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Journal of Parkinson’s Disease 5 (2015) 125–130 DOI 10.3233/JPD-140470 IOS Press
Research Report
Abnormal Visual Contrast Acuity in Parkinson’s Disease Tanya P. Lina , Heather Rigbyb , Jennifer S. Adlerc , Joseph G. Hentzd , Laura J. Balcere , Steven L. Galettae , Steve Devickf , Richard Croninf and Charles H. Adlerg,∗ a Department
of Neurology, University of Arizona, Tucson, AZ, USA of Neurology, Dalhousie University, Halifax, NS, Canada c University of Arizona, Tucson, AZ, USA d Department of Biostatistics, Mayo Clinic College of Medicine, Scottsdale, AZ, USA e Department of Neurology, NYU School of Medicine, New York, NY, USA f King-Devick Test LLC, Oakbrook Terrace, IL, USA g Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, USA b Department
Abstract. Background: Low-contrast vision is thought to be reduced in Parkinson’s disease (PD). This may have a direct impact on quality of life such as driving, using tools, finding objects, and mobility in low-light condition. Low-contrast letter acuity testing has been successful in assessing low-contrast vision in multiple sclerosis. We report the use of a new iPad application to measure low-contrast acuity in patients with PD. Objective: To evaluate low- and high-contrast letter acuity in PD patients and controls using a variable contrast acuity eye chart developed for the Apple iPad. Methods: Thirty-two PD and 71 control subjects were studied. Subjects viewed the Variable Contrast Acuity Chart on an iPad with both eyes open at two distances (40 cm and 2 m) and at high contrast (black and white visual acuity) and 2.5% low contrast. Acuity scores for the two groups were compared. Results: PD patients had significantly lower scores (indicating worse vision) for 2.5% low contrast at both distances and for high contrast at 2 m (p < 0.003) compared to controls. No significant difference was found between the two groups for high contrast at 40 cm (p = 0.12). Conclusions: Parkinson’s disease patients have reduced low and high contrast acuity compared to controls. An iPad app, as used in this study, could serve as a quick screening tool to complement more formal testing of patients with PD and other neurologic disorders. Keywords: Parkinson’s disease, vision, contrast sensitivity, visual acuity
INTRODUCTION Patients with Parkinson’s disease (PD) often note visual difficulties, but these symptoms are easily overlooked as many have normal or near normal highcontrast visual acuity (VA) on routine eye exams [1–4]. Contrast sensitivity is one of several aspects of visual function known to be affected in Parkinson’s ∗ Correspondence to: Charles H. Adler, MD, PhD, Professor, Department of Neurology, Mayo Clinic College of Medicine, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. Tel: +1 480 301 8100; Fax: +1 480 301 8451; E-mail: [email protected].
disease [5–8], and is postulated to be due to dopaminecontaining amacrine cell loss and ␣-synuclein deposits in the retina [2, 9]. Deficits in color discrimination [10, 11], higher cortical visual processing [12, 13], and oculomotor control [14] have also been shown in PD. These impairments may have a significant impact on their function and quality of life [15, 16]. Contrast sensitivity is measured in a grey scale spectrum, and detects a threshold for the eyes to see the differences in the amount of light reflecting from two adjacent surfaces, or light-dark transition. Several methods have been developed to test contrast
ISSN 1877-7171/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
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sensitivity. Much of the work on contrast sensitivity in PD has been done with sine wave grating contrast sensitivity testing in which parallel bars of varying width and contrast are presented to the patient [5–8].The width of the bars and distance apart provide a measure of spatial frequency. However, some suggest that letter acuity charts are at least as sensitive, provide similar diagnostic information, and may be a more suitable test of contrast sensitivity in the clinical setting [1]. In a commonly used version of contrast sensitivity letter chart, the Pelli-Robson chart, the size of the letters is kept constant, but contrast decreases across the page during testing [16–18]. Alternatively, testing of lowcontrast vision can be incorporated into routine high contrast visual acuity testing to evaluate low contrast letter acuity. In this method, both the letter size and contrast decrease during testing, with each page having the same level of contrast [19]. Low-contrast letter acuity testing may have an advantage over the Pelli-Robson chart in that it is able to capture “notch loss” of contrast, or reduction in low-contrast vision at small letter sizes. In studies of patients with MS, low-contrast acuity had a greater capacity to distinguish MS vs. disease-free control participants compared to Pelli-Robson contrast sensitivity [20]. Prior studies showed that low-contrast acuity is a highly sensitive and reliable measure of visual dysfunction in a number of disorders including multiple sclerosis [21, 22], ocular hypertension [1], and glaucoma [1]. Other studies have also shown that lowcontrast acuity correlates well with structural markers such as retinal nerve fiber layer thickness, and visionspecific quality of life in MS, PD and other neurologic disorders [16, 23]. However, low-contrast acuity as a clinical measure of low-contrast vision in PD has only been reported in a few studies with small numbers of patients [1, 3]. In addition, there is conflicting evidence whether high contrast (black on white) visual acuity is also affected in Parkinson’s disease [1, 3, 5, 17, 24]. The main objective of this study was to evaluate low-and high-contrast letter acuity in PD patients and controls using a variable contrast acuity eye chart that was recently developed for the Apple iPad. METHODS Subjects Thirty-two patients with PD and 71 control subjects were studied. Twenty-two of the PD patients were tested in the movement disorders clinic at Mayo Clinic Arizona based on proximity to the researchers.
Ten additional PD patients and all controls were recruited from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) in the Arizona PD Consortium/Banner Sun Health Research Institute Brain and Body Donation Program. Subjects from AZSAND were local community dwelling seniors who were participating in the brain and body donation program. All participants signed written informed consent from either the Mayo Clinic or Banner Sun Health Research Institute IRB. PD was clinically diagnosed according to the UK brain bank criteria. Subjects with a clinical diagnosis of dementia and those with a history of macular degeneration, glaucoma, cataract, or blindness were excluded from the study. All subjects had a neurological examination including the Unified Parkinson’s Disease Rating Scale (UPDRS) on the same day as vision testing (with the exception of one patient whose UPDRS was scored three weeks later). Eleven of the 32 PD subjects had motor fluctuations and all but three of them were assessed in the practically defined off state. Variable contrast acuity test Subjects viewed the Variable Contrast Acuity Chart (King-Devick Test LLC, Oakbrook Terrace, IL) on an Apple iPad2, and were asked to wear their usual corrective lenses. The chart design and testing protocol were based on the Bailey-Lovie and Early Treatment of Diabetic Retinopathy Study (EDTRS) visual acuity tests that are the standards in ophthalmology clinical trials. Visual acuity (for high-contrast, or black letters on white background) may be specified in this chart by Snellen notation for descriptive purposes (i.e. 20/20), by the number of letters identified correctly [25]. Other similar apps exist; however, they do not use the required ETDRS mandated Sloan letters and protocol. The iPad app used in this study was specifically developed for Apple devices because Apple guarantees no luminosity fluctuation among their devices. Participants were tested at distances of 40 cm and 2 m, with 100% and 2.5% contrast at each distance (Fig. 1) with both eyes open following similar parameters to those used in multiple sclerosis trials [21, 25]. Binocular testing provides a measure of overall visual function representative of daily activities. It has been used successfully in several methodologic studies, and was recommended as a primary measure of visual function by recent studies [24]. Letter sizes decreased from page to page during testing. The background lighting for the iPad was set at maximum for all testing. Direct sunlight was shielded from the examination rooms.
T.P. Lin et al. / Abnormal Visual Contrast Acuity in PD
A
127
B
Fig. 1. Variable contrast acuity eye chart at two contrast levels on iPad: 100% (A) & 10% (B). The 10% contrast was for illustration purpose only. The actual contrasts used in this study were 100% and 2.5%.
contrast) at both 40 cm and 2 m. High contrast scores (100% contrast) were worse in the PD group at 2 m but not at 40 cm (Table 1). Low contrast acuity scores correlated with disease severity as measured by the Hoehn and Yahr scale at both distances after correcting p-values for multiple comparisons by using the Hochberg-Bonferroni method (Table 2). Correlations of high and low contrast acuity scores versus motor function as measured by the UPDRS III were nominally significant (unadjusted P < 0.05) at both distances. High and low contrast acuity scores also correlated with Activities of Daily Living scores measured by the UPDRS II and PD disease duration at 40 cm but not at 2 m.
Low and high contrast acuity at each distance was converted into a numeric score determined by the number of letters identified correctly. The maximum number of points was 90 at 40 cm (equivalent to visual acuity of 20/25) and 75 at 2 m (visual acuity of 20/10; 60 = 20/20) [25]. Statisical analysis Mean contrast acuity scores adjusted for age and gender were compared between groups using a general linear model. Pearson correlation coefficients were used to assess the correlations of contrast acuity scores with activities of daily living (UPDRS II), motor function (UPDRS III and Hoehn & Yahr), and disease duration.
DISCUSSION Using a novel method for studying visual contrast acuity, PD patients in this study had worse low contrast acuity scores compared to controls at both near and far viewing distances, while high-contrast acuity scores were lower at 2 m. These findings are in keeping with others that have found reduced low contrast vision in PD but also suggest that high contrast acuity may be affected at farther distances. In contrast to several studies that have shown normal or near normal high contrast acuity scores in PD [1, 3, 5], our findings are in agreement with others that found impairment of high contrast visual acuity [17, 24]. These data there-
RESULTS PD subjects were younger (mean ± SD, 69.1 ± 13 years) than controls (82.7 ± 6.6 years, p < 0.001). Proportion of gender was not statistically different between the two groups (50% vs. 66% male, p = 0.16). Mean PD disease duration was 6.0 ± 4.7 years. The mean scores on the UPDRS parts II and III were 10.3 ± 6.6 and 20.9 ± 12, respectively. The mean Hoehn and Yahr staging was 1.98 ± 0.82. After adjusting for age and gender, PD patients had significantly worse low-contrast acuity scores (2.5%
Table 1 Adjusted mean (SE) contrast acuity scores in PD patients vs. controls Contrast acuity testing conditions (contrast level, distance) 100%, 40 cm 100%, 2 m 2.5%, 40 cm 2.5%, 2 m ∗ P-values
PD (n = 32)
Controls (n = 71)
95% CI
P value∗
82.3 (1.3) 51.3 (1.7) 47.9 (2.7) 23.1 (2.0)
84.9 (0.8) 58.6 (1.1) 58.6 (1.7) 31.5 (1.2)
−2.6 −7.2 −10.7 −8.5
−5.9 to 0.7 −11.7 to −2.9 −17.6 to −3.9 −13.4 to −3.5
0.12 0.001 0.003 0.001
from general linear models, adjusting for age and gender.
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Table 2 Correlations of contrast acuity scores with activities of daily living (UPDRS II), motor function (UPDRS III and Hoehn & Yahr), and disease duration Contrast acuity testing conditions (contrast level, distance) 100%, 40 cm 100%, 2 m 2.5%, 40 cm 2.5%, 2 m
UPDRS II
UPDRS III
Hoehn & Yahr
PD Duration
r = −0.43, n = 28 (p = 0.02) −0.02, 27 (0.90) −0.54, 27 (0.004) −0.30, 26 (0.14)
−0.46, 29 (0.01) −0.48, 28 (0.01) −0.37, 28 (0.05) −0.43, 27 (0.02)
−0.52, 30 (0.003) −0.35, 29 (0.06) −0.56, 29 (0.002) −0.55, 28 (0.003)
−0.54, 31 (0.002) 0.02, 30 (0.93) −0.48, 30 (0.008) −0.19, 29 (0.33)
Note: Correlations with nominal P < 0.005 are significant (overall ␣ < 0.05) using the Hochberg-Bonferroni method; P < 0.05 is nominally significant in an exploratory sense.
fore argue that although low contrast acuity testing may be more sensitive, both high and low contrast acuity are affected by the disease [24]. Vision changes showed a positive correlation with PD severity defined by UPDRS III and Hoehn & Yahr staging at both viewing distances. Although the study is limited by the small sample size, and further study is needed for confirmation, these results are in line with others who have also found a correlation between contrast sensitivity and disease severity [7, 8, 17]. Interestingly, our study showed that contrast acuity scores correlated with UPDRS II and PD duration at 40 cm but not 2 m. The lack of statistical significance at 2 m suggests that contrast acuity for far distance may be affected early in the disease process since all PD patients performed poorly at this viewing distance regardless of disease duration. Visual contrast deterioration at near viewing distance, on the other hand, appears to be progressive as evidenced by the significant correlations between contrast acuity scores at 40 cm and disease duration as well as UPDRS II. With increasing interest in the pre-motor diagnosis of PD, it will be valuable to verify with further studies whether deterioration in contrast acuity precedes motor involvement and therefore could serve as an additional pre-motor biomarker. Several limitations exist in this study. In addition to the small sample size, PD patients were not tested in the practically defined OFF state. Visual contrast deterioration resulting in functional disability has been shown to respond to treatment with levodopa therapy [26, 27]. If this hypothesis is confirmed, our results may underestimate the degree of impairment since PD subjects were on their medications, possibly resulting in less significant difference between PD subjects and controls. Another limitation of this study is that control subjects in this study were older than PD subjects due to selection bias. Age may be associated with loss of contrast sensitivity [28] and was accounted for in our data analysis; furthermore, with control subjects being older, the contrast acuity score difference seen between
the PD and control groups in our study may underestimate the true difference between the two groups. The negative effect on accommodation due to the use of amantadine or anticholinergics was not accounted for in this study. Correlation of contrast acuity to illusions, minor and major hallucinations was not addressed in this study. Visual impairment due to deterioration in contrast acuity can have a significant impact on quality of life and on the practical aspects of day-to-day function. Correlations have been reported between low contrast visual impairment and driving performance [15, 29], mobility and walking speed [16, 30], falls [31], reading speed [32], computer performance [33], and activities of daily living [34]. However, impaired contrast sensitivity in PD patients is a topic that has received relatively little attention in clinical practice. The electronic form of low contrast acuity letter chart we used in this study combines contrast sensitivity with visual acuity testing and is quick and easy to administer. It is portable, quantitative, and adjustable for testing distances and contrast levels. These are advantages over the sine wave grating and paper letter charts for contrast sensitivity that have been used historically. The iPad app could be used as a quick screening tool to supplement formal visual testing in PD patients and to electronically store data. We believe that an assessment of low contrast acuity should be considered as part of the standard eye exam in PD, as it may reveal an otherwise missed visual impairment in these patients, help clinicians define a set of criteria for counseling them regarding safety while walking and driving at low-light conditions, and guide both pharmacologic and non-pharmacologic interventions that increase functional capacity. ACKNOWLEDGMENTS The Arizona Parkinson’s Disease Consortium and the Brain and Body Donation Program are supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue
T.P. Lin et al. / Abnormal Visual Contrast Acuity in PD
Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), and Mayo Clinic Foundation.
[12]
CONFLICT OF INTEREST
[16]
TP Lin, H Rigby, JS Adler, JG Hentz, LJ Balcer, SL Galetta, and CH Adler have no conflict of interest to report. S Devick is the principal shareholder and managing partner of the King-Devick Test DE, LLC which developed and owns the Variable Contrast Acuity Chart. R Cronin is a paid independent engineer and consultant to King-Devick Test LLC, which developed and owns the Variable Contrast Acuity Chart.
[13]
[14] [15]
[17]
[18]
[19] [20]
REFERENCES [1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Regan D, & Neima D (1984) Low-contrast letter charts in early diabetic retinopathy, ocular hypertension, glaucoma, and Parkinson’s disease. Br J Ophthalmol, 68, 885-889. Nguyen-Legros J (1988) Functional neuroarchitecture of the retina: Hypothesis on the dysfunction of retinal dopaminergic circuitryinParkinson’sdisease.SurgRadiolAnat,10,137-144. Regan D, & Maxner C (1987) Orientation-selective visual loss in patients with Parkinson’s disease. Brain, 110(Pt 2), 415-432. Davidsdottir S, Cronin-Golomb A, & Lee A (2005) Visual and spatial symptoms in Parkinson’s disease. Vision Res, 45, 1285-1296. Bulens C, Meerwaldt JD, van der Wildt GJ, & Keemink CJ (1986) Contrast sensitivity in Parkinson’s disease. Neurology, 36, 1121-1125. Bodis-Wollner I, Marx MS, Mitra S, Bobak P, Mylin L, & Yahr M (1987) Visual dysfunction in Parkinson’s disease. Loss in spatiotemporal contrast sensitivity. Brain, 110(Pt 6), 16751698. Diederich NJ, Raman R, Leurgans S, & Goetz CG (2002) Progressive worsening of spatial and chromatic processing deficits in Parkinson disease. Arch Neurol, 59, 1249-1252. Hutton JT, Morris JL, Elias JW, Varma R, & Poston JN (1991) Spatial contrast sensitivity is reduced in bilateral Parkinson’s disease. Neurology, 41, 1200-1202. Beach TG, Carew J, Serrano G, Adler CH, Shill HA, Sue LI, Sabbagh MN, Akiyama H, & Cuenca N (2014) Phosphorylated alpha-synuclein-immunoreactive retinal neuronal elements in Parkinson’s disease subjects. Neurosci Lett, 571, 34-38. Buttner T, Kuhn W, Muller T, Patzold T, Heidbrink K, & Przuntek H (1995) Distorted color discrimination in ‘de novo’ parkinsonian patients. Neurology, 45, 386-387. Price MJ, Feldman RG, Adelberg D, & Kayne H (1992) Abnormalities in color vision and contrast sensitivity in Parkinson’s disease. Neurology, 42, 887-890.
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
129
Botha H, & Carr J (2012) Attention and visual dysfunction in Parkinson’s disease. Parkinsonism Relat Disord, 18, 742-747. Diederich NJ, Goetz CG, Raman R, Pappert EJ, Leurgans S, & Piery V (1998) Poor visual discrimination and visual hallucinations in Parkinson’s disease. Clin Neuropharmacol, 21, 289-295. Shibasaki H, Tsuji S, & Kuroiwa Y (1979) Oculomotor abnormalities in Parkinson’s disease. Arch Neurol, 36, 360-364. Uc EY, Rizzo M, Anderson SW, Dastrup E, Sparks JD, & Dawson JD (2009) Driving under low-contrast visibility conditions in Parkinson disease. Neurology, 73, 1103-1110. Moes E, & Lombardi KM (2009) The relationship between contrast sensitivity, gait, and reading speed in Parkinson’s disease. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn, 16, 121-132. Uc EY, Rizzo M, Anderson SW, Qian S, Rodnitzky RL, & Dawson JD (2005) Visual dysfunction in Parkinson disease without dementia. Neurology, 65, 1907-1913. Pelli DG, Robson JG, & Wilkins AJ (1988) The design of a new letter chart for measuring contrast sensitivity. Clinical Vision Sciences, 2, 187-199. Regan D, & Neima D (1983) Low-contrast letter charts as a test of visual function. Ophthalmology, 90, 1192-1200. Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, Pfohl DC, Mills M, Bowen J, Ford C, Heidenreich FR, Jacobs DA, Markowitz CE, Stuart WH, Ying GS, Galetta SL, Maguire MG, & Cutter GR (2003) Contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite. Neurology, 61, 1367-1373. Baier ML, Cutter GR, Rudick RA, Miller D, Cohen JA, Weinstock-Guttman B, Mass M, & Balcer LJ (2005) Lowcontrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis. Neurology, 64, 992995. Balcer LJ, Baier ML, Pelak VS, Fox RJ, Shuwairi S, Galetta SL, Cutter GR, & Maguire MG (2000) New low-contrast vision charts: Reliability and test characteristics in patients with multiple sclerosis. Mult Scler, 6, 163-171. Mowry EM, Loguidice MJ, Daniels AB, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Cutter GR, Maguire MG, & Balcer LJ (2009) Vision related quality of life in multiple sclerosis: Correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry, 80, 767-772. Jones RD, Donaldson IM, & Timmings PL (1992) Impairment of high-contrast visual acuity in Parkinson’s disease. Mov Disord, 7, 232-238. Balcer LJ, Galetta SL, Polman CH, Eggenberger E, Calabresi PA, Zhang A, Scanlon JV, & Hyde R (2012) Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS. J Neurol Sci, 318, 119-124. Bulens C, Meerwaldt JD, Van der Wildt GJ, & Van Deursen JB (1987) Effect of levodopa treatment on contrast sensitivity in Parkinson’s disease. Ann Neurol, 22, 365-369. Hutton JT, Morris JL, & Elias JW (1993) Levodopa improves spatial contrast sensitivity in Parkinson’s disease. Arch Neurol, 50, 721-724. Mestre D, Blin O, Serratrice G, & Pailhous J (1990) Spatiotemporal contrast sensitivity differs in normal aging and Parkinson’s disease. Neurology, 40, 1710-1714. Owsley C, Ball K, McGwin G Jr, Sloane ME, Roenker DL, White MF, & Overley ET (1998) Visual processing impairment and risk of motor vehicle crash among older adults. JAMA, 279, 1083-1088.
130 [30] [31] [32] [33]
T.P. Lin et al. / Abnormal Visual Contrast Acuity in PD Marron JA, & Bailey IL (1982) Visual factors and orientationmobility performance. Am J Optom Physiol Opt, 59, 413-426. Lord SR (2006) Visual risk factors for falls in older people. Age Ageing, 35(Suppl 2), ii42-ii45. Whittaker SG, & Lovie-Kitchin J (1993) Visual requirements for reading. Optom Vis Sci, 70, 54-65. Scott IU, Feuer WJ, & Jacko JA (2002) Impact of visual function on computer task accuracy and reaction time in a
[34]
cohort of patients with age-related macular degeneration. Am J Ophthalmol, 133, 350-357. Haymes SA, Johnston AW, & Heyes AD (2002) Relationship between vision impairment and ability to perform activities of daily living. Ophthalmic Physiol Opt, 22, 79-91.
Journal of Parkinson’s Disease 5 (2015) 125–130 DOI 10.3233/JPD-140470 IOS Press
Research Report
Abnormal Visual Contrast Acuity in Parkinson’s Disease Tanya P. Lina , Heather Rigbyb , Jennifer S. Adlerc , Joseph G. Hentzd , Laura J. Balcere , Steven L. Galettae , Steve Devickf , Richard Croninf and Charles H. Adlerg,∗ a Department
of Neurology, University of Arizona, Tucson, AZ, USA of Neurology, Dalhousie University, Halifax, NS, Canada c University of Arizona, Tucson, AZ, USA d Department of Biostatistics, Mayo Clinic College of Medicine, Scottsdale, AZ, USA e Department of Neurology, NYU School of Medicine, New York, NY, USA f King-Devick Test LLC, Oakbrook Terrace, IL, USA g Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, USA b Department
Abstract. Background: Low-contrast vision is thought to be reduced in Parkinson’s disease (PD). This may have a direct impact on quality of life such as driving, using tools, finding objects, and mobility in low-light condition. Low-contrast letter acuity testing has been successful in assessing low-contrast vision in multiple sclerosis. We report the use of a new iPad application to measure low-contrast acuity in patients with PD. Objective: To evaluate low- and high-contrast letter acuity in PD patients and controls using a variable contrast acuity eye chart developed for the Apple iPad. Methods: Thirty-two PD and 71 control subjects were studied. Subjects viewed the Variable Contrast Acuity Chart on an iPad with both eyes open at two distances (40 cm and 2 m) and at high contrast (black and white visual acuity) and 2.5% low contrast. Acuity scores for the two groups were compared. Results: PD patients had significantly lower scores (indicating worse vision) for 2.5% low contrast at both distances and for high contrast at 2 m (p < 0.003) compared to controls. No significant difference was found between the two groups for high contrast at 40 cm (p = 0.12). Conclusions: Parkinson’s disease patients have reduced low and high contrast acuity compared to controls. An iPad app, as used in this study, could serve as a quick screening tool to complement more formal testing of patients with PD and other neurologic disorders. Keywords: Parkinson’s disease, vision, contrast sensitivity, visual acuity
INTRODUCTION Patients with Parkinson’s disease (PD) often note visual difficulties, but these symptoms are easily overlooked as many have normal or near normal highcontrast visual acuity (VA) on routine eye exams [1–4]. Contrast sensitivity is one of several aspects of visual function known to be affected in Parkinson’s ∗ Correspondence to: Charles H. Adler, MD, PhD, Professor, Department of Neurology, Mayo Clinic College of Medicine, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. Tel: +1 480 301 8100; Fax: +1 480 301 8451; E-mail: [email protected].
disease [5–8], and is postulated to be due to dopaminecontaining amacrine cell loss and ␣-synuclein deposits in the retina [2, 9]. Deficits in color discrimination [10, 11], higher cortical visual processing [12, 13], and oculomotor control [14] have also been shown in PD. These impairments may have a significant impact on their function and quality of life [15, 16]. Contrast sensitivity is measured in a grey scale spectrum, and detects a threshold for the eyes to see the differences in the amount of light reflecting from two adjacent surfaces, or light-dark transition. Several methods have been developed to test contrast
ISSN 1877-7171/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
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sensitivity. Much of the work on contrast sensitivity in PD has been done with sine wave grating contrast sensitivity testing in which parallel bars of varying width and contrast are presented to the patient [5–8].The width of the bars and distance apart provide a measure of spatial frequency. However, some suggest that letter acuity charts are at least as sensitive, provide similar diagnostic information, and may be a more suitable test of contrast sensitivity in the clinical setting [1]. In a commonly used version of contrast sensitivity letter chart, the Pelli-Robson chart, the size of the letters is kept constant, but contrast decreases across the page during testing [16–18]. Alternatively, testing of lowcontrast vision can be incorporated into routine high contrast visual acuity testing to evaluate low contrast letter acuity. In this method, both the letter size and contrast decrease during testing, with each page having the same level of contrast [19]. Low-contrast letter acuity testing may have an advantage over the Pelli-Robson chart in that it is able to capture “notch loss” of contrast, or reduction in low-contrast vision at small letter sizes. In studies of patients with MS, low-contrast acuity had a greater capacity to distinguish MS vs. disease-free control participants compared to Pelli-Robson contrast sensitivity [20]. Prior studies showed that low-contrast acuity is a highly sensitive and reliable measure of visual dysfunction in a number of disorders including multiple sclerosis [21, 22], ocular hypertension [1], and glaucoma [1]. Other studies have also shown that lowcontrast acuity correlates well with structural markers such as retinal nerve fiber layer thickness, and visionspecific quality of life in MS, PD and other neurologic disorders [16, 23]. However, low-contrast acuity as a clinical measure of low-contrast vision in PD has only been reported in a few studies with small numbers of patients [1, 3]. In addition, there is conflicting evidence whether high contrast (black on white) visual acuity is also affected in Parkinson’s disease [1, 3, 5, 17, 24]. The main objective of this study was to evaluate low-and high-contrast letter acuity in PD patients and controls using a variable contrast acuity eye chart that was recently developed for the Apple iPad. METHODS Subjects Thirty-two patients with PD and 71 control subjects were studied. Twenty-two of the PD patients were tested in the movement disorders clinic at Mayo Clinic Arizona based on proximity to the researchers.
Ten additional PD patients and all controls were recruited from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) in the Arizona PD Consortium/Banner Sun Health Research Institute Brain and Body Donation Program. Subjects from AZSAND were local community dwelling seniors who were participating in the brain and body donation program. All participants signed written informed consent from either the Mayo Clinic or Banner Sun Health Research Institute IRB. PD was clinically diagnosed according to the UK brain bank criteria. Subjects with a clinical diagnosis of dementia and those with a history of macular degeneration, glaucoma, cataract, or blindness were excluded from the study. All subjects had a neurological examination including the Unified Parkinson’s Disease Rating Scale (UPDRS) on the same day as vision testing (with the exception of one patient whose UPDRS was scored three weeks later). Eleven of the 32 PD subjects had motor fluctuations and all but three of them were assessed in the practically defined off state. Variable contrast acuity test Subjects viewed the Variable Contrast Acuity Chart (King-Devick Test LLC, Oakbrook Terrace, IL) on an Apple iPad2, and were asked to wear their usual corrective lenses. The chart design and testing protocol were based on the Bailey-Lovie and Early Treatment of Diabetic Retinopathy Study (EDTRS) visual acuity tests that are the standards in ophthalmology clinical trials. Visual acuity (for high-contrast, or black letters on white background) may be specified in this chart by Snellen notation for descriptive purposes (i.e. 20/20), by the number of letters identified correctly [25]. Other similar apps exist; however, they do not use the required ETDRS mandated Sloan letters and protocol. The iPad app used in this study was specifically developed for Apple devices because Apple guarantees no luminosity fluctuation among their devices. Participants were tested at distances of 40 cm and 2 m, with 100% and 2.5% contrast at each distance (Fig. 1) with both eyes open following similar parameters to those used in multiple sclerosis trials [21, 25]. Binocular testing provides a measure of overall visual function representative of daily activities. It has been used successfully in several methodologic studies, and was recommended as a primary measure of visual function by recent studies [24]. Letter sizes decreased from page to page during testing. The background lighting for the iPad was set at maximum for all testing. Direct sunlight was shielded from the examination rooms.
T.P. Lin et al. / Abnormal Visual Contrast Acuity in PD
A
127
B
Fig. 1. Variable contrast acuity eye chart at two contrast levels on iPad: 100% (A) & 10% (B). The 10% contrast was for illustration purpose only. The actual contrasts used in this study were 100% and 2.5%.
contrast) at both 40 cm and 2 m. High contrast scores (100% contrast) were worse in the PD group at 2 m but not at 40 cm (Table 1). Low contrast acuity scores correlated with disease severity as measured by the Hoehn and Yahr scale at both distances after correcting p-values for multiple comparisons by using the Hochberg-Bonferroni method (Table 2). Correlations of high and low contrast acuity scores versus motor function as measured by the UPDRS III were nominally significant (unadjusted P < 0.05) at both distances. High and low contrast acuity scores also correlated with Activities of Daily Living scores measured by the UPDRS II and PD disease duration at 40 cm but not at 2 m.
Low and high contrast acuity at each distance was converted into a numeric score determined by the number of letters identified correctly. The maximum number of points was 90 at 40 cm (equivalent to visual acuity of 20/25) and 75 at 2 m (visual acuity of 20/10; 60 = 20/20) [25]. Statisical analysis Mean contrast acuity scores adjusted for age and gender were compared between groups using a general linear model. Pearson correlation coefficients were used to assess the correlations of contrast acuity scores with activities of daily living (UPDRS II), motor function (UPDRS III and Hoehn & Yahr), and disease duration.
DISCUSSION Using a novel method for studying visual contrast acuity, PD patients in this study had worse low contrast acuity scores compared to controls at both near and far viewing distances, while high-contrast acuity scores were lower at 2 m. These findings are in keeping with others that have found reduced low contrast vision in PD but also suggest that high contrast acuity may be affected at farther distances. In contrast to several studies that have shown normal or near normal high contrast acuity scores in PD [1, 3, 5], our findings are in agreement with others that found impairment of high contrast visual acuity [17, 24]. These data there-
RESULTS PD subjects were younger (mean ± SD, 69.1 ± 13 years) than controls (82.7 ± 6.6 years, p < 0.001). Proportion of gender was not statistically different between the two groups (50% vs. 66% male, p = 0.16). Mean PD disease duration was 6.0 ± 4.7 years. The mean scores on the UPDRS parts II and III were 10.3 ± 6.6 and 20.9 ± 12, respectively. The mean Hoehn and Yahr staging was 1.98 ± 0.82. After adjusting for age and gender, PD patients had significantly worse low-contrast acuity scores (2.5%
Table 1 Adjusted mean (SE) contrast acuity scores in PD patients vs. controls Contrast acuity testing conditions (contrast level, distance) 100%, 40 cm 100%, 2 m 2.5%, 40 cm 2.5%, 2 m ∗ P-values
PD (n = 32)
Controls (n = 71)
95% CI
P value∗
82.3 (1.3) 51.3 (1.7) 47.9 (2.7) 23.1 (2.0)
84.9 (0.8) 58.6 (1.1) 58.6 (1.7) 31.5 (1.2)
−2.6 −7.2 −10.7 −8.5
−5.9 to 0.7 −11.7 to −2.9 −17.6 to −3.9 −13.4 to −3.5
0.12 0.001 0.003 0.001
from general linear models, adjusting for age and gender.
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Table 2 Correlations of contrast acuity scores with activities of daily living (UPDRS II), motor function (UPDRS III and Hoehn & Yahr), and disease duration Contrast acuity testing conditions (contrast level, distance) 100%, 40 cm 100%, 2 m 2.5%, 40 cm 2.5%, 2 m
UPDRS II
UPDRS III
Hoehn & Yahr
PD Duration
r = −0.43, n = 28 (p = 0.02) −0.02, 27 (0.90) −0.54, 27 (0.004) −0.30, 26 (0.14)
−0.46, 29 (0.01) −0.48, 28 (0.01) −0.37, 28 (0.05) −0.43, 27 (0.02)
−0.52, 30 (0.003) −0.35, 29 (0.06) −0.56, 29 (0.002) −0.55, 28 (0.003)
−0.54, 31 (0.002) 0.02, 30 (0.93) −0.48, 30 (0.008) −0.19, 29 (0.33)
Note: Correlations with nominal P < 0.005 are significant (overall ␣ < 0.05) using the Hochberg-Bonferroni method; P < 0.05 is nominally significant in an exploratory sense.
fore argue that although low contrast acuity testing may be more sensitive, both high and low contrast acuity are affected by the disease [24]. Vision changes showed a positive correlation with PD severity defined by UPDRS III and Hoehn & Yahr staging at both viewing distances. Although the study is limited by the small sample size, and further study is needed for confirmation, these results are in line with others who have also found a correlation between contrast sensitivity and disease severity [7, 8, 17]. Interestingly, our study showed that contrast acuity scores correlated with UPDRS II and PD duration at 40 cm but not 2 m. The lack of statistical significance at 2 m suggests that contrast acuity for far distance may be affected early in the disease process since all PD patients performed poorly at this viewing distance regardless of disease duration. Visual contrast deterioration at near viewing distance, on the other hand, appears to be progressive as evidenced by the significant correlations between contrast acuity scores at 40 cm and disease duration as well as UPDRS II. With increasing interest in the pre-motor diagnosis of PD, it will be valuable to verify with further studies whether deterioration in contrast acuity precedes motor involvement and therefore could serve as an additional pre-motor biomarker. Several limitations exist in this study. In addition to the small sample size, PD patients were not tested in the practically defined OFF state. Visual contrast deterioration resulting in functional disability has been shown to respond to treatment with levodopa therapy [26, 27]. If this hypothesis is confirmed, our results may underestimate the degree of impairment since PD subjects were on their medications, possibly resulting in less significant difference between PD subjects and controls. Another limitation of this study is that control subjects in this study were older than PD subjects due to selection bias. Age may be associated with loss of contrast sensitivity [28] and was accounted for in our data analysis; furthermore, with control subjects being older, the contrast acuity score difference seen between
the PD and control groups in our study may underestimate the true difference between the two groups. The negative effect on accommodation due to the use of amantadine or anticholinergics was not accounted for in this study. Correlation of contrast acuity to illusions, minor and major hallucinations was not addressed in this study. Visual impairment due to deterioration in contrast acuity can have a significant impact on quality of life and on the practical aspects of day-to-day function. Correlations have been reported between low contrast visual impairment and driving performance [15, 29], mobility and walking speed [16, 30], falls [31], reading speed [32], computer performance [33], and activities of daily living [34]. However, impaired contrast sensitivity in PD patients is a topic that has received relatively little attention in clinical practice. The electronic form of low contrast acuity letter chart we used in this study combines contrast sensitivity with visual acuity testing and is quick and easy to administer. It is portable, quantitative, and adjustable for testing distances and contrast levels. These are advantages over the sine wave grating and paper letter charts for contrast sensitivity that have been used historically. The iPad app could be used as a quick screening tool to supplement formal visual testing in PD patients and to electronically store data. We believe that an assessment of low contrast acuity should be considered as part of the standard eye exam in PD, as it may reveal an otherwise missed visual impairment in these patients, help clinicians define a set of criteria for counseling them regarding safety while walking and driving at low-light conditions, and guide both pharmacologic and non-pharmacologic interventions that increase functional capacity. ACKNOWLEDGMENTS The Arizona Parkinson’s Disease Consortium and the Brain and Body Donation Program are supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue
T.P. Lin et al. / Abnormal Visual Contrast Acuity in PD
Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), and Mayo Clinic Foundation.
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CONFLICT OF INTEREST
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TP Lin, H Rigby, JS Adler, JG Hentz, LJ Balcer, SL Galetta, and CH Adler have no conflict of interest to report. S Devick is the principal shareholder and managing partner of the King-Devick Test DE, LLC which developed and owns the Variable Contrast Acuity Chart. R Cronin is a paid independent engineer and consultant to King-Devick Test LLC, which developed and owns the Variable Contrast Acuity Chart.
[13]
[14] [15]
[17]
[18]
[19] [20]
REFERENCES [1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Regan D, & Neima D (1984) Low-contrast letter charts in early diabetic retinopathy, ocular hypertension, glaucoma, and Parkinson’s disease. Br J Ophthalmol, 68, 885-889. Nguyen-Legros J (1988) Functional neuroarchitecture of the retina: Hypothesis on the dysfunction of retinal dopaminergic circuitryinParkinson’sdisease.SurgRadiolAnat,10,137-144. Regan D, & Maxner C (1987) Orientation-selective visual loss in patients with Parkinson’s disease. Brain, 110(Pt 2), 415-432. Davidsdottir S, Cronin-Golomb A, & Lee A (2005) Visual and spatial symptoms in Parkinson’s disease. Vision Res, 45, 1285-1296. Bulens C, Meerwaldt JD, van der Wildt GJ, & Keemink CJ (1986) Contrast sensitivity in Parkinson’s disease. Neurology, 36, 1121-1125. Bodis-Wollner I, Marx MS, Mitra S, Bobak P, Mylin L, & Yahr M (1987) Visual dysfunction in Parkinson’s disease. Loss in spatiotemporal contrast sensitivity. Brain, 110(Pt 6), 16751698. Diederich NJ, Raman R, Leurgans S, & Goetz CG (2002) Progressive worsening of spatial and chromatic processing deficits in Parkinson disease. Arch Neurol, 59, 1249-1252. Hutton JT, Morris JL, Elias JW, Varma R, & Poston JN (1991) Spatial contrast sensitivity is reduced in bilateral Parkinson’s disease. Neurology, 41, 1200-1202. Beach TG, Carew J, Serrano G, Adler CH, Shill HA, Sue LI, Sabbagh MN, Akiyama H, & Cuenca N (2014) Phosphorylated alpha-synuclein-immunoreactive retinal neuronal elements in Parkinson’s disease subjects. Neurosci Lett, 571, 34-38. Buttner T, Kuhn W, Muller T, Patzold T, Heidbrink K, & Przuntek H (1995) Distorted color discrimination in ‘de novo’ parkinsonian patients. Neurology, 45, 386-387. Price MJ, Feldman RG, Adelberg D, & Kayne H (1992) Abnormalities in color vision and contrast sensitivity in Parkinson’s disease. Neurology, 42, 887-890.
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
129
Botha H, & Carr J (2012) Attention and visual dysfunction in Parkinson’s disease. Parkinsonism Relat Disord, 18, 742-747. Diederich NJ, Goetz CG, Raman R, Pappert EJ, Leurgans S, & Piery V (1998) Poor visual discrimination and visual hallucinations in Parkinson’s disease. Clin Neuropharmacol, 21, 289-295. Shibasaki H, Tsuji S, & Kuroiwa Y (1979) Oculomotor abnormalities in Parkinson’s disease. Arch Neurol, 36, 360-364. Uc EY, Rizzo M, Anderson SW, Dastrup E, Sparks JD, & Dawson JD (2009) Driving under low-contrast visibility conditions in Parkinson disease. Neurology, 73, 1103-1110. Moes E, & Lombardi KM (2009) The relationship between contrast sensitivity, gait, and reading speed in Parkinson’s disease. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn, 16, 121-132. Uc EY, Rizzo M, Anderson SW, Qian S, Rodnitzky RL, & Dawson JD (2005) Visual dysfunction in Parkinson disease without dementia. Neurology, 65, 1907-1913. Pelli DG, Robson JG, & Wilkins AJ (1988) The design of a new letter chart for measuring contrast sensitivity. Clinical Vision Sciences, 2, 187-199. Regan D, & Neima D (1983) Low-contrast letter charts as a test of visual function. Ophthalmology, 90, 1192-1200. Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, Pfohl DC, Mills M, Bowen J, Ford C, Heidenreich FR, Jacobs DA, Markowitz CE, Stuart WH, Ying GS, Galetta SL, Maguire MG, & Cutter GR (2003) Contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite. Neurology, 61, 1367-1373. Baier ML, Cutter GR, Rudick RA, Miller D, Cohen JA, Weinstock-Guttman B, Mass M, & Balcer LJ (2005) Lowcontrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis. Neurology, 64, 992995. Balcer LJ, Baier ML, Pelak VS, Fox RJ, Shuwairi S, Galetta SL, Cutter GR, & Maguire MG (2000) New low-contrast vision charts: Reliability and test characteristics in patients with multiple sclerosis. Mult Scler, 6, 163-171. Mowry EM, Loguidice MJ, Daniels AB, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Cutter GR, Maguire MG, & Balcer LJ (2009) Vision related quality of life in multiple sclerosis: Correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry, 80, 767-772. Jones RD, Donaldson IM, & Timmings PL (1992) Impairment of high-contrast visual acuity in Parkinson’s disease. Mov Disord, 7, 232-238. Balcer LJ, Galetta SL, Polman CH, Eggenberger E, Calabresi PA, Zhang A, Scanlon JV, & Hyde R (2012) Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS. J Neurol Sci, 318, 119-124. Bulens C, Meerwaldt JD, Van der Wildt GJ, & Van Deursen JB (1987) Effect of levodopa treatment on contrast sensitivity in Parkinson’s disease. Ann Neurol, 22, 365-369. Hutton JT, Morris JL, & Elias JW (1993) Levodopa improves spatial contrast sensitivity in Parkinson’s disease. Arch Neurol, 50, 721-724. Mestre D, Blin O, Serratrice G, & Pailhous J (1990) Spatiotemporal contrast sensitivity differs in normal aging and Parkinson’s disease. Neurology, 40, 1710-1714. Owsley C, Ball K, McGwin G Jr, Sloane ME, Roenker DL, White MF, & Overley ET (1998) Visual processing impairment and risk of motor vehicle crash among older adults. JAMA, 279, 1083-1088.
130 [30] [31] [32] [33]
T.P. Lin et al. / Abnormal Visual Contrast Acuity in PD Marron JA, & Bailey IL (1982) Visual factors and orientationmobility performance. Am J Optom Physiol Opt, 59, 413-426. Lord SR (2006) Visual risk factors for falls in older people. Age Ageing, 35(Suppl 2), ii42-ii45. Whittaker SG, & Lovie-Kitchin J (1993) Visual requirements for reading. Optom Vis Sci, 70, 54-65. Scott IU, Feuer WJ, & Jacko JA (2002) Impact of visual function on computer task accuracy and reaction time in a
[34]
cohort of patients with age-related macular degeneration. Am J Ophthalmol, 133, 350-357. Haymes SA, Johnston AW, & Heyes AD (2002) Relationship between vision impairment and ability to perform activities of daily living. Ophthalmic Physiol Opt, 22, 79-91.
