Exp. Eye Res. (1991) 53, 685-690

LETTERS

S Cone-driven

TO THE EDITORS

but not S Cone-type Enhanced S Cone

The ‘enhanced S cone syndrome ’ is a newly recognized retinal degeneration with a diversity of clinical expression but a single pattern of retinal dysfunction that includes severely reduced rod function, long (L) and middle (M) wavelength cone dysfunction, and hypersensitivity of the S (short wavelength, blue) cone system (Jacobson et al., 1990, 1991; Marmor et al., 1990 ; Kellner, Foerster and Zrenner, 199 1). The large atypical ERG in this syndrome, originally thought to be from the rod system (Gouras et al., 1985: Fishman and Peachey, 1989; Marmor, 19891, was shown to be predominantly S cone-mediated and its resemblance to published normal S cone ERG waveforms led to the speculation that it may be simply a super-normal S cone ERG (Jacobson et al., 1990 ; Marmor et al., 1990). We examined this notion in the present study by comparing the response properties of patients’ ERGS with those of normal S cone ERGS using short duration, long duration and flickering light stimuli on a bright yellow adapting field. The results indicate that the patients’ waveforms, although S cone-driven, are clearly not just large amplitude replicas of normal S cone ERGS. Five patients with the enhanced S cone syndrome (diagnosed. as in Marmor et al., 1990) and five normal subjects were studied with spectral ERGS. Two stimulus conditions were used to elicit ERGS. First, a strobe source (Nicolet GS-2000 Ganzfeld stimulator ; maximum luminance of the unattenuated white flash, 8.9 cd-s-m-“) with different intensities of five colors (Wratten 98,44,61,16 and 29) was flashed on a yellow adapting field (1300 cd rnm2: three halogen DNF lamps with Schott filter OG 530). Second, a continu0u.s light source (halogen ENG projector lamp: maximum. ganzfeld luminance of unattenuated white light, 1700 cd m-‘) interrupted by an electromechanical shutter was used to produce variable duration (loo-700 msec) full field flashes using the same colored filters on the same yellow adapting field. ERGS were recorded in light-adapted subjects with fully dilated pupils using Burian-Allen contact lens electrodes and a computer-based system (Nicolet Pathfinder II; bandpass 0.5-500 Hz). For strobe stimuli, 50-500 responses were averaged; for longer duration stimuli. 7 5 single responses were recorded and the traces without large eye movement artefacts were later summed by computer. Informed consent was obtained from subjects after the nature of the procedures was explained. Figure 1 (A) compares spectral ERGS to strobe 00144835/91/110685+06

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stimuli at 4.9 Hz on the bright yellow background in a normal subject and two patients. In the normal subject, yellow-orange elicits the largest ERG and there are similar but smaller waveforms to blue-green, green and red. The photopic efficiencies of these four stimuli suggest that L/M cones mainly mediate these ERGS. The ERG to blue light has slower timing and its waveform resembles published S cone ERGS (van Norren and Padmos, 1973: Miyake, Yagasaki and Ichikawa, 198 5 ; Sawusch, Pokorny and Smith, 19 8 7 ; Gouras and MacKay, 1990). Spectral ERGS in the five patients differed from normal. As the results of patients 1 and 3 exemplify, there were large ERGS to blue and blue-green and small or non-detectable ERGS to other colors. The patients’ waveforms were not all the same. Patient 1, for example, has some negativity followed by a larger positivity, whereas patient 3 has more negativity than positivity. S cone efficiencies of the stimuli indicate that the patients’ ERGS, independently of waveform, are mediated mainly by S cones. Scotopic efficiencies show that the waveforms could not be primarily rodmediated. Evidence for S cone-mediation is also provided in the graphs of ERG amplitude versus stimulus intensity weighted for the S cone mechanism. Both the positivity in patient 1 and the negativity in patient 3 show intensity-response functions to blue, blue-green and green that are coincident on the S cone intensity axis (Jacobson et al., 1990). Not shown in the graphs are the small fast waveforms to yelloworange (see below) and the non-detectable ERGS to red. For comparison, the range of normal intensityresponse functions to blue are plotted on the graph of patient 3’s data. Figure 1 (B) shows the diversity of S cone-mediated waveforms in the patients and how they compare to normal ERGS elicited with the same stimuli. A series of intensities of blue light at 4.9 Hz on the bright yellow background elicits positive waveforms from normal subjects. The amplitudes (at ‘ 0 ’ intensity : x = 8.4 ,uV, S.D. = 1.1 ,uV. n = 4) and implicit times (X = 39 msec, S.D. = 1.6 msec, n = 4) of this positive waveform and its intensity-response function [Fig.1 (A)] that appears to saturate (some contamination by L/M cones at higher intensities can occur: Gouras and MacKay, 1990) resemble data previously published for normal S cone ERGS (van Norren and Padmos, 1973 ; Miyake et al., 1985; Sawusch et al., 1987; Gouras and MacKay, 1990). In contrast, patients 1 and 2 have waveforms with negativity and positivity ; both com0 1991 Academic Press Limited

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ponents are present at the lowest stimulus intensities used. Patients 3 and 4 have predominantly negative waveforms and the responses near threshold appear varied widely among negative. ERG amplitudes patients and intensity-response functions of the negativity and positivity [Fig. 1 (A)] did not saturate. The mean implicit time of the positivity in patients 1, 2. and 5 was 57 msec (s.D. = 56 msec) and the timing of the negativity in the five patients was 26 msec (s.D. = 4.2 msec). Figure l(B) shows that with yellow-orange light and averaging of 400 responses, a small fast waveform was detectable in patients 1 and 3; the other patients had no clear responses to this stimulus. Implicit times for the a-wave (patient 1, 12 msec ; patient 3,ll msec) and b-wave (2 3 msec and 25 msec, respectively) of this waveform are similar to those of the large L/M cone response in normals (a-wave : 1c= 14.5 msec. s.D. = 1.3 msec; b-wave : x = 23 msec, S.D. = 0.6 msec, II = 4). Patient l’s ERG appeared to have a slower component also. With decreased levels of yellow adaptation, the fast component increased in amplitude. On- and off-responses in the patients’ ERGS were studied with 400-msec duration spectral stimuli on the bright yellow background and compared with normal ERGS (Fig. 2). As with the strobe stimuli [Fig. 1 (A)], yellow-orange elicits the largest ERGS in normals while blue and blue-green produce the largest responses in the patients. The normal ERGS in Fig. 2 have a transient on- and off-response (d-wave: Evers and Gouras. 19 86) to yellow-orange at the two higher intensities and to green at maximum intensity; onresponses are also present to blue-green, red and blue. Patients 1 and 3’s waveforms following onset of blue and blue-green resemble those with the strobe [Fig. 1 (A)], but after the initial negative and positive waves there is a return to negativity for the duration of the stimulus. This negative sustained response is most evident in patient 3’s responses to blue and blue-green but also appears to be present in patient l’s traces to blue-green (waveforms to blue were more complicated by eye movements). In patient 3’s traces, lower intensities of blue and blue-green and the maximum intensity of green appear to elicit mainly the negative sustained response. At light offset, there appear to be small positive-going waves in patient 1.

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Figure 3 (A) demonstrates the consistent behavior of patient 3’s unusual waveform with different durations of blue light on the bright yellow background and illustrates how these responses relate to the ERG elicited with a strobe (inset). An intensity series with 400 msec blue stimuli in Fig. 3 (B) shows that at threshold there is mainly a negative sustained response ; the positive transient component at light onset becomes more discernible at higher intensities. Figure 3 (C) shows waveforms in response to light offset following continuous stimulus presentation for about 2 set in a normal subject and patients 1 and 2, two patients with large positive components to their waveforms [Fig. 1 (B)]. This stimulus sequence was used to optimize recording of any off-response by decreasing the confounding effects of eye movement artefact that can follow light onset. To different intensities of blue light on the bright yellow background, the normal subject had no detectable responses but these patients had slow positive responses. Flickered spectral stimuli at 34 Hz on bright yellow background [Fig. 4(A)] elicit ERGS (computer averaging of 500 sweeps) in a normal subject that suggest that only L/M cones mediate the responses [see photopic efficiencies in Fig. 1 (A)] ; there is no detectable response to blue. The timing of the four responses appears very similar. Patient 3 shows responses to blue, blue-green and yellow-orange but no detectable responses to green and red. Timing of the yellow-orange response is like that of the normal ERGS but timing of the blue and blue-green responses is different. This pattern can be interpreted as showing S cone-mediated responses to blue and blue-green and an L/M-mediated response to yellow-orange. Flicker frequency plotted against ERG amplitude for the blue stimulus [Fig. 4(B)] indicates that normal subjects did not have detectable ERGS above 29 Hz (with these stimuli) while patients still had responses at 34 Hz (the highest frequency tested in three of the four patients). Patient 5. a severely affected patient. had amplitudes near the normal range at lower frequencies but responding persisted at 34 Hz. Patient 3 was tested at frequencies up to 44 Hz and responses, albeit small, were still detectable. This study demonstrates that although the ERG in patients with the enhanced S cone syndrome is S conedriven, its properties are distinctly different from those

Frc. 1. A (Upper). Spectral ERGS elicited with blue (B), blue-green (B-G), green (G), yellow-orange (YO) and red (R) strobe flashes at 4.9 Hz (maximum, ‘0’ strobe intensity) on a bright yellow background in a normal subject (age 30) and patients 1 and 3. Relative effectiveness of these colors for a photopic mechanism (CIE photopic spectral luminous efficiency function). S cones (Stiles pi-3 field sensitivity function), and a scotopic mechanism (CIE scotopic spectral luminous efficiency function) are shown to the right of the waveforms (Wyszecki and Stiles, 1982). A (Lower), Intensity response functions for spectral ERGS for patients 1 and 3. Amplitudes of the positive component of the waveform for patient 1 and the negative component for patient 3 are plotted against intensity weighted for S cones (Jacobson et al., 1990). In the graph of patient 3. hatching defines the range of amplitudes in four normal subjects (ages 20-46) for blue flashes on the yellow background. (0) Blue: (m) blue-green: (A) green. B, ERGS to different intensities of blue and maximum intensity of yellow-orange light on a bright yellow background in a normal subject (age 46) and patients 1.2, 3 and 4 (ages 31.2 5,49 and 37, respectively). Patients 1 and 3 had the only clear responses to the yellow-orange stimulus. Insets show responses to the same intensity of yelloworange stimulus but at two lower levels ( -0% and - 1.1 log units) of yellow background adaptation. Stimulus onset is trace onset. Calibrations for amplitude and timing are indicated.

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FIG. 2. Spectral ERGS to 400 msec duration lights on the bright yellow background in a normal subject (age 20) and patients 1 and 3. Relative effectiveness of the five stimulus colors for the photopic, S cone and scotopic mechanisms are similar to those of the strobe source [Fig. 1 (A)]. The three stimulus intensities shown for most colors, in relative log units, are ‘0’ or maximum (top), -0.4 (middle), and - 1.0 (bottom). For some colors, only the higher two intensities were recorded. The stimulus duration calibration (bottom trace in each column) is the output of a photometer centered in the ganzfeld and recorded with the same system as with the ERGS. B, Blue: B-G, blue-green; G, green: Y-G, yellow-orange: R, red.

of normal S cone ERGS. S cone ERGS to relatively short duration stimuli in normal human subjects have a

small positive waveform with slower implicit time than L/M cone ERGS and an intensity-response function that saturates at higher stimulus intensities (van Norren and Padmos, 1973 ; Miyake et al., 1985 : Sawusch et al., 1987; Gouras and MacKay, 1990). In contrast, the patients’ S cone-mediated ERGS had different degrees of negativity and positivity to strobe stimuli, amplitudes that could be similar to normal or much larger, implicit times that were slower than normal and intensity-response functions that did not saturate at the highest intensities used. Flicker responses were detectable in the patients’ S cone-driven ERGS up to 44 Hz compared to our normal flicker fusion frequency for this mechanism of less than 30 Hz, a value similar to one other ERG estimate (Miyake et al., 198 5) but lower than another (van Norren and Padmos, 1973) and lower than psychophysical estimates (Hess, Mullen and Zrenner,

1989). Although some of the patients’ ERGS may have responded at higher stimulus frequencies simply because they were larger than normal, this does not explain the data of patient 5, whose ERG was normal or smaller than normal at all the lower frequencies. The flicker results in this study suggest that the small amplitude ERG to 30 Hz white stimuli recorded by clinical techniques in these patients (Marmor et al., 1990) likely represents both L/M and S cones. Previously unrecognized features of the ERG in the enhanced S cone syndrome were revealed by the recordings to longer duration light stimuli. The prominent negativity in patient 3’s ERGS with strobe stimuli appears to be the leading edge of a negative sustained response. The positivity that dominates some patients’ waveforms (e.g. patients 1 and 2) is a transient component triggered at stimulus onset. A simple interpretation of the various waveforms found in this syndrome is that they are the result of differing amplitudes of a negative sustained potential and a

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positive transient response.More complex component analysis and waveform modelling basedon underlying physiology would be of significant interest. The positive responseor d-wave to stimulus offset in the S cone-mediated waveforms of patients 1 and 2 is in contrast to the lack of any detectable off-responsein our normal subjects with the same stimulus and recording conditions and to reports of a negative off-

response in S cone (and rod) ERGS in monkeys (Evers and Gouras, 1986). Cornea1 positive waves at light offset are usually associated with the L/M cone mechanism and off-center bipolar system and not the

S cone mechanism.

S cone signals have been thought

to operate only through on-center bipolar systems

(Evers and Gouras, 1986; Knapp and Schiller, 1984) but recent evidence suggests that the off system is

involved in S cone signal processing (Smith et al., 19 89). Whether the off-positivity in the patients’ ERGS (as recorded with AC-coupled amplifiers) is only an apparent d-wave due to the algebraic sum of various waveform components or is evidence for an abnormal post-receptoral mechanism in this syndrome needs to be clarified.

Acknowledgements This work wassupportedin part by Public Health Service Research Grant EY-05627 (SGJ), National Institutes of Health (Bethesda,MD), and the National Retinitis Pigmentosa Foundation, Inc. (Baltimore,MD). The authors thank Drs C. M. Kempand R. W. Knighton for critical advice: MS K. Stewart. M. I. Roman, L. Tieffembergand V. Zwaan for

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FIG. 4. A, Flicker spectral strobe ERGS [at log relative intensity, -0.7: see Fig. 1 (B)] on a bright yellow background at 34 Hz in a normal subject (age 46) and patient 3. Onset of stimuli are denoted as vertical bars along a line below each column of traces. B, Flicker frequency to a blue light (log relative intensity, -0.7) on the yellow background versus amplitude (measured from negative trough to positive peak), in four normal subjects (range of amplitudes shown in hatching) and patients 1 (a). 2 ( 0 ). 3 (0) and 5 (*) (age 35). Patient 3 was the only patient testedwith frequencies greater than 34 Hz. help with recordings; and Mrs fl. Koernig coordination of the study.

for clinical

ALEJANDRO J. ROMAN SAMUEL G. JACOBSON* Department of Ophthalmology, University of Miami School of Medicine, &scorn Palmer Eye Institute, Miami, FL 33101, U.S.A. *For correspondence at: Bascom Palmer Eye Institute. 10th

Avenue,

Miami,

FL 33136.

J 63X N.W.

U.S.A.

References Evers, H. LJ. and Gouras, P. (1986). Three cone mechanisms in the primate electroretinogram: two with, one without off-center bipolar responses. Vision Res. 26, 245-54. Fishman. G. A. and Peachey. N. S. (1989). Rod-cone dystrophy associated with a rod system electroretinogram obtained under photopic conditions. Ophthalmolugg 96, 913-18. Gouras, P.. MacKay, C., Evers. H. and Eggers, H. (1985). Computer assisted spectral electroretinography (CASE) : a tool for examining hereditary retinal degenerations. In Retinal Degeneration. Experimental and Clinical Studies. (Eds LaVail, M. M., Hollyfield, J. G. and Anderson, R. E.) Pp. 115-30. Alan R. Liss, Inc: New York. Gouras. P. and MacKay, C. J. (1990). Electroretinographic responses of the short-wavelength-sensitive cones. Inwest. Ophthahnol. Vis. Sci. 31, 1203-g. Hess, R. F., Mullen, K. T. and Zrenner, E. (19 89). Human photopic vision with only short wavelength cones: post-receptoral properties. 1. Phgsiol. 417, 15 l-72. Jacobson, S. G., Marmor, M. F., Kemp, C. M. and Knighton. R. W. (1990). SWS (blue) cone hypersensitivity in a (Received

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newly identified retinal degeneration. Invest. Oph thahd. Vis. Sci. 31. 827-38. Jacobson, S. G., Romgn. A. J.. Romrin. M. I.. Gass, J. U. M. and Parker. J. A. ( 199 1). Relatively enhanced S (blue) cone function in the Goldmann-Favre syndrome. Am. 1. Ophthalmol. 111, 446-5 3. Kellner. U., Foerster. M. H. and Zrenner. E. ( 19Y 1). Enhanced S cone sensitivity syndrome : electrophysiological and psychophysical findings. Invest. Ophthalmol. Vis. Sri. (Suppl.) 32. 902. Knapp, A. G. and Schiller, P. H. (1984). The contribution of on-bipolars to the electroretinogram of rabbits and monkeys : a study using 2-amino-4-phosphonobutyrate (APB). Vision Res. 24. 1841-6. Marmor, M. F. ( 1989). Large rod-like photopic signals in a possible new form of congenital night blindness. Dot. Ophthalmol. 71, 265-9. Marmor, M. F.. Jacobson, S. G., Foerster, M. H.. Kellner. U. and Weleber, R. G. (1990). Diagnostic clinical findings of a new syndrome with night blindness, maculopathy and enhanced S cone sensitivity. Am. 1. Ophthalmol. 110. 124-34. Miyake. Y.. Yagasaki, K. and Ichikawa. H. (1985). Differential diagnosis of congenital tritanopia and dominantly inherited juvenile optic atrophy. Arch. Ophthalmol. 103. 1496-501. Sawusch, M.. Pokorny, J. and Smith, V. C. (1987). Clinical electroretinography for short wavelength sensitive cones. Invest. Ophthalmol. Vis. Sci. 28, 966-74. Smith, E. L.. Harwerth. R. S.. Crawford, M. L. J. and Duncan, G. C. (1989)Xontribution of the retinal ON channels to scotopic and photopic spectral sensitivity. Visual Neurosci. 3, 225-39. van Norren, D. and Padmos, P. ( 19 7 3 ). Human and macaque blue cones studied with electroretinography. Vision Res. 13, 1241-54. Wyszecki, G. and Stiles, W. S. ( 1982). Color Science: Concepts and Methods, QuantitativeData and Formulae. 2nd edn. John Wiley CI Sons: New York. and accepted

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1997)

S cone-driven but not S cone-type electroretinograms in the enhanced S cone syndrome.

Exp. Eye Res. (1991) 53, 685-690 LETTERS S Cone-driven TO THE EDITORS but not S Cone-type Enhanced S Cone The ‘enhanced S cone syndrome ’ is a ne...
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