Evaluation of Retinal Changes in Progressive Supranuclear Palsy and Parkinson Disease

Differentiating Parkinson disease (PD) from progressive supranuclear palsy (PSP) can be challenging early in the clinical course. The aim of our study was to see if specific retinal changes could serve as a distinguishing feature. We used spectral domain optical coherence tomography (SD-OCT) with automatic segmentation to measure peripapillary nerve fiber layer thickness and the thickness and volume of retinal layers at the macula. Thicknesses of superior peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer, inner plexiform layer, inner nuclear layer, and macular volume were more affected in PSP compared with PD (P < 0.05). Thicker inferotemporal pRNFL and lower macular volume were detected in levodopa users compared with nonusers in patients with PD. PD and PSP are associated with distinct changes in retinal morphology, which can be assessed with SD-OCT.

Original Contribution Evaluation of Retinal Changes in Progressive Supranuclear Palsy and Parkinson Disease Duygu Gulmez Sevim, MD, Metin Unlu, MD, Murat Gultekin, MD, Cagatay Karaca, MD, Meral Mirza, MD, Galip Ertugrul Mirza, MD Background: Differentiating Parkinson disease (PD) from progressive supranuclear palsy (PSP) can be challenging early in the clinical course. The aim of our study was to see if specific retinal changes could serve as a distinguishing feature. Methods: We used spectral domain optical coherence tomography (SD-OCT) with automatic segmentation to measure peripapillary nerve fiber layer thickness and the thickness and volume of retinal layers at the macula. Results: Thicknesses of superior peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer, inner plexiform layer, inner nuclear layer, and macular volume were more affected in PSP compared with PD (P , 0.05). Thicker inferotemporal pRNFL and lower macular volume were detected in levodopa users compared with nonusers in patients with PD. Conclusions: PD and PSP are associated with distinct changes in retinal morphology, which can be assessed with SD-OCT. Journal of Neuro-Ophthalmology 2018;38:151-155 doi: 10.1097/WNO.0000000000000591 © 2017 by North American Neuro-Ophthalmology Society I n Parkinson disease (PD), there is a dopaminergic neural loss in the substantia nigra and dopamine dysfunction in the retina (1,2). Retinal involvement has been detected with optical coherence tomography (OCT) (3), and various changes have been demonstrated in different types of PD Departments of Ophthalmology (DGS, MU, CK, GEM) and Neurology (MG, MM), Faculty of Medicine, Erciyes University, Kayseri, Turkey. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Duygu Gulmez Sevim, MD, Department of Ophthalmology, Faculty of Medicine, Erciyes University, 38039 Kayseri, Turkey; E-mail: [e-mail] Gulmez Sevim et al: J Neuro-Ophthalmol 2018; 38: 151-155 (4,5). This is especially true using single-layer retinal analysis (3,6). There is mention in the literature that specific OCT changes may be able to delineate progressive supranuclear palsy (PSP) from other Parkinsonian syndromes (4,5). The aim of our study was to determine whether there are specific retinal changes detected by OCT that could differentiate patients with PD, PSP, and healthy controls. We also investigated whether the duration of disease and the use of levodopa had any impact on these parameters. METHODS We conducted a nonrandomized prospective study involving patients with PD, PSP, and healthy controls. A single eye was chosen randomly for inclusion in the study. When the image on OCT for measurement, the other eye was included. The diagnosis of PD was made using the UK Parkinson's Disease Society Brain Bank criteria, whereas the Neuroprotection and Natural History In Parkinson Plus Syndrome criteria were used to establish the diagnosis of PSP (7,8). All patients were diagnosed by neurologists specializing in movement disorders (M.G. and M.M.). The patients' usage of levodopa was recorded. Healthy participants of similar age and sex were recruited as controls from volunteers evaluated in the ophthalmology clinic for routine examination and they also were examined by the neurologists and found to be free of neurologic disease. A complete ophthalmic examination was performed on all patients and controls by experienced ophthalmologists (D.G.S. and M.U.). All patients had funduscopy after pupillary dilation. The study was approved by the Institutional Review Board of the Medical School of Erciyes University (No: 2016/24, date: August 1, 2015) and was conducted in accordance with the Helsinki Declaration. Informed consent was obtained from all participants. 151 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Exclusion criteria were: diabetes mellitus, dependency on alcohol, regular smoking, and autoimmune inflammatory diseases of the central nervous system. The patients' eyes with any of the following ophthalmologic pathologies also were excluded: high myopia (. 26.00 diopters), high astigmatism ($3.00 diopters), previous intraocular surgery, or coexisting ocular disease (ie, retinal pathology, glaucoma, shallow anterior chamber, and cataract resulting in poor-quality images). Singlelayer retinal analysis was performed with commercial spectral domain OCT (SD-OCT) (Spectralis; Heidelberg Engineering, Heidelberg, Germany) with a w840-nm wavelength. For SDOCT, only those images with a signal-to-noise score higher than 25 dB were analyzed. Scans with misalignment, segmentation failure, decentration of the measurement circle, and poor illumination or those out of focus were excluded from the analysis. Manual correction of plotting errors of automated segmentation was not performed in this study. Average thicknesses were calculated for peripapillary retinal nerve fiber layer (pRNFL), macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), inner and outer segments of the photoreceptors (PRs), and retinal pigment epithelium (RPE). The results of the paramacular volumetric and different retinal layers measurements were automatically segmented. The measurement of inner retinal layer (IRL) included internal limiting membrane, mRNFL, GCL, and IPL, whereas the outer retinal layer (ORL) consists INL, Henle fiber layer, ONL, and inner and outer segments of the PRs up to the RPE as defined by the SDOCT software (3). To assess the pRNFL, a circular scan with a diameter of approximately 3.4 mm was performed after manually positioning the center on the middle of the optic disc. The pRNFL Spectralis protocol generated a map showing the average thickness and maps with 6 sector thicknesses (superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal) (9). Macular volumes were quantified using the SD-OCT software based on the Early Treatment Diabetic Retinopathy Study protocol. Three retinal volumes were obtained, centered on the foveola with radii of 1.5, 3, and 6 mm. Statistical Analysis All statistical analyses were performed using the IBM SPSS Statistics 22.0 package program (IBM Corp, Armonk, NY). An analysis of variance (ANOVA) was performed. Data were expressed as mean ± SD for metric variables and as frequency (percentage) for categorical variables. Tukey honest significant difference test and Dunnett multiple comparison post hoc tests for comparison of all groups to controls were performed for multiple comparisons in conjunction with a 1-way ANOVA (post hoc analysis). t test was used to compare the OCT parameters of patients with levodopa use or not. Spearman correlation analysis was used to determine the relationships between the duration of the diseases with the OCT parameters. A value of P , 0.05 was determined as statistically significant. RESULTS A total of 72 participants were enrolled in our study (Table 1). The mean disease duration of the PD was 5.3 years (range: 1-25 years) and 3.5 years (range: 1-6 years) for PSP. There was no significant difference regarding the duration of the disease between the groups (P = 0.398). Five patients in the PD group and 4 patients in the PSP group did not have levodopa as their treatment regimen. There was no significant difference in age and sex between the groups (P . 0.05). Patients with PSP showed thinner pRNFL values in all sectors compared with PD group and controls, but this difference only reached statistical significance in the superior quadrant (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A272). The total inner and outer macular volumes of PSP group were significantly less than PD group and controls (P , 0.05). All single retinal layers except RPE showed thinning in the PSP group compared with PD group and controls (Fig. 1). These differences reached statistical significance in GCL, IPL, INL, and IRL (P , 0.05) (see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A273). All measurements of the retinal layers were compared in the PD group between levodopa users and nonusers. The ratio of ONL/OPL was 2.12 ± 0.33 in patients with levodopa use, whereas it was 1.93 ± 0.37 without levodopa use, and this difference was statistically significant (P = 0.023). The average pRNFL thickness in the inferotemporal sector was thinner in levodopa nonusers (121.06 ± 27.38 mm) compared with users (142.41 ± 19.97 mm) (P = 0.009). TABLE 1. Demographic and clinical parameters of patients with Parkinson disease (PD), progressive supranuclear palsy (PSP), and healthy controls N PD PSP Controls 152 Sex Subject Eyes Age, yr M (%) F (%) Duration, yr 29 10 33 29 10 33 57.3 ± 9.9 65.9 ± 6.2 58.9 ± 7.8 16 (55.2) 4 (40) 19 (55.6) 13 (44.8) 6 (60) 14 (44.4) 5.3 ± 5.1 3.5 ± 1.8 - Gulmez Sevim et al: J Neuro-Ophthalmol 2018; 38: 151-155 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Mean values for macular volumes, and significant retinal layer thicknesses for patients with Parkinson disease (PD), progressive supranuclear palsy (PSP), and healthy controls. The duration of disease in the PD group was significantly associated with thinner average pRNFL (P = 0.042) (rho = 0.288) and RPE thickness (P = 0.037) (rho = 0.301), although there was no significant relationship between duration of the disease and ages of the patients (P = 0.331). Gulmez Sevim et al: J Neuro-Ophthalmol 2018; 38: 151-155 In the PSP group, increased age (P = 0.006, rho = 0.593), thinner central corneal thickness (P = 0.042, rho = 20.437), reduced foveal (P = 0.039, rho = 0.472), macular (P = 0.013, rho = 0.552), and inner macular volume (P = 0.017, rho = 0.528), thinner mRNFL (P = 0.014, 153 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution rho = 0.543), ONL (P , 0.001, rho = 0.768), IRL (P = 0.012, rho = 0.547), and ORL (P = 0.010, rho = 0.557) were found to correlate with longer duration of the disease. With ONL and ORL, the correlations with the duration of PSP were found to be significant at the 0.01 level (2-tailed). DISCUSSION Although the difference reached statistical significance only in the superior quadrant, our study demonstrated thinner pRNFL values in all sectors in patients with PSP compared to patients with PD and controls. Albrecht et al (4) also found lower pRNFL values in PSP patients compared with PD patients in all sectors except those located nasally, and they also found that the differences did not reach statistical significance. We also detected thinner retinal segment layers in the PSP group compared with the PD and control groups. However, this only reached statistical significance in the GCL, IPL, INL, and IRL. Previous studies of retinal singlelayer analysis in patients with movement disorders are limited in number and report conflicting results. Using SDOCT with a semiautomatic algorithm, Schneider et al (5) examined the average thickness of retinal layers in 65 PD, 16 PSP, and 12 multiple system atrophy (MSA) patients and 41 matched controls to determine whether there were specific patterns of retinal layer pathology as a potential marker of neurodegeneration. They showed that only patients with PSP and MSA had a significant reduction of retinal layers in comparison with controls. Thickening of the ONL in PSP and of the OPL in MSA was highly specific for these disease entities. They also reported that there were no significant differences in OCT findings between PSP and PD or between the PD and control groups. In our study, the mean disease duration was 3.5 years for PSP and 5.3 years for PD. While the duration of PSP in the report by Schneider et al was similar to ours (3.9 years), their PD duration was longer (8.9 years). The conflicting results could be due to more rapid retinal degeneration in patients with PSP compared with those with PD. In later years of PD, possibly retinal thinning may reach levels similar to the changes seen in the early years of PSP, as Schneider et al demonstrated. We identified significant differences between PSP and PD in certain OCT parameters including GCL, IPL, INL, and IRL and believe that SD-OCT can be useful in the differential diagnosis of PD and PSP. Albrecht et al (4) used SD-OCT with manual segmentation to analyze the thickness of all retinal layers in various movement disorders, including PD (40 patients), MSA (19 patients), corticobasal syndrome (10 patients), and PSP (15 patients), along with 35 age- and sex-matched controls. They found that mean paramacular thickness and volume were reduced in PSP while mean average pRNFL did not 154 differ significantly, similar to our study. They detected opposite changes in ONL (decreased) and OPL (increased) and calculated the ratio between these 2 layers. With a cutoff of 3.1, ONL/OPL ratio was able to differentiate between PSP and PD with a sensitivity of 96% and a specificity of 59%. This enabled the authors to confidently determine a negative likelihood ratio but a rather weak positive likelihood ratio due to the low specificity. To our knowledge, there is no previously established value for a healthy population. In our study, the mean ONL/OPL ratios were 2.04 ± 0.36, 1.95 ± 0.32, and 1.97 ± 0.23 in the PD, PSP, and control groups, respectively, and we did not find a significant difference in ONL/OPL ratios between groups. This difference might be due to the manual segmentation technique used by Albrecht et al, in contrast to automatic segmentation used in our report. Our study revealed a decrease in pRNFL and RPE layer thickness with longer duration of PD. Altintas et al (1) examined the link between retinal morphological and functional findings and clinical severity in patients with PD. They identified a significant reduction in foveal retinal thickness as the total and motor subscores of the Unified PD rating scale increased in patients. In another study where the PD group included early-stage patients (disease duration ,3 years), no difference was detected between the PD group and controls in retinal and pRNFL thicknesses (10). Sari et al (11) found that PD duration was not correlated with any quadrant of pRNFL thickness, but macular ganglion cell-inner plexiform layer thicknesses were inversely correlated with both PD severity and duration, contrary to our findings. Garcia-Martin et al (12) found that the thickness of IRLs to be reduced with disease duration in PD, likely an indicator of axonal damage, especially with GCL reduction. We detected only a reduction of RPE thickness in the retinal layers in the PD group. However, in the PSP group, we found significant reductions in pRNFL, ONL, IRL, and ORL thicknesses and foveal, macular, and inner macular volumes as disease duration increased. This suggests a more rapid progression of retinal degenerative in PSP than in PD. Sen et al (13) found no differences in pRNFL thickness and macular ganglion cell complex layers between patients with PD using levodopa and untreated patients. They suggested that this might be due to levodopa's protective effect on the retina. Yavas et al (14) reported that rim area, rim volume, and pRNFL were significantly greater in the group treated with levodopa and thinnest in the group receiving dopamine agonists. The only difference related to levodopa use that we observed was decreased ONL/OPL ratio in patients without levodopa use compared with those taking the medication. This is consistent with the findings of Albrecht et al (4). Levodopa may protect retinal neurons by increasing the stores of dopamine. All patients in our study had normal visual acuity. Yet patients with PD frequently complain of impaired visual Gulmez Sevim et al: J Neuro-Ophthalmol 2018; 38: 151-155 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution function which may, in part, be due to decreased contrast sensitivity, abnormal color vision, and impaired spatial processing (15). Many of these functions are mediated by dopamine. Yet our results support the previous observation that retinal thinning occurs before involvement of visual signal transmission (6). This tissue loss is probably associated with dopaminergic amacrine cells and pathologic changes due to synuclein, which is found throughout the retina (16,17). Further studies with assessment of these other parameters of visual performance would likely give use better information regarding visual function in these patients. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: D. G. Sevim, M. Unlu, M. Gultekin, C. Karaca, M. Mirza, and G. E. Mirza; b. Acquisition of data: D. G. Sevim, M. Unlu, and M. Gultekin; c. Analysis and interpretation of data: D. G. Sevim, M. Unlu, M. Gultekin, and C. Karaca. Category 2: a. Drafting the manuscript: D. G. Sevim, M. Unlu, and M. Gultekin; b. Revising it for intellectual content: D. G. Sevim, M. Unlu, M. Gultekin, C. Karaca, M. Mirza, and G. E. Mirza. Category 3: a. Final approval of the completed manuscript: D. G. Sevim, M. Unlu, M. Gultekin, C. Karaca, M. Mirza, and G. E. Mirza. REFERENCES 1. Altintas O, Iseri P, Ozkan B, Caglar Y. 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