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Show Retinal Nerve Fiber Layer Thickness in Parkinson Disease Serkan Kirbas, MD, Kemal Turkyilmaz, MD, Ahmet Tufekci, MD, Mustafa Durmus, MD Abstract: Dopaminergic neuronal cells have been identified in the inner nuclear and inner plexiform layers of the human retina. The dopaminergic content of the retina is reduced in patients with idiopathic Parkinson disease (PD). These observations led us to study the retinal nerve fiber layer (RNFL) thickness in patients with PD without visual impair-ment compared to healthy controls using spectral-domain optical coherence tomography (SD-OCT). Eighty-two subjects, including 42 patients with PD, newly diagnosed and untreated (24 men, 18 women, age range: 47-66 years), and 40 healthy controls, were enrolled. Both eyes of patients with PD and controls were imaged with SD-OCT. The mean RNFL thickness was 77 ± 11.5 mm in PD patients and 89 ± 8.7 mm in healthy controls (P = 0.001). Selective thinning of the RNFL was found in the temporal region with mean temporal RNFL thickness of 66 ± 6.7 mm in PD patients and 75 ± 4.8 mm in controls (P = 0.001). The thickness of the RNFL is decreased in PD patients. Demonstrating progressive thinning of RNFL over time will be critical for validating optical coherence tomography as a viable biomarker of patients with PD. Journal of Neuro-Ophthalmology 2013;33:62-65 doi: 10.1097/WNO.0b013e3182701745 © 2012 by North American Neuro-Ophthalmology Society Parkinson disease (PD), the second most common neuro-degenerative disease of the elderly, is characterized by bradykinesia, tremor, progressive rigidity, and postural instabil-ity. Both prevalence and incidence increase with age, estimated at 0.3% and of 8-18 per 100,000 person-years, respectively (1). The pathologic lesion in PD is the loss of pigmented neurons in the substantia nigra and selected brainstem dopaminergic cell groups (2). Visual deficits are common in PD and include abnormal contrast sensitivity, motion perception abnormalities, impaired visual acuity and color vision, and visual hallucina-tions (3). Visual hallucinations are a predictor of cognitive decline, as well as institutional care and mortality (1,4). Dopaminergic neuronal cells have been identified in the inner nuclear and inner plexiform layers of the human retina (4,5). Dopamine (DA) has been established as a major neurotransmitter or modulator in the retina. The DA con-tent of the retina, as measured at postmortem, is low in PD patients (6). The role of retinal dopaminergic neuronal cells in visual function has been studied in both primate models and humans, and these cells seem to modulate the receptive fields of retinal ganglion cells (RGCs) to provide spatial contrast sensitivity and color vision (6,7). Thinning of the retinal nerve fiber layer (RNFL) and macular thickness in PD patients has been documented in several small studies (5,7-9). Although the consequences of RNFL loss in PD are not clearly understood, depletion of retinal DA may affect the integrity of RGCs (6). The aim of this study was to investigate RNFL thickness mea-sured with spectral-domain optical coherence tomography (SD-OCT) in patients with PD without visual impairment and to compare results with data from healthy controls. METHODS Our prospective study was conducted in the neurology and ophthalmology clinics of Rize University School of Medi-cine, Rize, Eastern Blacksea, Turkey. Forty-two patients were enrolled and comprised 24 men, 18 women, ranging in age from 47 to 66 years (mean age: 59.3 ± 4.9 years). The PD patients were newly diagnosed according to the brain bank clinical diagnostic criteria for idiopathic PD (10) and all were untreated. Severity ratings of PD patients were between Hoehn and Yahr stage 1 and 2 (range: 0-5) (11). Control group consisted of 40 healthy individuals (24 men, 16 women, mean age of 57.0 ± 4.9 years, range: 45-67 years). All patients and controls underwent ophthalmologic testing, including assessment of visual acuity and color vision, slit-lamp examination with intraocular pressure measurement, visual fields with automated perimetry (Octopus 900; Haag Streit, Koeniz, Switzerland), and funduscopy. Optical coherence tomography (OCT) imaging was performed with the Cirrus HD SD-OCT (Carl Zeiss Meditec, Dub-lin, CA). The OCT imaging was performed with the Departments of Neurology (SK, AT) and Ophthalmology (KT, MD), Faculty of Medicine, Rize University, Rize, Turkey. The authors report no conflicts of interest. Address correspondence to: Serkan Kirbas, MD, Department of Neurology, Faculty of Medicine, Rize University, 53100 Rize, Turkey; E-mail: drskirbas@gmail.com 62 Kirbas et al: J Neuro-Ophthalmol 2013; 33: 62-65 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. participants' pupils dilated to obtain higher signal qual-ity and discarded if signal strength was ,8. Average temporal, nasal, inferior, superior quadrant peripapillary RNFL thicknesses were obtained from the OCT with optic disc 200 · 200 cube scan protocol. Excluded participants included those with glaucoma (diagnosis was based on cup-to-disc ratio .50%, cup-to-disc ratio asymmetry between 2 eyes .20%, corrected intraoc-ular pressure .21 mm Hg, and glaucomatous visual field defects), pseudoexfoliation syndrome, high myopia (greater than 26.0 diopters), diabetes, anomalous optic disc, age-related macular degeneration, peripheral vasospasm, sleep-related breathing disorder, family history of glaucoma, history of ocular trauma, optic neuropathy, and use of cor-ticosteroid and glaucoma medications. All study procedures were in accordance with the revised form of the Helsinki Declaration 2008, and all participants gave informed consent. The study protocol was approved by the local ethical committee. All statistical analyses were performed using the Statis-tical Package for the Social Sciences (SPSS), version 15.0, for Windows (SPSS, Chicago, IL). Data were expressed as mean ± SD. The normality of the distribution for all variables was assessed by the Kolmogorov-Smirnov test. Student t test was used for normally distributed variables, and Mann-Whitney U test was used for nonparametric variables. Relationships between variables were analyzed by Pearson or Spearman correlation analysis according to the distribution type of the variables. P , 0.05 was con-sidered to be statistically significant. RESULTS There were no significant differences in age, sex, and body mass index between patients with PD and healthy controls. The average RNFL thickness was 77 ± 11.56 mm in PD patients and 89 ± 8.7 mm in healthy controls (P = 0.001). Selective thinning of the RNFL was found in the temporal quadrant (Fig. 1). Mean temporal RNFL thickness was 66 ± 6.7 mm in FIG. 1. Spectral-domain optical coherence tomography in a patient with Parkinson disease demonstrates reduced average retinal nerve fiber layer thickness with selective thinning temporally. Kirbas et al: J Neuro-Ophthalmol 2013; 33: 62-65 63 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. PD patients and 75 ± 4.8 mm in controls (P = 0.001). The RNFL thickness did not differ significantly between PD patients and controls in inferior quadrant (108 ± 3.4 mm in PD patients, 110 ± 3.6 mm in controls; P = 0.569), superior quadrant (116 ± 6.7 mm in PD patients, 118 ± 7.3 mm in controls; P = 0.763), and nasal quadrant (75 ± 3.8 mm in PD patients, 76 ± 2.7 mm in controls; P = 0.856). DISCUSSION Our study showed that RNFL thickness of idiopathic PD patients was thinner than in healthy controls, and this difference was most prominent in the temporal quadrant. We selected patients in the early stages of PD; those who were newly diagnosed and not prescribed any PD medica-tion. This was important for 2 reasons. First, one might suspect that with increasing age and in the late stages of PD, there would be reduced RNFL thickness. Second, we removed any potential effect of L-dopa and other DA ago-nist drugs. Histopathologic studies on postmortem PD patients never treated with levodopa showed significantly lower retinal DA concentrations than controls or individuals with PD whose death occurred less than 15 hours after their last dose of L-dopa (6,12). RNFL thinning has been described previously in PD (5,7-9) (Table 1). However, these studies examined fewer patients with lower resolution time-domain OCT. Inzelberg et al (9) and Moschos et al (5) also found selective thinning of RNFL in the temporal quadrant, whereas other reports documented thinning in the superior (8), inferior (5,9), and nasal (8) quadrants. We postulate that RNFL thinning observed in PD patients using OCT may be a result of DA depletion. DA plays an important role in retinal neurotransmitter systems, including glutamate, g-aminobutyric acid (GABA), and glycine. Pre-cisely, how DA deficiency, as seen in PD, might affect the retina is uncertain (13). DA acts through G-protein-coupled receptors, which regulate the production of cyclic adenosine monophosphate. DA receptor subtypes D1 and D5, often collectively referred to as the D1 receptor family, increase cyclic adenosine monophosphate levels and, in this context, are excit-atory, whereas subtypes D2, D3, and D4, part of the D2 receptor family, act in an opposing fashion (1). Rod and cone photoreceptors are inhibited by activation of D2 family recep-tors, whereas bipolar, horizontal, RGCs, and amacrine cells are excited by D1 receptors. Dopaminergic cells use an autorecep-tor of the D2 family to modulate their own DA release. DA has direct effects on gap junction permeability both at the level of rod and cone interactions with horizontal cells. DA cells receive "excitatory" (glutamatergic) bipolar cell and "inhibi-tory" (GABAergic and glycinergic) amacrine cell inputs, which alter the action potential firing rate and, hence, DA release. As well as direct synaptic effects on amacrine and bipolar cells, diffusion of DA in the retinal extracellular matrix exerts a para-crine effect, obviating the need for direct synaptic contact and TABLE 1. Literature summary of RNFL thickness as measured by OCT in patients with Parkinson disease Author (Reference) No. Patients (n) = 1 OCT Average RNFL Thickness (mm) Superior RNFL Thickness (mm) Inferior RNFL Thickness (mm) Nasal RNFL Thickness (mm) Temporal RNFL Thickness (mm) Inzelberg et al (9) PD = 10 TD PD = 125 ± 31 PD = 160 ± 22 PD = 147 ± 20 PD = 99 ± 34 PD = 101 ± 29 C = 10 HC = 143 ± 26 HC = 154 ± 16 HC = 173 ± 12 HC = 117 ± 19 HC = 126 ± 11 P (unknown) P (unknown) P = 0.002* P (unknown) P = 0.019* Altintas et al (8) PD = 17 TD PD = 98.7 ± 10.9 PD = 125.4 ± 24.4 PD = 126.2 ± 35.3 PD = 75.9 ± 19.0 PD = 70.8 ± 18.1 C = 11 HC = 114.5 ± 5.7 HC = 138.7 ± 17.7 HC = 142.7 ± 19.8 HC = 99.4 ± 36.8 HC = 71.9 ± 16.7 P = 0.000* P = 0.022* P = 0.052 P = 0.003* P = 0.832 Aeker et al (7) PD = 9 TC PD = 97 PD = 130 PD = 139 PD = 74 PD = 71 C = 16 HC = 97 HC = 134 HC = 141 HC = 72 HC = 74 P = 0.911 P = 0.306 P = 0.593 P = 0.613 P = 0.315 Moschos et al (5) PD = 16 TD PD = 95.43 ± 11.8 PD = 119.5 ± 23.3 PD = 124.2 ± 16,1 PD = 74.0 ± 18.0 PD = 64 ± 15.3 C = 20 HC = 102.9 ± 29.2 HC = 123.1 ± 6.3 HC = 137.6 ± 7.3 HC = 78.2 ± 7.9 HC = 72.35 ± 8.6 P = 01504 P = 0.626 P , 0.0001* P = 0.227 P = 0.0042* Current study PD = 42 SD PD = 77 ± 11.5 PD = 116 ± 6.7 PD = 108 ± 3.4 PD = 75 ± 3.8 PD = 66 ± 6.7 C = 40 HC = 89 ± 8.7 HC = 118 ± 7.3 HC = 110 ± 3.6 HC = 76 ± 2.7 HC =75 ± 4.8 P = 0.001* P = 0.763 P = 0.569 P = 0.856 P = 0.001* *P , 0.05. HC, healthy controls; OCT, optical coherence tomography; PD, Parkinson disease; RNFL, retinal nerve fiber layer; SD, spectral domain; TD, time domain. 64 Kirbas et al: J Neuro-Ophthalmol 2013; 33: 62-65 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. extending the range of action potentials over many microns. The net effect is a reduction in gap junction permeability with rising DA concentrations and a resultant reduction in receptive field size. In addition to this highly variable excitatory and inhibitory feedback system, there is a more "tonic" diurnal variation in retinal DA concentration, with low levels at night and higher levels during the day. This circadian rhythm is in counterphase with the concentrations of melatonin, with DA and melatonin having mutually inhibitory effects on each other's production, acting as a "biological clock" for the retina. DA is a chemical messenger for light adaptation, promoting the flow of information through cone circuits while diminish-ing that through rod circuits (1,6,13). Retinal signaling occurs in 2 directions, vertically and horizontally. Vertical neurotransmission takes place predom-inantly from photoreceptor to bipolar cell to RGC, and it is the RGC that acts as the final common pathway in the flow of visual information to the optic nerve. The principal neurotransmitter of the vertical system is glutamate, in general terms, acting via excitatory ionotropic and inhibitory metabotropic glutamate receptors. Horizontal transmission involving horizontal and amacrine cells is mediated primar-ily by the inhibitory transmitters, GABA and glycine, in addition to electrical gap junctions. Signal transmission occurs on a one-to-one basis for cone-to-midget bipolar cell-to-midget ganglion cell in the central fovea, facilitating high acuity and color vision (1,6,14). Retinal DA deficiency is believed to alter visual processing by modification of receptive field properties of ganglion cells, whose axons form the RNFL. It is noteworthy that when a color vision abnormality is detected in patients with PD, it usually in-volves blue-sensitive cones (1,5,6). Visual impairment is also observed in the animal model of PD using 1-methyl,4-phenyl,1-2-3-6-tetrahydropyridine. The retina shows dopaminergic deficiency with loss of a subset of ret-inal amacrine cells that provide input to RGCs (12,15). Investigating the underlying cause of vision impairment in patients with PD requires further study. Examining the RNFL thickness with larger patient cohorts using SD-OCT is needed to confirm our findings. Evaluation of macular thickness and volume in PD patients has yet to be done. Finally, demonstrating progressive thinning of RNFL over time in neurodegenerative disorders will be critical for validating OCT technology as a viable biomarker. REFERENCES 1. 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