.Meredith JT, Celesia GG: Pattern reversal visual evoked potentials and retinal eccentricity. Electroencephalogr Clin Neurophysiol

1982; 53:243–253.

24.Parry NRA, Murray IJ, Hadjzenonous C: Spatio-temporal tuning of VEPs: Effect of mode of stimulation. Vision Res 1999; 39:3491–3497.

25.Potts AM, Nagaya T: Studies on the visual evoked response: III. Strabismus amblyopia and hysterical amblyopia. Doc Ophthalmol 1969; 26:394–402.

26.Rietveld WJ, Tordoir WEM, Hagenouw JR, et al: Visual evoked responses to blank and to checkerboard patterned flashes. Acta Physiol Pharmacol Neerl 1967; 14:259–285.

27.Rover J, Bach M: Pattern electroretinogram plus visual evoked potential: A decisive test in patients suspected of malingering. Doc Ophthalmol 1987; 66:245–251.

28.Sokol S, Moskowitz A: Effect of retinal blur on the peak latency of the pattern evoked potential. Vision Res 1981; 21:1279–1286.

29.Tan CT, Murray NMF, Sawyers D, et al.: Deliberate alteration of the visual evoked potential. J Neurol Neurosurg Psych 1984; 47:518–523.

30.Towle VL, Sutcliffe E, Sokol S: Diagnosing functional visual deficits with the P300 component of the visual evoked potential. Arch Ophthalmol 1985; 103:47–50.

31.Walsh FB, Hoyt WF: The ocular signs of neurasthenia, hysteria, malingering, and the psychoses. In Walsh FB, Hoyt WF (eds): Clinical Neuroophthalmology. Baltimore, Williams & Wilkins, 1969, pp 2519–2537.

32.Wildberger H: Contrast evoked notentials in the evaluation of suspected malingering. Doc Ophthalmol Proc Ser 1981; 27:425–430.

33.Xu S, Meyer D, Yoser S, Mathews D, Elfervig JL. Pattern visual evoked potential in the diagnosis of functional visual loss. Ophthalmology 2001; 108:76–80.

34.Yiannakis C, Walsh JC: The variation of the pattern shift visual evoked response with the size of the stimulus field. In Chiappa KH (ed): Evoked Potentials in Clinical Medicine. New York, Raven Press, 1983, p 51.