Abnormalities in color vision and contrast sensitivity in Parkinson’s disease Michael J. Price, MD, FRCSC; Robert G. Feldman, MD; Daniel Adelberg, MD; and Herbert Kayne, PhD
Article abstract-Dopamine is a neurotransmitter found in the retina. Delays in the visual evoked responses and abnormalities in contrast sensitivity occur in patients with Parkinson’s disease. Improvement in the PlOO has followed L-dopa therapy. Suspected abnormalities at the retinal level in Parkinson’s disease are observed in reductions in photopic, scotopic, and pattern-derived electroretinograms. We studied 35 patients with Parkinson’s disease and 26 controls of comparable age and visual acuities using visual evoked responses, color vision, and contrast sensitivity testing. Contrast sensitivity thresholds were significantly different at most frequencies tested, using both stationary and temporally modulated sinusoidal gratings. The total error score of the Farnsworth-Munsell 100 Hue Test revealed significant differences between the patients and controls. The contrast thresholds derived from certain spatial frequencies and the total error in color score were significantly related to the duration of disease. A stepwise discriminant analysis correctly identified 94% of the patients and 945% of the controls. The significant error in chromatic discrimination observed in Parkinson’s disease patients may be due to altered intraretinal dopaminergic synaptic activity in these patients. NEUROLOGY 1992;42:887-890
Abnormal visual evoked responses a n d contrast sensitivity functions are described in patients with Parkinson’s disease (PD). Delays i n t h e visual evoked p o t e n t i a l ( V E P ) a r e found, i n c l u d i n g improvement of the PlOO after L-dopa therapy.’-5 Bodis-Wollner and YahrG reported t h a t fully two thirds of their patients showed delayed evoked potential responses. They described a n increase in the latency with discontinuation of the medication. Dopamine is present in the retina as a neurotransmitter in many specie^,^ and PD appears to repres e n t a s t a t e of g e n e r a l i z e d d o p a m i n e r g i c deficiency.x,9 C o n t r a s t sensitivity t e s t i n g is a b n o r m a l in p a t i e n t s w i t h PD.s,10-13R e g a n a n d Maxner14 described the maximum loss of contrast sensitivity with a horizontal orientation of the stimulus grating. Bulens et all5 also reported a n orientation-specific loss in grating contrast sensitivity in 17 of 25 affected eyes. Further, as in the VEP, Bulens et all6 described an improvement in the contrast sensitivit y function curve with levodopa treatment. Other tests, such a s critical flicker frequency, demonstrate a relation to the severity of the disease.I7
We performed this study to determine whether p a t i e n t s w i t h P D a n d p r e s u m a b l y deficient intraretinal dopamine would have abnormal colorvision testing with t h e Farnsworth-Munsell 100 Hue Test. Color vision was reported as normal in patients with PD, b u t only pseudoisochromatic plates were used.8 Color-vision defects occur in acquired retinal disease and optic nerve disease, including glaucoma.’8 Deficiencies in color vision also occur in toxic maculopathies-for example, chloroquine toxicity. l9 Further evidence of suspected abnormalities a t the retinal level in PD is supported by reductions in the photopic, scotopic, and pattern-derived electroretinograms (ERGs).~O-’~ Stanzione e t a122described improvement in the pattern ERG responses after treatment with L-dopa in all 18 patients tested. We also compared contrast sensitivity tested with stationary contrast plates with t h a t tested with modulated patterns. We utilized various psychophysical and electrodiagnostic results, derived in a stepwise discriminant fashion, to determine which of these tests are most sensitive in separating controls from patients with PD. We were also
From the Departments of Ophthalmology (Drs. Price and Adelberg), Neurology (Drs. Price and Feldman 1, and Epidemiology and Biostatistics, School of Public Health (Dr. Kayne), Boston University School of Medicine, Boston Veterans Administration Hospital Medical Center, and The University Hospital a t Boston University Medical Center, Boston, MA. Supported in part by the United Parkinson Foundation through a grant from the J. Robert Porter Foundation, the Massachusetts Lions Eye Research Fund, and the Harold and Ellen Wald Parkinson’s Disease Fund. Received April 22, 1991. Accepted for publication in final form September 25, 1991 Address correspondence and reprint requests to Dr. M. Price, 720 Harrison Avenue, Suite 701, Boston, MA 02118 April 1992 NEUROLOGY 42 887
interested in determining the relation between changes in psychophysical and electrodiagnostic testing and the duration of the disease. Methods. A total of 61 subjects was studied; 35 of these were patients with PD and 26 were controls. Patients were t r e a t e d with combinations of bromocriptine, a dopaminergic agonist, a n d levodopa-carbidopa. Both groups had complete ophthalmologic examinations, with 20130 acuity or better in all but two patients, in whom it was 20140. Pupillary examination and slit lamp examination were normal. The intraocular pressures were all less than 20, and the optic disks were normal. The mean age of the controls was 60 years, SD, 12.7 ( N = 26) and that of the patients was 63 years, SD, 7.3 ( n = 35). The mean Snellen acuity for the controls was 20124.5 and for the patients, 20122.5. There was no statistically significant difference between the ages and Snellen acuity of the two groups (via t tests). The patients were classified using the Hoehn and Yahr2’jstages of disability. There were 17 patients classified as stage 11, 12 as stage 111, and six as stage IV. Only data from a single eye (right eye) were included in the analysis. The VEP was recorded monocularly for each eye. The pattern was generated by a Nicolet 1015 visual stimulator. The contrast of the pattern was 80%. The pattern was surrounded by a background of steady light comparable in brightness to the average luminance of the pattern. Three sizes of checks were used: 15, 30, and 60 minutes of visual arc per side. The field size was 20 degrees. The stimulus repetition rates were 2.1 contrast reversals per second, and bandpass filters were set at 1 to 100 Hz. The epoch was 250 msec. The recordings were made using standard gold cup electrodes at Oz, referenced at Fz and grounded at the earlobe. Signals were amplified by a NIC S M amplifier and 100 summations averaged by the Nicolet Pathfinder I1 signal averager. Color vision was tested in a monocular fashion using the Farnsworth-Munsell 100 Hue Test. The illumination was provided by a MacBeth easel lamp in a n otherwise darkened room. There was no time limit applied to the completion of this test. Contrast sensitivity functions were recorded monocularly using two different methods. T h e Cadwell CTS 5000 was used to record contrast sensitivity functions. The stimulus consisted of temporally modulated vertical sinusoidal gratings on a video display monitor. Before each presentation, the subject was shown a preview of the next spatial frequency. The presentations were randomly presented three times, using spatial frequencies of 1.56, 3.12, 6.24, 12.4, 16.6, and 24.9 cycles per degree. The testing distance was 5 feet with a field size of 8 degrees. The subject’s corrective lenses were worn during t h e test. The subject used a hand-held controller a n d pressed a button until t h e grating was no longer discernible; on release of the button, the contrast increased from zero t o threshold, and the subject again depressed t h e button until t h e grating was j u s t discernible. The mean and standard deviations of t h e thresholds were determined a t each spatial frequency, averaged over t h r e e trials, a n d a contrast sensitivity function w a s derived for each subject. Contrast sensitivity functions were also derived using stationary targets provided by the Vistech VCTS charts. Presented with each chart, the subject had to give a verbal response on the orientation of the grating: vertical, horizontal, or right or left oblique. The spatial frequencies were 1 . 5 , 3 , 6 , 12, and 18 cycles per degree. Each row 888 NEUROLOGY 42 April 1992
Table 1. Contrast sensitivity using the CTS 5000 Cycles
Controls
pt,$:
per degree
(mean)
(mean)
P
1.56 3.12 6.24 12.4 16.6 24.9
49.09 96.36 95.36 44.40 31.22 18.54
50.53 61.65 51.03 22.62 11.98 8.71
NS 0.009 0.0004 0.006 0.0001 0.0004
’ Includes Parkinson’s disease stages 11. 111, a n d 1V. N S Not significant.
contained a sinusoidal grating of t h e same spatial frequency b u t decreasing contrast from left to right. The number of the last discernible target was recorded a s the threshold. All subjects were tested using both contrast methods. The occasional patient had diffculty in pressing the hand-held controller button and had to be assisted. The use of the Vistech contrast charts obviated this problem.
Results. Visual evoked potential. An analysis of the results of the VEP data was performed using standard t test comparison between the controls and t h e patients with PD. Using a probability value of 0.05, no significant difference was found between the two groups a t the check sizes o f 3 0 and 60-minute visual arc per side. Using 15-minute checks, the results approached significance, with p = 0.06 when comparing the patients with the control group. Contrast sensitivity w i t h Cadwell CTS 5000. Table 1 indicates the results of the analysis using the Wilcoxon two-sample test for nonparametric data at all spatial frequencies tested. The thresholds were significantly different a t all spatial frequencies except 1.56. There was a generalized reduction in sensitivity. We could not comment on worsening of contrast threshold with worsening stage, as we had too few (six) patients a t stage IV. An analysis of variance was performed using the threshold values determined for all four groups: controls, and stage 11, stage 111, and stage IV PD. A Scheffe’s multiple comparison test was carried out to determine the most significant subsets. The spatial frequencies of 6.24 and 16.6 could separate the controls from stage I11 patients, and the spatial frequencies of 12.4, 16.6, and 24.9 could separate the controls from stage I1 patients. All comparisons were significant a t the 0.05 level or less. Contrast sensitivity with Vistech plates. Table 2 indicates the results of the analysis using t test comparisons between the controls and patients a t all spatial frequencies tested. The threshold data were significant at all thresholds tested. An analysis of variance was performed as above using all four groups: controls and the three stages of PD. Spatial frequencies of 6 and 12 could separate the controls from stage I11 patients. All comparisons were significant at the 0.05 level or less.
Table 2. Contrast sensitivity using the Vistech plates
I
Cycles
Controls
pts":
per degree
(mean)
(mean)
1.5
5.59 5.88 5.29 4.53 4.00
4.81 4.93
3 6 12
18
4.06 3.00 2.03
P 0.02 0.01 0.004
0.003 0.0001
Includes Parkinson's disease stages 11, 111,and IV
Color vision. The total error score derived from the Farnsworth-Munsell 100 Hue Test was analyzed in nonparametric fashion using the Wilcoxon test. There was a significant difference between the patients and the controls ( p < 0.0001). The mean total error score for the controls was 73.12; for stage I1 patients with PD, 195.06; for stage 111, 289.75; and for stage IV, 258.00. To determine the presence of a significant axis, the total error scores were partitioned into blue-yellow a n d red-green partial scores, as described by Smith et aLZ4Eight of the 35 patients showed a discernible trend on the 100-Hue Test: six of the patients demonstrated a blue-yellow deficiency, and two demonstrated predominantly red-green deficiencies. An analysis of variance and a Scheffe's multiple comparison test determined that the total rack error score could separate the controls from all three stages of disability. Duration of disease. We performed a Pearson's correlation analysis to determine whether the contrast and color vision data were correlated to the duration of the disease. The duration of disease was defined from the first date of diagnosis to the date of the testing period. The following variables were significantly correlated with the duration of the disease: Vistech spatial frequencies of 3 ( p < 0.021 and 6 ( p < 0.02) cycles per degree; the Cadwell CTS 5000 spatial frequencies of 1.56 ( p < 0.008), 3.12 ( p < 0.009), 6.24 ( p < 0.011, and 12.4 ( p < 0.04) cycles per degree; and the total error score on the FarnsworthMunsell 100 Hue Test ( p < 0.03). Discriminant analysis. Stepwise discriminant analysis was carried out on all t h e controls and patients. All stepwise discriminant analyses were taken to the 5% significant level. The total error score on the Farnsworth-Munsell 100 Hue Test (F, 14.84; d f , 1,471, the contrast sensitivity functions determined with the Vistech plates a t 18 cycles per degree (F, 1.79; df, 1,45) and 12 cycles per degree (F, 4.92; d f , 1,441, a n d t h e contrast sensitivity thresholds with the Cadwell CTS 5000 a t spatial frequencies of 16.6 cycles per degree (F, 23.92; df, 1,461 and 12.4 cycles per degree (F, 2.48; d f , 1,431 correctly identified 94% of the patients and 94% of the controls. Discussion. A significant error in chromatic discrimination was demonstrated in the patients with
PD. The total error score of all four racks of the Farnsworth-Munsell 100 Hue Test could separate all three groups from the normal subjects. A trend in the error scores occurred in only eight patients. Various ocular diseases, including glaucoma,18 and retinal diseases, such as diabetes,25demonstrate an acquired deficiency in color vision. Schafer and McKeanZfifirst suggested that monoamine deficiencies can alter the VEP. Since dopamine-containing amacrine cells exist in the retina, Bodis-Wollner a t all suggested t h a t alteration i n t h e retinal dopaminergic p a t h w a y could l e a d to delayed evoked potentials in PD. Deficiency in color vision could also reflect abnormalities in dopaminergic synaptic activity in the retina of affected patients. B ~ d i s - W o l l n e rhas ~ ~ further emphasized the possible importance of dopamine in the center-surround organization of retinal receptive fields in various mammalian species. Abnormalities in t h e flash ERGs representing mainly outer retinal activity a n d in t h e pattern-derived ERGs representing mainly inner retinal layer activity provide further evidence for dysfunction a t t h e retinal level in patients with PD. Also, reduction in both dopamine and homovanillic acid in the retinas of patients with PD is reported in postmortem studies.2i We could not determine whether chromatic discrimination worsened in a statistical fashion with t h e severity of t h e disease, as we h a d too few patients in stage IV. Color loss appeared to correlate with t h e duration of the disease ( p < 0.03). Worsening in color discrimination does occur with increasing age. Our patients with PD did not differ from the controls in age, and age correction of the color vision error scores resulted in similar differences between the two groups. In our patients and control subjects, we found no significant difference with the VEP, although there was a difference with 15-minute checks ( p < 0.06). This may reflect our use of a checkerboard pattern rather t h a n gratings.28Others have described no c h a n g e i n t h e V E P when compared with normal.2g,30These differences may reflect variations in response to alterations i n temporal a n d spatial modulation of the stimulus.31 Both t h e stationary contrast plates (Vistech plates) a n d t h e phase-reversal contrast testing showed that the contrast thresholds were significantly different in the patients from the controls. This did not appear to be limited to a high- or lowfrequency reduction in threshold but was present throughout t h e spatial frequencies tested. The midrange of spatial frequencies using the Vistech plates was highly correlated with the duration of the disease. With the Cadwell CTS 5000, the duration of the disease was significantly correlated with threshold results determined a t spatial frequencies from 1.56 to 12.4 cycles per degree. There was no significant correlation with the higher end of spatial frequencies tested. Our study showed t h a t t h e patients with PD could be separated from the controls by a combinaApril 1992 NEUROLOGY 42 A89
tion of tests. A combination of color vision and contrast testing correctly identified 94%of the controls and 94% of the patients. The stationary contrast plates and the 100-Hue chips are tests that are relatively easy to administer. Abnormalities in color vision in PD using the 100-Hue Test are observed in this study. Mergler and Blains2 were able t o show t h a t the quicker Lanthony 15-hue desaturated panel (D-15-d) was an adequate instrument in assessing color vision loss among workers exposed t o various solvents and was highly correlated with the results of the 100-Hue Test. Only one false positive was noted by the use of the 100-Hue Test. The D-15 panel would be a quick and easy method of assessing loss of chromatic discrimination in patients with PD and may become the test of choice if shown to be highly correlated with the 100-Hue results in patients with PD. Studies are underway to validate our findings, including the stepwise discriminant function, in a larger population of PD patients a t all stages of progression, including previously untreated cases.
References 1. Bodis-Wollner I, Y a h r MD, Mylin L, T h o r n t o n J . Dopaminergic deficiency and delayed visual evoked potentials in humans. Ann Neurol 1982;11:478-483. 2. Sollazzo D. Influence of L-dopdcarbidopa on pattern reversal VEP: behavioural differences in primary a n d secondary p a r k i n s o n i s m . Electroencephalogr Clin Neurophysiol 1985;61:236-242. 3. Jorg J , Gerhard H. Somatosensory, motor, and spatial visual evoked potentials t o single a n d double-stimulation i n Parkinson’s disease: a n early diagnostic test. J Neural Transm 1987;25:81-88. 4. Bhaskar PA, Vanchilingam S , Bhaskar EA, Devaprabhu A, Ganesan RA. Effect of L-dopa on visual evoked potential in patients with Parkinson’s disease. Neurology 1986;36: 11191121. 5. Cosi V, Romani A, Callieco R, Zerbi F. Acute effects of levodopa plus carbidopa on evoked potentials in Parkinson’s Ital Biol Sper 1989;60:603-609. disease. Boll SOC 6. Bodis-Wollner I, Yahr M. Measurements of visual evoked potentials in Parkinson’s disease. Brain 1978;101:661-671. 7. Dowling J E , Ehinger B, Hedden WL. The interplexiform cell: a new type of retinal n e u r o n . I n v e s t Ophthalmol 1976;15:916-926. 8. Kupersmith MJ, Shakin E , Siege1 IM, Lieberman A. Visual system abnormalities in patients with Parkinson’s disease. Arch Neurol 1982;39:284-286. 9. Barbeau A, Campanella G, Butterworth RF, Yamada K. Uptake and efflux of I4C-dopamine in platelets: evidence for a generalized defect in Parkinson’s disease. Neurology 1975;25:1-9. 10. Bodis-Wollner I, Marx MS, Mitra S , Bobak P, Mylin L, Yahr M. Visual dysfunction in Parkinson’s disease. Loss in spa-
890 NEUROLOGY 42 April 1992
tiotemporal contrast sensitivity. Brain 1987;110:1675-1698. 11. Bulens C, Meerwaldt JD, van der Wildt GJ, Keemink CJ. C o n t r a s t sensitivity in Parkinson’s disease. Neurology 1986;36:1121-1125. 12. Skrandies W, Gottlob I. Alterations of visual contrast sensit i v i t y i n P a r k i n s o n ’ s d i s e a s e . H u m a n Neurobiology 1986;5:255-259. 13. Hutton J T , Morris J L , Elias J W , Varma R , Poston J N . Spatial contrast sensitivity is reduced in bilateral Parkinson’s disease. Neurology 1991;41:1200-1202. 14. Regan D, Maxner C. Orientation selective visual loss in patients with Parkinson’s disease. Brain 1987;110:415-432. 15. Bulens C, Meerwaldt J D , Van der Wildt GJ. Effect of stimulus orientation on contrast sensitivity in Parkinson’s disease. Neurology 1988;38:76-81. 16. Bulens C, Meerwaldt JD, Van der Wildt GJ, Van Deursen JB. Effect of levodopa treatment on contrast sensitivity in Parkinson’s disease. Ann Neurol 1987;22:365-369. 17. Riklan M, Levitan E, Misiak H. Critical flicker frequency a n d i n t e g r a t i v e functions i n parkinsonism. J Psycho1 1970;75:45-51. 18. Drance SM, Lakowski R, Schulzer M, Douglas GR. Acquired color vision changes in glaucoma. Use of 100-hue test and Pickford anomaloscope a s predictors of glaucomatous field change. Arch Ophthalmol 1981;99:829-831. 19. Earnshaw ER, Miles D, Stewart TW. Screening for chloroquine retinopathy. Br J Dermatol 1966;78:669-674. 20. Gottlieb I, Schneider E, Heider W, Skrandies W. Alterations of visual evoked potentials a n d electroretinograms i n Parkinson’s disease. Electroencephalogr Clin Neurophysiol 1987;66:349-357. 21. Nightingale S , Mitchell KW, Howe JW. Visual evoked potentials and pattern electroretinograms in Parkinson’s disease a n d control subjects. J Neurol N e u r o s u r g P s y c h i a t r y 1986;49:1280-1287. 22. Stanzione P, Pienelli F, Peppe A, e t al. P a t t e r n visual evoked potentials and electroretinogram abnormalities in Parkinson’s disease: effects of L-dopa therapy. Clin Vision Sci 1989;4:115-127. 23. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427-442. 24. Smith VC, Pokorny J , Pass AS. Color-axis determination on the Farnsworth-Munsell 100-hue test. Am J Ophthalmol 1985;100:176-182. 25. Kinnear PR, Aspinal PA, Lakowski R. The diabetic eye and colour vision. Trans Ophthalmol SOCUK 1972;92:69-78. 26. Schafer EWP, McKean C. Evidence that monoamines influence human evoked potentials. Brain Res 1975;99:49-58. 27. Bodis-Wollner I. Visual deficits related to dopamine deficiency i n e x p e r i m e n t a l a n i m a l s a n d P a r k i n s o n ’ s d i s e a s e patients. TINS 1990;13:296-302. 28. Tartaglione A, Pizio N, Bin0 G, Spadovecchia L, Favale E . VEP changes in Parkinson’s disease a r e stimulus dependent. J Neurol Neurosurg Psychiatry 1984;47:305-307. 29. Ehle AL, Stewart RM, Lelleli NE, Leventhal NA. Normal checkerboard pattern reversal evoked potentials in parkinsonism. Electroencephalogr Clin Neurophysiol 1982;54:336338. 30. Dinner DS, Luders H, Hanson M , Lesser RP, Klem G. Pattern evoked potentials (PEPS) in Parkinson’s disease. Neurology 1985;35:610-613. 31. Marx M, Bodis-Wollner I , Bobak P, Harnois L, Mylin L, Yahr M. Temporal frequency-dependent VEP changes in Parkinson’s disease. Vision Res 1986;26:185-193. 32. Mergler D, Blain L. Assessing color vision loss among solvent-exposed workers. Am J Ind Med 1987;12:195-203.
Abnormalities in color vision and contrast sensitivity in Parkinson's disease Michael J. Price, Robert G. Feldman, Daniel Adelberg, et al. Neurology 1992;42;887 DOI 10.1212/WNL.42.4.887 This information is current as of April 1, 1992 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1992 by AAN Enterprises, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Article abstract-Dopamine is a neurotransmitter found in the retina. Delays in the visual evoked responses and abnormalities in contrast sensitivity occur in patients with Parkinson’s disease. Improvement in the PlOO has followed L-dopa therapy. Suspected abnormalities at the retinal level in Parkinson’s disease are observed in reductions in photopic, scotopic, and pattern-derived electroretinograms. We studied 35 patients with Parkinson’s disease and 26 controls of comparable age and visual acuities using visual evoked responses, color vision, and contrast sensitivity testing. Contrast sensitivity thresholds were significantly different at most frequencies tested, using both stationary and temporally modulated sinusoidal gratings. The total error score of the Farnsworth-Munsell 100 Hue Test revealed significant differences between the patients and controls. The contrast thresholds derived from certain spatial frequencies and the total error in color score were significantly related to the duration of disease. A stepwise discriminant analysis correctly identified 94% of the patients and 945% of the controls. The significant error in chromatic discrimination observed in Parkinson’s disease patients may be due to altered intraretinal dopaminergic synaptic activity in these patients. NEUROLOGY 1992;42:887-890
Abnormal visual evoked responses a n d contrast sensitivity functions are described in patients with Parkinson’s disease (PD). Delays i n t h e visual evoked p o t e n t i a l ( V E P ) a r e found, i n c l u d i n g improvement of the PlOO after L-dopa therapy.’-5 Bodis-Wollner and YahrG reported t h a t fully two thirds of their patients showed delayed evoked potential responses. They described a n increase in the latency with discontinuation of the medication. Dopamine is present in the retina as a neurotransmitter in many specie^,^ and PD appears to repres e n t a s t a t e of g e n e r a l i z e d d o p a m i n e r g i c deficiency.x,9 C o n t r a s t sensitivity t e s t i n g is a b n o r m a l in p a t i e n t s w i t h PD.s,10-13R e g a n a n d Maxner14 described the maximum loss of contrast sensitivity with a horizontal orientation of the stimulus grating. Bulens et all5 also reported a n orientation-specific loss in grating contrast sensitivity in 17 of 25 affected eyes. Further, as in the VEP, Bulens et all6 described an improvement in the contrast sensitivit y function curve with levodopa treatment. Other tests, such a s critical flicker frequency, demonstrate a relation to the severity of the disease.I7
We performed this study to determine whether p a t i e n t s w i t h P D a n d p r e s u m a b l y deficient intraretinal dopamine would have abnormal colorvision testing with t h e Farnsworth-Munsell 100 Hue Test. Color vision was reported as normal in patients with PD, b u t only pseudoisochromatic plates were used.8 Color-vision defects occur in acquired retinal disease and optic nerve disease, including glaucoma.’8 Deficiencies in color vision also occur in toxic maculopathies-for example, chloroquine toxicity. l9 Further evidence of suspected abnormalities a t the retinal level in PD is supported by reductions in the photopic, scotopic, and pattern-derived electroretinograms (ERGs).~O-’~ Stanzione e t a122described improvement in the pattern ERG responses after treatment with L-dopa in all 18 patients tested. We also compared contrast sensitivity tested with stationary contrast plates with t h a t tested with modulated patterns. We utilized various psychophysical and electrodiagnostic results, derived in a stepwise discriminant fashion, to determine which of these tests are most sensitive in separating controls from patients with PD. We were also
From the Departments of Ophthalmology (Drs. Price and Adelberg), Neurology (Drs. Price and Feldman 1, and Epidemiology and Biostatistics, School of Public Health (Dr. Kayne), Boston University School of Medicine, Boston Veterans Administration Hospital Medical Center, and The University Hospital a t Boston University Medical Center, Boston, MA. Supported in part by the United Parkinson Foundation through a grant from the J. Robert Porter Foundation, the Massachusetts Lions Eye Research Fund, and the Harold and Ellen Wald Parkinson’s Disease Fund. Received April 22, 1991. Accepted for publication in final form September 25, 1991 Address correspondence and reprint requests to Dr. M. Price, 720 Harrison Avenue, Suite 701, Boston, MA 02118 April 1992 NEUROLOGY 42 887
interested in determining the relation between changes in psychophysical and electrodiagnostic testing and the duration of the disease. Methods. A total of 61 subjects was studied; 35 of these were patients with PD and 26 were controls. Patients were t r e a t e d with combinations of bromocriptine, a dopaminergic agonist, a n d levodopa-carbidopa. Both groups had complete ophthalmologic examinations, with 20130 acuity or better in all but two patients, in whom it was 20140. Pupillary examination and slit lamp examination were normal. The intraocular pressures were all less than 20, and the optic disks were normal. The mean age of the controls was 60 years, SD, 12.7 ( N = 26) and that of the patients was 63 years, SD, 7.3 ( n = 35). The mean Snellen acuity for the controls was 20124.5 and for the patients, 20122.5. There was no statistically significant difference between the ages and Snellen acuity of the two groups (via t tests). The patients were classified using the Hoehn and Yahr2’jstages of disability. There were 17 patients classified as stage 11, 12 as stage 111, and six as stage IV. Only data from a single eye (right eye) were included in the analysis. The VEP was recorded monocularly for each eye. The pattern was generated by a Nicolet 1015 visual stimulator. The contrast of the pattern was 80%. The pattern was surrounded by a background of steady light comparable in brightness to the average luminance of the pattern. Three sizes of checks were used: 15, 30, and 60 minutes of visual arc per side. The field size was 20 degrees. The stimulus repetition rates were 2.1 contrast reversals per second, and bandpass filters were set at 1 to 100 Hz. The epoch was 250 msec. The recordings were made using standard gold cup electrodes at Oz, referenced at Fz and grounded at the earlobe. Signals were amplified by a NIC S M amplifier and 100 summations averaged by the Nicolet Pathfinder I1 signal averager. Color vision was tested in a monocular fashion using the Farnsworth-Munsell 100 Hue Test. The illumination was provided by a MacBeth easel lamp in a n otherwise darkened room. There was no time limit applied to the completion of this test. Contrast sensitivity functions were recorded monocularly using two different methods. T h e Cadwell CTS 5000 was used to record contrast sensitivity functions. The stimulus consisted of temporally modulated vertical sinusoidal gratings on a video display monitor. Before each presentation, the subject was shown a preview of the next spatial frequency. The presentations were randomly presented three times, using spatial frequencies of 1.56, 3.12, 6.24, 12.4, 16.6, and 24.9 cycles per degree. The testing distance was 5 feet with a field size of 8 degrees. The subject’s corrective lenses were worn during t h e test. The subject used a hand-held controller a n d pressed a button until t h e grating was no longer discernible; on release of the button, the contrast increased from zero t o threshold, and the subject again depressed t h e button until t h e grating was j u s t discernible. The mean and standard deviations of t h e thresholds were determined a t each spatial frequency, averaged over t h r e e trials, a n d a contrast sensitivity function w a s derived for each subject. Contrast sensitivity functions were also derived using stationary targets provided by the Vistech VCTS charts. Presented with each chart, the subject had to give a verbal response on the orientation of the grating: vertical, horizontal, or right or left oblique. The spatial frequencies were 1 . 5 , 3 , 6 , 12, and 18 cycles per degree. Each row 888 NEUROLOGY 42 April 1992
Table 1. Contrast sensitivity using the CTS 5000 Cycles
Controls
pt,$:
per degree
(mean)
(mean)
P
1.56 3.12 6.24 12.4 16.6 24.9
49.09 96.36 95.36 44.40 31.22 18.54
50.53 61.65 51.03 22.62 11.98 8.71
NS 0.009 0.0004 0.006 0.0001 0.0004
’ Includes Parkinson’s disease stages 11. 111, a n d 1V. N S Not significant.
contained a sinusoidal grating of t h e same spatial frequency b u t decreasing contrast from left to right. The number of the last discernible target was recorded a s the threshold. All subjects were tested using both contrast methods. The occasional patient had diffculty in pressing the hand-held controller button and had to be assisted. The use of the Vistech contrast charts obviated this problem.
Results. Visual evoked potential. An analysis of the results of the VEP data was performed using standard t test comparison between the controls and t h e patients with PD. Using a probability value of 0.05, no significant difference was found between the two groups a t the check sizes o f 3 0 and 60-minute visual arc per side. Using 15-minute checks, the results approached significance, with p = 0.06 when comparing the patients with the control group. Contrast sensitivity w i t h Cadwell CTS 5000. Table 1 indicates the results of the analysis using the Wilcoxon two-sample test for nonparametric data at all spatial frequencies tested. The thresholds were significantly different a t all spatial frequencies except 1.56. There was a generalized reduction in sensitivity. We could not comment on worsening of contrast threshold with worsening stage, as we had too few (six) patients a t stage IV. An analysis of variance was performed using the threshold values determined for all four groups: controls, and stage 11, stage 111, and stage IV PD. A Scheffe’s multiple comparison test was carried out to determine the most significant subsets. The spatial frequencies of 6.24 and 16.6 could separate the controls from stage I11 patients, and the spatial frequencies of 12.4, 16.6, and 24.9 could separate the controls from stage I1 patients. All comparisons were significant a t the 0.05 level or less. Contrast sensitivity with Vistech plates. Table 2 indicates the results of the analysis using t test comparisons between the controls and patients a t all spatial frequencies tested. The threshold data were significant at all thresholds tested. An analysis of variance was performed as above using all four groups: controls and the three stages of PD. Spatial frequencies of 6 and 12 could separate the controls from stage I11 patients. All comparisons were significant at the 0.05 level or less.
Table 2. Contrast sensitivity using the Vistech plates
I
Cycles
Controls
pts":
per degree
(mean)
(mean)
1.5
5.59 5.88 5.29 4.53 4.00
4.81 4.93
3 6 12
18
4.06 3.00 2.03
P 0.02 0.01 0.004
0.003 0.0001
Includes Parkinson's disease stages 11, 111,and IV
Color vision. The total error score derived from the Farnsworth-Munsell 100 Hue Test was analyzed in nonparametric fashion using the Wilcoxon test. There was a significant difference between the patients and the controls ( p < 0.0001). The mean total error score for the controls was 73.12; for stage I1 patients with PD, 195.06; for stage 111, 289.75; and for stage IV, 258.00. To determine the presence of a significant axis, the total error scores were partitioned into blue-yellow a n d red-green partial scores, as described by Smith et aLZ4Eight of the 35 patients showed a discernible trend on the 100-Hue Test: six of the patients demonstrated a blue-yellow deficiency, and two demonstrated predominantly red-green deficiencies. An analysis of variance and a Scheffe's multiple comparison test determined that the total rack error score could separate the controls from all three stages of disability. Duration of disease. We performed a Pearson's correlation analysis to determine whether the contrast and color vision data were correlated to the duration of the disease. The duration of disease was defined from the first date of diagnosis to the date of the testing period. The following variables were significantly correlated with the duration of the disease: Vistech spatial frequencies of 3 ( p < 0.021 and 6 ( p < 0.02) cycles per degree; the Cadwell CTS 5000 spatial frequencies of 1.56 ( p < 0.008), 3.12 ( p < 0.009), 6.24 ( p < 0.011, and 12.4 ( p < 0.04) cycles per degree; and the total error score on the FarnsworthMunsell 100 Hue Test ( p < 0.03). Discriminant analysis. Stepwise discriminant analysis was carried out on all t h e controls and patients. All stepwise discriminant analyses were taken to the 5% significant level. The total error score on the Farnsworth-Munsell 100 Hue Test (F, 14.84; d f , 1,471, the contrast sensitivity functions determined with the Vistech plates a t 18 cycles per degree (F, 1.79; df, 1,45) and 12 cycles per degree (F, 4.92; d f , 1,441, a n d t h e contrast sensitivity thresholds with the Cadwell CTS 5000 a t spatial frequencies of 16.6 cycles per degree (F, 23.92; df, 1,461 and 12.4 cycles per degree (F, 2.48; d f , 1,431 correctly identified 94% of the patients and 94% of the controls. Discussion. A significant error in chromatic discrimination was demonstrated in the patients with
PD. The total error score of all four racks of the Farnsworth-Munsell 100 Hue Test could separate all three groups from the normal subjects. A trend in the error scores occurred in only eight patients. Various ocular diseases, including glaucoma,18 and retinal diseases, such as diabetes,25demonstrate an acquired deficiency in color vision. Schafer and McKeanZfifirst suggested that monoamine deficiencies can alter the VEP. Since dopamine-containing amacrine cells exist in the retina, Bodis-Wollner a t all suggested t h a t alteration i n t h e retinal dopaminergic p a t h w a y could l e a d to delayed evoked potentials in PD. Deficiency in color vision could also reflect abnormalities in dopaminergic synaptic activity in the retina of affected patients. B ~ d i s - W o l l n e rhas ~ ~ further emphasized the possible importance of dopamine in the center-surround organization of retinal receptive fields in various mammalian species. Abnormalities in t h e flash ERGs representing mainly outer retinal activity a n d in t h e pattern-derived ERGs representing mainly inner retinal layer activity provide further evidence for dysfunction a t t h e retinal level in patients with PD. Also, reduction in both dopamine and homovanillic acid in the retinas of patients with PD is reported in postmortem studies.2i We could not determine whether chromatic discrimination worsened in a statistical fashion with t h e severity of t h e disease, as we h a d too few patients in stage IV. Color loss appeared to correlate with t h e duration of the disease ( p < 0.03). Worsening in color discrimination does occur with increasing age. Our patients with PD did not differ from the controls in age, and age correction of the color vision error scores resulted in similar differences between the two groups. In our patients and control subjects, we found no significant difference with the VEP, although there was a difference with 15-minute checks ( p < 0.06). This may reflect our use of a checkerboard pattern rather t h a n gratings.28Others have described no c h a n g e i n t h e V E P when compared with normal.2g,30These differences may reflect variations in response to alterations i n temporal a n d spatial modulation of the stimulus.31 Both t h e stationary contrast plates (Vistech plates) a n d t h e phase-reversal contrast testing showed that the contrast thresholds were significantly different in the patients from the controls. This did not appear to be limited to a high- or lowfrequency reduction in threshold but was present throughout t h e spatial frequencies tested. The midrange of spatial frequencies using the Vistech plates was highly correlated with the duration of the disease. With the Cadwell CTS 5000, the duration of the disease was significantly correlated with threshold results determined a t spatial frequencies from 1.56 to 12.4 cycles per degree. There was no significant correlation with the higher end of spatial frequencies tested. Our study showed t h a t t h e patients with PD could be separated from the controls by a combinaApril 1992 NEUROLOGY 42 A89
tion of tests. A combination of color vision and contrast testing correctly identified 94%of the controls and 94% of the patients. The stationary contrast plates and the 100-Hue chips are tests that are relatively easy to administer. Abnormalities in color vision in PD using the 100-Hue Test are observed in this study. Mergler and Blains2 were able t o show t h a t the quicker Lanthony 15-hue desaturated panel (D-15-d) was an adequate instrument in assessing color vision loss among workers exposed t o various solvents and was highly correlated with the results of the 100-Hue Test. Only one false positive was noted by the use of the 100-Hue Test. The D-15 panel would be a quick and easy method of assessing loss of chromatic discrimination in patients with PD and may become the test of choice if shown to be highly correlated with the 100-Hue results in patients with PD. Studies are underway to validate our findings, including the stepwise discriminant function, in a larger population of PD patients a t all stages of progression, including previously untreated cases.
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Abnormalities in color vision and contrast sensitivity in Parkinson's disease Michael J. Price, Robert G. Feldman, Daniel Adelberg, et al. Neurology 1992;42;887 DOI 10.1212/WNL.42.4.887 This information is current as of April 1, 1992 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1992 by AAN Enterprises, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
