ORIGINAL STUDY

Comparison of Optical Coherence Tomography Findings in Patients With Primary Open-angle Glaucoma and Parkinson Disease Muhsin Eraslan, MD,* Sevcan Y. Balci, MD,w Eren Cerman, MD, FEBO,* Ahmet Temel, MD,* Devran Suer, MD,z and Nese T. Elmaci, MDz

Purpose: To evaluate the peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex, and macular thickness as well as their correlation with the severity of diseases. Materials and Methods: This is a cross-sectional study and comparing both eyes of 26 patients with primary open-angle glaucoma, 25 patients with Parkinson disease (PD), and 23 healthy subjects. RNFL, ganglion cell complex, and macular thickness were measured and analyzed with optical coherence tomography (OCT) in all cases and correlation with severity of the disease was assessed in PD group. Results: The mean RNFL of PD was significantly thinner compared with controls (P = 0.002). In glaucoma group, the mean RNFL was significantly thinner (96.28 ± 12.49 mm) than PD (105.43 ± 13.45 mm) and the controls (113.75 ± 8.53 mm) (P < 0.001; P < 0.001, respectively). The global loss volume (GLV) rates in the glaucoma and PD group were significantly higher than controls, respectively (P = 0.006; P < 0.001/P = 0.002, P = 0.013). However, the GLV rate was significantly lower in PD group compared with glaucoma group (P = 0.001). There was no significant correlation between OCT measurements and disease duration or severity in the PD patients. Conclusions: Although RNFL thickness and GLV changes may show the ganglion cell loss in both disease but none of the OCT parameters are correlated with the severity of PD. OCT may help to reveal the ganglion cell damage but may not help in determination of severity during the clinical follow-up of PD patients. Key Words: optical coherence tomography, neurodegenerative disorders, ganglion cell complex

(J Glaucoma 2016;25:e639–e646)

G

laucoma is regarded as an optic neuropathy that is characterized by progressive degeneration of the retinal ganglion cells (RGC) usually associated with elevated intraocular pressure (IOP). However, apoptotic progression has not yet been fully elucidated, and it has been clinically and

Received for publication July 2, 2014; accepted January 9, 2015. From the Departments of *Ophthalmology; zNeurology, School of Medicine, Marmara University, Istanbul; and wIgdir State Hospital, Igdir, Turkey. Design of the study: S.Y.B., M.E., A.T.; conduct of the study: S.Y.B., M.E., E.C., A.T., D.S., E.N.T.E.; collection: S.Y.B., D.S.; management: M.E.; analysis and interpretation of the data: S.Y.B., M.E., E.C., A.T.; preparation: S.Y.B., M.E., E.C.; review: M.E., E.C., A.T., D.S., E.N.T.E. Disclosure: The authors declare no conflict of interest. Reprints: Muhsin Eraslan, MD, Hamam Sok. Ansen Apt. No: 9/6, Kadikoy, Istanbul 34738, Turkey (e-mail: muhsineraslan@hotmail. com). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000239

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Volume 25, Number 7, July 2016

experimentally indicated that RGC death in glaucoma is initiated with apoptosis as in other neurodegenerative disorders.1,2 Parkinson disease (PD) is a common neurodegenerative disorder that occurs in approximately 1% of the elderly population.3 It is characterized by degeneration of the nigrostriatal dopaminergic path and by the presence of specific motor symptoms.4 In recent years, evidence for the role of apoptotis in pathogenesis of cell death of nigrostriatal dopaminergic neurons in PD has arisen.5 Visual problems likely to be encountered in PD are alterations in visual acuity, contrast sensitivity, color discrimination, visual field sensitivity, and visual processing speeds. These changes in visual function suggest structural changes at a microscopic level in the retina. One such postmortem study has suggested swelling of photoreceptors and loss of RGCs as well as pale intracellular inclusions in the outer plexiform layer of the retina in postmortem patients with dementia with Lewy bodies.6 Other human and animal studies also have shown that there is a decrease in the level of dopamine in amacrine, horizontal, and interplexiform cells of the retina, and that dopamine-containing layers of the retina become thinner.7–8 The ganglion cell damage or alterations in retinal dopamine-containing cells has also been shown with 2 electroretinograpy studies.9,10 The amplitudes of the scotopic and photopic b wave, as well as the amplitudes of the photopic a waves, were significantly reduced in PD than in controls, even in dopaminergic-treated patients.9 Optic coherence tomography (OCT) is a safe and easily reproducible method which has been used to assess retinal degeneration in various ophthalmologic and neurological disorders.11–13 OCT enables distinguishing retinal layers in vivo and analysis of retinal nerve fiber layers (RNFL) and RGC. Attempts to measure RNFL thickness in PD using OCT have been undertaken by several investigators. They found alterations in RNFL thickness, and using these anatomic changes for the clinical follow-up of the disease has come into question.11–13 Thinning of the RNFL layer is not specific for PD, it has also been shown in other neurodegenerative diseases like multiple sclerosis and Alzheimer disease.14,15 The macula is an ideal region to detect early ganglion cell loss because of its high density. Recently spectraldomain OCT instruments have enabled automatic measurements of the macular ganglion cell complex (GCC) thickness, which represents the thickness of nerve fibers, ganglion cells, and the inner plexiform layer.16 All 3 layers, collectively known as the GCC and the thickness of GCC directly measured provide the percent loss of these layers compared with a normative database. Previous studies in www.glaucomajournal.com |

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glaucoma patients have shown a substantial decrease in the RGC population before detectable visual field deficits and therefore the measurement of GCC thickness is expected to be a useful method for detection of glaucoma at an earlier stage. Global loss volume (GLV) and focal loss volume (FLV) are pattern-based parameters that reflect different aspects of GCC loss. They sum up the volume of GCC loss in the macula with differing levels of focality.17 The FLV parameter is more focal because it only sums loss in regions where the GCC is thin in both absolute (GCC < normal) and relative (pattern deviation less than fifth percentile) terms. GLV is total volume of significant GCC loss. Higher diagnostic accuracy with GLV than with mean GCC thickness for glaucoma were showed in previous reports, regardless of disease severity.17 To date there has only been 1 study comparing GCC in treated and untreated PD patients.17–19 In our study, we evaluated in vivo analysis of peripapillary RNFL, GCC, and macular thickness measurements that are known to be affected in the glaucoma and compared those findings with PD and healthy controls. To the best of our knowledge, this is the first study comparing OCT findings including GCC measurements of 2 neurodegenerative diseases belonging to the visual system and the central nervous system (CNS).

MATERIALS AND METHODS This is a cross-sectional study including both eyes of 26 patients with glaucoma, 25 patients with PD, and 23 healthy subjects who had a complete ophthalmologic examination at Marmara University School of Medicine, Clinic of Ophthalmology, between November 2011 and August 2013. This study was conducted in accordance with the amended Declaration of Helsinki, and ethical clearance was obtained from the Human Research Ethics Committee of the University of Marmara. Informed consent for the research was obtained from the patients and subjects.

Subjects Patients were included if they had corrected visual acuity of 6/10 or above, 4 to + 3 D of spherical refractive error or r ± 3 D of cylindrical refractive error. Patients diagnosed with uveitic, retinal, and optic nerve diseases (except glaucoma) which can affect RNFL, and diagnosed with ocular media opacities and severe cataracts, which can affect OCT images were excluded.

Glaucoma Patients Subjects in the glaucoma group were selected from patients diagnosed with primary open-angle glaucoma and who were under medical treatment with regulated IOP measurements (20 mm Hg or less) and for at least 1 year with at least 3 check-ups. Reliable visual field analysis [Humphrey Visual Field Analyzer (Carl Zeiss Inc., Dublin, CA)] were undertaken using the Swedish Interactive Thresholding Algorithm standard 30-2 perimetry for all glaucoma patients. The severity of glaucoma was graded due to visual field mean deviation (MD) parameter as mild (MD >  6 dB), moderate ( 12 dB < MD < 6 dB), or severe (MD < 12 dB) glaucoma.18 Patients who did not have neurological disorders and patients with mild glaucoma were included.



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PD Patients Criterias of the United Kingdom Parkinson’s Disease Society Brain Bank were used in diagnosis of the subjects in the PD group at the neurology department. PD patients were receiving levodopa therapy and dopamine agonists for treatment. Patients that have neurological disorders other than PD; history or evidence of glaucoma or patients who have ophthalmic pathologies other than refractive errors were excluded.

Control Group The healthy control group was composed of people who applied for routine eye examinations. Patients who have ophthalmic pathologies other than refractive errors and those who had neurological disorders were excluded. IOP of all patients was measured using the Goldmann applanation tonometer; CCT measurements were done using ultrasonic pachymetry (Tomey, SP-3000, Germany). Adjustments of IOP through central corneal thickness were applied to all patients according to the linear formula of Shih et al (Corrected IOP = Measured IOP  (CCT 545)/ 50  2.5 mm Hg).19 Patients with PD were examined by a neurologist and severity of the disease was evaluated with the Unified Parkinson’s Disease Rating Scale (UPDRS). The scale itself has 4 components (part I, Mentation, Behavior and Mood; part II, Activities of Daily Living; part III, Motor; part IV, Complications) which are composed of 42 questions in total and a neurologist scores each question according to the patient’s performance from 0 (normal) to 4 (severe). Therefore, higher total scores describe an increased severity and greater disability from PD (total score 0 to 154).20 OCT (RTVue-100 5.1, FourierDomain Optical Coherence Tomography; Optovue Inc., Fremont, CA) scans were done and RNFL, GCC, and macular thickness measurements were analyzed in all cases.

RNFL The area with 3.45 mm diameters around the disc center was used to determine the RNFL thickness map. Optic nerve head was scanned with 12 radial scanners passing through the optic disc, each of which was 3.7 mm long, whereas peripapillary RNFL thickness was measured using 13 concentric rings with diameters changing between 1.3 and 4.9 mm. In this protocol, a total of 51.813 A-scans were obtained in the 5  5 mm area with 101 horizontal lines and 20-degree nasal fixation within 2 seconds. The average, temporal (temporal-upper, temporal-lower), superior (superior-temporal, superior-nasal), nasal (nasal-upper, nasal-lower), and inferior (inferior-temporal, inferior-nasal) quadrants of RNFL thickness measurements of the cases were analyzed.

GCC The GCC scan pattern, which sampled the macula with 933 scans over a 7 mm2 area in 0.58 seconds, consists of 1 horizontal line and 15 vertical lines at 0.5-mm intervals. The scans were centered 1 mm temporal to the 7 mm2 area of fovea. The significance map was used to analyze the average GCC thickness, superior GCC thickness, inferior GCC thickness, FLV (%), and GLV (%).

Macular Thickness and Volume Macular thickness was measured using the EMM5 program and 3-dimensional macula scanning programs. In this study, macular thickness (mm) and volume (mm3) were

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J Glaucoma



Volume 25, Number 7, July 2016

Comparison of OCT Findings in POAG and Parkinson Disease

TABLE 1. The Demographic Features of Groups

n (%) Sex Female Male Age (mean ± SD)

P

Glaucoma (n = 52)

Parkinson Disease (n = 50)

Normal (n = 46)

8 (30.8) 18 (69.2) 56.34 ± 9.61

9 (36) 16 (64) 58.64 ± 10.31

8 (34.7) 15 (65.3) 56.65 ± 9.61

0.467 0.248

Patients with glaucoma, patients with Parkinson disease, and normal subjects. w2 test/ANOVA (Tukey test)/Kruskal-Wallis.

analyzed for the whole retina and inner retinal layer (IRL) on fovea, parafoveal, and perifoveal areas and the superior, inferior, temporal, and nasal quadrants. Data were statistically analyzed using SPSS (Statistical Package for Social Sciences) Windows version 17.0. The average ± SD and ratio values were used for the descriptive statistics of the data. Data distribution was tested using the Kolmogorov Smirnov test. The analysis of variance (Tukey test) and Kruskal-Wallis (Mann-Whitney U test) tests were used to analyze the differences between group means, whereas proportional data were analyzed using the w2 test. P values 0.05). The difference between the corrected visual acuity and CCT measurements of the 3 groups was not statistically significant (P > 0.05). The mean IOP levels were significantly higher in glaucoma group (14.60 ± 2.33 mm Hg) when compared with PD and control group (13.34 ± 2.01 mm Hg, P = 0.011;

12.48 ± 2.13 mm Hg, P < 0.001) and were not significantly different among the PD and control group (P = 0.124). The average UPDRS total score was 34.40 ± 16.27 (range, 11 to 75) in PD patients. The average RNFL in the glaucoma group was significantly thinner than in the PD and control group (P < 0.001; P < 0.001). In addition, the mean RNFL in the PD was significantly thinner compared with the controls (P = 0.002). When the RNFL thickness of the glaucoma and PD was compared with the control group, the inferior-temporal quadrant was found to be the thinnest (Table 2) (Fig. 1). The average, superior, and inferior GCC thickness was statistically significantly thinner in glaucoma’s compared with the PD and the control group (P < 0.05). In addition, the FLV and GLV rates in the glaucoma group were statistically significantly higher compared with the controls (P = 0.006; P < 0.001). Similarly, the FLV and GLV rates in the PD were significantly higher than in the control group (P = 0.002, P = 0.013). However, when the PD was compared with the glaucoma group, the GLV rate was statistically significantly lower (P = 0.001) (Table 3) (Fig. 2). The mean retinal thickness of the glaucoma group was statistically significantly less in all quadrants compared with the control group and was significantly thinner in the parafoveal temporal, inferior, perifoveal temporal, superior, and nasal quadrants compared with the PD (P = 0.016, P = 0.019, P = 0.001, P = 0.007, and P = 0.026, respectively) and the volume values were significantly lower in the same quadrants (P < 0.05). The mean retinal thickness of the

TABLE 2. Distribution of Mean RNFL Thickness Measurements by Quadrants in the Groups

RNFL Thickness (lm) Quadrants ST SN I˙T IN NU NL TU TL AvgRNFL (mm)

Mean (SD)

P

Glaucoma (n = 52)

Parkinson Disease (n = 50)

Normal (n = 46)

114.17 ± 20.44 104.87 ± 18.39 123.50 ± 22.52 116.63 ± 22.89 86.35 ± 15.74 73.12 ± 15.29 74.42 ± 11.13 73.90 ± 13.13 96.28 ± 12.49

130.42 ± 27.89* 114.24 ± 20.25 140.30 ± 22.11* 120.56 ± 26.30 88.92 ± 19.81 76.64 ± 14.36 87.26 ± 22.03* 85.62 ± 19.01* 105.43 ± 13.45*

141.65 ± 18.84*z 128.26 ± 21.69*z 155.00 ± 16.41*z 133.85 ± 26.93*z 94.87 ± 14.49* 79.91 ± 12.88 89.48 ± 15.26* 87.50 ± 14.57* 113.75 ± 8.53*z

< 0.001 < 0.001 < 0.001 0.003 0.042 0.065 < 0.001 < 0.001 < 0.001

ANOVA (Tukey test). Bold values are statistically significant. *The differences compared with Glaucoma group, P < 0.05. zThe differences compared with Parkinson group, P < 0.05. Avg indicates average; IN, inferior-nasal; IT, inferior-temporal; NL, nasal-lower; NU, nasal-upper; RNFL, retinal nerve fiber layer; SN, superior-nasal; ST, superior-temporal; TL, temporal-lower; TU, temporal-upper.

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FIGURE 1. Average retinal nerve fibre layer thickness (RNFL) in glaucoma, Parkinson disease (PD) patients, and healthy controls. The average RNFL in the glaucoma group was significantly thinner than in the PD and control group (P < 0.001; P < 0.001). The mean RNFL in the PD was significantly thinner compared with the controls (P = 0.002).

PD was significantly thinner only in the perifoveal superior compared with the control group (284.26 ± 37.20 mm, 294.67 ± 11.04 mm; P = 0.019) (Table 4). Table 5 shows the mean macular thickness and volume of the intraretinal layers by groups. In the PD group, the macular thickness of IRL was significantly less in the parafoveal superior (118.62 ± 27.48 mm, 129.35 ± 13.17 mm; P = 0.024), perifoveal temporal (104.50 ± 17.75 mm, 112.65 ± 8.40 mm; P = 0.019), superior (106.14 ± 23.84 mm, 116.22 ± 7.80 mm; P = 0.005), and inferior (106.72 ± 15.67 mm, 112.76 ± 11.01 mm; P = 0.026) quadrants compared with controls (Table 5). There was a moderate negative correlation between disease duration and RNFL thickness (r = 0.325, P = 0.019) in the glaucoma group and there was no correlation between disease duration or UPDRS score and OCT parameters in the PD group (Table 6).

DISCUSSION Glaucoma is regarded as a neurodegenerative disease of the ophthalmic system.21 Recently, identification of common threads in the neurodegenerative diseases of the CNS and



Volume 25, Number 7, July 2016

FIGURE 2. Global loss volume (%) in glaucoma, Parkinson disease (PD) patients, and healthy controls. The global loss volume rates in the glaucoma group and PD were significantly higher compared with the controls, respectively (P = 0.006; P < 0.001) (P = 0.002, P = 0.013). Also, the global loss volume rate was statistically significantly higher in the glaucoma group compared with the PD group (P = 0.001).

developed usage of neuroprotection therapies in glaucoma have been proposed.22 In this study, we compared retinal structural changes caused by 2 different neurodegenerative diseases and analyzed in vivo neuronal damage. The present study indicates that the average RNFL thickness was significantly less in the glaucoma group compared with the PD and control group, and in subanalysis it was thinner in the PD than in controls. The inferior-temporal quadrant was the maximal thinning area in both groups. Inzelberg et al12 compared patients with PD (average disease duration, 7 ± 4 y; average age, 57 ± 11 y) with normal controls and reported that the maximum RNFL thinning in the inferior-temporal quadrant, similar to our results. Altintas¸ et al13 conducted a study of 17 patients with a mean age of 59.29 ± 12.78 years and found that the mean RNFL thickness was thinner in the PD group than in controls [98.76 ± 10.90 mm; 114.54 ± 5.72 (P < 0.05)] and that the RNFL thickness was reduced significantly in all quadrants. They also reported the maximum thinning in the superior and nasal quadrants. Kirbas et al23 compared newly diagnosed PD who had not yet started therapy with normal subjects and found the mean

TABLE 3. Analyzing the GCC Thickness and the Rates of FLV and GLV in Groups

Mean (SD) AvgGCC supGCC infGCC FLV (%) GLV (%)

P

Glaucoma (n = 52)

Parkinson Disease (n = 50)

Normal (n = 46)

86.82 ± 8.58 86.63 ± 8.45 87.00 ± 9.37 1.98 ± 2.47 12.23 ± 7.74

96.11 ± 12.67* 96.56 ± 16.02* 95.83 ± 11.70* 2.13 ± 2.81 7.44 ± 7.33*

99.02 ± 7.00* 98.72 ± 8.07* 99.46 ± 6.32* 0.59 ± 0.46*z 3.61 ± 3.30*z

< 0.001 < 0.001 < 0.001 0.001 < 0.001

ANOVA (Tukey test) Bold values are statistically significant. *The differences compared with glaucoma, P < 0.05. zThe differences compared with Parkinson disease, P < 0.05. Avg indicates average; FLV, focal loss volume; GCC, ganglion cell complex; GLV, global loss volume; inf, inferior; sup, superior.

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J Glaucoma



Volume 25, Number 7, July 2016

Comparison of OCT Findings in POAG and Parkinson Disease

TABLE 4. The Mean Total Macular Thickness and Volume of the Groups

Mean (SD) Macular thickness (mm) Fovea Parafovea Temporal Superior Nasal Inferior Perifovea Temporal Superior Nasal Inferior Volume (mm3) Fovea Parafovea Temporal Superior Nasal Inferior Perifovea Temporal Superior Nasal Inferior

P

Glaucoma (n = 52)

Parkinson Disease (n = 50)

Normal (n = 46)

246.83 ± 23.62

252.26 ± 31.99

248.59 ± 19.46

292.56 ± 21.99 307.40 ± 25.36 310.04 ± 23.84 304.75 ± 25.71

303.48 ± 26.32* 312.82 ± 38.62 312.32 ± 28.38 313.98 ± 21.20*

308.02 ± 14.89* 321.96 ± 18.24* 321.37 ± 15.51* 318.24 ± 15.38*

< 0.001 0.004 0.029 0.004

258.44 ± 42.98 269.54 ± 42.16 291.10 ± 38.87 268.73 ± 36.88

278.58 ± 26.70* 284.26 ± 37.20* 297.56 ± 37.47* 274.18 ± 26.84

285.70 ± 15.31* 294.67 ± 11.04*z 308.59 ± 15.04* 280.24 ± 27.69*

< 0.001 < 0.001 0.001 0.023

0.20 ± 0.03

0.20 ± 0.04

0.20 ± 0.02

0.279

0.47 ± 0.08 0.48 ± 0.04 0.49 ± 0.04 0.47 ± 0.07

0.48 ± 0.04* 0.49 ± 0.06 0.49 ± 0.05 0.49 ± 0.04*

0.48 ± 0.02* 0.51 ± 0.03* 0.50 ± 0.02* 0.50 ± 0.02*

0.001 0.004 0.048 0.002

0.85 ± 0.24 0.88 ± 0.23 0.91 ± 0.12 0.84 ± 0.12

0.92 ± 0.21* 0.93 ± 0.19* 0.94 ± 0.14* 0.88 ± 0.12

0.90 ± 0.05* 0.92 ± 0.04* 1.16 ± 1.34* 0.88 ± 0.09*

< 0.001 < 0.001 < 0.001 0.019

0.371

Kruskal-Wallis (Mann-Whitney U test). Bold values are statistically significant *The differences compared with glaucoma group, P < 0.05. zThe differences compared with Parkinson disease group, P < 0.05.

TABLE 5. The Mean Macular Thickness and Volume of Intraretinal Layers by Groups

Mean (SD) IRL thickness (mm) Fovea Parafovea Temporal Superior Nasal Inferior Perifovea Temporal Superior Nasal Inferior Volume (mm3) Fovea Parafovea Temporal Superior Nasal Inferior Perifovea Temporal Superior Nasal Inferior

P

Glaucoma (n = 52)

Parkinson Disease (n = 50)

Normal (n = 46)

71.46 ± 11.83

79.14 ± 18.46*

71.46 ± 11.83

108.85 ± 11.39 122.65 ± 13.89 125.10 ± 13.84 120.38 ± 13.90

113.84 ± 17.97* 118.62 ± 27.48 122.06 ± 25.33 122.00 ± 18.15

120.46 ± 8.47* 129.35 ± 13.17*z 130.33 ± 11.55* 127.13 ± 12.48*

< 0.001 0.020 0.127 0.059

95.54 ± 16.76 103.42 ± 16.28 117.56 ± 17.19 103.92 ± 15.97

104.50 ± 17.75* 106.14 ± 23.84 115.36 ± 22.90 106.72 ± 15.67

112.65 ± 8.40*z 116.22 ± 7.80*z 123.07 ± 13.79 112.76 ± 11.01*z

< 0.001 < 0.001 0.122 0.001

0.06 ± 0.01

0.07 ± 0.08*

0.06 ± 0.01

0.17 ± 0.02 0.19 ± 0.02 0.20 ± 0.02 0.19 ± 0.02

0.18 ± 0.03* 0.19 ± 0.04 0.19 ± 0.04 0.19 ± 0.03

0.19 ± 0.01* 0.20 ± 0.02*z 0.21 ± 0.02* 0.20 ± 0.02*

< 0.001 0.018 0.107 0.032

0.30 ± 0.06 0.33 ± 0.06 0.38 ± 0.08 0.33 ± 0.06

0.33 ± 0.06* 0.33 ± 0.07 0.36 ± 0.07 0.34 ± 0.05

0.35 ± 0.028*z 0.36 ± 0.02*z 0.39 ± 0.04 0.35 ± 0.03*z

< 0.001 < 0.001 0.149 0.003

0.035

0.026

Kruskal-Wallis (Mann-Whitney U test). Bold values are statistically significant *The differences compared with glaucoma group, P < 0.05. zThe differences compared with Parkinson disease group, P < 0.05. IRL indicates inner retinal layer.

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Pearson correlation. Avg indicates average; DD, duration of disease; FLV, focal loss volume; GCC, ganglion cell complex; GLV, global loss volume; IRL, inner retinal layer; RNFL, retinal nerve fiber layer; UPDRS, Unified Parkinson’s Disease Rating Scale.

0.220 0.126 0.133 0.358 0.288 0.053 0.162 0.262 0.162 0.262 0.155 0.283 0.030 0.837  0.063 0.666 0.017 0.906

0.161 0.263

 0.046 0.782 0.230 0.166

0.173 0.298

 0.197 0.280 0.237 0.088

0.149 0.370

0.161 0.334

0.161 0.334

0.040 0.813

0.201 0.226

 0.095 0.569

J Glaucoma

UPDRS r P DD r P

Total Retina Perifoveal Thickness Total Retina Foveal Total Retina Thickness Parafoveal Thickness GLV FLV DD AvgRNFL AvgGCC Parkinson Disease

TABLE 6. Correlation Between Duration of Disease, UPDRS Score, and OCT Parameters in the Parkinson Disease Group

IRL Foveal Thickness

IRL Parafoveal Thickness

IRL Perifoveal Thickness

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RNFL significantly thinner (77 ± 11.5 mm) in the PD group compared with the control group (89 ± 8.7 mm, P = 0.001). However, Aaker et al24 and Archibald et al25 conducted studies in PD patients with a higher average age (64 y; 71.3 ± 7.7 y) and reported that, taking the RNFL thickness measurements into consideration, there was no statistically significant difference between the PD and control group (97 mm, 97 mm, P = 0.911; 83.47 ± 9.4 mm, 89.24 ± 9.4 mm, P = 0.071, respectively). Similar to these 2 studies, Tsironi et al26 reported no significant difference in RNFL thickness between patients with PD and controls with an average age of 66.6 ± 10.2 years (P = 0.982). The mean RNFL thickness of the PD group and the control group varied between studies. The variance may have resulted from the fact that PD patients involved in the previous studies were different from one another in terms of age and duration of disease and treatment. Also, the OCT devices and measurement techniques used were different in each study. The studies involving PD patients with a higher average age could not find significant differences in RNFL thickness compared with the control groups. In those studies, the mean RNFL thickness in PD patients was thinner than the RNFL thickness measured in our PD group.24,25 This discrepancy in measurements is possibly because of the agedependent decrease in RNFL thickness. It is well known that 10 years of aging leads to an approximate 4 mm decrease in RNFL thickness measured with OCT.27 Sen et al28 reported that the average RNFL thickness of the untreated (106.76 ± 10.55 mm) and treated (104.62 ± 8.23 mm) patients with PD were significantly thinner than the control group (115.60 ± 9.11 mm) (P < 0.005). However, there was no significant difference between the untreated and treated patients with PD (P = 0.780). Although the severity of the disease was higher in the treated patients, there was no significant difference in retina thickness between the 2 groups; therefore, they suggested that levodopa might have a protective effect on the retina in patients with PD. In our study, all PD patients underwent levodopa therapy. We found no correlation between severity of the PD and OCT findings, which may lead us to think that ganglion cell loss and RNFL thinning are not related with severity of disease unlike glaucoma, or levodopa may have a protective effect on the ganglion cell loss. Detecting RNFL thinning may help in diagnosing at early stages of PD for patients without glaucoma or other neurodegenerative disease leading to ganglion cell loss. Although RNFL thinning by quadrants showed a difference between the studies, thinning level was higher in superior and inferior regions, which are thicker and include more nerve fiber bundle. Some reports showed a preferential loss of fibers in the inferior-temporal quadrants, consistent with the involvement of the papillomacular bundle.12,13,29,30 It is also known that the RNFL damage started in the same quadrants in the patients with glaucoma.31 Similar to these reports we also found that the inferior-temporal quadrant has the highest RNFL thinning in both disease groups. Glaucomatous damage occurs not only in the RGC axons but also in dendrites, the cell body, and dendritic structures. These regions could also be evaluated with GCC measurements in new OCT devices. In recent years, GCC thickness measurements have been investigated and emphasized as important for early diagnosis of glaucoma.32 The study of Arintawati et al33 aimed to investigate if the thicknesses of the different parameters of the GCC and peripapillary RNFL can be used to differentiate eyes with glaucoma from normal eyes. Two hundred sixty-one eyes, including normal eyes and preperimetric glaucoma, early

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J Glaucoma



Volume 25, Number 7, July 2016

glaucoma, and advanced glaucoma were analyzed in the study. The 2 largest area under receiver operating characteristic (AUROC) curves for all glaucoma stages were those for the GCC parameters. The GLV was always one of the 2 highest values of the AUROC curve. The GLV also had the highest sensitivity at a fixed specificity to identify glaucoma at early and advanced stage. The FLV had the largest AUROC curve value and the highest sensitivity at a fixed specificity for advanced glaucoma. The logistic regression analysis showed that the GLV was one of the factors that predicted preperimetric glaucoma and early glaucoma, whereas the FLV was useful for detecting advanced glaucoma. According to these results the GLV and the FLV performed well in discriminating glaucomatous eyes from normal eyes and these parameters have high sensitivity and specificity in detection of ganglion cell loss in early stages. In our study, the average, inferior, and superior GCC thicknesses, FLV, and GLV measurements in the glaucoma group showed significant differences compared with the PD group and control group which led us think that there is an RGC damage in the former. In the PD group, only the FLV and GLV rates were statistically higher than the control group (P = 0.002; P = 0.013). But also in PD the GLV rate was significantly lower than the glaucoma group. (P = 0.001) There are only a few studies investigating GCC measurements in PD patients. Sen et al28 compared the patients receiving levodopa therapy with patients who did not receive therapy and controls, but did not observe any significant difference in mean values of GCC layer average thickness among controls, untreated PD patients, or treated PD patients (P = 0.304). Although all GCC thickness was affected in the glaucoma patients, in the PD patients, it seems the RGC axons are much more affected than the RGC dendrites and bodies. GCC measurements also showed no correlations with severity of the PD. GLV can reveal the ganglion cell loss accurately but results confirm that OCT may not be used in the follow-up of the PD patients under treatment. In the present study, we observed that, although they are not as significant as in glaucoma, RNFL thinning and GCC loss (in volume) were also present in PD. These findings are the indicators of RGC damage in PD. Dopamine functions as a neurotransmitter between amacrine cells and RGC.34 Loss of dopaminergic neurons may lead to dysfunction and degeneration of the RGC because of their close relationship. In this study, all study subjects with PD were receiving levodopa and dopamine agonist treatment. Although animal experiments have shown that exogenous dopamine increases retinal dopamine, it is not clear whether it reaches a sufficient concentration to regulate retinal functions.35 Despite dopamine treatment, patients may experience RGC damage; this fact led us to think that other neurodegenerative mechanisms seen in PD may contribute to that damage. There are apoptotic genes in the etiopathogenesis of PD; this apoptotic process may cause neuron damage in the retina, which is regarded as an extension of brain. As a result of abnormalities in the a-synuclein gene, mutant a-synuclein protein plays a role in PD and accumulates in amyloid fibrillar and nonfibrillar oligomeric structures seen in Lewy bodies.36 This accumulation is held responsible for neuron degeneration in the disease. Mutant forms of a-synuclein formation of protofibrils and these protofibrils may lead to breakdown/disruption of synaptic vesicle membranes. In this case, excessive release of dopamine in vesicles into the cell creates oxidative stress and thus may lead to toxicity in RGC.36 We observed in the study that peripheral macular areas, where ganglion cells are more denser, were affected more in the eyes of glaucoma group. In the PD group, Copyright

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Comparison of OCT Findings in POAG and Parkinson Disease

thickness and volume values of IRL decreased significantly in the outer quadrants where rich amounts of amacrine and interplexiform cells are located. A decreased dopamine level may give rise to dysfunction in cells and reduction of cell concentration, which may lead to thinning of IRLs. This study has proven that PD has a larger effect on IRLs. Variously, Altintas¸ et al13 found that total retinal thickness was statistically significantly thinner in the PD compared with controls (P < 0.05). Hajee et al11 separated inner and outer retinal layers using auto-adjust on the RTVue OCT device, same method used in our study; they observed that inner retinal thickness was statistically significantly lower in superior and inferior macular quadrants, similar to our findings (P = 0.01, P = 0.01). The present study showed that there is no correlation between disease duration or severity that evaluated by the UPDRS score and the average RNFL and GCC thickness, FLV, GLV, total macular thickness, and thickness of IRLs in PD patients. Altintas¸ et al13 identified a statistically significant negative correlation between UPDRS scores and fovea thickness (P = 0.004; r = 0.625). Therefore, the usefulness of these finding may be to assist in documenting general CNS nerve fiber loss, as occurs in PD, as well as multiple sclerosis and other CNS disease, in patients without glaucoma or other disease that leads to ganglion cell loss. OCT measurements may help to evaluate retinal anatomic changes and detect the pathologic changes in the early stages of disease before the clinical findings of PD appear. Recently, some of the similarities between glaucoma and common neurodegenerative diseases have been discussed.22 To our knowledge, however, this is the first study comparing anatomic changes in the retinal layers including GCC caused by 2 different neurodegenerative diseases of CNS, as optic nerve and retina are also parts of the CNS, via OCT device and analyzing in vivo neuron damage. Our study reveals that, despite normal IOP in PD patients, there were similar structural changes in the retinal layers similar but not as severe as glaucomatous damage. According to these findings, RNFL and GCC measurements, which show early RGC damage in neurodegeneration, can be used as an objective marker for assessment of early neurodegenerative changes of PD. But they may not be used to judge the severity of the disease or the effectiveness of any treatment. The present study shows that, in summary, in PD there is loss of RNFL and ganglion cells, similar to glaucoma, but with some differences. First, while the RNFL thickness and ganglion cell layer measurements are less than in the normal population, it is not as severe as in glaucoma. Moreover, the loss revealed by OCT is not related to the severity of disease, unlike glaucoma. The usefulness of these finding may be to assist in documenting OCT findings in even early stages of PD and in general CNS nerve fiber loss. Further studies investigating interactions between age, distribution of the disease time, and treatment of PD is needed. Also in vitro studies will be valuable for assessing the common retinal changes between glaucoma and PD. REFERENCES 1. Guo L, Moss SE, Alexander RA, et al. Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix. Invest Ophthalmol Vis Sci. 2005;46:175–182. 2. Garcia-Valenzuela E, Shareef S, Walsh J, et al. Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res. 1995;61:33–44.

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3. de Rijk MC, Breteler MM, Graveland GA, et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam Study. Neurology. 1995;45:2143–2146. 4. Copeland RL Jr, Leggett YA, Kanaan YM, et al. Neuroprotective effects of nicotine against salsolinol-induced cytotoxicity: implications for Parkinson’s disease. Neurotox Res. 2005;8:289–293. 5. Lev N, Melamed E, Offen D. Apoptosis and Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27: 245–250. 6. Devos D, Tir M, Maurage CA, et al. ERG and anatomical abnormalities suggesting retinopathy in dementia with Lewy bodies. Neurology. 2005;65:1107–1110. 7. Denis P, Normdan J, Elena PP, et al. Physiological roles of dopamine and neuropeptides in the retina. Fundam Clin Pharmacol. 1993;7:293–304. 8. Harnois C, Di Paolo T. Decreased dopamine in the retinas of patients with Parkinson’s disease. Invest Ophthalmol Vis Sci. 1990;31:2473–2475. 9. Gottlob I, Scneider E, Heider W, et al. Alteration of visual evoked potentials and electroretinograms in Parkinson’s disease. Electroencephalogr Clin Neurophysiol. 1987;66:349–357. 10. Langheinrich T, Tebartz van Elst L, Lagreze WA, et al. Visual contrast response functions in Parkinson’s disease: evidence from electroretinograms, visually evoked potentials and psychophysics. Clin Neurophysiol. 2000;111:66–74. 11. Hajee M, March W, Lazzaro D, et al. Inner retinal layer thinning in Parkinson disease. Arch Ophthalmol. 2009;127:737–741. 12. Inzelberg R, Ramirez JA, Nisipeanu P, et al. Retinal nerve fiber layer thinning in Parkinson disease. Vision Res. 2004;44:2793–2797. 13. Altintas O, Iseri PK, Ozkan B, et al. Correlation between retinal morphological and functional findings and clinical severity in Parkinson’s disease. Doc Ophthalmol. 2007;116:137–146. 14. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology. 2006;113:324–332. 15. Paquet C, Boissonnot M, Roger F, et al. Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett. 2007;420:97–99. 16. Kita Y, Kita R, Takeyama A, et al. Relationship between macular ganglion cell complex thickness and macular outer retinal thickness: a spectral-domain optical coherence tomography study. Clin Exp Ophthalmol. 2013;41:674–682. 17. Kim NR, Lee ES, Seong GJ, et al. Structure-function relationship and diagnostic value of macular ganglion cell complex measurement using Fourier-domain OCT in glaucoma. Investig Ophthalmol Vis Sci. 2010;51:4646–4651. 18. Hodapp E, Parrish RK II, Anderson DR. Clinical Decisions in Glaucoma. St Louis: Mosby-Year Book; 1993. 19. Shih CY, Graff Zivin JS, Trokel SL, et al. Clinical significance of central corneal thickness in the management of glaucoma. Arch Ophthalmol. 2004;122:1270–1275.

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20. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord. 2003;18:738–750. 21. Gupta N, Yu¨cel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol. 2007;18:110–114. 22. Kersey T, Clement CI, Bloom P, et al. New trends in glaucoma risk, diagnosis & management. Indian J Med Res. 2013;137: 659–668. 23. Kirbas S, Turkyilmaz K, Tufekci A. Retinal nerve fiber layer thickness in Parkinson disease. J Neuroophthalmol. 2013;33:62–65. 24. Aaker GD, Myung JS, Ehrlich JR, et al. Detection of retinal changes in Parkinson’s disease with spectral-domain optical coherence tomography. Clin Ophthalmol. 2010;6:1427–1432. 25. Archibald NK, Clarke MP, Mosimann UP, et al. Retinal thickness in Parkinson’s disease. Parkinsonism Relat Disord. 2011;17:431–436. 26. Tsironi EE, Dastiridou I, Katsanos A, et al. Perimetric and retinal nerve fiber layer findings in patients with Parkinson’s disease. BMC Ophthalmol. 2012;12:54. 27. Alamouti B, Funk J. Retinal thickness decreases with age: an OCT study. Br J Ophthalmol. 2003;87:899–901. 28. Sen A, Tugcu B, Coskun C, et al. Effects of levodopa on retina in Parkinson disease. Eur J Ophthalmol. 2013;24:114–119. 29. Yavas GF, Yilmaz O, Ku¨sbeci T, et al. The effect of levodopa and dopamine agonists on optic nerve head in Parkinson disease. Eur J Ophthalmol. 2007;17:812–816. 30. Moschos MM, Tagaris G, Markopoulos I, et al. Morphologic changes and functional retinal impairment in patients with Parkinson disease without visual loss. Eur J Ophthalmol. 2011;21:24–29. 31. Leung CK, Choi N, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: pattern of RNFL defects in glaucoma. Ophthalmology. 2010;117:2337–2344. 32. Firat PG, Doganay S, Demirel EE, et al. Comparison of ganglion cell and retinal nerve fiber layer thickness in primary open-angle glaucoma and normal tension glaucoma with spectral-domain OCT. Graefes Arch Clin Exp Ophthalmol. 2013;251:831–838. 33. Arintawati P, Sone T, Akita T, et al. The applicability of ganglion cell complex parameters determined from SD-OCT images to detect glaucomatous eyes. J Glaucoma. 2013;22:713–718. 34. Witkovsky P. Dopamine and retinal function. Doc Ophthalmol. 2004;108:17–40. 35. Mao JF, Liu SZ, Qin WJ, et al. Exogenous levodopa increases the neuro retinal dopamine of Guinea pig myopic eyes in vitro. Yan Ke Xue Bao. 2011;26:211–216. 36. Tanaka Y, Engelender S, Igarashi S, et al. Inducible expression of mutant a-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Gen. 2001;10:919–926.

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Comparison of Optical Coherence Tomography Findings in Patients With Primary Open-angle Glaucoma and Parkinson Disease.

To evaluate the peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex, and macular thickness as well as their correlation with the sev...
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