ORIGINAL ARTICLE
Central corneal thickness and its relationship to Parkinson’s disease severity Durdane Aksoy, MD,* Huseyin Ortak, MD,† Semiha Kurt, MD,* Emre Cevik, MD,* Betul Cevik, MD* ABSTRACT ● RÉSUMÉ Objective: To investigate the effect of Parkinson’s disease (PD) on blink rate (BR), tear breakup time test (TBUT), Schirmer’s test, and corneal thickness, and the relationship of these effects with disease severity. Design: Prospective controlled study. Participants: Fifty-five eyes from 55 patients with PD and 40 eyes from 40 healthy subjects were analyzed in the study. Methods: The patients were divided into 2 groups according to their Hoehn–Yahr (H-Y) scores; patients classified as H-Y 1–2 were designated as the mild group, and those classified as H-Y 3–5 were designated as the moderate group. Subjects were screened for BR, TBUT, and Schirmer’s test, and the central corneal thickness (CCT) was measured. Results: The BR, Schirmer’s test, TBUT, and CCT values of the patient group were significantly lower than those of the control group. The BR and TBUT of the mild group were significantly lower than those of the control group, but the decreases in the Schirmer’s test values and CCT were not statistically significant. In addition, significant decreases in the BR, TBUT, Schirmer’s test scores, and CCT were observed in the patient group as the H-Y score increased. Conclusions: A reduced BR and poor tear quality in the early stages of PD, as well as decreased tear production as the disease progresses, can result in reduced CCT. The possibility of a thin cornea should be taken into consideration while measuring the intraocular pressure in patients with severe PD. Objet : Examen des effets de la maladie de Parkinson sur le taux de clignotement, le temps de la rupture lacrymale, le test de Schirmer, ainsi que l'épaisseur de la cornée et la relation de ces effets avec la gravité de la maladie. Nature : Étude prospective contrôlée. Participants : Cinquante-cinq yeux de 55 patients atteints de la maladie de Parkinson et 40 sujets en santé ont été analysés. Méthodes : Les patients ont été répartis en deux groupes selon leurs données Hoehn-Yahr; ceux qui étaient classés Hoehn-Yahr 12 étaient considérés comme 0 groupe léger T et ceux classés Hoehn-Yahr 3-5, comme 0 groupe modéré T. Les sujets ont subi des tests de fréquence de clignotement et de temps de rupture lacrymale et le test Schirmer, et l'on a mesuré l'épaisseur du centre de la cornée. Résultats : Le taux de clignotement, le test Schirmer, le temps de rupture lacrymale et l'épaisseur du centre de la cornée du groupe de patients étaient significativement inférieurs à ceux du groupe témoin. Les taux de clignotement et de le temps de la rupture lacrymale du groupe léger étaient significativement inférieurs à ceux du groupe témoin, mais la baisse des valeurs du test Schirmer et de l'épaisseur du centre de la cornée n'étaient pas importante statistiquement. En outre, on a observé une baisse significative du taux de clignotement, du temps de la rupture lacrymale, des résultats du test Schirmer et de l'épaisseur du centre de la cornée alors que s'accroissaient les données Hoehn-Yahr du groupe de patients. Conclusions : Une réduction du taux de clignotement et une piètre qualité lacrymale dans les premières étapes de la maladie de Parkinson, ainsi qu'une production réduite de larmes alors que la maladie progresse, peut réduire l'épaisseur du centre de la cornée. L'on devrait aussi tenir compte de la possibilité d'amincissement de la cornée en mesurant la pression intraoculaire des patients qui ont une grave maladie de Parkinson.
Parkinson’s disease (PD) is a neurodegenerative disorder accompanied by both motor and nonmotor symptoms. Nonmotor symptoms, including visual problems, autonomic dysfunction, gastrointestinal symptoms, and impairments in sleep and cognitive function, are common, yet they are often under-recognized in clinical practice.1–3 Visual symptoms, such as colour discrimination, visuospatial deficit, reduced blink rate (BR), dry eye, transient diplopia, vergence dysfunction, hypometric saccades, impaired smooth pursuit with catch-up saccades, mild impairment of upgaze, convergence insufficiency, visual hallucinations, ocular discomfort, and pain, are reported in patients with PD, and these problems negatively impact
activities of daily living such as ambulation, use of stairs, and driving.3–6 Corneal thickness of the central and midperipheral cornea is significantly decreased in individuals with dry eyes.7 A reduced BR and dry eye syndrome are well described in the PD literature.3,5,8–10 However, the effects of PD and the disease severity on corneal thickness are unknown. In this study, the BR, tear breakup time test (TBUT), Schirmer’s test score, and central corneal thickness (CCT) were analyzed in a group of patients with PD and compared with healthy individuals. The effects of PD severity on the BR, tear tests, and corneal thickness were also investigated.
From the Departments of *Neurology and †Ophthalmology, Gaziosmanpasa University Faculty of Medicine, Tokat, Turkey
Can J Ophthalmol 2014;49:152–156 0008-4182/14/$-see front matter & 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2013.12.010
Originally received Aug. 22, 2013. Final revision Dec. 22, 2013. Accepted Jan. 3, 2014 Correspondence to Durdane Aksoy, Gaziosmanpasa University Faculty of Medicine, Department of Neurology, Kaleardi mah, Muhittin Fusunuglu cad. Tokat 60100, Turkey; [email protected]
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Central corneal thickness in Parkinson’s disease—Aksoy et al. METHODS Fifty-five patients with PD and 40 healthy subjects were enrolled in this study. Patients with PD met the Parkinson’s Disease Society Brain Bank (London, U.K.) clinical diagnostic criteria and were diagnosed by an experienced neurologist. Patients diagnosed with diabetes mellitus, glaucoma, keratoconus, corneal dystrophy and keratitis, active uveitis, systemic therapy with pharmaceutical drugs with known corneal toxicity were excluded from the study, as were contact lens users, patients receiving topical therapy with antiglaucoma drugs, and patients who had a previous history of ophthalmic surgery. Patients treated with drugs other than L-dopa and dopamine agonists were also excluded. The hospital ethics committee approved the study, and patients provided written informed consent after the nature and purpose of the study were fully explained. All experiments were performed in accordance with the Declaration of Helsinki. A detailed neurologic examination was performed on patients with PD, their Hoehn–Yahr (H-Y) scores were calculated, and sex, age, disease duration, and duration of 11 L-dopa and/or dopamine agonist therapy were recorded. The patients were divided into 2 groups according to their H-Y scores; patients who scored H-Y 1–2 were designated as the mild group, and those scored H-Y 3–5 were designated as the moderate group. Fifty-five eyes from 55 patients with PD (32 male, 23 female) and 40 eyes from 40 healthy individuals (23 male, 17 female), consistent in age and sex with the patients, were examined. A full ophthalmologic evaluation was performed on each subject. All patients were screened for BR, TBUT, Schirmer test under topical anaesthesia, and CCT; CCT was measured using an ultrasonic pachymeter. BR was determined by 1 examiner recording the average number of blinks per minute during a 3-minute resting period. A blink was defined as bilateral paroxysmal closure of the eyelids in the absence of external stimulus. One eye of each patient was chosen at random for statistical analysis. The patient’s cornea was anaesthetized with topical proparacaine hydrochloride 0.5% (AlconCouvreur, Puurs, Belgium), and CCT measurements were obtained by a single ophthalmologist using an ultrasonic pachymeter (Optikon 2000 SPA; Pacline, Rome, Italy). The TBUT test was performed using a sterile fluorescein strip that was placed in the wet surface of the lower fornix of the conjunctiva. The patient was asked to blink twice and then look straight ahead without blinking. The time before the first defect appeared in the stained tear film was recorded as the tear film TBUT. The average value of 3 consecutive TBUT tests was obtained. The Schirmer test was performed under anaesthesia. Three minutes after 2 proparacaine hydrochloride 0.5% eye drops were instilled, the lid margin was dried with cotton. The Schirmer’s test strip was placed in the lower temporal fornix at the junction of the middle and lateral
thirds of the eyelid. The patient was asked to keep both eyes immobile and 5 minutes later, the strip was removed and the amount of wetting was recorded in millimeters. All dry eye tests were performed during the same daily time interval (from 10:00 AM to 2:00 PM) at a temperature between 201C and 251C and relative humidity between 35% and 45%. The Kolmogorov–Smirnov normality test was used to test the normal distribution of continuous variables. Continuous variables were compared using Student t test for independent samples and the Mann–Whitney U test. For the comparison of the mild, moderate, and control groups, 1-way ANOVA and Kruskal–Wallis variance analysis were used. Tukey honestly significant difference (HSD) and Mann–Whitney U tests were used for post hoc tests. The correlation between the test parameters and H-Y scores in the patient group was evaluated using the Pearson correlation coefficient. The p values less than 0.05 were considered statistically significant. Calculations were made using statistical analysis software (IBM SPSS Statistics 19; SPSS Inc, Chicago, Ill.).
RESULTS The average ages of the patient group and the control group were (mean ⫾ SD) 63.44 ⫾ 10.10 and 61.05 ⫾ 7.87, respectively. There was no significant age difference between the 2 groups (Table 1). The average duration of disease in the PD group was 4.81 years, and the average H-Y score was 2.17 ⫾ 0.95. The BR, Schirmer’s test, TBUT, and CCT values of the PD group were significantly lower than those of the control group (Table 1). Patients with PD were subdivided into 2 groups (mild and moderate). When the 3 groups (mild, moderate, and control) were compared using 1-way ANOVA and Kruskal–Wallis variance analysis, a statistically significant difference in the BR, TBUT, Schirmer’s test, and CCT values was observed (Table 2). Tukey test analysis revealed that the BR and TBUT values were significantly lower in the mild group than in Table 1—Comparison of age, blink rate, tear breakup time test, Schirmer, and central corneal thickness mean values with t test for independent samples for patients with PD and control groups
Age Blink rate TBUT Schirmer CCT
Group
Mean
SD
PD Control PD Control PD Control PD Control PD Control
63.44 61.05 6.27 11.55 6.49 10.65 8.95 11.28 541.89 558.92
10.10 7.87 3.61 4.39 2.36 4.27 3.68 3.41 12.81 12.25
t
z
p
1.24
—
0.22
—
–2.69
0.007*
—
–4.77
0.0001*
3.13
—
0.002
3.63
—
0.0001
TBUT, tear breakup time test; CCT, central corneal thickness. *Because data do not follow normal distribution, Mann–Whitney U test was applied.
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Central corneal thickness in Parkinson’s disease—Aksoy et al. Table 2—Comparison of mild, moderate, and control groups in terms of blink rate, Schirmer’s test, tear breakup time test, and central corneal thickness values (1-way ANOVA/Kruskal–Wallis variance analysis) Control (mean ⫾ SD) Blink rate TBUT Schirmer’s test CCT
11.55 10.65 11.28 558.92
⫾ ⫾ ⫾ ⫾
Mild (mean ⫾ SD)
4.39 4.27 3.41 12.25
7.09 7.00 10.88 549.36
⫾ ⫾ ⫾ ⫾
4.04 2.19 2.95 12.77
Moderate (mean ⫾ SD)
F
χ²
p
⫾ ⫾ ⫾ ⫾
— — 22.63 12.17
31.15 25.02 — —
0.0001* 0.0001* 0.0001 0.0001
5.05 5.73 6.05 530.68
2.43 2.45 2.64 10.14
TBUT, tear breakup time test; CCT, central corneal thickness. *Because data do not follow normal distribution, Kruskal–Wallis variance analysis was used.
the control group. The Schirmer’s and CCT values were also lower in the mild group, but the differences were not statistically significant (Table 3). The Pearson correlation coefficient was used to determine the correlation between the BR, tear test, and CCT values and diseases severity (H-Y scores). A strong and significant negative correlation was detected between the H-Y scores and CCT values, as well as between the H-Y scores and Schirmer’s test scores. Analysis also revealed a weak but significant negative correlation between the H-Y scores and BR and TBUT values (Table 4). These results suggest that in patients with PD, the BR, TBUT, Schirmer’s test, and CCT values significantly decrease as the H-Y score increases.
DISCUSSION Ocular motility impairments, dry eye, and ocular surface irritation are common clinical ophthalmologic findings in patients with PD.3,6,8 Reduced BR in patients with PD has been reported in several studies, and reduced BR is considered a symptom that supports a PD diagnosis.3,5,6,12,13 Reduced BR in patients with PD is associated with hypokinesia resulting from reduced dopaminergic activity.3 In a study that evaluated the BR in patients with PD in a variety of circumstances (while being interviewed, watching a video, and reading from a book), the BR was significantly lower in the patient group than in the control group in all situations; however, no correlation was found between BR and disease severity.10 Other studies have reported a negative correlation between the H-Y scores and BR in patients with PD.8,13 The results of our study are consistent with previous reports, suggesting a statistically significant negative correlation between the H-Y scores and BR. Table 3—Comparison of mild group and control group in terms of blink rate, tear breakup time test, Schirmer’s test, and central corneal thickness values using Tukey test Mild Group (mean ⫾ SD) Age (y) Blink rate TBUT Schirmer’s test CCT
63.21 7.09 7.00 10.88 549.36
⫾ ⫾ ⫾ ⫾ ⫾
9.97 4.04 2.19 2.95 12.77
Control Group (mean ⫾ SD)
p
⫾ ⫾ ⫾ ⫾ ⫾
0.30 0.001 0.001 0.59 0.07
61.05 11.55 10.65 11.28 558.92
7.87 4.39 4.27 3.41 12.25
TBUT, tear breakup time test; CCT, central corneal thickness.
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Abnormalities in tear secretion are frequently reported among patients with PD.3,7–9 In a study of patients with early-stage PD who had not received any treatment, dry eye syndrome was detected in almost two thirds of the patients. Moreover, when tear tests were evaluated separately, the TBUT values of early-stage patients were lower than those of the control group. In addition, increased ocular surface disease and tear film abnormalities in patients with PD were highlighted in a recent study, whereas noting that these patients could be asymptomatic because of reduced corneal sensitivity.9 These studies all indicate poor tear film quality in patients with PD. Another study, evaluating the Schirmer’s test, BR, TBUT and Rose bengal stain, and phenol red thread tests, reported that patients with PD had abnormalities in at least 1 of the tear tests.8 In our study, patients with early-stage PD had significantly lower BRs and TBUT values than subjects in the control group. The Schirmer’s test and CCT values were also, although not significantly, lower. A reduced spontaneous BR in patients with PD may contribute to ocular discomfort caused by dry eye syndrome. Blinking is necessary to heal the tear– cornea optical interface and maintain a smooth and regular tear film.3,14–16 Our findings and those of prior studies in the field suggest that impairments in the BR and tear quality may occur even in the early stages of the disease.3,8 A significant difference was detected in the BR, TBUT, Schirmer’s test, and CCT values between the mild, moderate, and control groups in this study. The BR and TBUTs were significantly lower in the mild group than in the control group, whereas the Schirmer’s test values and CCT were slightly lower. Furthermore, the same values had significant negative correlation with the H-Y scores. As a result, we report that the BR and TBUT are decreased during the mild stages of PD and, as the disease progresses, the BR, TBUT, Schirmer’s test, and CCT values decrease in correlation with increasing H-Y scores.
Table 4—Evaluation of relation between Hoehn–Yahr scores and central corneal thickness, Schirmer’s test, tear breakup time test, and blink rate using simple correlation analysis by Pearson correlation coefficient test
Hoehn–Yahr/blink rate Hoehn–Yahr/TBUT Hoehn–Yahr/Schirmer Hoehn–Yahr/CCT
r
p
–0.412 –0.316 –0.581 –0.535
0.002 0.019 0.0001 0.0001
TBUT, tear breakup time test; CCT, central corneal thickness.
Central corneal thickness in Parkinson’s disease—Aksoy et al. Patients with tear dysfunction typically report irritation symptoms that include foreign body sensation, burning, and dryness, as well as vision-related symptoms such as photophobia and blurred and fluctuating vision.17,18 The aqueous layer of the tear film is normally isotonic or slightly hypotonic. In all forms of dry eye syndrome, however, there is an increase in the osmolarity of the tear film, and hypertonic tear film causes a decrease in the corneal thickness.18,19 A chronic state of desiccation and immune activation in dry eye syndrome may contribute to the observed corneal thinning.17,20 A reduced BR and reduced tear quality in the early stages of the disease, and the dry eye symptoms that result from impairments in tear production as the disease manifests, may have contributed to a decrease in the CCT in our patients with PD. In addition, corneal epithelial disruptions, changes in corneal thickness, corneal endothelial damage, and corneal edema are reported in patients with PD who are on amantadine therapy for a long period.21–23 Patients on amantadine or other drugs that are known to affect the cornea were excluded from our study. Only patients using L-dopa and dopamine agonists, which have no significant effect on the lacrimal glands, were enrolled in the study.8 A high incidence of glaucomatous visual field defects and enlarged cup-to-disk ratios has been reported in patients with Alzheimer’s disease and PD. In addition, the identification of probable glaucoma in 24.5% of patients with Alzheimer’s disease and 23.7% of patients with PD was significantly higher than in the normal population.24,25 CCT has an important impact on the intraocular pressure (IOP) measurement when diagnosing and treating glaucoma, and eyes with a greater mean CCT tend to have a higher IOP. Because an increased CCT may lead to falsely high IOP readings, and thin corneas may lead to falsely low IOP readings, there should be a correlation between the CCT and baseline IOP.26–29 Accumulating evidence suggests that the CCT is a crucial ocular parameter in glaucoma that should be measured in patients of advanced age.30 The relationship between the CCT and PD severity has not yet been established. Our findings suggest that BR and tear quality are impaired even in the early stages of PD. The Schirmer’s test and CCT values also decrease as the disease becomes more severe. We found a significant negative correlation between the H-Y scores and the CCT values. PD and glaucoma have a higher prevalence with increasing age, and glaucoma tends to occur more frequently in patients with PD. Therefore, the possibility of a thin cornea should be taken into consideration when measuring the IOP in patients with severe PD. Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article.
Acknowledgements: The authors are grateful to Dr. Ilker Etikan, Biostatistics Department of Gaziosmanpasa University, for his contribution on the statistical analysis.
REFERENCES 1. Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. Neurology. 2002;59: 408-13. 2. Bonnet AM, Jutras MF, Czernecki V, et al. Nonmotor symptoms in Parkinson’s disease in 2012: relevant clinical aspects. Parkinson’s Dis. 2012;2012:1-15. 3. Biousse V, Skibell BC, Watts RL, et al. Ophthalmologic features of Parkinson’s disease. Neurology. 2004;62:177-80. 4. Zesiewicz TA, Cimino CR, Malek AR, et al. Driving safety in Parkinson’s disease. Neurology. 2002;59:1787-8. 5. Clark D, Eggenberger E. Neuro-ophthalmology of movement disorders. Curr Opin Ophthalmol. 2012;23:491-6. 6. Pieri V, Diederich NJ, Raman R, Goetz CG. Decreased color discrimination and contrast sensitivity in Parkinson’s disease. J Neurol Sci. 2000;172:7-11. 7. Liu Z, Pflugfelder SC. Corneal thickness is reduced in dry eye. Cornea. 1999;18:403-7. 8. Tamer C, Melek IM, Duman T, et al. Tear film tests in Parkinson’s disease patients. Ophthalmology. 2005;112:1795. 9. Reddy VC, Patel SV, Hodge DO, Leavitt JA. Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease. Cornea. 2013;32:631-5. 10. Fitzpatrick E, Hohl N, Silburn P, O’Gorman C, Broadley SA. Casecontrol study of blink rate in Parkinson’s disease under different conditions. J Neurol. 2012;259:739-44. 11. Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord. 2004;19:1020-8. 12. Agostino R, Bologna M, Dinapoli L, et al. Voluntary, spontaneous, and reflex blinking in Parkinson’s disease. Mov Disord. 2008;23: 669-75. 13. Karson CN, LeWitt PA, Calne DB, et al. Blink rates in parkinsonism. Ann Neurol. 1982;12:580-3. 14. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol. 2000;118:1264-8. 15. Huang FC, Tseng SH, Shih MH, et al. Effect of artificial tears on corneal surface regularity, contrast sensitivity, and glare disability in dry eyes. Ophthalmology. 2002;109:1934-40. 16. Bye L, Vamadevan P, Chaudhuri KR. Ophthalmological aspects of Parkinson’s disease. In: Chaudhuri KR, Tolosa E, Schapira A, Poewe W, eds. Non-motor Symptoms of Parkinson’s Disease. New York: Oxford University Press; 2009. 297-308. 17. Stephen C. Pflugfelder tear dysfunction and the cornea: LXVII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2011;152:900-9. 18. Horwath-Winter J, Berghold A, Schmut O, et al. Evaluation of the clinical course of dry eye syndrome. Arch Ophthalmol. 2003;121:1364-8. 19. Karadayi K, Ciftci F, Akin T, et al. Increase in central corneal thickness in dry and normal eyes with application of artificial tears: a new diagnostic and follow-up criterion for dry eye. Ophthalmic Physiol Opt. 2005;25:485-91. 20. Dayanir V, Sakarya R, Ozcura F, et al. Effect of corneal drying on central corneal thickness. J Glaucoma. 2004;13:6-8. 21. Chang KC, Jeong JH, Kim MK, et al. The effect of amantadine on corneal endothelium in subjects with Parkinson’s disease. Ophthalmology. 2010;117:1214-9. 22. Kubo S, Iwatake A, Ebihara N, et al. Visual impairment in Parkinson’s disease treated with amantadine: case report and review of the literature. Parkinsonism Relat Disord. 2008;14:166-9. 23. Dubow JS, Rezak M, Berman AA. Reversible corneal edema associated with amantadine use: an unrecognized problem. Mov Disord. 2008;23:2096-7. 24. Bayer AU, Keller ON, Ferrari F, et al. Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer’s disease and Parkinson’s disease. Am J Ophthalmol. 2002; 133:135-7. 25. Yenice O, Onal S, Midi I, et al. Visual field analysis in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2008;14:193-8. 26. Su DH, Wong TY, Foster PJ, et al. Central corneal thickness and its associations with ocular and systemic factors: the Singapore Malay Eye Study. Am J Ophthalmol. 2009;147:709-16.
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29. Shah S, Chatterjee A, Mathai M, et al. Relationship between corneal thickness and measured intraocular pressure in a general ophthalmology clinic. Ophthalmology. 1999;106:2154-60. 30. Guedes G, Tsai JC, Loewen NA. Glaucoma and aging. Curr Aging Sci. 2011;4:110-7.
Central corneal thickness and its relationship to Parkinson’s disease severity Durdane Aksoy, MD,* Huseyin Ortak, MD,† Semiha Kurt, MD,* Emre Cevik, MD,* Betul Cevik, MD* ABSTRACT ● RÉSUMÉ Objective: To investigate the effect of Parkinson’s disease (PD) on blink rate (BR), tear breakup time test (TBUT), Schirmer’s test, and corneal thickness, and the relationship of these effects with disease severity. Design: Prospective controlled study. Participants: Fifty-five eyes from 55 patients with PD and 40 eyes from 40 healthy subjects were analyzed in the study. Methods: The patients were divided into 2 groups according to their Hoehn–Yahr (H-Y) scores; patients classified as H-Y 1–2 were designated as the mild group, and those classified as H-Y 3–5 were designated as the moderate group. Subjects were screened for BR, TBUT, and Schirmer’s test, and the central corneal thickness (CCT) was measured. Results: The BR, Schirmer’s test, TBUT, and CCT values of the patient group were significantly lower than those of the control group. The BR and TBUT of the mild group were significantly lower than those of the control group, but the decreases in the Schirmer’s test values and CCT were not statistically significant. In addition, significant decreases in the BR, TBUT, Schirmer’s test scores, and CCT were observed in the patient group as the H-Y score increased. Conclusions: A reduced BR and poor tear quality in the early stages of PD, as well as decreased tear production as the disease progresses, can result in reduced CCT. The possibility of a thin cornea should be taken into consideration while measuring the intraocular pressure in patients with severe PD. Objet : Examen des effets de la maladie de Parkinson sur le taux de clignotement, le temps de la rupture lacrymale, le test de Schirmer, ainsi que l'épaisseur de la cornée et la relation de ces effets avec la gravité de la maladie. Nature : Étude prospective contrôlée. Participants : Cinquante-cinq yeux de 55 patients atteints de la maladie de Parkinson et 40 sujets en santé ont été analysés. Méthodes : Les patients ont été répartis en deux groupes selon leurs données Hoehn-Yahr; ceux qui étaient classés Hoehn-Yahr 12 étaient considérés comme 0 groupe léger T et ceux classés Hoehn-Yahr 3-5, comme 0 groupe modéré T. Les sujets ont subi des tests de fréquence de clignotement et de temps de rupture lacrymale et le test Schirmer, et l'on a mesuré l'épaisseur du centre de la cornée. Résultats : Le taux de clignotement, le test Schirmer, le temps de rupture lacrymale et l'épaisseur du centre de la cornée du groupe de patients étaient significativement inférieurs à ceux du groupe témoin. Les taux de clignotement et de le temps de la rupture lacrymale du groupe léger étaient significativement inférieurs à ceux du groupe témoin, mais la baisse des valeurs du test Schirmer et de l'épaisseur du centre de la cornée n'étaient pas importante statistiquement. En outre, on a observé une baisse significative du taux de clignotement, du temps de la rupture lacrymale, des résultats du test Schirmer et de l'épaisseur du centre de la cornée alors que s'accroissaient les données Hoehn-Yahr du groupe de patients. Conclusions : Une réduction du taux de clignotement et une piètre qualité lacrymale dans les premières étapes de la maladie de Parkinson, ainsi qu'une production réduite de larmes alors que la maladie progresse, peut réduire l'épaisseur du centre de la cornée. L'on devrait aussi tenir compte de la possibilité d'amincissement de la cornée en mesurant la pression intraoculaire des patients qui ont une grave maladie de Parkinson.
Parkinson’s disease (PD) is a neurodegenerative disorder accompanied by both motor and nonmotor symptoms. Nonmotor symptoms, including visual problems, autonomic dysfunction, gastrointestinal symptoms, and impairments in sleep and cognitive function, are common, yet they are often under-recognized in clinical practice.1–3 Visual symptoms, such as colour discrimination, visuospatial deficit, reduced blink rate (BR), dry eye, transient diplopia, vergence dysfunction, hypometric saccades, impaired smooth pursuit with catch-up saccades, mild impairment of upgaze, convergence insufficiency, visual hallucinations, ocular discomfort, and pain, are reported in patients with PD, and these problems negatively impact
activities of daily living such as ambulation, use of stairs, and driving.3–6 Corneal thickness of the central and midperipheral cornea is significantly decreased in individuals with dry eyes.7 A reduced BR and dry eye syndrome are well described in the PD literature.3,5,8–10 However, the effects of PD and the disease severity on corneal thickness are unknown. In this study, the BR, tear breakup time test (TBUT), Schirmer’s test score, and central corneal thickness (CCT) were analyzed in a group of patients with PD and compared with healthy individuals. The effects of PD severity on the BR, tear tests, and corneal thickness were also investigated.
From the Departments of *Neurology and †Ophthalmology, Gaziosmanpasa University Faculty of Medicine, Tokat, Turkey
Can J Ophthalmol 2014;49:152–156 0008-4182/14/$-see front matter & 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2013.12.010
Originally received Aug. 22, 2013. Final revision Dec. 22, 2013. Accepted Jan. 3, 2014 Correspondence to Durdane Aksoy, Gaziosmanpasa University Faculty of Medicine, Department of Neurology, Kaleardi mah, Muhittin Fusunuglu cad. Tokat 60100, Turkey; [email protected]
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Central corneal thickness in Parkinson’s disease—Aksoy et al. METHODS Fifty-five patients with PD and 40 healthy subjects were enrolled in this study. Patients with PD met the Parkinson’s Disease Society Brain Bank (London, U.K.) clinical diagnostic criteria and were diagnosed by an experienced neurologist. Patients diagnosed with diabetes mellitus, glaucoma, keratoconus, corneal dystrophy and keratitis, active uveitis, systemic therapy with pharmaceutical drugs with known corneal toxicity were excluded from the study, as were contact lens users, patients receiving topical therapy with antiglaucoma drugs, and patients who had a previous history of ophthalmic surgery. Patients treated with drugs other than L-dopa and dopamine agonists were also excluded. The hospital ethics committee approved the study, and patients provided written informed consent after the nature and purpose of the study were fully explained. All experiments were performed in accordance with the Declaration of Helsinki. A detailed neurologic examination was performed on patients with PD, their Hoehn–Yahr (H-Y) scores were calculated, and sex, age, disease duration, and duration of 11 L-dopa and/or dopamine agonist therapy were recorded. The patients were divided into 2 groups according to their H-Y scores; patients who scored H-Y 1–2 were designated as the mild group, and those scored H-Y 3–5 were designated as the moderate group. Fifty-five eyes from 55 patients with PD (32 male, 23 female) and 40 eyes from 40 healthy individuals (23 male, 17 female), consistent in age and sex with the patients, were examined. A full ophthalmologic evaluation was performed on each subject. All patients were screened for BR, TBUT, Schirmer test under topical anaesthesia, and CCT; CCT was measured using an ultrasonic pachymeter. BR was determined by 1 examiner recording the average number of blinks per minute during a 3-minute resting period. A blink was defined as bilateral paroxysmal closure of the eyelids in the absence of external stimulus. One eye of each patient was chosen at random for statistical analysis. The patient’s cornea was anaesthetized with topical proparacaine hydrochloride 0.5% (AlconCouvreur, Puurs, Belgium), and CCT measurements were obtained by a single ophthalmologist using an ultrasonic pachymeter (Optikon 2000 SPA; Pacline, Rome, Italy). The TBUT test was performed using a sterile fluorescein strip that was placed in the wet surface of the lower fornix of the conjunctiva. The patient was asked to blink twice and then look straight ahead without blinking. The time before the first defect appeared in the stained tear film was recorded as the tear film TBUT. The average value of 3 consecutive TBUT tests was obtained. The Schirmer test was performed under anaesthesia. Three minutes after 2 proparacaine hydrochloride 0.5% eye drops were instilled, the lid margin was dried with cotton. The Schirmer’s test strip was placed in the lower temporal fornix at the junction of the middle and lateral
thirds of the eyelid. The patient was asked to keep both eyes immobile and 5 minutes later, the strip was removed and the amount of wetting was recorded in millimeters. All dry eye tests were performed during the same daily time interval (from 10:00 AM to 2:00 PM) at a temperature between 201C and 251C and relative humidity between 35% and 45%. The Kolmogorov–Smirnov normality test was used to test the normal distribution of continuous variables. Continuous variables were compared using Student t test for independent samples and the Mann–Whitney U test. For the comparison of the mild, moderate, and control groups, 1-way ANOVA and Kruskal–Wallis variance analysis were used. Tukey honestly significant difference (HSD) and Mann–Whitney U tests were used for post hoc tests. The correlation between the test parameters and H-Y scores in the patient group was evaluated using the Pearson correlation coefficient. The p values less than 0.05 were considered statistically significant. Calculations were made using statistical analysis software (IBM SPSS Statistics 19; SPSS Inc, Chicago, Ill.).
RESULTS The average ages of the patient group and the control group were (mean ⫾ SD) 63.44 ⫾ 10.10 and 61.05 ⫾ 7.87, respectively. There was no significant age difference between the 2 groups (Table 1). The average duration of disease in the PD group was 4.81 years, and the average H-Y score was 2.17 ⫾ 0.95. The BR, Schirmer’s test, TBUT, and CCT values of the PD group were significantly lower than those of the control group (Table 1). Patients with PD were subdivided into 2 groups (mild and moderate). When the 3 groups (mild, moderate, and control) were compared using 1-way ANOVA and Kruskal–Wallis variance analysis, a statistically significant difference in the BR, TBUT, Schirmer’s test, and CCT values was observed (Table 2). Tukey test analysis revealed that the BR and TBUT values were significantly lower in the mild group than in Table 1—Comparison of age, blink rate, tear breakup time test, Schirmer, and central corneal thickness mean values with t test for independent samples for patients with PD and control groups
Age Blink rate TBUT Schirmer CCT
Group
Mean
SD
PD Control PD Control PD Control PD Control PD Control
63.44 61.05 6.27 11.55 6.49 10.65 8.95 11.28 541.89 558.92
10.10 7.87 3.61 4.39 2.36 4.27 3.68 3.41 12.81 12.25
t
z
p
1.24
—
0.22
—
–2.69
0.007*
—
–4.77
0.0001*
3.13
—
0.002
3.63
—
0.0001
TBUT, tear breakup time test; CCT, central corneal thickness. *Because data do not follow normal distribution, Mann–Whitney U test was applied.
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Central corneal thickness in Parkinson’s disease—Aksoy et al. Table 2—Comparison of mild, moderate, and control groups in terms of blink rate, Schirmer’s test, tear breakup time test, and central corneal thickness values (1-way ANOVA/Kruskal–Wallis variance analysis) Control (mean ⫾ SD) Blink rate TBUT Schirmer’s test CCT
11.55 10.65 11.28 558.92
⫾ ⫾ ⫾ ⫾
Mild (mean ⫾ SD)
4.39 4.27 3.41 12.25
7.09 7.00 10.88 549.36
⫾ ⫾ ⫾ ⫾
4.04 2.19 2.95 12.77
Moderate (mean ⫾ SD)
F
χ²
p
⫾ ⫾ ⫾ ⫾
— — 22.63 12.17
31.15 25.02 — —
0.0001* 0.0001* 0.0001 0.0001
5.05 5.73 6.05 530.68
2.43 2.45 2.64 10.14
TBUT, tear breakup time test; CCT, central corneal thickness. *Because data do not follow normal distribution, Kruskal–Wallis variance analysis was used.
the control group. The Schirmer’s and CCT values were also lower in the mild group, but the differences were not statistically significant (Table 3). The Pearson correlation coefficient was used to determine the correlation between the BR, tear test, and CCT values and diseases severity (H-Y scores). A strong and significant negative correlation was detected between the H-Y scores and CCT values, as well as between the H-Y scores and Schirmer’s test scores. Analysis also revealed a weak but significant negative correlation between the H-Y scores and BR and TBUT values (Table 4). These results suggest that in patients with PD, the BR, TBUT, Schirmer’s test, and CCT values significantly decrease as the H-Y score increases.
DISCUSSION Ocular motility impairments, dry eye, and ocular surface irritation are common clinical ophthalmologic findings in patients with PD.3,6,8 Reduced BR in patients with PD has been reported in several studies, and reduced BR is considered a symptom that supports a PD diagnosis.3,5,6,12,13 Reduced BR in patients with PD is associated with hypokinesia resulting from reduced dopaminergic activity.3 In a study that evaluated the BR in patients with PD in a variety of circumstances (while being interviewed, watching a video, and reading from a book), the BR was significantly lower in the patient group than in the control group in all situations; however, no correlation was found between BR and disease severity.10 Other studies have reported a negative correlation between the H-Y scores and BR in patients with PD.8,13 The results of our study are consistent with previous reports, suggesting a statistically significant negative correlation between the H-Y scores and BR. Table 3—Comparison of mild group and control group in terms of blink rate, tear breakup time test, Schirmer’s test, and central corneal thickness values using Tukey test Mild Group (mean ⫾ SD) Age (y) Blink rate TBUT Schirmer’s test CCT
63.21 7.09 7.00 10.88 549.36
⫾ ⫾ ⫾ ⫾ ⫾
9.97 4.04 2.19 2.95 12.77
Control Group (mean ⫾ SD)
p
⫾ ⫾ ⫾ ⫾ ⫾
0.30 0.001 0.001 0.59 0.07
61.05 11.55 10.65 11.28 558.92
7.87 4.39 4.27 3.41 12.25
TBUT, tear breakup time test; CCT, central corneal thickness.
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Abnormalities in tear secretion are frequently reported among patients with PD.3,7–9 In a study of patients with early-stage PD who had not received any treatment, dry eye syndrome was detected in almost two thirds of the patients. Moreover, when tear tests were evaluated separately, the TBUT values of early-stage patients were lower than those of the control group. In addition, increased ocular surface disease and tear film abnormalities in patients with PD were highlighted in a recent study, whereas noting that these patients could be asymptomatic because of reduced corneal sensitivity.9 These studies all indicate poor tear film quality in patients with PD. Another study, evaluating the Schirmer’s test, BR, TBUT and Rose bengal stain, and phenol red thread tests, reported that patients with PD had abnormalities in at least 1 of the tear tests.8 In our study, patients with early-stage PD had significantly lower BRs and TBUT values than subjects in the control group. The Schirmer’s test and CCT values were also, although not significantly, lower. A reduced spontaneous BR in patients with PD may contribute to ocular discomfort caused by dry eye syndrome. Blinking is necessary to heal the tear– cornea optical interface and maintain a smooth and regular tear film.3,14–16 Our findings and those of prior studies in the field suggest that impairments in the BR and tear quality may occur even in the early stages of the disease.3,8 A significant difference was detected in the BR, TBUT, Schirmer’s test, and CCT values between the mild, moderate, and control groups in this study. The BR and TBUTs were significantly lower in the mild group than in the control group, whereas the Schirmer’s test values and CCT were slightly lower. Furthermore, the same values had significant negative correlation with the H-Y scores. As a result, we report that the BR and TBUT are decreased during the mild stages of PD and, as the disease progresses, the BR, TBUT, Schirmer’s test, and CCT values decrease in correlation with increasing H-Y scores.
Table 4—Evaluation of relation between Hoehn–Yahr scores and central corneal thickness, Schirmer’s test, tear breakup time test, and blink rate using simple correlation analysis by Pearson correlation coefficient test
Hoehn–Yahr/blink rate Hoehn–Yahr/TBUT Hoehn–Yahr/Schirmer Hoehn–Yahr/CCT
r
p
–0.412 –0.316 –0.581 –0.535
0.002 0.019 0.0001 0.0001
TBUT, tear breakup time test; CCT, central corneal thickness.
Central corneal thickness in Parkinson’s disease—Aksoy et al. Patients with tear dysfunction typically report irritation symptoms that include foreign body sensation, burning, and dryness, as well as vision-related symptoms such as photophobia and blurred and fluctuating vision.17,18 The aqueous layer of the tear film is normally isotonic or slightly hypotonic. In all forms of dry eye syndrome, however, there is an increase in the osmolarity of the tear film, and hypertonic tear film causes a decrease in the corneal thickness.18,19 A chronic state of desiccation and immune activation in dry eye syndrome may contribute to the observed corneal thinning.17,20 A reduced BR and reduced tear quality in the early stages of the disease, and the dry eye symptoms that result from impairments in tear production as the disease manifests, may have contributed to a decrease in the CCT in our patients with PD. In addition, corneal epithelial disruptions, changes in corneal thickness, corneal endothelial damage, and corneal edema are reported in patients with PD who are on amantadine therapy for a long period.21–23 Patients on amantadine or other drugs that are known to affect the cornea were excluded from our study. Only patients using L-dopa and dopamine agonists, which have no significant effect on the lacrimal glands, were enrolled in the study.8 A high incidence of glaucomatous visual field defects and enlarged cup-to-disk ratios has been reported in patients with Alzheimer’s disease and PD. In addition, the identification of probable glaucoma in 24.5% of patients with Alzheimer’s disease and 23.7% of patients with PD was significantly higher than in the normal population.24,25 CCT has an important impact on the intraocular pressure (IOP) measurement when diagnosing and treating glaucoma, and eyes with a greater mean CCT tend to have a higher IOP. Because an increased CCT may lead to falsely high IOP readings, and thin corneas may lead to falsely low IOP readings, there should be a correlation between the CCT and baseline IOP.26–29 Accumulating evidence suggests that the CCT is a crucial ocular parameter in glaucoma that should be measured in patients of advanced age.30 The relationship between the CCT and PD severity has not yet been established. Our findings suggest that BR and tear quality are impaired even in the early stages of PD. The Schirmer’s test and CCT values also decrease as the disease becomes more severe. We found a significant negative correlation between the H-Y scores and the CCT values. PD and glaucoma have a higher prevalence with increasing age, and glaucoma tends to occur more frequently in patients with PD. Therefore, the possibility of a thin cornea should be taken into consideration when measuring the IOP in patients with severe PD. Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article.
Acknowledgements: The authors are grateful to Dr. Ilker Etikan, Biostatistics Department of Gaziosmanpasa University, for his contribution on the statistical analysis.
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