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Voluntary suppression of the multifocal electroretinogram
Voluntary Suppression of the Multifocal Electroretinogram Tamara R. Vrabec, MD,1 Elizabeth L. Affel, MS,1 John P. Gaughan, PhD,2 Rod Foroozan, MD,1 Matthew T. S. Tennant, MD,1 James M. Klancnik, Jr, MD,1 Christopher S. Jordan, BS,1 Peter J. Savino, MD1,2 Objective: To describe multifocal electroretinogram (mfERG) responses in 2 patients with nonorganic visual loss and in 11 eyes of 6 healthy persons who suppressed their mfERG responses. Design: Observational case series. Methods: The mfERG results were recorded in all individuals using the Veris Science 4.2 instrument. All subjects were instructed to adjust the hexagonal test pattern so that it was in best focus. A second mfERG was recorded subsequently in volunteers who attempted suppression with inattention and poor fixation and by adjusting the focus to greatest blur. Main Outcome Measures: Amplitude and latency of mfERG responses. Results: Suppressed mfERGs in patients with nonorganic visual loss and healthy volunteers demonstrated reduced amplitude, especially centrally. Amplitude reduction was statistically significant in the postsuppression as compared with the presuppression recordings in wave forms N1 and N2. Statistically significant shortening of postsuppression implicit times of P1 and N2 waveforms also was demonstrated. Conclusions: The mfERG responses may be suppressed voluntarily. Amplitude may be reduced. In contrast to most reported pathologic conditions, the implicit time is shortened. Ophthalmology 2004;111:169 –176 © 2004 by the American Academy of Ophthalmology.
The multifocal electroretinogram (mfERG) can record 100 or more focal responses from the macular retina in less than 10 minutes. It is recognized clinically as a valuable tool for evaluating small areas of retinal dysfunction that may be below the threshold of full-field ERG testing, as well as for differentiating diseases of the outer retina from those of the ganglion cells and optic nerve.1–3 An abnormal mfERG is considered by many clinicians to be an indication of posterior segment pathologic characteristics. This report describes abnormal mfERG results in 2 patients with nonorganic visual loss and in 11 eyes of 6 persons with normal vision who were able to suppress the mfERG response.
Originally received: June 19, 2002. Accepted: April 4, 2003. Manuscript no. 220418. 1 Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. 2 Department of Biostatistics, Temple University School of Medicine, Philadelphia, Pennsylvania. Presented at: Wills Eye Hospital Annual Conference, March 21, 2002, and Association for Research in Vision and Ophthalmology Annual Meeting, May 6, 2002. The authors have no proprietary interests in the products or devices mentioned herein. Correspondence to Tamara R. Vrabec, MD, Retina Service, Wills Eye Hospital, 900 Walnut Street, Philadelphia, PA 19107. © 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
Materials and Methods Wills Eye Hospital Institutional Review Board approval was obtained for the investigation. Between March 2001 and January 2002, 2 patients who underwent mfERG testing and subsequently were diagnosed as having nonorganic visual loss by one of the authors, and 6 healthy volunteers (the authors) with no history of ocular or medical problems underwent mfERG testing using the Veris Science 4.2 instrument (Electro-Diagnostic Imaging, Inc., San Mateo, CA). Fifteen of 16 eyes were tested in the following manner. Pupils were dilated with 2.5% phenylephedrine hydrochloride and 0.5% tropicamide. Corneas were anesthetized with topical proparacaine. The mfERG results were recorded with a bipolar contact lens electrode. A ground electrode was attached to the earlobe. Subjects were placed at a viewing distance of 40 cm. There was no head fixation device. The stimulus matrix consisted of 103 hexagons displayed on a monochrome 29⫻38-cm screen with a 1024⫻768 resolution monitor driven at a 75-Hz frame rate. Luminance was 100 cd/m2. The hexagons alternated between black (⬍5 cd/m2) and white (196 cd/m2) according to a binary m sequence of 215 elements. There was 1 frame per m step. Sessions consisted of 16 segments of approximately 27 seconds. Total recording time was approximately 8 minutes per eye. The responses from the trace arrays were summated spatially in 6 concentric rings. Patients and volunteers were instructed to adjust the focus dial of the Veris refractor camera so that the central fixation “x” was in the best focus. An initial mfERG was recorded as described. Immediately after the first recording, the 6 volunteers were asked to adjust the focus to greatest blur. A second mfERG was recorded. The technician who administered and monitored the test was ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.04.011
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Figure 1. Patient 1. The 3-dimensional plot (upper right) demonstrates reduced amplitude centrally that is also present on the trace array (left). Spatial summation wave forms generated with a ring stimulus pattern (lower right) show shortened implicit time in the P1 (positive) and N2 (second negative) wave forms, especially of the peripheral rings (the lower 3 of the 6 wave forms).
unable to detect abnormalities of focus or fixation in the video monitor image of the cornea in either patients or volunteers. After the test, several volunteers reported that additional techniques, including eccentric fixation and inattention, were used to augment suppression. Volunteer 2 reported avoiding central fixation by shifting focus among various points around the central “x” fixation target throughout the test. Volunteer 3 fixated on the edge of the pattern on the screen rather than on the fixation “x.” Volunteer 4 maintained central fixation, but “daydreamed” through out the test. Volunteer 5 maintained central fixation but reported concentrating on the shapes formed by the aggregates of the defocused hexagons. Best-corrected visual acuity, manifest refractive error, results of slit-lamp biomicroscopy, and examination of the macula with the 90-diopter (D) lens were recorded for all individuals. For the statistical analysis, the experimental design was a 4-factor (eye, trial [location of waveform], suppression strategy, and period [before vs. after suppression]) mixed design with repeated measures on 2 factors (trial, period). The null hypothesis was that there was no difference in the measured parameters among the periods or strategies. Before analysis, all data were tested for normality using the Shapiro-Wilk test. The data for all the dependent variables were significantly nonnormal. To apply analysis of variance methods, a “normalized-rank” transformation was applied to the data. The rank-transformed data were analyzed using a mixed-model analysis of variance for repeated measures. Multiple pair-wise comparisons on periods (vs. computer scores) used the Dunn-Bonferroni adjustment to maintain an experimentwise type I error of 0.05 or less. Differences between group means (rejection of the null hypothesis) were considered significant if the probability of chance occurrence was less than 0.05 using 2-tailed
170
tests. All data were analyzed using SAS software version 8.1 (SAS Institute, Cary, NC).
Case Reports Patient 1 A 34-year-old woman with a previous medical history significant for depression was referred for retinal evaluation. She reported blurred near vision of 8 months’ duration with “lots of dots and lines up close.” Visual loss began immediately after she fell down the steps. Central nervous system evaluation at the time of injury, including electroencephalogram, computed tomography scan, and magnetic resonance imaging scan results, was normal. Previous ocular examination, including ERG and visual evoked response results, also was normal. However, mfERG was remarkable for reduced amplitude in the central macula greater in the left eye than in the right eye. Implicit times were normal in the right eye and slightly shortened, especially in the N2 waveforms, in the left eye (Fig 1). Visual acuity was 20/300 in the right eye and 20/200 in the left eye. The patient was well groomed and was wearing flawless facial makeup. She had no difficulty ambulating in a darkened room or making direct eye contact. Pupils were normal. Anterior segment biomicroscopic examination and dilated fundus examination results were normal. An intravenous fluorescein angiogram revealed neither macular retinal pigment epithelial abnormalities nor delayed retinal or choroidal arterial filling. When the normal clinical findings and results of diagnostic testing were discussed with the patient, she stated that she was
Vrabec et al 䡠 Multifocal Electroretinogram
Figure 2. Patient 2. The 3-dimensional plot (upper right) demonstrates reduced amplitude centrally that is also present on trace array (left). Spatial summation wave forms generated with a ring stimulus pattern (lower right) show shortened implicit time in the P1 (positive) and N2 (second negative) in all but the uppermost, central wave form.
aware that her visual loss could be psychosomatic and that she believed that after undergoing electroconvulsive therapy, she would regain her vision.
Patient 2 A 46-year-old woman reported progressive visual loss in her left eye of several years’ duration and amblyopia in her right eye since childhood. Her past ocular history was remarkable for normal electrophysiologic evaluation and magnetic resonance imaging results 2 years earlier. Her medical history was remarkable for
anorexia. Her social history was remarkable for childhood in an orphanage, a troubled marriage, and a chronically ill child. Visual acuity was hand motions in the right eye and 20/100 in the left. The patient was perfectly coifed and her facial make-up was without flaw. Pupil responses were normal. Anterior segment biomicroscopy and dilated posterior segment examination results were normal. Repeat ERG and visual evoked response results were normal. The mfERG demonstrated reduced amplitudes in the central macula in both eyes. Implicit times were shortened in the peripheral macula in both eyes (Fig 2). The intravenous fluorescein angiogram was normal in both eyes. There was no evidence of
Table 1. Clinical Characteristics of Volunteers Volunteer No.
Age (yrs)
Gender
1
43
F
2 3
40 31
F M
4
28
M
5
29
M
6
25
M
Eye
BestCorrected Visual Acuity
Refractive Error (D)
Right Left Left Right Left Right Left Right Left Right Left
20/20 20/20 20/20 20/20 20/20 20/12 20/12 20/20 20/20 20/20 20/20
0.25–0.75 ⫻ 88 plano–1.00 ⫻ 85 0.75–0.25 ⫻ 75 ⫺0.5 ⫺0.75 ⫺4.25 ⫺5.25 ⫺6 ⫺5.5 ⫺7 ⫺7
Suppression Strategy Defocused image Defocused image, poor fixation Defocused image, eccentric fixation Defocused image, inattention Defocused image, inattention Defocused image
D ⫽ diopters; F ⫽ female; M ⫽ male.
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Figure 3. Presuppression (left) and postsuppression (right) multifocal electroretinogram 3-dimensional amplitude plots of volunteers 2, 6, 3, and 5 (top to bottom, respectively). Note the loss of amplitude of all central peaks, as well as the loss of blind spot as a result of poor fixation in volunteers 2 and 3.
macular retinal pigment epithelial abnormalities, and there was no delay in retinal arterial filling. Orbital Doppler studies demonstrated normal flow velocity in the posterior ciliary circulation as well as in the central retinal and ophthalmic arteries. Goldman fields demonstrated marked constriction to 4° in the right eye with a red test object and to 10° with a white test object. Multiple blindspots were present in both eyes. The examiner noted that the patient’s ability to navigate in an unfamiliar surrounding was not in keeping with the extent of visual field abnormality. She also was able to dial a telephone without assistance, until she realized that she had been observed. Sweep visual evoked potentials showed a visual acuity of 20/106 in the right eye and 20/48 in the left eye; tests were reported as reliable and were indicative of visual function of at least this level. When the patient learned her visual acuity did not meet requirements for driving, she requested to be retested
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and was able to read counting fingers in the right eye and 20/30 in the left eye.
Results The volunteers included 2 women and 4 men, aged 25 to 43 years (Table 1). Ocular and medical histories were negative. Visual acuity was 20/20 or better in all eyes. Manifest refractive errors ranged from ⫹0.75 to ⫺7.00 D of spherical aberration and up to ⫺1.00 D of astigmatism. Slit-lamp biomicroscopy and fundus examination with the 90-D lens were normal in all eyes. All mfERG recordings were reviewed by one of the authors (TRV). Results of volunteer mfERGs before and after voluntary suppression are illustrated in Figures 3 to 5. All postsuppression
Vrabec et al 䡠 Multifocal Electroretinogram Statistical analysis of the implicit times and amplitudes of waveforms N1, P1, and N2 was performed (Fig 6). Analysis of latency values (implicit times) demonstrated that there was no statistically significant difference for N1 values in fellow eyes of the volunteers between presuppression and postsuppression N1 values or between suppression strategies used (defocus vs. defocus plus inattention or eccentric fixation). For P1, no statistically significant difference could be demonstrated for values in fellow eyes of the volunteers; however, there was a statistically significant difference between presuppression and postsuppression values (P ⫽ 0.0039), but not between suppression strategies used. For N2, no statistically significant difference could be demonstrated for N2 values in fellow eyes of the volunteers; however, there was a statistically significant difference between presuppression and postsuppression values (P ⫽ 0.0009), but not between suppression strategies used. Analysis of amplitude values revealed no statistically significant difference for N1 or P1 values in fellow eyes of the volunteers or between suppression strategies used; however, there was a statistically significant difference between presuppression and postsuppression values for N1 (P ⫽ 0.0254). Also for N2, there was a statistically significant difference for N2 values in fellow eyes of the volunteers (P ⫽ 0.0482), as well as a statistically significant difference between presuppression and postsuppression values (P ⫽ 0.0207), but not between suppression strategies used. When the data from volunteers as a group were compared with the computer-generated normal values, no statistically significant difference could be detected in either latency or amplitude values for any wave forms.
Discussion
Figure 4. Spatial summation tracings from volunteers 2, 6, 3, and 5 (top to bottom, respectively) before (left) and after (right) suppression. A concentric ring stimulus pattern was used. Red tracings are Veris 4.2– generated normals. Implicit times are shortened after suppression. Shortening of implicit time is more noticeable in peripheral rings (lower 3 waveforms), especially in N2, the second negative wave.
3-dimensional plots demonstrated loss of central peaks (Fig 3). The plots of patients 2 and 3, who failed to maintain central fixation, also demonstrate loss of the optic nerve depression (blind spot). Trace arrays demonstrated diffuse amplitude reduction most pronounced centrally in all volunteers (Fig 5). Similar findings were observed in the patients with nonorganic visual loss (Figs 1 and 2). Latencies were not delayed. Implicit times for waveforms P1 and N2 in volunteers were shortened in all eyes compared with Veris 4.2-generated normals (Fig 4). Shortening of implicit time was most pronounced peripherally (wave forms 5 and 6). Similar findings were present in the patients with nonorganic visual loss, although shortening of implicit times was less pronounced in patient 1.
This report demonstrates that the amplitude of the mfERG signals may be suppressed by motivated persons who have healthy retinas and normal vision. We believe the data indicate that the volunteers, when analyzed as a group, were able to shorten implicit times of waveforms P1 and N2 and to reduce amplitude values for waveforms N1 and N2 after voluntary suppression, as indicated by the significant differences for each individual’s presuppression and postsuppression data. The mechanism for the reduction is likely complex and related in part to refractive error induced by purposeful blurring of the test image, eccentric fixation, and conscious efforts to ignore the hexagonal stimulus. The lack of statistical significance of postsuppression values with respect to computer-generated normal values may result from factors including small sample size and wide variability of volunteers’ values recorded for each waveform amplitude and latency. Refractive error could be adjusted from ⫺10 to ⫹10 D with the focusing dial on the Veris 4.2 instrument used in this study. For the individuals in this series whose refractive errors ranged from ⫺7.00 to ⫹0.75 D, this would allow for between ⫹10.75 and ⫺17 D of induced spherical refractive error when the testing image was adjusted to greatest blur. Previous reports have shown that refractive errors of up to 6.00 D did not influence the latency or amplitude of the mfERG response when viewing distance was adjusted to compensate for changes in image size.4 Our goal was to suppress the mfERG under standard testing conditions experienced by patients; therefore, no adjustments of viewing
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Figure 5. Trace array patterns from volunteers 2, 6, 3, and 5 (left to right, respectively) before (above) and after (below) suppression. Note the diffuse amplitude reduction in volunteers 2 and 3, who achieved suppression with blurring of the target and poor fixation. Remaining trace arrays demonstrate a loss of sensitivity centrally.
distance were made. We assumed that an examiner would not know that the patient purposefully had blurred the testing image if the patient claimed that it was in optimal focus and hence would have no reason to adjust the testing distance. The larger change of refractive error without viewing distance adjustment is likely in part to account for the abnormal mfERG amplitudes noted in this study. A possible mechanism for this amplitude reduction is that the larger area of retina stimulated by the defocused test image would generate the normally lower amplitude signals from more peripheral retina, which would lower the overall amplitude of the recording. It is also likely that poor fixation contributed to reduction of the mfERG amplitudes of several volunteers in this series. In addition to decreased amplitude of the central peak in the 3-dimensional plots, we observed that the optic nerve depression was lost in the 2 volunteers who fixated poorly. Poor fixation causes the hexagonal test pattern to stimulate areas of the retina other than the one it was intended to target. The responses from the surrounding retina contribute to the response of the intended field of stimulation. A blind spot may disappear if surrounding retinal signals are interpreted by the mfERG instrument to be present in the area where the blind spot would be expected. In a previous report, fixation quality did not adversely affect low-resolution stimuli (61 elements, 2.4 degrees). However, smaller stimuli were believed to be more susceptible to fixation fluctuations during mfERG recording.5 Greater amplitudes
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of suppression and loss of blind spot were noted in the volunteers tested with a 103-element stimulus who fixated poorly. Although the results of the current study did not seem to be influenced by inattention independent of the effects of blurred image and in some cases unsteady fixation, it is possible that inattention may have a role in the voluntary suppression of the mfERG in some cases. Voluntary alteration or obliteration of pattern-shift visual evoked potential amplitude was reported in 5 of 15 volunteers using various methods including meditation, daydreaming, and convergence.6 This report suggests that factitious abnormal responses to electrophysiologic studies such as visual evoked potential may be generated by motivated individuals. We are not certain which of the above-mentioned methods of voluntary suppression may have been used by the patients we report who had nonorganic visual loss. An additional possibility is suggested by reported changes in color processing regions of the brain illustrated by positron emission tomography scan in hypnotized individuals. The fusiform lingual region of the left and right hemispheres were active when individuals were instructed to see color regardless of whether the image they were shown was in color or monochrome.7 This suggests that test results may be affected by strong altered perceptions of reality, as may occur in persons with functional illness. Reported implicit times in various pathologic conditions typically are either delayed or normal.8 –16 In contrast, im-
Vrabec et al 䡠 Multifocal Electroretinogram
Figure 6. Results of statistical analysis of amplitude and latency values of N1, P1, and N2 waveforms before and after suppression. A, For latency values (implicit times), no statistically significant difference could be demonstrated between presuppression and postsuppression N1 values. There was a statistically significant difference between presuppression and postsuppression P1 values (P ⫽ 0.0039) and N2 values (P ⫽ 0.0009). B, For amplitude values, there was a statistically significant difference in presuppression and postsuppression values for N1 (P ⫽ 0.0254), but no statistically significant difference could be demonstrated between presuppression and postsuppression P1 values. There was a statistically significant difference between presuppression and postsuppression N2 values (P ⫽ 0.0207). Mean presuppression and postsuppression values for amplitude and latency of each waveform are indicated by the horizontal line with corresponding numbers on each plot.
plicit times of suppressed mfERGs of volunteers and patients with nonorganic visual loss were shortened for the P1 and especially N2 waveforms (Figs 1, 2, 4, and 6). The spatial distribution of implicit times after suppression deviated from previously reported topographic patterns for normals.17,18 Normal implicit time latency is longest in the periphery of the stimulated field. In this series, the implicit times were shortest in the peripheral rings. The reason for this observation in both the volunteers and patients with nonorganic visual loss is uncertain. In summary, this report demonstrates that the amplitude of the mfERG may be suppressed voluntarily. However, unlike pathologic conditions in which implicit times have been reported as normal or delayed, the implicit times of the voluntarily suppressed mfERGs were shortened. Shortening was most apparent in the N2 waveform and in the peripheral ring tracings. Similar findings were observed in patients
with nonorganic visual loss. Unlike patients with normal or near normal fundus examination results and underlying pathologic characteristics, including ocular ischemia, cone dystrophy, and diabetes mellitus, among others, which may have reduced mfERG amplitudes, the mfERG implicit times were not delayed. We conclude that in patients with abnormal mfERG amplitudes that do not correlate with clinical findings and especially if voluntary or functional suppression is suspected, it is also important to review implicit times for shortening.
References 1. Hood DC. Assessing retinal functions with the multifocal technique. Prog Retin Eye Res 2000;19:607– 46. 2. Kretschmann U, Bock M, Gockeln R, Zrenner E. Clinical
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3. 4. 5. 6. 7. 8. 9. 10.
applications of multifocal electroretinography. Doc Ophthalmol 2000;100:99 –113. Hasegawa S, Oshima A, Hayakawa Y, et al. Multifocal electroretinograms in patients with branch retinal artery occlusions. Invest Ophthalmol Vis Sci 2001;42:298 –305. Palmowski AM, Berninger T, Allgayer R, et al. Effects of refractive blur on the multifocal electroretinogram. Doc Ophthalmol 1999;99:41–54. Chisholm JA, Keating D, Parks S, Evans AL. The impact of fixation on the multifocal electroretinogram. Doc Ophthalmol 2001;102:131–9. Bumgartner J, Epstein CM. Voluntary alteration of visual evoked potentials. Ann Neurol 1982;12:475– 8. Kosslyn SM, Thompson WL, Constantini-Ferrando MF, et al. Hypnotic visual illusion alters color processing in the brain. Am J Psychiatry 2000;157:1279 – 84. Seeliger MW, Zrenner E, Apfelstedt-Sylla E, Jaissle GB. Identification of Usher syndrome subtypes by ERG implicit time. Invest Ophthlamol Vis Sci 2001;42:3066 –71. Kondo M, Miyake Y, Kondo N, et al. Multifocal ERG findings in complete type congenital stationary night blindness. Invest Ophthlamol Vis Sci 2001;42:1342– 8. Shimada Y, Li Y, Bearse MA Jr, et al. Assessment of early retinal changes in diabetes using a new multifocal ERG protocol. Br J Ophthalmol 2001;85:414 –9.
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11. Li J, Tso MO, Lam TT. Reduced amplitude and delayed latency in foveal response of multifocal electroretinogram in early age related macular degeneration. Br J Ophthalmol 2001;85:287–90. 12. Chappelow AV, Marmor MF. Multifocal electroretinogram abnormalities persist following resolution of central serous chorioretinopathy. Arch Ophthalmol 2000;118:1211–5. 13. Sasoh M, Yoshida S, Kuze M, Uji Y. The multifocal electroretinogram in retinal detachment. Doc Ophthalmol 1997–98; 94:239 –52. 14. Kretschmann U, Seeliger MW, Ruether K, et al. Multifocal electroretinography in patients with Stargardt’s macular dystrophy. Br J Ophthlamol 1998;82:267–75. 15. Arai M, Nao-i N, Sawada A, Hayashida T. Multifocal electroretinogram indicates visual field loss in acute zonal occult outer retinopathy. Am J Ophthalmol 1998;126:466 –9. 16. Piao CH, Kondo M, Tanikawa A, et al. Multifocal electroretinogram in occult macular dystrophy. Invest Ophthalmol Vis Sci 2000;41:513–7. 17. Seeliger MW, Kretschmann UH, Apfelstedt-Sylla E, Zrenner E. Implicit time topography of multifocal electroretinograms. Invest Ophthalmol Vis Sci 1998;39:718 –23. 18. Nagatomo A, Nao-i N, Maruiwa F, et al. Multifocal electroretinograms in normal subjects. Jpn J Ophthalmol 1998;42: 129 –35.
The multifocal electroretinogram (mfERG) can record 100 or more focal responses from the macular retina in less than 10 minutes. It is recognized clinically as a valuable tool for evaluating small areas of retinal dysfunction that may be below the threshold of full-field ERG testing, as well as for differentiating diseases of the outer retina from those of the ganglion cells and optic nerve.1–3 An abnormal mfERG is considered by many clinicians to be an indication of posterior segment pathologic characteristics. This report describes abnormal mfERG results in 2 patients with nonorganic visual loss and in 11 eyes of 6 persons with normal vision who were able to suppress the mfERG response.
Originally received: June 19, 2002. Accepted: April 4, 2003. Manuscript no. 220418. 1 Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. 2 Department of Biostatistics, Temple University School of Medicine, Philadelphia, Pennsylvania. Presented at: Wills Eye Hospital Annual Conference, March 21, 2002, and Association for Research in Vision and Ophthalmology Annual Meeting, May 6, 2002. The authors have no proprietary interests in the products or devices mentioned herein. Correspondence to Tamara R. Vrabec, MD, Retina Service, Wills Eye Hospital, 900 Walnut Street, Philadelphia, PA 19107. © 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
Materials and Methods Wills Eye Hospital Institutional Review Board approval was obtained for the investigation. Between March 2001 and January 2002, 2 patients who underwent mfERG testing and subsequently were diagnosed as having nonorganic visual loss by one of the authors, and 6 healthy volunteers (the authors) with no history of ocular or medical problems underwent mfERG testing using the Veris Science 4.2 instrument (Electro-Diagnostic Imaging, Inc., San Mateo, CA). Fifteen of 16 eyes were tested in the following manner. Pupils were dilated with 2.5% phenylephedrine hydrochloride and 0.5% tropicamide. Corneas were anesthetized with topical proparacaine. The mfERG results were recorded with a bipolar contact lens electrode. A ground electrode was attached to the earlobe. Subjects were placed at a viewing distance of 40 cm. There was no head fixation device. The stimulus matrix consisted of 103 hexagons displayed on a monochrome 29⫻38-cm screen with a 1024⫻768 resolution monitor driven at a 75-Hz frame rate. Luminance was 100 cd/m2. The hexagons alternated between black (⬍5 cd/m2) and white (196 cd/m2) according to a binary m sequence of 215 elements. There was 1 frame per m step. Sessions consisted of 16 segments of approximately 27 seconds. Total recording time was approximately 8 minutes per eye. The responses from the trace arrays were summated spatially in 6 concentric rings. Patients and volunteers were instructed to adjust the focus dial of the Veris refractor camera so that the central fixation “x” was in the best focus. An initial mfERG was recorded as described. Immediately after the first recording, the 6 volunteers were asked to adjust the focus to greatest blur. A second mfERG was recorded. The technician who administered and monitored the test was ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.04.011
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Figure 1. Patient 1. The 3-dimensional plot (upper right) demonstrates reduced amplitude centrally that is also present on the trace array (left). Spatial summation wave forms generated with a ring stimulus pattern (lower right) show shortened implicit time in the P1 (positive) and N2 (second negative) wave forms, especially of the peripheral rings (the lower 3 of the 6 wave forms).
unable to detect abnormalities of focus or fixation in the video monitor image of the cornea in either patients or volunteers. After the test, several volunteers reported that additional techniques, including eccentric fixation and inattention, were used to augment suppression. Volunteer 2 reported avoiding central fixation by shifting focus among various points around the central “x” fixation target throughout the test. Volunteer 3 fixated on the edge of the pattern on the screen rather than on the fixation “x.” Volunteer 4 maintained central fixation, but “daydreamed” through out the test. Volunteer 5 maintained central fixation but reported concentrating on the shapes formed by the aggregates of the defocused hexagons. Best-corrected visual acuity, manifest refractive error, results of slit-lamp biomicroscopy, and examination of the macula with the 90-diopter (D) lens were recorded for all individuals. For the statistical analysis, the experimental design was a 4-factor (eye, trial [location of waveform], suppression strategy, and period [before vs. after suppression]) mixed design with repeated measures on 2 factors (trial, period). The null hypothesis was that there was no difference in the measured parameters among the periods or strategies. Before analysis, all data were tested for normality using the Shapiro-Wilk test. The data for all the dependent variables were significantly nonnormal. To apply analysis of variance methods, a “normalized-rank” transformation was applied to the data. The rank-transformed data were analyzed using a mixed-model analysis of variance for repeated measures. Multiple pair-wise comparisons on periods (vs. computer scores) used the Dunn-Bonferroni adjustment to maintain an experimentwise type I error of 0.05 or less. Differences between group means (rejection of the null hypothesis) were considered significant if the probability of chance occurrence was less than 0.05 using 2-tailed
170
tests. All data were analyzed using SAS software version 8.1 (SAS Institute, Cary, NC).
Case Reports Patient 1 A 34-year-old woman with a previous medical history significant for depression was referred for retinal evaluation. She reported blurred near vision of 8 months’ duration with “lots of dots and lines up close.” Visual loss began immediately after she fell down the steps. Central nervous system evaluation at the time of injury, including electroencephalogram, computed tomography scan, and magnetic resonance imaging scan results, was normal. Previous ocular examination, including ERG and visual evoked response results, also was normal. However, mfERG was remarkable for reduced amplitude in the central macula greater in the left eye than in the right eye. Implicit times were normal in the right eye and slightly shortened, especially in the N2 waveforms, in the left eye (Fig 1). Visual acuity was 20/300 in the right eye and 20/200 in the left eye. The patient was well groomed and was wearing flawless facial makeup. She had no difficulty ambulating in a darkened room or making direct eye contact. Pupils were normal. Anterior segment biomicroscopic examination and dilated fundus examination results were normal. An intravenous fluorescein angiogram revealed neither macular retinal pigment epithelial abnormalities nor delayed retinal or choroidal arterial filling. When the normal clinical findings and results of diagnostic testing were discussed with the patient, she stated that she was
Vrabec et al 䡠 Multifocal Electroretinogram
Figure 2. Patient 2. The 3-dimensional plot (upper right) demonstrates reduced amplitude centrally that is also present on trace array (left). Spatial summation wave forms generated with a ring stimulus pattern (lower right) show shortened implicit time in the P1 (positive) and N2 (second negative) in all but the uppermost, central wave form.
aware that her visual loss could be psychosomatic and that she believed that after undergoing electroconvulsive therapy, she would regain her vision.
Patient 2 A 46-year-old woman reported progressive visual loss in her left eye of several years’ duration and amblyopia in her right eye since childhood. Her past ocular history was remarkable for normal electrophysiologic evaluation and magnetic resonance imaging results 2 years earlier. Her medical history was remarkable for
anorexia. Her social history was remarkable for childhood in an orphanage, a troubled marriage, and a chronically ill child. Visual acuity was hand motions in the right eye and 20/100 in the left. The patient was perfectly coifed and her facial make-up was without flaw. Pupil responses were normal. Anterior segment biomicroscopy and dilated posterior segment examination results were normal. Repeat ERG and visual evoked response results were normal. The mfERG demonstrated reduced amplitudes in the central macula in both eyes. Implicit times were shortened in the peripheral macula in both eyes (Fig 2). The intravenous fluorescein angiogram was normal in both eyes. There was no evidence of
Table 1. Clinical Characteristics of Volunteers Volunteer No.
Age (yrs)
Gender
1
43
F
2 3
40 31
F M
4
28
M
5
29
M
6
25
M
Eye
BestCorrected Visual Acuity
Refractive Error (D)
Right Left Left Right Left Right Left Right Left Right Left
20/20 20/20 20/20 20/20 20/20 20/12 20/12 20/20 20/20 20/20 20/20
0.25–0.75 ⫻ 88 plano–1.00 ⫻ 85 0.75–0.25 ⫻ 75 ⫺0.5 ⫺0.75 ⫺4.25 ⫺5.25 ⫺6 ⫺5.5 ⫺7 ⫺7
Suppression Strategy Defocused image Defocused image, poor fixation Defocused image, eccentric fixation Defocused image, inattention Defocused image, inattention Defocused image
D ⫽ diopters; F ⫽ female; M ⫽ male.
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Figure 3. Presuppression (left) and postsuppression (right) multifocal electroretinogram 3-dimensional amplitude plots of volunteers 2, 6, 3, and 5 (top to bottom, respectively). Note the loss of amplitude of all central peaks, as well as the loss of blind spot as a result of poor fixation in volunteers 2 and 3.
macular retinal pigment epithelial abnormalities, and there was no delay in retinal arterial filling. Orbital Doppler studies demonstrated normal flow velocity in the posterior ciliary circulation as well as in the central retinal and ophthalmic arteries. Goldman fields demonstrated marked constriction to 4° in the right eye with a red test object and to 10° with a white test object. Multiple blindspots were present in both eyes. The examiner noted that the patient’s ability to navigate in an unfamiliar surrounding was not in keeping with the extent of visual field abnormality. She also was able to dial a telephone without assistance, until she realized that she had been observed. Sweep visual evoked potentials showed a visual acuity of 20/106 in the right eye and 20/48 in the left eye; tests were reported as reliable and were indicative of visual function of at least this level. When the patient learned her visual acuity did not meet requirements for driving, she requested to be retested
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and was able to read counting fingers in the right eye and 20/30 in the left eye.
Results The volunteers included 2 women and 4 men, aged 25 to 43 years (Table 1). Ocular and medical histories were negative. Visual acuity was 20/20 or better in all eyes. Manifest refractive errors ranged from ⫹0.75 to ⫺7.00 D of spherical aberration and up to ⫺1.00 D of astigmatism. Slit-lamp biomicroscopy and fundus examination with the 90-D lens were normal in all eyes. All mfERG recordings were reviewed by one of the authors (TRV). Results of volunteer mfERGs before and after voluntary suppression are illustrated in Figures 3 to 5. All postsuppression
Vrabec et al 䡠 Multifocal Electroretinogram Statistical analysis of the implicit times and amplitudes of waveforms N1, P1, and N2 was performed (Fig 6). Analysis of latency values (implicit times) demonstrated that there was no statistically significant difference for N1 values in fellow eyes of the volunteers between presuppression and postsuppression N1 values or between suppression strategies used (defocus vs. defocus plus inattention or eccentric fixation). For P1, no statistically significant difference could be demonstrated for values in fellow eyes of the volunteers; however, there was a statistically significant difference between presuppression and postsuppression values (P ⫽ 0.0039), but not between suppression strategies used. For N2, no statistically significant difference could be demonstrated for N2 values in fellow eyes of the volunteers; however, there was a statistically significant difference between presuppression and postsuppression values (P ⫽ 0.0009), but not between suppression strategies used. Analysis of amplitude values revealed no statistically significant difference for N1 or P1 values in fellow eyes of the volunteers or between suppression strategies used; however, there was a statistically significant difference between presuppression and postsuppression values for N1 (P ⫽ 0.0254). Also for N2, there was a statistically significant difference for N2 values in fellow eyes of the volunteers (P ⫽ 0.0482), as well as a statistically significant difference between presuppression and postsuppression values (P ⫽ 0.0207), but not between suppression strategies used. When the data from volunteers as a group were compared with the computer-generated normal values, no statistically significant difference could be detected in either latency or amplitude values for any wave forms.
Discussion
Figure 4. Spatial summation tracings from volunteers 2, 6, 3, and 5 (top to bottom, respectively) before (left) and after (right) suppression. A concentric ring stimulus pattern was used. Red tracings are Veris 4.2– generated normals. Implicit times are shortened after suppression. Shortening of implicit time is more noticeable in peripheral rings (lower 3 waveforms), especially in N2, the second negative wave.
3-dimensional plots demonstrated loss of central peaks (Fig 3). The plots of patients 2 and 3, who failed to maintain central fixation, also demonstrate loss of the optic nerve depression (blind spot). Trace arrays demonstrated diffuse amplitude reduction most pronounced centrally in all volunteers (Fig 5). Similar findings were observed in the patients with nonorganic visual loss (Figs 1 and 2). Latencies were not delayed. Implicit times for waveforms P1 and N2 in volunteers were shortened in all eyes compared with Veris 4.2-generated normals (Fig 4). Shortening of implicit time was most pronounced peripherally (wave forms 5 and 6). Similar findings were present in the patients with nonorganic visual loss, although shortening of implicit times was less pronounced in patient 1.
This report demonstrates that the amplitude of the mfERG signals may be suppressed by motivated persons who have healthy retinas and normal vision. We believe the data indicate that the volunteers, when analyzed as a group, were able to shorten implicit times of waveforms P1 and N2 and to reduce amplitude values for waveforms N1 and N2 after voluntary suppression, as indicated by the significant differences for each individual’s presuppression and postsuppression data. The mechanism for the reduction is likely complex and related in part to refractive error induced by purposeful blurring of the test image, eccentric fixation, and conscious efforts to ignore the hexagonal stimulus. The lack of statistical significance of postsuppression values with respect to computer-generated normal values may result from factors including small sample size and wide variability of volunteers’ values recorded for each waveform amplitude and latency. Refractive error could be adjusted from ⫺10 to ⫹10 D with the focusing dial on the Veris 4.2 instrument used in this study. For the individuals in this series whose refractive errors ranged from ⫺7.00 to ⫹0.75 D, this would allow for between ⫹10.75 and ⫺17 D of induced spherical refractive error when the testing image was adjusted to greatest blur. Previous reports have shown that refractive errors of up to 6.00 D did not influence the latency or amplitude of the mfERG response when viewing distance was adjusted to compensate for changes in image size.4 Our goal was to suppress the mfERG under standard testing conditions experienced by patients; therefore, no adjustments of viewing
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Figure 5. Trace array patterns from volunteers 2, 6, 3, and 5 (left to right, respectively) before (above) and after (below) suppression. Note the diffuse amplitude reduction in volunteers 2 and 3, who achieved suppression with blurring of the target and poor fixation. Remaining trace arrays demonstrate a loss of sensitivity centrally.
distance were made. We assumed that an examiner would not know that the patient purposefully had blurred the testing image if the patient claimed that it was in optimal focus and hence would have no reason to adjust the testing distance. The larger change of refractive error without viewing distance adjustment is likely in part to account for the abnormal mfERG amplitudes noted in this study. A possible mechanism for this amplitude reduction is that the larger area of retina stimulated by the defocused test image would generate the normally lower amplitude signals from more peripheral retina, which would lower the overall amplitude of the recording. It is also likely that poor fixation contributed to reduction of the mfERG amplitudes of several volunteers in this series. In addition to decreased amplitude of the central peak in the 3-dimensional plots, we observed that the optic nerve depression was lost in the 2 volunteers who fixated poorly. Poor fixation causes the hexagonal test pattern to stimulate areas of the retina other than the one it was intended to target. The responses from the surrounding retina contribute to the response of the intended field of stimulation. A blind spot may disappear if surrounding retinal signals are interpreted by the mfERG instrument to be present in the area where the blind spot would be expected. In a previous report, fixation quality did not adversely affect low-resolution stimuli (61 elements, 2.4 degrees). However, smaller stimuli were believed to be more susceptible to fixation fluctuations during mfERG recording.5 Greater amplitudes
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of suppression and loss of blind spot were noted in the volunteers tested with a 103-element stimulus who fixated poorly. Although the results of the current study did not seem to be influenced by inattention independent of the effects of blurred image and in some cases unsteady fixation, it is possible that inattention may have a role in the voluntary suppression of the mfERG in some cases. Voluntary alteration or obliteration of pattern-shift visual evoked potential amplitude was reported in 5 of 15 volunteers using various methods including meditation, daydreaming, and convergence.6 This report suggests that factitious abnormal responses to electrophysiologic studies such as visual evoked potential may be generated by motivated individuals. We are not certain which of the above-mentioned methods of voluntary suppression may have been used by the patients we report who had nonorganic visual loss. An additional possibility is suggested by reported changes in color processing regions of the brain illustrated by positron emission tomography scan in hypnotized individuals. The fusiform lingual region of the left and right hemispheres were active when individuals were instructed to see color regardless of whether the image they were shown was in color or monochrome.7 This suggests that test results may be affected by strong altered perceptions of reality, as may occur in persons with functional illness. Reported implicit times in various pathologic conditions typically are either delayed or normal.8 –16 In contrast, im-
Vrabec et al 䡠 Multifocal Electroretinogram
Figure 6. Results of statistical analysis of amplitude and latency values of N1, P1, and N2 waveforms before and after suppression. A, For latency values (implicit times), no statistically significant difference could be demonstrated between presuppression and postsuppression N1 values. There was a statistically significant difference between presuppression and postsuppression P1 values (P ⫽ 0.0039) and N2 values (P ⫽ 0.0009). B, For amplitude values, there was a statistically significant difference in presuppression and postsuppression values for N1 (P ⫽ 0.0254), but no statistically significant difference could be demonstrated between presuppression and postsuppression P1 values. There was a statistically significant difference between presuppression and postsuppression N2 values (P ⫽ 0.0207). Mean presuppression and postsuppression values for amplitude and latency of each waveform are indicated by the horizontal line with corresponding numbers on each plot.
plicit times of suppressed mfERGs of volunteers and patients with nonorganic visual loss were shortened for the P1 and especially N2 waveforms (Figs 1, 2, 4, and 6). The spatial distribution of implicit times after suppression deviated from previously reported topographic patterns for normals.17,18 Normal implicit time latency is longest in the periphery of the stimulated field. In this series, the implicit times were shortest in the peripheral rings. The reason for this observation in both the volunteers and patients with nonorganic visual loss is uncertain. In summary, this report demonstrates that the amplitude of the mfERG may be suppressed voluntarily. However, unlike pathologic conditions in which implicit times have been reported as normal or delayed, the implicit times of the voluntarily suppressed mfERGs were shortened. Shortening was most apparent in the N2 waveform and in the peripheral ring tracings. Similar findings were observed in patients
with nonorganic visual loss. Unlike patients with normal or near normal fundus examination results and underlying pathologic characteristics, including ocular ischemia, cone dystrophy, and diabetes mellitus, among others, which may have reduced mfERG amplitudes, the mfERG implicit times were not delayed. We conclude that in patients with abnormal mfERG amplitudes that do not correlate with clinical findings and especially if voluntary or functional suppression is suspected, it is also important to review implicit times for shortening.
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