A C T A O P H T H A L M O L O G I C A VOL. 5 6 1 9 7 8
Department of Ophthalmology, Danderyds sjukhus, Stockholm (Head: K . G . Nyman, former head: G . Aurell) and Department of Clinical Neurophysiology, Sodersjukhuset, Stockholm (Head: L. Kirstein)
VISUAL EVOKED RESPONSES TO PATTERN-REVERSAL STIMULATION IN PATIENTS WITH AMBLYOPIA AND/OR DEFECTIVE BINOCULAR FUNCTIONS BY
PETER WANGER and BENGT YNGVE NILSSON
The visual evoked responses to monocular and binocular pattern-reversal stimulation were recorded in ten normal subjects and in ten cases with amblyopia and/or defective binocular functions. Seven of the ten patients showed a considerable amplitude asymmetry to monocular stimulation or lack of normal increase of amplitude to binocular stimulation. Two patients displayed prolonged latency on stimulation of the amblyopic eye.
Key words: visual evoked response - pattern-reversal stimulation - monocular stimulation - binocular stimulation - amblyopia - defective binocular functions.
Functional amblyopia is by definition a unilateral reduction in visual acuity without visible pathological changes in the afflicted eye, occurring in some 3 O/O of the population, often in combination with strabismus, and is in appropriate cases, curable by treatment (Burian & Von Noorden 1974). For studies of the visual evoked response (VER) in amblyopic patients a reversing pattern is an adequate stimulus, since this procedure avoids contamination with luminance-induced responses. The VER to pattern-reversal stimulation shows waveforms and latencies which are consistent both within and between individuals (Barrett et al. 1976). A reduced amplitude of the patReceived August 10, 1977.
617 Acta ophthal. 56, 4
40
Peter Wanger and Bengt Yngve Nilsson tern-reversal evoked cortical response to stimulation of the amblyopic eye com-
pared to the normal eye has been reported (Spekreijse et al. 1972; A r d e n et al. 1974; Bornstein 1976). Sokol & Shaterian (1976) recently showed that the magnitude of the amplitude asymmetry is related to the spatial frequency of the stimulus pattern. A r d e n et al. (1974) analysed “steady-state”-responses to reversal rates of 6-16 Hz using a sinusoidally changing pattern a n d f o u n d t h a t the response f r o m the amblyopic eye showed a phase reversal a n d also a reduced amplitude when visual acuity was lower t h a n 0.3 (6/18). Binocular stimulation gave various results; loss of normal summation a s well a s total absence of binocular response was described. Binocular respcnses of “transient” type to square-wave-modulated reversals of low frequency d o not seem to
have been systematically studied. T h i s pilot study was started with the intention of identifying features of
the VER to monocular a n d binocular stimulation in patients with amblyopia a n d l o r defective binocular functions, which could be a useful aid i n diagnosis a n d follow-up of treatment results. W e also tried t o establish a rapid a n d simple procedure in order to make investigations in young children possible.
Material Ten normal subjects (20-36 years of age) were examined; they all had a visual acuity of 1.0 bilaterally with correction, a stereo acuity of 40 seconds of arc on the Titmus’ stereo test, positive response to the Bagolini striated glass test and no adjustment movement to monocular cover test. The patient group consisted of ten individuals aged 10-22 years, who had varying degrees of unilateral amblyopia (see Table II), adjustment movement to monocular cover test less than 5 O , stereo acuity less than 200 seconds of arc (Titmus’ stereo test) and pathological response to Bagolini striated glass test. All patients except one confcsrm to the entity of “Mikrostrabismus” (Lang & Witmer 1973) or “monofixation syndrome (Parks 1969). Case No. 3 has a left hypertropia of 3O. All patients had clear media and fundcscopic appearance judged normal by at least two ophthalmologists. The difference in age between the normal and the pathological group is not thought to be of any relevance for the parameters under discussion.
Methods Stimulation procedure
Pattern-reversal stimulation was achieved by means of a commercially available device (Digitimer). A black-and-white checkerboard pattern was backprojected via a turnable mirror on a translucent screen placed in front of the patient at a distance of 1 m. Pattern reversal was obtained by rapid rotations of the mirror to and fro through 618
Visual Evoked Responses in Amblyopia a small angle, thereby displacing the pattern sideways exactly one square width. As the number of black-and-white checks on the screen did not change, overall luminance was kept constant. Reversal time (mirror movement) was measured and found to be 5 ms. The individual checks subtended a visual angle of 23'; the whole stimulating field constituted a square with a side length of 154 mm, corresponding to a visual angle of 8.8'. The luminance of the white squares was 1200 cdlmz and that of the black squares 12 cdlmz. The contrast was thus high, 98 O/o. Transient responses to a pattern-reversal frequency of 1.4 Hz were recorded in all subjects and steady-state responses to a 14 Hz reversal rate were recorded in some of the subjects. Monocular stimulation of each eye and binocular (dioptic) stimulation was used.
Recording technique
The VER was recorded between two silver - silver chloride electrodes applied to the scalp at Oz and Fz positions according to the International 10-20 system. The EEG activity was fed into a Grass P511 preamplifier with low and high frequency filters set at 0.1 and 1000 Hz respectively. Responses to 100 reversals were summated using a Didac 800 average computer. Analysis time was 200 ms, the signal being sampled at 0.25 ms intervals. The subjects were comfortably seated in a dark room without previous dark adaptation. Refractive errors, when present, were fully corrected. The subjects were requested to fixate on the centre of the screen and to pay constant attention to the pattern. At least two summations were made in each stimulus situation. When variations occurred, the largest response was used, as it was thought that all sources of error tended to give a decrease in amplitude. The responses were sometimes seen to deteriorate towards the end of prolonged experimental sessions. The obtained curves were written out on an X-Y-recorder (Hewlett-Packard 7005 B) and amplitude manually measured; 1 mm corresponding to 0.25 fiV. Latencies were electronically measured on the computer with a measurement accuracy of 0.25 ms (= one sampling interval). The amplitude of the responses was measured from the preceding negative peak to the trough of the major positive wave. Latency was taken as the time from the pattern reversal to the point of maximal positivity.
Results I. Steady-state responses
In the first part of this study, which included five normal subjects and five patients, the steady-state responses to square-wave pattern reversals at a rate of 14 Hz were obtained in addition to the transient responses (see below). A preliminary analysis cf the steady-state responses did not reveal any obvious differences when the normal group and the patient group were compared; thus this type of stimulation was not used in subsequent recordings in order to 619 40*
Subject No.
Sex, age (years)
0. s.
11.5 8.8 14.8 13.8 6.5 12.3 12.3 12.3 9.8 13.5
0.D.
11.5 7.3 14.3 17.0 6.8 12.8 9.5 11.8 7.8 13.8
VER amplitude (pV)
14.5 12.5 20.3 20.0 8.3 15.3 17.5 17.0 11.8 18.5
Binoc.
90 95 93 98 88 96
100
101 93 93
0.D.
100 93 93 100 93 95 95 103 88 98
0. s.
VER latency (ms)
Table I. VER parameters in the normal group.
95 93 90 98 90 90 92 98 88 98
Binoc.
I
23 4 20 2
4
0 17 3 19 4
Side diff.
126 142 137 118 122 120 142 138 120 134
Monoc.
Binoc. -
Relative VER ampl.
Sex, age
(years)
Case
No.
O.D.
O.S.
Visual acuity
Cover test
O.D.
O.S. Binoc.
VER amplitude (pV)
Relative VER ampl.
93 92 106 121 124 83 143
115
10 4 3 36 34 37 0 13
5
123 135
Binoc. (W Monoc.
39
(W
Side diff.
7
VER latency (ms)
Peter Wanger and Bengt Y n g v e Nilsson
shorten the procedure. The negative results with steady-state responses are at variance with findings reported by Arden et al. (1974). Differences in stimulus presentation may account for this: we used rapid square-wave modulation of the pattern while the apparatus used by Arden et al. (1974) produced a sinewave modulated stimulus. Differences in check size also affect the results (Sokol & Shaterian 1976).
I I. Transient responses
The VER amplitudes and latencies in individual cases are given in Tables I and 11. Representative examples of original recordings are shown in Fig. 1. In concordance with previously published VER studies the responses to pattern-reversal stimulation show a considerable interindividual variation in amplitude in the normal group as well as among the patients. Therefore, we shall in this context only discuss differences in amplitude to stimulation of right resp. left eye and to monocular versus binocular stimulus presentations in the
B
A
I
0
I
200rns
C
200 rns
0
-
0
200rns
Fig. I . Monocular and binocular visual evoked responses to pattern-reversal stimulation. Positivity at the occipital electrode gives downward deflection. A. Normal individual. Subject No. 6. B. Case No. 1. Considerable side difference in amplitude on monocular stimulation. C. Case No. 4. Lack of normal increase in amplitude on binocular stimulation.
622
Visual Evoked Responses in Amblyopia
B. Binocular amplitude
Side difference
'la 40
-
30
-
20
-
10
-
140
-
120
-
110
-
100
-
130
- 90-
0 -
a
a
N
P
N
P
Fig. 2. Comparison of monocular and binocular evoked responses to pattern-reversal stimulation in normal subjects (N) and in patients (P). A. The difference in response amplitude to monocular stimulation of right and left eyes is expressed in per cent of the largest response. B. The amplitude of the binocular response is given as per cent of the amplitude of the best monocular response (100 O/o indicates binocular response equal to monocular response).
same individual. Latency and waveform are fairly constant (Barrett et al. 1976; Nilsson 1976). In the normal subjects (Table I) the VER were found to fulfil the following criteria: 1. The amplitude difference between right and left eyes on monocular stimulaticn was less than 27 O/O (mean - 2 SD).
2. On binocular stimulation the response amplitude increased more than 12 O/O (mean - 2 s ~ above ) the best monocular response.
3. The latency differences between responses from left and right eyes were less than 5 ms.
In the patient groufi (Table 11) seven out of ten cases fell outside the normal range described above in at least one respect (cf. Fig. 2). Four patients (cases Nos. 1, 6, 7 and 8) exhibited a side difference of more than 300/0.In one patient (case No. 6) the amplitude increase on binocular stimulation was small 623
Peter Wanger and Bengt Yngve Nilsson
and in three further cases (Nos. 4, 5 and 9) the responses elicited by binocular stimulation were even smaller than the best monocular response (see Fig. 1 C). In Fig. 2 the relative amplitudes on monocular and binocular stimulation are graphically displayed. On monocular stimulation two patients (cases Nos. 1 and 4) demonstrated large side differences in latency ( 1 1 and 13 ms respectively). These cases, in addition to two further cases (Nos. 6 and 7 ) , presented latencies above the upper normal limit for this laboratory (107 ms; Nilsson 1976) when the amblyopic eye was stimulated. It was often observed that the response enlargement on binocular stimulation was, to a great extent, due to an enhancement of the negative peak immediately preceeding the major positive wave (see Fig. 1). In this respect there was no difference between the patients and the normal subjects.
Discussion Judging from earlier published VER studies (Arden et al. 1974; Spekreijse et al. 1972; Bornstein 1976) it was expected that pattern-reversal stimulation of the amblyopic eye should give a response of lower amplitude than stimulation of the normal eye. This expectation was not fulfilled in some cases. Only in four cases was an asymmetry of more than 27 O/O found. In addition, although a large side difference in amplitude was found in those cases, it was not always the normal eye that gave the greatest response. Such a “supernormal” amplitude to stimulation of the amblyopic eye was also seen by Tsutsui et al. (1973) and Grall et al. (1975), who used diffuse and patterned flash stimulation. In a paper published during the course of this study, Sokol & Shaterian (1976) have shown that normal and amblyopic eyes have different spatial frequency sensitivities. When the normal eye was stimulated, the maximal response amplitudes were usually found when individual checks in the checkerboard-pattern corresponded to a visual angle of 7.5 to 15 min, while stimulation of the amblyopic eyes elicited maximal responses when check-size was 30 min of arc or more. Spekreijse et al. (1972) also found a better response in the amblyopic eye when large checks were used. The check-size used in our study (23 min of arc) seems to fall in between these two ranges, which might explain the small and in some cases paradoxical side difference observed among our patients. The latency of the response to monocular stimulation was abnormally increased in four patients and a considerable left - right difference was seen in two of them. Yinon et al. (1974), using patterned flash stimulation, also described prolonged latencies when amblyopic eyes were compared to normal 624
Visual Evoked Responses in Amblyopia
eyes. The physiological reason for this delay is unknown. However, Ikeda & Wright (1976) have demonstrated an increased latency of neuron discharges in cells of the lateral geniculate nucleus in kittens reared with artificially induced unilateral squints and similar mechanisms may be operating in human patients with amblyopia. In all normal subjects and in several of the patients a considerable increase in amplitude was seen to binocular stimulation. It is not possible to decide whether this reflects the activation of a n additional group of predominantly binocularly driven neurons or a summation of the activity from two groups of monocularly driven neurons (Hubel & Wiesel 1968). An interesting observation is that the mean amplitude to binocular stimulation in the normal group (15.6 p V ) exceeds the mean amplitude to monocular stimulation ( 1 1.3 p V ) by a factor of 1.38, which is very close to the 1/?improvement factor found when binocular and monocular performance are compared in psychophysical measurements of contrast sensitivity, flicker sensitivity, increment threshold and spatial sensitivity (Blake & Fox 1973; Blake & Levinson 1977). This finding might be regarded as a support for the integration model of signal detection theory (Green & Swets 1966) for neural summation between the eyes, outlined by Campbell & Green (1965). This model assumes complete summation of the output from the two monocular channels, containing uncorrelated noise. With binocular viewing, the signal strength is doubled, but because of the uncorrelated noise the summed signal is only increased by a factor of The present study has shown that recordings of the response to binocular stimulation give potentially valuable information in cases of amblyopia and/or defective binocular functions. The normal enlargement of the potential was absent in four cases; in three of them the binocular response was even smaller than the best monocular response, which might indicate that the amblyopic eye exerts an inhibitive effect on neurons excited by the normal eye. Tsutsui et al. (1973) also found a negative effect of binocular stimulation with patterned flash in scme amblyopic patients. Arden et al. (1974), however, assessed their results with binocular pattern-reversal stimuli as equivocal. If a side difference in amplitude of more than 27 O/O or an increase of amplitude on binocular stimulation of less than 120/0, or a side difference in latency of more than 5 ms are considered pathological, seven of our ten patients are abnormal in at least one aspect; three of them are pathological in more than one aspect. This means that if the functional state of amblyopic patients is to be estimated from VER recordings, all these different aspects must be taken into account. The regular occurrence of increased amplitude and also slightly shortened latency cn binocular stimulation in the normal group is thought to indicate
vr
625
Peter Wanger and Bengt Y n g v e Nilsson lack of suppression. In the pathological g r o u p these features w e r e noted i n six cases. T h i s finding might indicate that suppression did not occur in these cases a n d that suppression a s explanation for t h e occurrence of amblyopia (Franceschetti & Burian 1971) is not valid in all cases. A n o t h e r explanation m a y be that the suppression scotoma i n these cases is very small a n d affects visual channels with higher spatial frequency sensitivity than tested by the checksize used in this study. When pattern-reversal VER is used for the diagnosis of lesions in t h e visual pathways, a s e. g. in multiple sclerosis, the possibility that an observed amplitude a n d latency difference between left a n d right eyes might be d u e t o an amblyopia must always be considered.
References Arden G. B., Barnard W. M. & Mushin A. S. (1974) Visually evoked responses in amblyopia. Brit. 1.Ophthal. 58, 183-192. Barrett G., Blumhardt L., Halliday A. M., Halliday E. & Kriss A. (1976) A paradox in the lateralisation of the visual evoked response. Nature (Lond.) 261, 253-255. Blake R. & Fox R. (1973) The psychophysical inquiry into binocular summation. Percept. Psychophys. 14, 161-185. Blake R. & Levinson E. (1977) Spatial properties of binocular neurones in the human visual system. Exp. Brain Res. 27, 221-232. Bornstein Y. (1976) “Visual evoked response” bei der Schielamblyopie. Ophthalmologica 172, 188-193. Burian H. M. & Von Noorden G. K. (1974) Binocular vision and ocular mobility. Theory and management of strabismus. C. V. Mosby Co., St. Louis. Campbell F. W. & Green D. G. (1965) Monocular versus binocular visual acuity. Nature (Lond.) 208, 191-192. Franceschetti A. T. & Burian H. M. (1971) Visually evoked responses in alternating strabismus. Amer. /. Ophthal. 71. 1292-1297. Green D. M. & Swets J. A. (1966) Signal Detection Theory and Psychophysics. Wiley, New York. Grall Y., Klein M., Delthil S., Keller J., Menguy C., Ninnin E. & GuCris H. (1975) Etude des potentiels CvoquCs visuels dans I’amblyopie fonctionelle. Ann. Oculist. 208, 429-435. Hubel D. H. & Wiesel T. N. (1968) Receptive fields and functional architecture of monkey striate cortex. J . Physiol. (Lond.) 195, 215-243. Ikeda H. & Wright M. J. (1976) Properties of LGN cells in kittens reared with convergent squint: A neurophysiological demonstration of amblyopia. E x p . Brain Res. 25, 6 3 4 7 . Lang J. & Witmer R. (1973) Mikrostrabismus. Buech. Augenarzt. 62, 1-121. Nilsson B. Y. (1976) Visuella “evoked responses” framkallade genom “pattern-reversal”-stimulering. Actn SOC.Med. Suec. 8.5, 241. Parks M. M. (1969) The monofixation syndrome. Trans. amer. ophthal. SOC. 67, 609-657.
626
Visual Evoked Responses in Amblyopia Sokol S. & Shaterian E. T. (1976) The pattern-evoked cortical potential in amblyopia as an index of visual function. In: Moore S. & Mein Y., Eds. Orthopics: past, present, future, pp. 59-67. Stratton, New York. Spekreijse H., Khoe L. H. & van der Tweel L. H. (1972) A case of amblyopia; electrophysiology and psychophysics of luminance and contrast. In: Arden G. B., Ed. The visual system, pp. 141-156. Plenum Press, New York. Tsutsui J., Nakamura Y., Takenaka J. & Fukai S. (1973) Abnormality of the visual evoked response in various types of amblyopia. / u p . /. Ophthal. 17, 83-93. Yinon U., Jakobovitz L. & Auerbach E. (1974) The visual evoked response to stationary checkerboard patterns in children with strabismic amblyopia. Invest. Ophthaf. 13, 293-296.
Author’s address: Dr. Peter Wanger, Ugonmottagningen, Vlrdcentralen, Dragonvagen 92, S-194 00 Upplands Vasby. Sweden.
627
Department of Ophthalmology, Danderyds sjukhus, Stockholm (Head: K . G . Nyman, former head: G . Aurell) and Department of Clinical Neurophysiology, Sodersjukhuset, Stockholm (Head: L. Kirstein)
VISUAL EVOKED RESPONSES TO PATTERN-REVERSAL STIMULATION IN PATIENTS WITH AMBLYOPIA AND/OR DEFECTIVE BINOCULAR FUNCTIONS BY
PETER WANGER and BENGT YNGVE NILSSON
The visual evoked responses to monocular and binocular pattern-reversal stimulation were recorded in ten normal subjects and in ten cases with amblyopia and/or defective binocular functions. Seven of the ten patients showed a considerable amplitude asymmetry to monocular stimulation or lack of normal increase of amplitude to binocular stimulation. Two patients displayed prolonged latency on stimulation of the amblyopic eye.
Key words: visual evoked response - pattern-reversal stimulation - monocular stimulation - binocular stimulation - amblyopia - defective binocular functions.
Functional amblyopia is by definition a unilateral reduction in visual acuity without visible pathological changes in the afflicted eye, occurring in some 3 O/O of the population, often in combination with strabismus, and is in appropriate cases, curable by treatment (Burian & Von Noorden 1974). For studies of the visual evoked response (VER) in amblyopic patients a reversing pattern is an adequate stimulus, since this procedure avoids contamination with luminance-induced responses. The VER to pattern-reversal stimulation shows waveforms and latencies which are consistent both within and between individuals (Barrett et al. 1976). A reduced amplitude of the patReceived August 10, 1977.
617 Acta ophthal. 56, 4
40
Peter Wanger and Bengt Yngve Nilsson tern-reversal evoked cortical response to stimulation of the amblyopic eye com-
pared to the normal eye has been reported (Spekreijse et al. 1972; A r d e n et al. 1974; Bornstein 1976). Sokol & Shaterian (1976) recently showed that the magnitude of the amplitude asymmetry is related to the spatial frequency of the stimulus pattern. A r d e n et al. (1974) analysed “steady-state”-responses to reversal rates of 6-16 Hz using a sinusoidally changing pattern a n d f o u n d t h a t the response f r o m the amblyopic eye showed a phase reversal a n d also a reduced amplitude when visual acuity was lower t h a n 0.3 (6/18). Binocular stimulation gave various results; loss of normal summation a s well a s total absence of binocular response was described. Binocular respcnses of “transient” type to square-wave-modulated reversals of low frequency d o not seem to
have been systematically studied. T h i s pilot study was started with the intention of identifying features of
the VER to monocular a n d binocular stimulation in patients with amblyopia a n d l o r defective binocular functions, which could be a useful aid i n diagnosis a n d follow-up of treatment results. W e also tried t o establish a rapid a n d simple procedure in order to make investigations in young children possible.
Material Ten normal subjects (20-36 years of age) were examined; they all had a visual acuity of 1.0 bilaterally with correction, a stereo acuity of 40 seconds of arc on the Titmus’ stereo test, positive response to the Bagolini striated glass test and no adjustment movement to monocular cover test. The patient group consisted of ten individuals aged 10-22 years, who had varying degrees of unilateral amblyopia (see Table II), adjustment movement to monocular cover test less than 5 O , stereo acuity less than 200 seconds of arc (Titmus’ stereo test) and pathological response to Bagolini striated glass test. All patients except one confcsrm to the entity of “Mikrostrabismus” (Lang & Witmer 1973) or “monofixation syndrome (Parks 1969). Case No. 3 has a left hypertropia of 3O. All patients had clear media and fundcscopic appearance judged normal by at least two ophthalmologists. The difference in age between the normal and the pathological group is not thought to be of any relevance for the parameters under discussion.
Methods Stimulation procedure
Pattern-reversal stimulation was achieved by means of a commercially available device (Digitimer). A black-and-white checkerboard pattern was backprojected via a turnable mirror on a translucent screen placed in front of the patient at a distance of 1 m. Pattern reversal was obtained by rapid rotations of the mirror to and fro through 618
Visual Evoked Responses in Amblyopia a small angle, thereby displacing the pattern sideways exactly one square width. As the number of black-and-white checks on the screen did not change, overall luminance was kept constant. Reversal time (mirror movement) was measured and found to be 5 ms. The individual checks subtended a visual angle of 23'; the whole stimulating field constituted a square with a side length of 154 mm, corresponding to a visual angle of 8.8'. The luminance of the white squares was 1200 cdlmz and that of the black squares 12 cdlmz. The contrast was thus high, 98 O/o. Transient responses to a pattern-reversal frequency of 1.4 Hz were recorded in all subjects and steady-state responses to a 14 Hz reversal rate were recorded in some of the subjects. Monocular stimulation of each eye and binocular (dioptic) stimulation was used.
Recording technique
The VER was recorded between two silver - silver chloride electrodes applied to the scalp at Oz and Fz positions according to the International 10-20 system. The EEG activity was fed into a Grass P511 preamplifier with low and high frequency filters set at 0.1 and 1000 Hz respectively. Responses to 100 reversals were summated using a Didac 800 average computer. Analysis time was 200 ms, the signal being sampled at 0.25 ms intervals. The subjects were comfortably seated in a dark room without previous dark adaptation. Refractive errors, when present, were fully corrected. The subjects were requested to fixate on the centre of the screen and to pay constant attention to the pattern. At least two summations were made in each stimulus situation. When variations occurred, the largest response was used, as it was thought that all sources of error tended to give a decrease in amplitude. The responses were sometimes seen to deteriorate towards the end of prolonged experimental sessions. The obtained curves were written out on an X-Y-recorder (Hewlett-Packard 7005 B) and amplitude manually measured; 1 mm corresponding to 0.25 fiV. Latencies were electronically measured on the computer with a measurement accuracy of 0.25 ms (= one sampling interval). The amplitude of the responses was measured from the preceding negative peak to the trough of the major positive wave. Latency was taken as the time from the pattern reversal to the point of maximal positivity.
Results I. Steady-state responses
In the first part of this study, which included five normal subjects and five patients, the steady-state responses to square-wave pattern reversals at a rate of 14 Hz were obtained in addition to the transient responses (see below). A preliminary analysis cf the steady-state responses did not reveal any obvious differences when the normal group and the patient group were compared; thus this type of stimulation was not used in subsequent recordings in order to 619 40*
Subject No.
Sex, age (years)
0. s.
11.5 8.8 14.8 13.8 6.5 12.3 12.3 12.3 9.8 13.5
0.D.
11.5 7.3 14.3 17.0 6.8 12.8 9.5 11.8 7.8 13.8
VER amplitude (pV)
14.5 12.5 20.3 20.0 8.3 15.3 17.5 17.0 11.8 18.5
Binoc.
90 95 93 98 88 96
100
101 93 93
0.D.
100 93 93 100 93 95 95 103 88 98
0. s.
VER latency (ms)
Table I. VER parameters in the normal group.
95 93 90 98 90 90 92 98 88 98
Binoc.
I
23 4 20 2
4
0 17 3 19 4
Side diff.
126 142 137 118 122 120 142 138 120 134
Monoc.
Binoc. -
Relative VER ampl.
Sex, age
(years)
Case
No.
O.D.
O.S.
Visual acuity
Cover test
O.D.
O.S. Binoc.
VER amplitude (pV)
Relative VER ampl.
93 92 106 121 124 83 143
115
10 4 3 36 34 37 0 13
5
123 135
Binoc. (W Monoc.
39
(W
Side diff.
7
VER latency (ms)
Peter Wanger and Bengt Y n g v e Nilsson
shorten the procedure. The negative results with steady-state responses are at variance with findings reported by Arden et al. (1974). Differences in stimulus presentation may account for this: we used rapid square-wave modulation of the pattern while the apparatus used by Arden et al. (1974) produced a sinewave modulated stimulus. Differences in check size also affect the results (Sokol & Shaterian 1976).
I I. Transient responses
The VER amplitudes and latencies in individual cases are given in Tables I and 11. Representative examples of original recordings are shown in Fig. 1. In concordance with previously published VER studies the responses to pattern-reversal stimulation show a considerable interindividual variation in amplitude in the normal group as well as among the patients. Therefore, we shall in this context only discuss differences in amplitude to stimulation of right resp. left eye and to monocular versus binocular stimulus presentations in the
B
A
I
0
I
200rns
C
200 rns
0
-
0
200rns
Fig. I . Monocular and binocular visual evoked responses to pattern-reversal stimulation. Positivity at the occipital electrode gives downward deflection. A. Normal individual. Subject No. 6. B. Case No. 1. Considerable side difference in amplitude on monocular stimulation. C. Case No. 4. Lack of normal increase in amplitude on binocular stimulation.
622
Visual Evoked Responses in Amblyopia
B. Binocular amplitude
Side difference
'la 40
-
30
-
20
-
10
-
140
-
120
-
110
-
100
-
130
- 90-
0 -
a
a
N
P
N
P
Fig. 2. Comparison of monocular and binocular evoked responses to pattern-reversal stimulation in normal subjects (N) and in patients (P). A. The difference in response amplitude to monocular stimulation of right and left eyes is expressed in per cent of the largest response. B. The amplitude of the binocular response is given as per cent of the amplitude of the best monocular response (100 O/o indicates binocular response equal to monocular response).
same individual. Latency and waveform are fairly constant (Barrett et al. 1976; Nilsson 1976). In the normal subjects (Table I) the VER were found to fulfil the following criteria: 1. The amplitude difference between right and left eyes on monocular stimulaticn was less than 27 O/O (mean - 2 SD).
2. On binocular stimulation the response amplitude increased more than 12 O/O (mean - 2 s ~ above ) the best monocular response.
3. The latency differences between responses from left and right eyes were less than 5 ms.
In the patient groufi (Table 11) seven out of ten cases fell outside the normal range described above in at least one respect (cf. Fig. 2). Four patients (cases Nos. 1, 6, 7 and 8) exhibited a side difference of more than 300/0.In one patient (case No. 6) the amplitude increase on binocular stimulation was small 623
Peter Wanger and Bengt Yngve Nilsson
and in three further cases (Nos. 4, 5 and 9) the responses elicited by binocular stimulation were even smaller than the best monocular response (see Fig. 1 C). In Fig. 2 the relative amplitudes on monocular and binocular stimulation are graphically displayed. On monocular stimulation two patients (cases Nos. 1 and 4) demonstrated large side differences in latency ( 1 1 and 13 ms respectively). These cases, in addition to two further cases (Nos. 6 and 7 ) , presented latencies above the upper normal limit for this laboratory (107 ms; Nilsson 1976) when the amblyopic eye was stimulated. It was often observed that the response enlargement on binocular stimulation was, to a great extent, due to an enhancement of the negative peak immediately preceeding the major positive wave (see Fig. 1). In this respect there was no difference between the patients and the normal subjects.
Discussion Judging from earlier published VER studies (Arden et al. 1974; Spekreijse et al. 1972; Bornstein 1976) it was expected that pattern-reversal stimulation of the amblyopic eye should give a response of lower amplitude than stimulation of the normal eye. This expectation was not fulfilled in some cases. Only in four cases was an asymmetry of more than 27 O/O found. In addition, although a large side difference in amplitude was found in those cases, it was not always the normal eye that gave the greatest response. Such a “supernormal” amplitude to stimulation of the amblyopic eye was also seen by Tsutsui et al. (1973) and Grall et al. (1975), who used diffuse and patterned flash stimulation. In a paper published during the course of this study, Sokol & Shaterian (1976) have shown that normal and amblyopic eyes have different spatial frequency sensitivities. When the normal eye was stimulated, the maximal response amplitudes were usually found when individual checks in the checkerboard-pattern corresponded to a visual angle of 7.5 to 15 min, while stimulation of the amblyopic eyes elicited maximal responses when check-size was 30 min of arc or more. Spekreijse et al. (1972) also found a better response in the amblyopic eye when large checks were used. The check-size used in our study (23 min of arc) seems to fall in between these two ranges, which might explain the small and in some cases paradoxical side difference observed among our patients. The latency of the response to monocular stimulation was abnormally increased in four patients and a considerable left - right difference was seen in two of them. Yinon et al. (1974), using patterned flash stimulation, also described prolonged latencies when amblyopic eyes were compared to normal 624
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eyes. The physiological reason for this delay is unknown. However, Ikeda & Wright (1976) have demonstrated an increased latency of neuron discharges in cells of the lateral geniculate nucleus in kittens reared with artificially induced unilateral squints and similar mechanisms may be operating in human patients with amblyopia. In all normal subjects and in several of the patients a considerable increase in amplitude was seen to binocular stimulation. It is not possible to decide whether this reflects the activation of a n additional group of predominantly binocularly driven neurons or a summation of the activity from two groups of monocularly driven neurons (Hubel & Wiesel 1968). An interesting observation is that the mean amplitude to binocular stimulation in the normal group (15.6 p V ) exceeds the mean amplitude to monocular stimulation ( 1 1.3 p V ) by a factor of 1.38, which is very close to the 1/?improvement factor found when binocular and monocular performance are compared in psychophysical measurements of contrast sensitivity, flicker sensitivity, increment threshold and spatial sensitivity (Blake & Fox 1973; Blake & Levinson 1977). This finding might be regarded as a support for the integration model of signal detection theory (Green & Swets 1966) for neural summation between the eyes, outlined by Campbell & Green (1965). This model assumes complete summation of the output from the two monocular channels, containing uncorrelated noise. With binocular viewing, the signal strength is doubled, but because of the uncorrelated noise the summed signal is only increased by a factor of The present study has shown that recordings of the response to binocular stimulation give potentially valuable information in cases of amblyopia and/or defective binocular functions. The normal enlargement of the potential was absent in four cases; in three of them the binocular response was even smaller than the best monocular response, which might indicate that the amblyopic eye exerts an inhibitive effect on neurons excited by the normal eye. Tsutsui et al. (1973) also found a negative effect of binocular stimulation with patterned flash in scme amblyopic patients. Arden et al. (1974), however, assessed their results with binocular pattern-reversal stimuli as equivocal. If a side difference in amplitude of more than 27 O/O or an increase of amplitude on binocular stimulation of less than 120/0, or a side difference in latency of more than 5 ms are considered pathological, seven of our ten patients are abnormal in at least one aspect; three of them are pathological in more than one aspect. This means that if the functional state of amblyopic patients is to be estimated from VER recordings, all these different aspects must be taken into account. The regular occurrence of increased amplitude and also slightly shortened latency cn binocular stimulation in the normal group is thought to indicate
vr
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Peter Wanger and Bengt Y n g v e Nilsson lack of suppression. In the pathological g r o u p these features w e r e noted i n six cases. T h i s finding might indicate that suppression did not occur in these cases a n d that suppression a s explanation for t h e occurrence of amblyopia (Franceschetti & Burian 1971) is not valid in all cases. A n o t h e r explanation m a y be that the suppression scotoma i n these cases is very small a n d affects visual channels with higher spatial frequency sensitivity than tested by the checksize used in this study. When pattern-reversal VER is used for the diagnosis of lesions in t h e visual pathways, a s e. g. in multiple sclerosis, the possibility that an observed amplitude a n d latency difference between left a n d right eyes might be d u e t o an amblyopia must always be considered.
References Arden G. B., Barnard W. M. & Mushin A. S. (1974) Visually evoked responses in amblyopia. Brit. 1.Ophthal. 58, 183-192. Barrett G., Blumhardt L., Halliday A. M., Halliday E. & Kriss A. (1976) A paradox in the lateralisation of the visual evoked response. Nature (Lond.) 261, 253-255. Blake R. & Fox R. (1973) The psychophysical inquiry into binocular summation. Percept. Psychophys. 14, 161-185. Blake R. & Levinson E. (1977) Spatial properties of binocular neurones in the human visual system. Exp. Brain Res. 27, 221-232. Bornstein Y. (1976) “Visual evoked response” bei der Schielamblyopie. Ophthalmologica 172, 188-193. Burian H. M. & Von Noorden G. K. (1974) Binocular vision and ocular mobility. Theory and management of strabismus. C. V. Mosby Co., St. Louis. Campbell F. W. & Green D. G. (1965) Monocular versus binocular visual acuity. Nature (Lond.) 208, 191-192. Franceschetti A. T. & Burian H. M. (1971) Visually evoked responses in alternating strabismus. Amer. /. Ophthal. 71. 1292-1297. Green D. M. & Swets J. A. (1966) Signal Detection Theory and Psychophysics. Wiley, New York. Grall Y., Klein M., Delthil S., Keller J., Menguy C., Ninnin E. & GuCris H. (1975) Etude des potentiels CvoquCs visuels dans I’amblyopie fonctionelle. Ann. Oculist. 208, 429-435. Hubel D. H. & Wiesel T. N. (1968) Receptive fields and functional architecture of monkey striate cortex. J . Physiol. (Lond.) 195, 215-243. Ikeda H. & Wright M. J. (1976) Properties of LGN cells in kittens reared with convergent squint: A neurophysiological demonstration of amblyopia. E x p . Brain Res. 25, 6 3 4 7 . Lang J. & Witmer R. (1973) Mikrostrabismus. Buech. Augenarzt. 62, 1-121. Nilsson B. Y. (1976) Visuella “evoked responses” framkallade genom “pattern-reversal”-stimulering. Actn SOC.Med. Suec. 8.5, 241. Parks M. M. (1969) The monofixation syndrome. Trans. amer. ophthal. SOC. 67, 609-657.
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Visual Evoked Responses in Amblyopia Sokol S. & Shaterian E. T. (1976) The pattern-evoked cortical potential in amblyopia as an index of visual function. In: Moore S. & Mein Y., Eds. Orthopics: past, present, future, pp. 59-67. Stratton, New York. Spekreijse H., Khoe L. H. & van der Tweel L. H. (1972) A case of amblyopia; electrophysiology and psychophysics of luminance and contrast. In: Arden G. B., Ed. The visual system, pp. 141-156. Plenum Press, New York. Tsutsui J., Nakamura Y., Takenaka J. & Fukai S. (1973) Abnormality of the visual evoked response in various types of amblyopia. / u p . /. Ophthal. 17, 83-93. Yinon U., Jakobovitz L. & Auerbach E. (1974) The visual evoked response to stationary checkerboard patterns in children with strabismic amblyopia. Invest. Ophthaf. 13, 293-296.
Author’s address: Dr. Peter Wanger, Ugonmottagningen, Vlrdcentralen, Dragonvagen 92, S-194 00 Upplands Vasby. Sweden.
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