Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive loss of selective dopaminergic neurons, mainly in the nigrostriatal pathway (1). Clinical manifestations include comprised movement alterations and nonmotor symptoms such as dementia, depression, and autonomic dysfunction (2). Visual symptoms also are common among the nonmotor symptoms in patients with PD and manifest as visual acuity loss and reduced color discrimination and contrast sensitivity (3). Recognition of the nonmotor symptoms has gained importance in understanding the pathophysiology and early diagnosis of the disease (4).
It has been shown that the human retina contains dopaminergic amacrine cells, which provide visual input to the retinal ganglion cells through their rich interconnections in the inner plexiform layer (5). Ganglion cells act as the final common pathway in the flow of visual information to the optic nerve through the retinal nerve fiber layer (RNFL) (6). Retinal cells that produce the dopamine precursor (levodopa) seem to be reduced in patients with PD, leading to the thinning of the inner retinal layers, including the RNFL and the ganglion cell–inner plexiform layer (GC-IPL) (7).
The introduction of spectral domain optical coherence tomography (SD-OCT) has allowed detailed analysis of retinal structure and quantitative maps of retinal thickness with high spatial resolution (8). Although many studies have demonstrated peripapillary RNFL thinning in patients with PD using SD-OCT (4,7,9), the pathogenesis of disease involves degeneration of not only axons but also cell bodies and dendrites. Therefore, a more useful measure would be the thickness profile of the retinal GC-IPL. To date, there are few reports of measurements of ganglion cell layer thickness in patients with PD (10,11), all of which focus on average thickness. The Cirrus SD-OCT (Carl Zeiss Meditec Inc., Dublin, CA) macular GC-IPL thickness algorithm has the advantage of segmenting the layers automatically and provides 8-parameter measurements rather than average thickness alone. This option allows objective comparison and parameter selection.
The purpose of our study is to evaluate the thickness of macular GC-IPL and peripapillary RNFL in different sectors in patients with PD compared with age-matched controls. In addition, we assessed whether thickness parameters correlated with disease duration and severity. The latter is based on the Hoehn and Yahr (HY) scale.
This prospective and observational study adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee. All subjects provided informed consent to participate in the study. Consecutive patients diagnosed with PD and age-matched healthy controls were recruited from the Neurology Department in our hospital. Randomly selected eyes of all subjects were included in the study. All subjects underwent neurologic and ophthalmic examination, including best-corrected Snellen visual acuity (BCVA), intraocular pressure (IOP), and dilated ophthalmoscopy. The required inclusion criteria were as follows: BCVA of 20/40 or better; refractive error within ±5.00 diopters (D), (spheric equivalent) and 2.00 D astigmatism. Exclusion criteria were corneal opacity or cataract formation (nuclear color/opalescence and cortical or posterior subcapsular lens opacity >1, according to the Lens Opacities Classification System III system), glaucoma, history of previous intraocular surgery, diabetes, or other diseases or medications that affect vision, the visual field, or any portions of the neuro-ophthalmic system. The diagnosis of PD was based on criteria from the United Kingdom Parkinson Disease Society Brain Bank (12), and all patients were clinically stable on medical therapy. Medical records of patients with PD were reviewed, including duration and severity of disease. Disease severity was evaluated according to the HY scale by 1 neurologist (R.K.). The HY scale (13) is widely used to categorize the progression of PD symptoms and quantify the patients according to 5 stages. The first stage represents the early phase of the disease and is characterized by symptoms, such as tremor, muscle stiffness, slowness of movement, and postural problems, which appear only on 1 side of the body. The fifth stage corresponds to the advanced disease phase, where the patient is immobile and requires total assistance. The neurologist was masked to the results of optical coherence tomography (OCT) examinations.
Optical Coherence Tomography
All examinations were performed by the same physician with the Cirrus HD-OCT Model 4000 (Carl Zeiss Meditec Inc.,). Two scans obtained from each patient were averaged. In all cases, the pupil was dilated before the examination with tropicamide 1% (Tropamid; Bilim, Istanbul, Turkey). While performing the OCT, the pupil was centered and focused in the iris viewport. The autofocus mode was used to obtain an optimized view of the retina with the line-scanning ophthalmoscope. To maximize the OCT signal, the Z-offset was optimized with the center mode and the scan polarization was optimized with the enhance mode. Motion artifacts that were detected by vascular discontinuity in the overlay images of the line-scanning ophthalmoscope, and OCT were avoided by repeated scanning. GCL-IPL thickness was calculated with the macular cube 512 × 128 analysis protocol. The macular GCL-IPL thickness was measured within a 14.13-mm2 elliptical annulus area centered on the fovea, which has the following dimensions: vertical inner and outer radius of 0.5 and 2.0 mm, respectively, and horizontal inner and outer radius of 0.6 and 2.4 mm, respectively. The average, minimum, and 6-sectoral (superior, superotemporal, superonasal, inferonasal, inferior, and inferotemporal) GC-IPL thickness values were obtained from this elliptical annulus. Average and 4-sectoral (inferior, superior, temporal, and nasal) peripapillary RNFL thickness was evaluated using a previously described protocol (14). For GC-IPL and RNFL measurements, only SD-OCT scans with a signal strength of at least 6/10 were analyzed. Any image with inadequate fixation due to head movements or postural instability was re-evaluated. If the OCT examination could not be completed for any patient with PD after several attempts, they were excluded from the study.
Data was calculated as mean ± SD (range). One eye from each subject was randomly selected for the analyses. The SPSS statistics software package version 15.0 for Windows (SPSS, Chicago, IL) was used for statistical analysis. Normality of all data samples was checked by means of the Kolmogorov–Smirnov test. When parametric analysis was possible, the Student t test for paired data was performed in all parameter comparisons between patients with PD and age-matched healthy controls. When parametric analysis was not possible, the Wilcoxon rank-sum test was used. In addition, correlation coefficients (Pearson or Spearman depending on whether normality condition could be assumed) were calculated to assess the correlation between SD-OCT measurements and PD severity and duration. Intraclass correlation coefficient (ICC) also was performed for interobserver and intraobserver reliabilities. A P value less than 0.05 was considered statistically significant.
Initially, 59 consecutive patients with PD were recruited. Three patients with stage 5 and 2 patients with stage 4 disease who could not complete OCT examination due to inadequate fixation were excluded from the study. Therefore, 54 eyes of 54 patients with PD (30 men and 24 women), with a mean age of 66.62 ± 8.71 years (range, 50–81 y) and 54 eyes of 54 patients (28 men and 26 women) with a mean age of 66.68 ± 7.85 years (50–81 y) were included in the study. Disease duration ranged from 1 to 15 years with a mean of 5.12 years. The mean PD severity according to the HY scale was 2.26; 14 patients (25.9%) stage 1, 22 patients (40.8%) stage 2, 10 patients (18.5%) stage 3, 6 patients (11.1%) stage 4, and 2 patients (3.7%) stage 5. There was no statistically significant difference between the patient cohort and healthy controls in terms of age, gender, BCVA, and IOP (Table 1).
The intraobserver and interobserver reliabilities for SD-OCT examination were assessed with ICC, and the values were between 0.997 and 0.974 with high reproducibility. The differences in peripapillary RNFL thickness between patients with PD and age-matched healthy controls are shown in Table 2. SD-OCT measurements revealed significant differences only in inferior and temporal peripapillary RNFL values between groups (P = 0.018 and P = 0.031, respectively). Average peripapillary RNFL thickness did not significantly differ between the groups (P = 0.245). Average, minimum, and 6-sectoral GC-IPL thicknesses were also analyzed in this study (Table 2). All GC-IPL thickness parameters were statistically lower in the patients with PD when compared with the healthy controls (P < 0.001). Figures E1 and E2, Supplemental Digital Contents, http://links.lww.com/WNO/A122; http://links.lww.com/WNO/A123 show the GC-IPL thickness analyses of a patient with PD and a control subject, respectively.
Correlation analyses are shown in Table 3. Disease severity was correlated directly with disease duration (r = 0.332, P = 0.007). Disease duration was not correlated to any of the RNFL thicknesses, but it was inversely correlated with average (P = 0.001), inferior (P < 0.001), inferotemporal (P = 0.004), and superotemporal (P = 0.010) GC-IPL thicknesses. Disease severity was correlated inversely with inferior peripapillary RNFL thickness (P = 0.006). Average (P = 0.019), inferior (P = 0.011), inferotemporal (P = 0.007), and superotemporal (P = 0.007) GC-IPL thicknesses were also inversely correlated with disease severity.
A progressive retinal dopominergic degeneration causes the loss of retinal amacrine cells that provide input to retinal ganglion cells (6). Macular GC-IPL thickness, which can be directly affected in PD, is a relatively new parameter that accurately reflects the thicknesses of macular ganglion cells and their axons. In this study, we found that average, minimum, and 6-sectoral macular GC-IPL thickness measurements within the macula in patients with PD and performed the correlation analyses between the measurements and disease severity and duration.
In 2004, RNFL damage in PD was first demonstrated by Inzelberg et al (9). The authors showed a reduction in the inferotemporal peripapillary RNFL thickness, which was topographically matched to the visual field defects in a small number of patients. Some subsequent studies reported evidence of peripapillary RNFL thinning in patients with PD (15,16), although others did not (17,18). Moschos et al (16) found decreased inferior and temporal peripapillary RNFL thicknesses, and no difference in mean RNFL thickness in 32 eyes of 16 patients with PD compared with controls. In accordance with previous investigations, our findings revealed significant differences only in inferior and temporal peripapillary RNFL values between both groups. Average RNFL thickness was lower in patients with PD than in healthy controls but did not reach statistical significance.
Foveal and perifoveal thickness measurements have previously been used to estimate ganglion cell degeneration in patients with PD (15,19), because approximately 50% of the ganglion cells are localized within the 4.5 mm of the fovea (20). It is now possible to directly measure ganglion cell bodies and their dendrites with the GC-IPL analysis: program of the Cirrus SD-OCT device (21). Yet there are very few reports of GC-IPL measurements in patients with PD (7,11). Adam et al (11) investigated the internal retinal layer (RNFL + GC-IPL) thickness in 14 eyes of 28 patients with PD and observed significant differences between groups in the nasal, superior, temporal, and inferior quadrants of perifoveal locations. Hajee et al (7) also evaluated internal retinal layer thickness in 46 eyes of 23 patients with PD with the same device and reported similar results. More recently, Garcia-Martin et al (10) examined the thickness of 10 retinal layers using an average value of macular thickness and demonstrated that the average ganglion cell layer thickness was significantly reduced in the PD group. In all of these studies, sectoral analyses of GC-IPL thickness were not provided. In our study, average, minimum, and 6-sectoral thicknesses were measured, and all GC-IPL thickness parameters were statistically significantly lower in the patients with PD when compared with healthy controls. In contrast to peripapillary RNFL thickness measurements, GC-IPL thickness is reduced globally in patients with PD without any specific sectoral preference.
The question arises whether the thickness of retinal layers correlates with the severity and duration of disease. Altintas et al (15) showed a correlation of disease severity with inner foveal thickness but not with peripapillary RNFL thickness in 17 patients with PD. Another study with 52 patients reported that the average and RNFL quadrants, except the nasal sector, were significantly correlated with disease severity (22). These authors found that average, inferior, and nasal peripapillary RNFL thinning were the parameters, which correlated with disease duration. In this study, an inverse correlation was observed between inferior peripapillary RNFL thickness and PD severity, but no correlation existed for disease duration and any of the peripapillary RNFL parameters. Only 1 previous study specifically examined GC-IPL measurements and their correlation in patients with PD. Garcia-Martin et al (10) found that the average ganglion cell layer correlated inversely with HY scale and disease duration. However, that study did not provide sectoral analyses of GC-IPL thickness. We performed correlation analyses with 8 different GC-IPL parameters. Average, inferior, inferotemporal, and superotemporal GC-IPL thicknesses were inversely correlated with disease severity; similar results were observed regarding disease duration. It is difficult to speculate why the significant correlation was not observed in all sectors.
Laboratory studies in both human (23) and monkey (24) eyes have shown that in the macular area, inferior and temporal sectors have the thinnest GC-IPL thickness followed by the superior and nasal sectors, respectively. Interestingly, the inferior and temporal sectors were those found to be correlated with disease severity in this study. However, it is possible that our results might be biased due to the relatively small sample size.
Some limitations of this study must be addressed. First, our PD group consisted of patients in relatively early stages of the disease. The patients with PD in advanced stages often have impaired quality of OCT examinations and, therefore, such patients were excluded, possibly leading to selection bias. Second, the physician performing OCT was not masked because disease symptoms are evident.
In conclusion, we observed that macular GC-IPL thickness was significantly lower in patients with PD than controls. This may be due to loss of dopaminergic amacrine cell dendrites suggesting dopaminergic neurodegeneration. Macular GC-IPL thickness also correlated with disease severity and duration. Accordingly, macular GC-IPL measurements with SD-OCT may be a useful tool in the following patients with PD. Further large cohort studies are needed to possibly detect predictive parameters leading to early diagnosis of PD, before the appearance of serious motor and nonmotor impairment in PD.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: E. S. Sari and A. Yazici; b. Acquisition of data: E. S. Sari, A. Yazici, and R. Koç; c. Analysis and interpretation of data: E. S. Sari, A. Yazici, G. Sahin, and S. S. Ermis. Category 2: a. Drafting the article: E. S. Sari and A. Yazici; b. Revising it for intellectual content: E. S. Sari, A. Yazici, and R. Koc. Category 3: a. Final approval of the completed article: E. S. Sari, A. Yazici, and R. Koc.
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