Analysis of the retinal nerve fiber and ganglion cell – Inner plexiform layer by optical coherence tomography in Parkinson’s patients

Accepted Manuscript Analysis of the retinal nerve fiber and ganglion cell – Inner plexiform layer by optical coherence tomography in Parkinson's patients Turgay Ucak, Aybala Alagoz, Burcin Cakir, Erkan Celik, Erdinc Bozkurt, Gursoy Alagoz PII:

S1353-8020(16)30261-9

DOI:

10.1016/j.parkreldis.2016.07.004

Reference:

PRD 3069

To appear in:

Parkinsonism and Related Disorders

Received Date: 3 October 2015 Revised Date:

30 June 2016

Accepted Date: 6 July 2016

Please cite this article as: Ucak T, Alagoz A, Cakir B, Celik E, Bozkurt E, Alagoz G, Analysis of the retinal nerve fiber and ganglion cell – Inner plexiform layer by optical coherence tomography in Parkinson's patients, Parkinsonism and Related Disorders (2016), doi: 10.1016/j.parkreldis.2016.07.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Analysis of the retinal nerve fiber and ganglion cell - inner plexiform layer by optical coherence tomography in Parkinson's patients Turgay Ucak a , Aybala Alagoz b , Burcin Cakir c , Erkan Celik c , Erdinc Bozkurt c , Gursoy Alagoz c Department of Ophthalmology, University of Erzincan, Erzincan, Turkey

b

Department of Neurology, University of Sakarya, Sakarya,Turkey

c

Department of Ophthalmolrrogy, Sakarya University Hospital, Sakarya, Turkey

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a

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*Corresponding author: Department of Ophthalmology, University of Erzincan, No:21, 24040, Erzincan, Tel: +90 446 2122215, Fax: +90 446 2122216 E-mail address: [email protected]

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Abstract

AIM: To measure and evaluate the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) in patients with Parkinson's disease using optical coherence tomography (OCT).

METHODS: 58 eyes of 30 patients with Parkinson’s disease and 60 eyes of 30 healthy individuals

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were enrolled to this study according to defined criteria. RNFL thickness, central macular thickness (CMT) and ganglion cell-inner plexiform layer (GC-IPL) thickness were measured in these groups.

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The Parkinson’s patient group was also subjected to Unified Parkinson’s Disease Rating Scale (UPDRS) and Mini Mental Status Exam (MMSE).

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RESULTS: No difference was found between the two groups with respect to age, sex and the best corrected visual acuity (BCVA). Mean, superior, and inferior quadrant RNFL values in the Parkinson’s patients were found statistically significantly lower than those in the control group (P<0.001, P<0.049, P<0.001, respectively). While CMT was statistically similar between the groups, GC-IPL thickness was statistically significantly lower in Parkinson’s patients (p=0.028). There was no significant correlation between the duration of Parkinson’s disease and RNFL thickness. While there was not any correlation between UPDRS total and motor scores and superior and temporal quadrant RNFL thicknesses, a significant negative correlation was established

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between RNFL nasal, inferior quadrant and RNFL mean thicknesses (P=0.022; P=0.035; P=0.002, respectively). A significant positive correlation was found between MMSE and nasal and mean RNFL thicknesses (P=0.046; P=0.019, respectively). CONCLUSION: RNFL and GC-IPL thicknesses were found lower in Parkinson’s patients. These

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parameters may be useful to evaluate neurodegeneration and to monitorize neuroprotective therapies.

KEY WORDS: Ganglion cell complex, optical coherence tomography, Parkinson’s disease, retina,

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retinal nerve fiber layer.

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INTRODUCTION

Retina is a peripheral extension of the central nervous system. Of the chemical messengers in the retina, the one that plays the most evident physiological role is dopamine[1,2]. Dopamine which is found in amacrine and interplexiform retinal cells is the major mediator transmitter of the retina[3]. Any disturbance in the dopamine mechanism brings about complex synaptic effects in the long

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term. Reduced dopaminergic stimulation of the ganglion cells is likely to cause abnormal glutamate production and consequently atrophy in nerve fibers[4].

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Parkinson’s Disease (PD) is characterized by loss of dopaminergic neurons in the substantianigra[5]. Symptoms like impaired vision, color vision defects, decreased contrast

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sensitivity are common in Parkinson’s patients[6–9]. These visual symptoms may be associated with curtailed dopaminergic activity in the retina amacrine cells[8,10]. Post-mortem studies showed lower retina dopamine concentrations in Parkinson’s patients[11]. Although it is possible to have an idea about the diagnosis, differential diagnosis of Parkinson’s disease using sophisticated imaging methods, as well as clinical signs, the methods used to monitor the progression of the disease have limitations[12]. In the follow-up of Parkinson’s disease, the thinning of the retinal nerve fiber layer (RNFL) may be a critical marker to monitor the progression of the disease[13].

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It is possible to identify retina ganglion cell and RNFL losses using the Optical Coherence Tomography (OCT), a non-invasive, fast, and objective method that also allows repeated measurements[14]. Many studies about neurodegenerative diseases have demonstrated that OCT had high sensitivity in identifying the changes in RNFL and macula following permanent

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damage[15,16]. In this study we aim to measure and evaluate the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) in patients with Parkinson's disease using OCT.

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measure the thickness and compare the results with those found in the control group. METHODS

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This prospective study was conducted in accordance with the provisions of the Helsinki Declaration after the approval of Sakarya University Ethics Committee was obtained through the committee decision dated 2th October 2013 and the number 050.01.04/37. All the patients registered in the study were informed about the study and the written consent of each was taken. The study included 30 patients as control group and 30 patients with Parkinson’s disease as PD

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group. The mean ages and distrubition of gender were similar in both groups. Patients in control group had presbyopia symptoms and no cognitive complaints. Patients in PD group were referred

polyclinic.

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during the ‘on’ period of the disease to the Department of Ophthalmology by the Neurology

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Patients whose best corrected visual acuity (BCVA) was 0.5 or higher, intraocular pressure (IOP) was 21 mmHg and lower, spherical and cylindrical refractive error was ±4.0 dioptria or lower, who did not have any other ophthalmologic disease (glaucoma, retinal detachment or degeneration, uveitis, ocular surface disease, optic disc pathology, etc.), did not have a history of intraocular surgery or trauma, did not have any pathology that prevents retina imaging (intense cataract, corneal nebula), and was free of any neurological disease except Parkinson’s disease (in PD group) were included in the study.

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After the cases included in the study were questioned to find out if they had any systemic diseases, their visual acuity was measured according to Snellen threshold and the values obtained as such were converted to logMAR values. Intraocular pressure was measured using Goldmann Applanation Tonometry. After inducing mydriasis with 1% tropicamide, fundus examination was

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performed by using +90 dioptric aspheric lens. Following this detailed eye examination, RNFL, GC-IPL thickness and central macular thickness (CMT) of each case were analyzed using Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA, USA)

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(Figure 1). RNFL thickness was measured according to “Optic Disc Cube 200x200” method and macula and ganglion cell analysis was conducted in accordance with “Macular Cube 512x128”

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program. OCT system calculates the RNFL thickness at each point on a set-diameter (3.46-mm) circle consisting of 256 A-scans that were positioned automatically around the optic disc, thus generating a circular diagram of average RNFL thickness of four 90° RNFL quadrants and twelve 30° RNFL clock-hour sectors. (RNFL thickness are shown in green as they fall within the ≤95th to ≥5th; yellow within the ≤5th to ≥1th and red below the 1st percentile of the normal distribution

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percentiles provided by the manufacturer’s inbuilt database.) RNFL thickness in the inferior, superior, nasal and temporal quadrants, mean RNFL thickness, CMT and mean GC-IPL thickness

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were included in the evaluation. All the measurements were carried out by the same physician. Three measurements were conducted per eye. Of the measurements, the best one was used for

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analysis on condition that the signal power was not below 7/10. All Parkinson’s patients were subjected to Unified Parkinson’s Disease Rating Scale (UPDRS) and Mini Mental Status Exam (MMSE). The motor assessment was done using the part III of the UPDRS. Statistical Analyses: Continuous variables used in the study were evaluated according to the Kolmogorov-Smirnov test and it was seen that the distribution of all variables was consistent with normal distribution. Accordingly, t-test for two independent samples was employed to compare the age and vision parameters between control and Parkinson’s groups. Continuous variables were presented as mean and standard deviation. Chi-square test was utilized to compare categorical

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variables. Categorical variables were expressed in numbers and percentages. Pearson correlation coefficient was used to establish the correlations between disease length and severity scores on one hand and visual parameters on the other. P values lower than 0.05 were considered statistically significant. The calculations were conducted using ready-made statistical software (IBM SPSS

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Statistics 20, SPSS Inc. An IBM Corp. Armonk, NY). RESULTS

The study registered 58 eyes of 30 Parkinson’s patients and 60 eyes of 30 control group cases. In

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the Parkinson’s group, one eye of one patient was excluded due to signs of unilateral age related macular degeneration, and another patient due to central serous chorioretinopathy signs in one eye.

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The mean age of Parkinson’s patients was 68.50±7.63 (50-81 years) years and the mean age in the control group was 66.23±8.93 (50-85 years) years.

Of the Parkinson’s patients, 11 (36.7%) were female and 19 (63.3%) were male. In the control group, 14 cases (46.7%) were female and 16 (53.3%) were male. No significant difference was found between groups in terms of mean age and sex (p=0.295, p=0.600, respectively). There was

(P=0.524) (Table 1).

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also no significant difference between the visual acuity of Parkinson’s patients and control cases

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Figure 2 shows the RNFL thickness in the quadrants and the mean RNFL thickness in Parkinson’s and control groups. Mean RNFL measured 89.38±7.51 µm in the Parkinson’s group and 94.63±8.09

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µm in the control group. Mean RNFL measurements in the Parkinson’s patients were found statistically significantly lower relative to the measurements in the control group (P<0.001). Superior quadrant RNFL values were found to be 111.98±13.28 µm in the Parkinson’s group and 116.82±13.23 µm in the control group. Parkinson’s patients were found to have statistically significantly lower superior quadrant RNFL thickness values than the control group (P=0.049). Inferior quadrant RNFL values were 111.71±15.37 µm in the Parkinson’s group and 122.68±12.94 µm in the control cases. Thus, inferior quadrant RNFL values in the Parkinson’s group were statistically significantly lower than those in the control group (P=0.001). Nasal and temporal

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quadrant RNFL values were70.84±10.55, 63.33±10.06, respectively, in the Parkinson’s group and 74.1±12.23, 65.45±9.78, respectively, in the control cases. There was no significant difference between nasal and temporal quadrant RNFL values of Parkinson’s patients and control cases (P=0.125; P=0.0247, respectively).

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Mean GC-IPL thickness was 78±8.09 µm in Parkinson’s patients and 80.97±6.34 µm in the control group. Mean GC-IPL thickness was found statistically significantly lower in Parkinson’s patients (P=0.028). No difference in the CMT was established between groups (P=0.165).

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Mean disease duration in the 30 Parkinson’s patients included in the study was 4.87±4.07 years. UPDRS total score was found 42.17±15.6 , UPDRS motor score was 15.26±4.10 and MMSE score

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was established to be 24.7±4.5. Levodopa equivalent dose of the patients was 531.2±119 mg/day. No statistically significant relation was identified between mean GC-IPL thickness and CMT on one hand, and disease duration, UPDRS total and motor scores and MMSE on the other (Table 2). There was not any significant correlation between disease duration and RNFL thickness. Likewise, no correlation was established between UPDRS total and motor scores and RNFL superior and

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temporal quadrant thicknesses, whereas there was a significant negative correlation between the former and nasal, inferior and mean RNFL thicknesses. There was no correlation between MMSE

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and superior, inferior and temporal quadrant RNFL thicknesses, but a significant positive correlation was found between MMSE and nasal and mean RNFL thicknesses (Table 3).

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DISCUSSION

In this study, we aimed to evaluate the thickness of the RNFL and GC-IPL in patients with Parkinson's disease and we found that mean, superior and inferior quadrant RNFL measurements in Parkinson’s patients set forth statistically significant lower results than in the control group while there was no significant difference between nasal and temporal quadrant RNFL thicknesses of the two groups. There are studies in the literature, which reported different results about the correlation of neurodegenerative diseases with RNFL measurements. Inzelberg et al[4] found out RNFL thickness

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in the inferior quadrant was significantly thinner in Parkinson’s patients. Kırbaş et al[17] reported significantly thinner mean RNFL and temporal quadrant RNFL in newly diagnosed Parkinson’s patients. Moschos et al[18] demonstrated a decrease in the thickness of inferior and temporal quadrant RNFL in Parkinson’s patients. Likewise, Satue et al[19] identified a significant decrease

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in inferior, inferior temporal and superior temporal quadrant RNFL thicknesses in the Parkinson’s patients. Similarly, Satue and colleagues evaluated 153 Parkinson’s patients and 242 control cases by using two different Fourier domain OCT and they determined significantly lower RNFL values

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in the Parkinson’s group [19]. However, some studies which compared RNFL thickness in Parkinson’s disease with control groups, did not identify any difference between the two groups

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[21,22,23]. These different results of studies may be due to different sample sizes and different including criterias.

In a study including 17 Parkinson’s patients receiving levodopa treatment and 18 patients not receiving levodopa treatment, along with 11 healthy control cases, Şen et al[20] demonstrated a

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decrease in the mean RNFL thickness in the Parkinson’s patients compared with control cases. They did not find any significant difference between Parkinson’s patients with and without levodopa treatment regarding the RNFL thicknesses [20]. This study, which was carried out in

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patients with Parkinson’s disease with or without levodopa treatment, is valuable in respect of its

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results indicating that this therapy has no effect on RNFL values. It was shown in several studies that macular thickness or volume was curtailed in Parkinson’s disease and that the curtailment resulted from the thinning of inner macular layers, while the outer macular thickness did not have any effect on it[24–26]. Sen et al[20] did not find any significant difference between GC-IPL values in the Parkinson’s and control groups. In our study, however, GC-IPL thickness in the Parkinson’s group was statistically significantly lower than in the control group (P<0.028). We already know that dopamine is found in the interplexiform cells and lack of dopamine in these cells may be related with the GC-IPL thickness. Further studies on this topic are needed.

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In our study, no significant difference was found between CMT of the groups. Aaker et al[21] compared 9 Parkinson’s patients with 9 controls and found out that CMT in Parkinson’s patients was significantly lower than in the control group. The results of the study might be affected by the small number of cases involved. On the other hand, Archibald et al [28] did not find a significant

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change in CMT. Altintas et al[25] reported a negative correlation between UPDRS and IRL. Garcia-Martin et al [27] noted that fovea thickness decreased in proportion to the diffuseness of the disease. In our study,

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however, no statistically significant correlation was found between mean GC-IPL thickness and CMT as well as between UPDRS total and motor scores and MMSE.

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There are studies in the literature comparing the cognitive state of the Parkinson’s with the OCT parameters. Moreno-Ramos et al[29] stated that RNFL thinned in correlation with MMSE in Parkinson’s patients with dementia. Garcia-Martin et al[30] did not find a relation between MMSE and RNFL. Likewise, La Morgia et al[31] did not identify any correlation between age, duration of the disease, UPDRS parameters, and RNFL. It is considered that the severity of Parkinson’s disease

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is proportional to the increase in dopamine deficiency. In this context, UPDRS and cognitive function tests (MMSE, etc.) which show the severity of the disease might be correlated with RNFL

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and GC-IPL measurements. In our study, while no correlation was found between UPDRS total and motor scores and RNFL superior and temporal quadrant thicknesses, there was a significant

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negative correlation between the former and nasal, superior quadrant and mean RNFL thicknesses. There was not any correlation between MMSE and RNFL superior, inferior and temporal quadrant thicknesses, but MMSE correlated positively with RNFL nasal and mean thicknesses. This study had certain limitations , conflicting results regarding GCC, RNFL and CMT measurements in other studies might be due to the difference in ages, patient population and devices. In conclusion, axonal loss and the resulting neurodegeneration can be assessed by RNFL measurements. In our study we found out that mean, superior and inferior quadrant RNFL

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thicknesses and GC-IPL values in Parkinson’s patients were lower than in the control group, which supported the mentioned claim. A significant negative correlation was demonstrated between UPDRS total and motor scores and nasal, inferior quadrant and mean RNFL thicknesses. On the other hand, MMSE and RNFL nasal and mean thicknesses displayed a positive correlation.

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OCT is a non-invasive and fast diagnostic method that is valuable in terms of patient compliance and repeatability. Although we can find out RNFL and CMT with OCT, we cannot evaluate amacrine and other cells in the retina. When the OCT technology advances in the future, it seems

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possible that more information will be acquired about the pathophysiology of many neurodegenerative diseases. including Parkinson’s Disease at the cellular level and this information

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will be used in the early diagnosis and treatment follow-up of the disease. More larger scale, prospective and homogenous studies will contribute to a better understanding of RNFL thickness and macular parameters using OCT in patients with PD.

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La Morgia C, Barboni P, Rizzo G, Carbonelli M, Savini G, Scaglione C, et al. Loss of temporal retinal nerve fibers in Parkinson disease: a mitochondrial pattern? Eur J Neurol 2013;20:198–201. doi:10.1111/j.1468-1331.2012.03701.x.

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[24]

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Table 1. Characteristics of the study groups. Results presented as mean (standard deviation) Control

PD

p-value

Male

16 (%53.3)

19 (%63.3)

Female

14 (%46.7)

11 (%36.7)

Age

66,23±8,94

68,5±7,63

Best corrected visual acuity

0,10±0,07

0,11±0,06

0.600

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Sex

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0.295

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PD: Parkinson’s Disease

0,524

Table 2. Distribution of relations between disease length and severity scores, and

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GC-IPL thickness and MT in Parkinson’s patients UPDRS

UPDRS

(Total)

(Motor)

Time

MMSE p

r

p

r

p

r

p

GC-IPL thickness

-0.087

0.518

-0.127

0.341

-0.117

0.320

0.239

0.071

CMT

-0.100

0.454

-0.057

0.670

-0.226

0.089

0.067

0.618

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r

r: Pearson correlation coefficient CMT: central macula thickness, GC-IPL: ganglion cell complex-inner plexiform layer

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p

r

p

UPDRS (Motor)

r

p

RNFL-Superior

-0.059

0.659

-0.172

0.196

-0.134

RNFL-Nasal

-0.212

0.111

-0.300

0.022

-0.277

RNFL-Inferior

-0.110

0.411

-0.277

0.035

-0.262

RNFL-Temporal

-0.036

0.789

-0.210

0.113

-0.194

RNFL-Mean

-0.173

0.194

-0.396

0.002

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r

UPDRS (Total)

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r 0.220

p 0.097

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-0.359

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RNFL: retinal nerve fiber layer

0.315

MMSE

0.035

0.263

0.046

0.047

0.176

0.186

0.144

0.063

0.640

0.307

0.019

0.006

A

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OD

OS

RNFL Thickness Map

RNFL Thickness Map

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RNFL TSNIT Normative Data

OD

OS

RNFL Deviation Map

RNFL Deviation Map

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RNFL Quadrants

Signal Strength:9/10

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Signal Strength:8/10

RNFL Clock Hours

B

OD

RNFL Thickness Map

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RNFL Thickness Map

OS

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RNFL TSNIT Normative Data

OD

OS

RNFL Deviation Map

RNFL Deviation Map

RNFL Quadrants

Signal Strength:9/10

Signal Strength:9/10

RNFL Clock Hours

Figure 1: An example of conventional circumpapillary retinal nerve fiber layer analysis as provided by Cirrus HD-OCT. ACCEPTED MANUSCRIPT On the left and right of the figure we show RNFL thickness and deiation maps. RNFL thickness map shows RNFL thickness along a color scale. RNFL deviation map provides visualization of the spatial distribution of RNFL defects in the 6 mm2 × 6 mm2 optic disc region. In the centre of the figure we show the distribution of the RNFL thickness measures circumferentially around the retina, retinal thickness by clockface and quadrant sector analyses.

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A) OCT report from a control subject with normal RNFL thickness. The values in green are normal based on information derived from a normative population database. B) OCT report from a patient with Parkinson’s disease.

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RNFL thickness in the temporal (right eye), superior and temporal quadrants (left eye) are shown in yellow as they fall within the ≤5th to ≥1th centile of the normal distribution percentiles provided by the manufacturer’s inbuilt database.

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T:temporal; S:superior; N:nasal; I: inferior, OD=right eye. OS=left eye

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Diversified distribution of normals: Distribution percentiles provided by the manufacturer’s inbuilt database

160

100 80

EP

120

Controls

AC C

RNFL Thickness (µm)

140

60

PD

40 20 0

Superior P<0.049

Nasal P>0.05

Inferior P<0.001

Temporal P>0.05

Mean P<0.001

Figure 2: All quadrants and mean RNFL thickness values were found lower in Parkinson's patients than the control group. Superior, inferior quadrant and mean RNFL values in the

Parkinson’s group were statistically significantly lower than those in the control group.

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

(Controls:60 eyes, PD: 58 eyes) PD: Parkinson's Disease

ACCEPTED MANUSCRIPT RNFL thickness, macular thickness, and GC-IPL thickness was examined Parkinson’s patient group was subjected to UPDRS and MMSE

AC C

EP

TE D

M AN U

SC

RI PT

OCT, a non-invasive, fast, and objective method that also allows repeated measurements