February 2014
Volume 55, Issue 2
Free
Visual Neuroscience  |   February 2014
Electrophysiology and Optical Coherence Tomography to Evaluate Parkinson Disease Severity
Author Affiliations & Notes
  • Elena Garcia-Martin
    Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain
    Aragones Institute of Health Sciences, Zaragoza, Spain
  • Diego Rodriguez-Mena
    Aragones Institute of Health Sciences, Zaragoza, Spain
    Neurophysiology Department, Miguel Servet University Hospital, Zaragoza, Spain
  • Maria Satue
    Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain
    Aragones Institute of Health Sciences, Zaragoza, Spain
  • Carmen Almarcegui
    Aragones Institute of Health Sciences, Zaragoza, Spain
    Neurophysiology Department, Miguel Servet University Hospital, Zaragoza, Spain
  • Isabel Dolz
    Aragones Institute of Health Sciences, Zaragoza, Spain
    Neurophysiology Department, Miguel Servet University Hospital, Zaragoza, Spain
  • Raquel Alarcia
    Aragones Institute of Health Sciences, Zaragoza, Spain
    Neurology Department, Miguel Servet University Hospital, Zaragoza, Spain
  • Maria Seral
    Aragones Institute of Health Sciences, Zaragoza, Spain
    Neurology Department, Miguel Servet University Hospital, Zaragoza, Spain
  • Vicente Polo
    Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain
    Aragones Institute of Health Sciences, Zaragoza, Spain
  • Jose M. Larrosa
    Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain
    Aragones Institute of Health Sciences, Zaragoza, Spain
  • Luis E. Pablo
    Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain
    Aragones Institute of Health Sciences, Zaragoza, Spain
  • Correspondence: Elena Garcia-Martin, Calle Padre Arrupe, Consultas externas de oftalmología, 50009. Zaragoza, Spain; egmvivax@yahoo.com
Investigative Ophthalmology & Visual Science February 2014, Vol.55, 696-705. doi:10.1167/iovs.13-13062
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      Elena Garcia-Martin, Diego Rodriguez-Mena, Maria Satue, Carmen Almarcegui, Isabel Dolz, Raquel Alarcia, Maria Seral, Vicente Polo, Jose M. Larrosa, Luis E. Pablo; Electrophysiology and Optical Coherence Tomography to Evaluate Parkinson Disease Severity. Invest. Ophthalmol. Vis. Sci. 2014;55(2):696-705. doi: 10.1167/iovs.13-13062.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To evaluate correlations between visual evoked potentials (VEP), pattern electroretinogram (PERG), and macular and retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) and the severity of Parkinson disease (PD).

Methods.: Forty-six PD patients and 33 age and sex-matched healthy controls were enrolled, and underwent VEP, PERG, and OCT measurements of macular and RNFL thicknesses, and evaluation of PD severity using the Hoehn and Yahr scale to measure PD symptom progression, the Schwab and England Activities of Daily Living Scale (SE-ADL) to evaluate patient quality of life (QOL), and disease duration. Logistical regression was performed to analyze which measures, if any, could predict PD symptom progression or effect on QOL.

Results.: Visual functional parameters (best corrected visual acuity, mean deviation of visual field, PERG positive (P) component at 50 ms -P50- and negative (N) component at 95 ms -N95- component amplitude, and PERG P50 component latency) and structural parameters (OCT measurements of RNFL and retinal thickness) were decreased in PD patients compared with healthy controls. OCT measurements were significantly negatively correlated with the Hoehn and Yahr scale, and significantly positively correlated with the SE-ADL scale. Based on logistical regression analysis, fovea thickness provided by OCT equipment predicted PD severity, and QOL and amplitude of the PERG N95 component predicted a lower SE-ADL score.

Conclusions.: Patients with greater damage in the RNFL tend to have lower QOL and more severe PD symptoms. Foveal thicknesses and the PERG N95 component provide good biomarkers for predicting QOL and disease severity.

Introduction
Parkinson disease (PD) is a neurodegenerative disorder resulting from pathologic changes in the dopaminergic neurons of the substantia nigra. 1 The cardinal motor symptoms of PD result primarily from the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, which leads to a severe depletion of dopamine in the striatum. 2  
The number of dopaminergic neurons throughout the brain, including areas such as the dopaminergic amacrine cells and the retinal ganglion cells, is greatly reduced in patients with PD. Levodopa, a dopamine precursor, is released by cells in the human RPE as an intermediate product in the melanin biosynthetic pathway. 3,4 The dopamine loss in PD patients may be due in part to thinning of the RPE. 5 The RPE can be measured using digital imaging technologies such as optical coherence tomography (OCT), which provide cross-sectional images of the retina and the optic disc in a noninvasive, rapid, objective, and reproducible manner for the evaluation of eye structure thickness and volume. 6,7 OCT is used to detect and measure ganglion cell loss in neurodegenerative diseases such as multiple sclerosis 8 and PD, 7 and is considered a useful tool for evaluating the retinal nerve fiber layer (RNFL) and the retinal layers (including the RPE) in several systemic and ophthalmic diseases. 9,10  
Foveal vision is one of the affected nonmotor systems in PD. Decreased contrast sensitivity and color vision, and altered visual evoked potentials (VEP) have been reported in PD patients. 11,12 The foveal vision alterations seem to be caused by dysfunction of the intraretinal dopaminergic circuitry and the final retinal output to the brain. 11 The visual pathway can be structurally evaluated using digital ocular imaging technologies such as OCT, and functionally evaluated using VEP and pattern electroretinograms (PERG). 13 Delayed VEP are reported in PD patients. 14 Early abnormalities in amplitude and latency in PERG, 15 as well as a specific distorted PERG spatial frequency response function and consequently attenuated PERG tuning ratio are observed in PD patients. 16 Although the precise origin of the PERG abnormalities has yet to be fully elucidated, current evidence suggests that the negative (N) component at 95 ms (N95) component is generated mainly by retinal ganglion cells. 17 The positive (P) component at 50 ms (P50) component is partly ganglion cell-derived, but the posterior visual pathway also affects this component. 18 Correlations between RNFL morphology and neurophysiology are also reported. 19,20  
Consideration of patient quality of life (QOL) is intrinsic to the practice of medicine, particularly when evaluating therapeutic approaches to chronic disease. 21 In PD, fatigue and fatigability levels are higher than in healthy individuals, and are negatively associated with QOL scores. 22 Long-term preservation of health-related QOL is a critical marker of therapeutic success in patients with chronic debilitating diseases. QOL measures take into account almost every aspect of a patient's existence, including their perception of the treatment benefit and functional deficits due to disease progression. In clinical practice, the use of health-related QOL instruments such as the Schwab and England Activities of Daily Living Scale (SE-ADL) enhance patient-physician communication. 23  
The Hoehn and Yahr scale is commonly used to describe the progression of PD symptoms 24,25 and categorizes PD into five stages: The first stage is the mildest phase of the disease (main symptoms—tremor, muscle stiffness, slowness of movement, and problems with posture—are only on one side of the body); and stage five is the worst (the patient is confined to a wheelchair or bed and requires total assistance). The SE-ADL scale is a means of assessing a person's ability to perform daily activities in terms of speed and independence through a percentage figure. The rating can be determined by the professional or by the person being tested according to the following criteria, with 100% indicating total independence, falling to 0%, which indicates a state of complete dependence. 26  
Several studies report the loss of RNFL and macular thickness in PD patients 6,7 and correlations between axonal loss in the optic nerve and functional disability in other neurodegenerative diseases, 27 but to date there are no reports of correlations between functional and structural alterations in the RNFL or macular thickness and decreased QOL scores or increased PD symptoms. In the present study, we analyzed the alterations in structural and functional parameters in PD patients, and the association between these parameters, health-related QOL scores, and symptom severity. 
Given the need to improve the diagnostic procedures and functional aspects of PD, the aim of this study was to evaluate the ability of OCT, VEP, and PERG as methods for detecting PD severity, symptom progression, or QOL decrease in patients with PD. 
Methods
Participants
Seventy-nine study participants were enrolled. Inclusion criteria were as follows: best-corrected visual acuity of 20/40 or better, refractive error within ±5.00 diopters (D) equivalent sphere and ±2.00 D astigmatism, and transparent ocular media (nuclear color/opalescence, cortical or posterior subcapsular lens opacity < 1) according to the Lens Opacities Classification System III system. 28 Exclusion criteria included: neurologic: other neurologic diseases; ophthalmologic: previous intraocular surgery, diabetes, or other diseases that affect the visual field, and current use of medications that affect visual function. Only one eye from each subject was randomly included in the study. 
Two independent samples of consecutive 46 idiopathic PD patients and 33 age and sex-matched healthy individuals were prospectively recruited from two clinics (one ophthalmologist and one neurologist) in the hospital area. The diagnosis of PD was based on criteria from the United Kingdom Parkinson's Disease Society Brain Bank and the United States National Institute of Neurological Disorders and Stroke: slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. In addition, three or more of the following features during onset or evolution were required: unilateral onset, tremor at rest, progression over time, asymmetry of motor symptoms, response to levodopa for at least 5 years, clinical course of at least 10 years, and appearance of dyskinesia induced by the intake of excessive levodopa. 29 Related medical information was carefully obtained from the records, including the duration of the disease and treatment. All patients presented with early or moderate disease and received treatment. 
Subjects referred for refraction that underwent routine examination without abnormal ocular findings were recruited as normal eye controls. A total of 33 eyes of subjects of white European origin were included in the statistical analysis. 
Standard Protocol Approval, Registration, and Patient Consent
All procedures adhered to the tenets of the Declaration of Helsinki, and local ethics committees approved the study protocol. All subjects provided written consent to participate in the study. 
Main Outcome Measures
All participants underwent a full neuro-ophthalmologic examination, including clinical history, best-corrected visual acuity, biomicroscopy of the anterior segment using a slit lamp, Goldmann applanation tonometry, and ophthalmoscopy of the posterior segment. At least one reliable standard automated perimetry test per eye was performed using an automated visual field analyzer (Humphrey Field Analyzer model 750i; Zeiss Humphrey Systems, Dublin, CA), with the Swedish Interactive Threshold Algorithm (SITA) Standard 30-2 strategy. If fixation losses were greater than 15% and false-positive or false-negative rates were greater than 20%, the test was repeated. 30 The subjects completed the perimetry tests before any clinical examination or structural test was performed. The perimetry was used to detect patients with neurologic alterations that affect vision, such as cerebrovascular accidents or hypophyseal tumors. Patients with these neurologic alterations were excluded from the study. 
We obtained peripapillary RNFL measurements and retinal thicknesses using OCT devices (Cirrus; Carl Zeiss Meditec, Inc., Jena, Germany; and Spectralis; Heidelberg Engineering GmbH, Carlsbad, CA) in random order to prevent fatigue bias. The same experienced operator performed all scans and did not apply manual correction to the OCT output. We used an internal fixation target because it provides the highest reproducibility and rejected poor quality scans prior to data analysis. 8 RNFL measurements: Using Cirrus OCT, we assessed mean RNFL thickness, and quadrant RNFL thicknesses (superior, inferior, temporal, and nasal). With the Spectralis OCT, we used the new analytics software (Nsite Axonal Analytics; Heidelberg Engineering GmbH) incorporating the fovea-to-disc technology (FoDi; Heidelberg Engineering GmbH) that correctly orients the anatomy for papillomacular bundle measurement accuracy and minimizes variability due to patient head orientation and comparison to the normative data. The RNFL-N Spectralis protocol generates a map showing the mean thickness; six-sector thicknesses (superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal in the clockwise direction for the right eye and counterclockwise for the left eye); and two new neuro-ophthalmologic parameters: the papillomacular bundle thickness and the nasal/temporal ratio. Retinal thickness map analysis of both OCT devices (Cirrus and Spectralis) generates a map showing measurements for each of the nine subfields, as defined by the Early Treatment Diabetic Retinopathy Study. 31 The Early Treatment Diabetic Retinopathy Study areas include the central 1-mm disc representing the foveal area, and the inner and outer rings measured at diameters of 2.2 mm and 3.45 mm from the center of the fovea. The inner and outer rings are divided into four quadrants: superior, nasal, inferior, and temporal. 32 Manual measurements of the thickness in the center of the fovea were obtained using the Spectralis cursor tool in the retinal map. 
Study investigators recorded VEPs with electrodes fixed (with collodion) at midoccipital and midfrontal locations, and using Cz as ground with a neurophysiology device for VEP and ERG record (Neuronic SenseWitness 4.0; Neuronic, Zaragoza Spain) in a dark room and with full refraction correction if necessary. We used monocular stimulation, and visual stimuli followed a checkerboard pattern (contrast, 80%; check size, 30′; mean luminance, 93 cd/m2) and reversed contrast patterns with a frequency of 1 Hz. Transient VEP response was characterized by the number of waves with three successive peaks of negative, positive, and negative polarity. In normal subjects, these peaks have latencies of 75, 100, and 145 ms (N75, P100, N145), respectively. Latency and peak-to-peak amplitude were recorded for the P100 wave. We obtained at least 2 records of 100 events and calculated the mean amplitude. 
PERGs were obtained using a neurophysiology device for VEP and ERG record (Neuronic) and following the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. 33 Stimuli were checkerboard patterns with a check size of 30 minutes of visual angle (min arc; contrast 90%; mean luminance, 93 cd/m2). Smaller sizes would have required perfect visual acuities in all subjects, which was not the case. On the other hand, larger sizes were not necessary for our subjects. The bioelectric signal was recorded through fiber corneal electrodes, as described by Dawson, Trick, and Litzkow (DTL) for clinical electroretinography. 34 Anesthetics were not necessary as DTL electrode placement is not painful. The DTL was draped horizontally across the cornea at the level of the lower lid. The reference electrode was positioned at the outer canthus and the ground at Fpz. Pattern reversals occurred at a frequency of 2 Hz. Stimulation was binocular. A satisfactory PERG usually requires a mean of 100 reversals, with a minimum of two trials. The evaluated parameters were N95 and P50 amplitudes and latencies, and the N95/P50 ratio. 
Disease severity was rated according to the Hoehn and Yahr scale and effect on QOL was evaluated using the SE-ADL scale. One neurologist performed both the Hoehn and Yahr and the SE-ADL evaluations. 35 The neurologists were blind regarding the results obtained by one another in the OCT, PEV, and PERG, and were previously trained on how to apply the scales. 
The patients were treated with the following groups of drugs (some patients received several treatments or drugs of different groups): 
  1.  
    Group 1—“Drugs that enhance levels of dopamine”: 5 patients (10.9%) received treatment with rasagiline (Azilect; H. Lundbeck A/S, Valby, Denmark); 3 patients (6.5%) received a combination of benserazide and levodopa (Madopar; Hoffmann-La Roche Ltd., Basel, Switzerland); 13 patients (28.3%) received a combination of carbidopa and levodopa (Sinemet; Merck & Co., Inc., Whitehouse Station, NJ); and 15 patients (32.6%) received a combination of carbidopa, levodopa, and entacapone (Stalevo; Novartis AG, Basel, Switzerland).
  2.  
    Group 2—“Dopamine agonists”: 15 patients (32.6%) received treatment with pramipexole (Mirapexin; Boehringer Ingelheim GmbH, Ingelheim, Germany) and 4 patients (8.7%) received ropinirole (Requip; GlaxoSmithKline plc, London, UK).
  3.  
    Group 3—“Drugs with no dopaminergic effects”: 2 patients (4.3%) received propranolol (Sumial; Icaro Laboratories, Inc., Madrid, Spain) and 2 patients (4.3%) received amitriptyline (Tryptizol; ROVI Pharmaceutics, Inc., Madrid, Spain).
“Drugs that enhance levels of dopamine” was the most prescribed category (78.6% of patients) and combination therapy with levodopa, carbidopa, and entacapone was the most frequent treatment (32.6%). 
Statistical Analysis
This was an observational, prospective cross-sectional study. All data analyses were performed using statistical software (SPSS version 20.0; IBM Corporation, Armonk, NY). The Kolmogorov-Smirnov test was used to assess sample distribution of OCT and for clinical measures. Given the parametric distribution of the data, the parameters between healthy and PD patients were compared using a Student's t-test. Values of P < 0.05 were considered to indicate statistical significance. The linear correlation between retinal and RNFL structural and functional parameters and Hoehn and Yahr and SE-ADL scales was determined using the Pearson correlation coefficient. The level of statistical significance for multiple comparisons was adjusted to 0.017 using the Bonferroni test. We performed a regression analysis to identify retinal and RNFL parameters that were predictors of QOL or more severe symptoms in PD patients. We used the change in QOL (SE-ADL punctuation from ≥80 to 80) and change in PD severity (Hoehn and Yahr punctuation from 0–1 to 2–4) during follow-up. Correlation analysis between disease stage (using Hoehn and Yahr punctuation) and VEP latency was performed. 
Results
Epidemiologic and disease characteristics of patients with PD and healthy subjects are shown in Table 1. The two groups did not differ significantly in age, sex, or intraocular pressure. The PD group included 29 men and 17 women with a mean age of 70.72 ± 7.88 years (range, 55–88 years). The duration of PD ranged from 6 months to 17 years, with a median of 7.7 years since diagnosis. 
Table 1
 
Epidemiologic, Disease Characteristics, and Functional Parameters of PD Patients and Healthy Subjects, and P
Table 1
 
Epidemiologic, Disease Characteristics, and Functional Parameters of PD Patients and Healthy Subjects, and P
Parkinson Disease Eyes Healthy Eyes P
Number, n 46 33
Age, y, mean (range) 70.72 (55−88) 69.67 (58−87) 0.544
Men:women (% men) 29:17 (63%) 21:12 (64%) 0.660
Intraocular pressure, mm Hg, mean (SD) 14.2 (1.6) 14.0 (1.5) 0.369
BCVA, Snellen scale, mean (SD) 0.72 (0.2) 0.86 (0.2) 0.013
MD, dB, mean (SD) −5.8 (3.1) −1.81 (1.8) <0.001
VEP P100, amplitude, mV (SD) 11.9 (4.5) 12.5 (4.4) 0.555
VEP P100, latency, ms (SD) 115.3 (8.2) 112.9 (7.8) 0.210
PERG P50, amplitude, mV (SD) 3.64 (0.9) 4.51 (0.9) <0.001
PERG P50, latency, ms (SD) 55.7 (3.2) 53.9 (2.5) 0.010
PERG N95, amplitude, mV (SD) 6.3 (1.5) 7.6 (1.3) <0.001
PERG N95, latency, ms (SD) 100.8 (6.1) 100.0 (8.2) 0.653
PERG N95/P50 ratio (SD) 1.8 (0.2) 1.7 (0.2) 0.330
Disease duration, y, mean (SD) 7.7 (2.1)
Hoehn and Yahr scale (SD) 2.2 (0.8)
SE-ADL scale (SD) 78.0 (24.8)
Functional assessments and significant differences between PD and healthy controls are shown in Table 1. Visual functional parameters (best corrected visual acuity, mean deviation of visual field, amplitude of P50 and N95 components of PERG, and latency of the P50 component of PERG) differed significantly (P < 0.05) between PD patients and healthy controls (Fig. 1). 
Figure 1
 
Representation of latency and amplitude of VEP and PERG in PD patients and healthy subjects. (A) Latencies. (B) Amplitudes.
Figure 1
 
Representation of latency and amplitude of VEP and PERG in PD patients and healthy subjects. (A) Latencies. (B) Amplitudes.
Structural parameters (RNFL and retinal thickness measurements provided by the Cirrus and Spectralis OCT devices) were decreased in PD patients compared with healthy controls in all RNFL measurements except for the nasal quadrant of the Cirrus OCT and the nasal and inferior sectors in the Spectralis OCT (Table 2), and in all retinal thicknesses except for the superior, nasal, and temporal outer areas of the Cirrus OCT and for the inferior and temporal outer areas of the Spectralis OCT (Table 3, Fig. 2). Manual measurements of the thickness in the center of the fovea showed a statistically significant reduction in PD patients compared with healthy subjects (160.12 μm vs. 168.45 μm, respectively; P = 0.003). 
Figure 2
 
Representation of retinal and retinal nerve fiber layer measurements in PD patients and healthy subjects. (A) Retinal measurements using Cirrus and Spectralis OCT. (B) RNFL measurements using Cirrus and Spectralis OCT.
Figure 2
 
Representation of retinal and retinal nerve fiber layer measurements in PD patients and healthy subjects. (A) Retinal measurements using Cirrus and Spectralis OCT. (B) RNFL measurements using Cirrus and Spectralis OCT.
Table 2
 
Mean and Standard Deviation of RNFL Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Table 2
 
Mean and Standard Deviation of RNFL Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Parkinson Patients Healthy Subjects P
Cirrus OCT parameters (SD)
 Mean thickness 92.62 (8.5) 94.66 (8.5) 0.001
 Superior thickness 113.33 (13.0) 115.80 (12.6) 0.006
 Nasal thickness 74.95 (10.3) 75.61 (12.6) 0.126
 Inferior thickness 119.57 (23.7) 121.41 (18.0) 0.002
 Temporal thickness 62.19 (10.5) 66.61 (10.7) <0.001
Axonal Nsite application of Spectralis OCT parameters (SD)
 Mean thickness 97.84 (8.4) 99.43 (10.1) 0.012
 Superior thickness 116.53 (12.7) 118.73 (14.7) 0.009
 Inferior thickness 127.37 (18.7) 128.33 (20.0) 0.266
 Superonasal thickness 105.38 (19.3) 110.42 (16.6) <0.001
 Nasal thickness 78.74 (14.6) 79.35 (15.5) 0.586
 Inferonasal thickness 114.03 (24.1) 118.16 (26.2) <0.001
 Inferotemporal thickness 138.63 (19.9) 140.70 (22.1) 0.036
 Temporal thickness 68.16 (11.2) 72.05 (9.6) 0.006
 Superotemporal thickness 122.68 (17.2) 132.18 (18.0) <0.001
 PMB sector 55.42 (11.2) 57.33 (10.5) 0.045
 N/T index 1.16 (0.3) 1.12 (0.26) 0.003
Table 3
 
Mean and Standard Deviation of Retina Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Table 3
 
Mean and Standard Deviation of Retina Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Parkinson Patients Healthy Subjects P
Cirrus OCT parameters (SD)
 Foveal thickness 257.45 (25.9) 259.10 (29.1) 0.009
 Superior inner thickness 319.48 (14.3) 322.86 (17.5) 0.011
 Nasal inner thickness 320.83 (16.1) 326.62 (18.4) <0.001
 Inferior inner thickness 314.98 (14.4) 318.38 (17.6) <0.001
 Temporal inner thickness 307.38 (17.4) 315.95 (20.9) <0.001
 Superior outer thickness 277.13 (16.4) 277.95 (17.3) 0.155
 Nasal outer thickness 289.25 (21.8) 291.33 (17.7) 0.007
 Inferior outer thickness 267.00 (16.9) 263.05 (17.9) <0.001
 Temporal outer 265.00 (16.6) 266.00 (20.2) 0.058
Spectralis OCT parameters (SD)
 Foveal thickness 270.80 (24.2) 276.63 (24.5) <0.001
 Superior inner thickness 331.95 (16.4) 335.89 (15.6) 0.015
 Nasal inner thickness 335.42 (17.4) 339.35 (15.8) 0.008
 Inferior inner thickness 327.68 (16.6) 329.80 (18.2) 0.020
 Temporal inner thickness 320.95 (15.3) 325.35 (17.8) 0.001
 Superior outer thickness 287.55 (16.8) 289.63 (20.7) 0.032
 Nasal outer thickness 302.41 (17.7) 307.20 (20.4) <0.001
 Inferior outer thickness 278.30 (21.1) 279.08 (16.4) 0.099
 Temporal outer 277.00 (15.9) 278.00 (13.7) 0.125
We conducted a correlation analysis to determine the association between PD severity (provided by Hoehn and Yahr scale); QOL (using SE-ADL scale); or disease duration; and the structural and functional measurements provided by OCT, VEP, PERG, best corrected visual acuity and visual field (Table 4). The Hoehn and Yahr score was strongly negatively correlated with several macular thicknesses (superior and nasal inner areas and nasal outer area of Cirrus OCT, and fovea and all inner areas provided by the Spectralis OCT), as well as with some RNFL measurements provided by the Spectralis OCT (nasal, inferotemporal, temporal, and papillomacular sectors). The SE-ADL scale was strongly correlated with retinal thicknesses, especially with measurements of the foveal and inner areas provided by the Spectralis OCT. Correlations with RNFL thicknesses were also detected, but the association was smaller. In general, reductions in retinal thickness were associated with more severe PD, greater number of symptoms, and reduced quality of life. The disease duration was slightly but significantly correlated with the amplitude and latency of VEP, and with the latency of the N95 component of PERG. No correlations between disease duration and structural parameters were observed (Table 4). The N/T index of Spectralis OCT was positively correlated with the Hoehn and Yahr score and negatively correlated with the SE-ADL score; so damage in the temporal sector was associated with more severe PD symptoms and a lower quality of life in PD patients. 
Table 4
 
Correlation Between Structural and Functional Ophthalmologic Measurements in PD Patients and Disease Duration, Severity, and QOL Parameters
Table 4
 
Correlation Between Structural and Functional Ophthalmologic Measurements in PD Patients and Disease Duration, Severity, and QOL Parameters
Disease Duration, y Hoehn and Yahr Scale, PD Severity SE-ADL Scale, QOL
Functional parameters
 BCVA 0.061 0.189 −0.049
 MD of visual field −0.452 0.328 −0.028
 VEP latency 0.566 0.132 −0.187
 VEP amplitude −0.476 −0.020 −0.067
 PERG P50 latency 0.161 0.486 −0.496
 PERG P50 amplitude 0.224 0.395 −0.324
 PERG N95 latency 0.395 −0.138 0.136
 PERG N95 amplitude 0.216 0.295 −0.212
 PERG N95/P50 ratio −0.080 −0.490 0.491
Structural parameters: RNFL thicknesses
 Cirrus OCT
  Average −0.104 0.031 0.016
  Superior −0.085 0.398 −0.312
  Nasal −0.144 −0.266 0.057
  Inferior −0.181 0.220 0.402
  Temporal 0.217 −0.251 −0.335
 Spectralis OCT
  Average −0.020 −0.324 0.304
  Superonasal 0.057 −0.192 0.383
  Nasal 0.000 −0.634 0.125
  Inferonasal −0.032 −0.085 0.187
  Inferotemporal −0.189 −0.539 0.569
  Temporal 0.215 −0.524 0.335
  Superotemporal −0.138 −0.236 0.076
  PMB sector −0.406 −0.744 0.610
  N/T index −0.101 0.731 −0.625
Structural parameters: retinal thicknesses
 Cirrus OCT
  Foveal −0.049 −0.510 0.404
  Superior inner 0.054 −0.704 0.581
  Nasal inner 0.219 −0.619 0.609
  Inferior inner 0.050 −0.579 0.253
  Temporal inner −0.118 −0.281 −0.280
  Superior outer −0.112 −0.404 0.098
  Nasal outer −0.109 −0.675 0.336
  Inferior outer −0.056 −0.204 0.515
  Temporal outer −0.212 −0.138 −0.033
 Spectralis OCT
  Foveal −0.197 −0.714 0.639
  Superior inner −0.032 −0.898 0.831
  Nasal inner 0.129 −0.925 0.875
  Inferior inner 0.049 −0.904 0.842
  Temporal inner −0.089 −0.785 0.718
  Superior outer 0.021 0.317 −0.360
  Nasal outer 0.132 −0.507 0.425
  Inferior outer 0.001 −0.570 0.526
  Temporal outer −0.090 −0.376 0.338
Based on regression analysis, foveal thickness provided by the Cirrus OCT predicted PD severity: a reduction in foveal thickness was associated with a score > 2 in the Hoehn and Yahr scale (B coefficient = −0.087; P = 0.044). The regression analysis was repeated to find parameters that predict a reduction in the QOL in PD patients, and a reduced foveal thickness measured by Cirrus OCT and a decreased amplitude of the N95 component of PERG predicted a lower SE-ADL score (lower QOL; foveal thickness provided by Cirrus OCT: B coefficient = −0.115; P = 0.048; amplitude of the N95 component of PERG: B coefficient = 2.06; P = 0.026). 
Using regression analysis, we found that reduction in fovea thickness provided by Cirrus OCT and decrease in amplitude of N95 component of PERG predict reduction in SE-ADL scale (lower QOL; fovea thickness provided by Cirrus OCT: B coefficient = −0.115; P = 0.048; amplitude of N95 component of PERG: B coefficient = 2.06; P = 0.026; Fig. 3A). The regression analysis was repeated to find parameters which predict PD severity and we found that fovea thickness reduction provided by Cirrus OCT was associate with punctuations > 2 in Hoehn and Yahr scale (B coefficient = −0.087; P = 0.044; Fig. 3B). Receiver operating characteristic (ROC) curves were plotted for both analyses (Fig. 3): The area under the ROC curve of the fovea thickness provided by Cirrus OCT to detect PD severity was 0.784 and the area under the ROC curve of the amplitude of the N95 component provided by the PERG to detect reduction in the QOL was 0.712. 
Figure 3
 
Representation of ROC curves of a two-regression analysis to demonstrate which parameters of OCT or neurophysiologic tests predict quality of life reduction or the degree of severity in patients with Parkinson disease. (A) The area under the ROC curve of the amplitude of the N95 component provided by the PERG to detect a reduction in the quality of life (punctuation < 80 in SE-ADL) was 0.712. (B) The area under the ROC curve of the fovea thickness provided by Cirrus OCT to detect Parkinson disease severity (punctuation ≥ 2 in Hoehn and Yahr scale) was 0.784.
Figure 3
 
Representation of ROC curves of a two-regression analysis to demonstrate which parameters of OCT or neurophysiologic tests predict quality of life reduction or the degree of severity in patients with Parkinson disease. (A) The area under the ROC curve of the amplitude of the N95 component provided by the PERG to detect a reduction in the quality of life (punctuation < 80 in SE-ADL) was 0.712. (B) The area under the ROC curve of the fovea thickness provided by Cirrus OCT to detect Parkinson disease severity (punctuation ≥ 2 in Hoehn and Yahr scale) was 0.784.
Positive association was found between disease stage (using Hoehn and Yahr punctuation) and VEP latency (r = 0.483; P = 0.034). 
Discussion
PD is associated with the death of pigmented dopamine neurons in the substantia nigra, but there is also a loss of other dopaminergic neurons (e.g., lateral geniculate nucleus, cholinergic nucleus basalis of Meynert, and visual cortex). 36 Experimental studies of Nguyen-Legros 37 suggested that a progressive retinal dopaminergic cell loss causes impaired input to the cortex. Retinal ganglion cells have axons that project via the optic nerve to diverse targets in the brain. 38 The reduction of retinal ganglion cells leads to a corresponding decrease in retinal and RNFL thicknesses that can be detected in PD patients using OCT. 39 Aaker et al. 40 reported that spectral domain OCT detects a significant reduction in macular thickness between PD patients and controls, but not in peripapillary RNFL thickness measurements. In our study, which included a larger population, we found a reduction in both macular and RNFL measurements. However, Jindahra et al. 41 and Reich et al. 42 both reported that RNFL loss occurs with retrogeniculate lesions, indicating that OCT measurements may reveal a combined anterior and posterior visual pathway disease. Our results are consistent with the findings of La Morgia et al. 39 and Inzelberg et al., 43 who demonstrated RNFL thickness reduction in PD patients using time domain OCT, and with the findings of Hajee et al. 4 and Spund et al., 44 who reported on inner retinal thinning in these patients. We assumed that RGCs and RNFL do not contribute to foveal thickness, and our manual measurements of the thickness in the center of the fovea demonstrated RPE thinning in PD patients. 
Neurophysiologic tests such as VEP and PERG have also been evaluated in PD patients. Based on previous studies, the N95 component is a better measure of retinal ganglion cell function. When the N95 component extends up from the peak of the P50 to the deflection of the N95, it influences the P50 component; thus, a better valuation of N95 in this case is the N95 to P50 ratio. Clinical application of these findings allows clinicians to identify the structures of the optical route that are altered in diverse diseases that affect vision. 45,46 Our results demonstrate a latency delay and amplitude reduction in the VEP and PERG of PD patients compared with healthy controls (Table 1; Fig. 1). We also found that the latency and amplitude of the VEP and the latency of N95 worsens with an increase in the disease duration. The VEP measurements showed little difference between PD and controls. This may be caused because our PD population comprised patients with early disease (patients with severe PD were excluded because they cannot complete the study). In addition, the association between disease stage and VEP latency suggest that PD patients with less severe affectation had normal VEP and patients with more severe stage present VEP abnormality. Bodis-Wollner et al. 47 also found this association between VEP and Hoehn and Yahr punctuation. 
The present study demonstrated reduced retinal and RNFL thicknesses and alterations in visual fields, VEP and PERG in patients with PD compared with healthy subjects, but the main objective of this study was to evaluate the ability of these parameters to predict which patients would have a lower QOL or more severe PD symptoms. We found that foveal thickness was the best parameter to predict more severe PD symptoms. Altintaş et al. also demonstrated a relation between PD severity and alterations in foveal thickness using time-domain OCT, but the RNFL measurements did not have a similar correlation. 5 Foveal thickness may be associated with PD severity because human RPE cells produce dopamine 3 and RPE in the fovea can be measured with OCT. Dopamine and levodopa have been used in cell therapeutic trials. 48,49 Although the presence of levodopa in RPE cells has been used to look for new treatments for PD, 50 the capability of these cells to quantify the phase of the disease or to monitor the progression of PD has not been evaluated. We demonstrated that retinal measurements provided by OCT could be used to predict QOL reduction, and worsening of the symptoms or disease progression in PD patients. 
We found an important correlation between OCT measurements and neurologic markers of PD: The negative correlation with the Hoehn and Yahr score demonstrates that patients with greater damage in the RPE or in ganglion cells tend to have more severe PD. The positive correlation between OCT parameters and the SE-ADL scores demonstrates that patients with greater damage in the RPE or in ganglion cells tend to have a lower QOL due to PD. Although we found correlations with retinal and RNFL measurements, the retinal thickness (specifically the foveal thickness provided by Cirrus OCT) seems to be the best parameter to predict PD severity and QOL. Our results also demonstrated that a decrease in the amplitude of the N95 component of PERG predicts reduced QOL in these patients, so this test seems useful for detecting patients with a higher risk of progression. 
RNFL and retinal thicknesses based on Cirrus OCT tend to be smaller than those recorded with Spectralis OCT. The Cirrus OCT considers the anterior RNFL limit to be the internal limiting membrane and the posterior RNFL limit to be the posterior border. In contrast, thickness measurements using the Spectralis OCT are derived from delineation of the anterior (internal limiting membrane) and posterior borders along a single A-scan at the appropriate eccentricity within each radial B-scan. 49 Previous studies demonstrated that the measurements obtained using the Cirrus and Spectralis OCT devices were not equivalent, indicating that the same tomography device should be used to detect the progression of changes of the RNFL in patients. The difference in RNFL thickness between the two devices is most likely due to differences in the algorithm between the two manufacturers for determining the inner and outer border of the RNFL. 51  
The main limitation of this study is that the statistical analysis performs multiple comparisons, but the significance levels were adjusted for multiple t-tests using Bonferroni. More studies evaluating the correlations between OCT parameters, disease severity, and QOL are needed to confirm our findings. 
Information about the effect of retinal and RNFL damage on PD symptoms and QOL are important for optimal care of PD patients and for improving knowledge about the pathologic mechanisms. Retinal ganglion cell loss and retinal thickness reduction are useful diagnostic tools in PD, but their utility as predictors of QOL have not been evaluated. The present findings indicate that structural evaluation, especially analysis of retinal thicknesses measured using Spectralis OCT and foveal thickness measured using Cirrus OCT, provides a good biomarker for predicting QOL and disease severity in PD patients, but the functional parameters provided by PERG have also demonstrated utility. Other functional analysis such as visual field or VEP did not demonstrate association with QOL and PD severity. Although we found an association between retinal thicknesses and QOL or PD severity (Table 4), the results must be carefully interpreted because some of the detected correlations could be statistical anomalies due to the small sample size, multiple comparisons, and number of statistical tests performed. Longitudinal studies with a larger population are needed to corroborate the value of retinal thicknesses and to evaluate the potential application of OCT parameters for PD patients in daily clinical practice. 
Acknowledgments
The authors alone are responsible for the content and writing of the paper. 
Disclosure: E. Garcia-Martin, None; D. Rodriguez-Mena, None; M. Satue, None; C. Almarcegui, None; I. Dolz, None; R. Alarcia, None; M. Seral, None; V. Polo, None; J.M. Larrosa, None; L.E. Pablo, None 
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Figure 1
 
Representation of latency and amplitude of VEP and PERG in PD patients and healthy subjects. (A) Latencies. (B) Amplitudes.
Figure 1
 
Representation of latency and amplitude of VEP and PERG in PD patients and healthy subjects. (A) Latencies. (B) Amplitudes.
Figure 2
 
Representation of retinal and retinal nerve fiber layer measurements in PD patients and healthy subjects. (A) Retinal measurements using Cirrus and Spectralis OCT. (B) RNFL measurements using Cirrus and Spectralis OCT.
Figure 2
 
Representation of retinal and retinal nerve fiber layer measurements in PD patients and healthy subjects. (A) Retinal measurements using Cirrus and Spectralis OCT. (B) RNFL measurements using Cirrus and Spectralis OCT.
Figure 3
 
Representation of ROC curves of a two-regression analysis to demonstrate which parameters of OCT or neurophysiologic tests predict quality of life reduction or the degree of severity in patients with Parkinson disease. (A) The area under the ROC curve of the amplitude of the N95 component provided by the PERG to detect a reduction in the quality of life (punctuation < 80 in SE-ADL) was 0.712. (B) The area under the ROC curve of the fovea thickness provided by Cirrus OCT to detect Parkinson disease severity (punctuation ≥ 2 in Hoehn and Yahr scale) was 0.784.
Figure 3
 
Representation of ROC curves of a two-regression analysis to demonstrate which parameters of OCT or neurophysiologic tests predict quality of life reduction or the degree of severity in patients with Parkinson disease. (A) The area under the ROC curve of the amplitude of the N95 component provided by the PERG to detect a reduction in the quality of life (punctuation < 80 in SE-ADL) was 0.712. (B) The area under the ROC curve of the fovea thickness provided by Cirrus OCT to detect Parkinson disease severity (punctuation ≥ 2 in Hoehn and Yahr scale) was 0.784.
Table 1
 
Epidemiologic, Disease Characteristics, and Functional Parameters of PD Patients and Healthy Subjects, and P
Table 1
 
Epidemiologic, Disease Characteristics, and Functional Parameters of PD Patients and Healthy Subjects, and P
Parkinson Disease Eyes Healthy Eyes P
Number, n 46 33
Age, y, mean (range) 70.72 (55−88) 69.67 (58−87) 0.544
Men:women (% men) 29:17 (63%) 21:12 (64%) 0.660
Intraocular pressure, mm Hg, mean (SD) 14.2 (1.6) 14.0 (1.5) 0.369
BCVA, Snellen scale, mean (SD) 0.72 (0.2) 0.86 (0.2) 0.013
MD, dB, mean (SD) −5.8 (3.1) −1.81 (1.8) <0.001
VEP P100, amplitude, mV (SD) 11.9 (4.5) 12.5 (4.4) 0.555
VEP P100, latency, ms (SD) 115.3 (8.2) 112.9 (7.8) 0.210
PERG P50, amplitude, mV (SD) 3.64 (0.9) 4.51 (0.9) <0.001
PERG P50, latency, ms (SD) 55.7 (3.2) 53.9 (2.5) 0.010
PERG N95, amplitude, mV (SD) 6.3 (1.5) 7.6 (1.3) <0.001
PERG N95, latency, ms (SD) 100.8 (6.1) 100.0 (8.2) 0.653
PERG N95/P50 ratio (SD) 1.8 (0.2) 1.7 (0.2) 0.330
Disease duration, y, mean (SD) 7.7 (2.1)
Hoehn and Yahr scale (SD) 2.2 (0.8)
SE-ADL scale (SD) 78.0 (24.8)
Table 2
 
Mean and Standard Deviation of RNFL Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Table 2
 
Mean and Standard Deviation of RNFL Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Parkinson Patients Healthy Subjects P
Cirrus OCT parameters (SD)
 Mean thickness 92.62 (8.5) 94.66 (8.5) 0.001
 Superior thickness 113.33 (13.0) 115.80 (12.6) 0.006
 Nasal thickness 74.95 (10.3) 75.61 (12.6) 0.126
 Inferior thickness 119.57 (23.7) 121.41 (18.0) 0.002
 Temporal thickness 62.19 (10.5) 66.61 (10.7) <0.001
Axonal Nsite application of Spectralis OCT parameters (SD)
 Mean thickness 97.84 (8.4) 99.43 (10.1) 0.012
 Superior thickness 116.53 (12.7) 118.73 (14.7) 0.009
 Inferior thickness 127.37 (18.7) 128.33 (20.0) 0.266
 Superonasal thickness 105.38 (19.3) 110.42 (16.6) <0.001
 Nasal thickness 78.74 (14.6) 79.35 (15.5) 0.586
 Inferonasal thickness 114.03 (24.1) 118.16 (26.2) <0.001
 Inferotemporal thickness 138.63 (19.9) 140.70 (22.1) 0.036
 Temporal thickness 68.16 (11.2) 72.05 (9.6) 0.006
 Superotemporal thickness 122.68 (17.2) 132.18 (18.0) <0.001
 PMB sector 55.42 (11.2) 57.33 (10.5) 0.045
 N/T index 1.16 (0.3) 1.12 (0.26) 0.003
Table 3
 
Mean and Standard Deviation of Retina Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Table 3
 
Mean and Standard Deviation of Retina Thicknesses of PD Patients and Healthy Subjects Using Cirrus and Spectralis OCT, and P
Parkinson Patients Healthy Subjects P
Cirrus OCT parameters (SD)
 Foveal thickness 257.45 (25.9) 259.10 (29.1) 0.009
 Superior inner thickness 319.48 (14.3) 322.86 (17.5) 0.011
 Nasal inner thickness 320.83 (16.1) 326.62 (18.4) <0.001
 Inferior inner thickness 314.98 (14.4) 318.38 (17.6) <0.001
 Temporal inner thickness 307.38 (17.4) 315.95 (20.9) <0.001
 Superior outer thickness 277.13 (16.4) 277.95 (17.3) 0.155
 Nasal outer thickness 289.25 (21.8) 291.33 (17.7) 0.007
 Inferior outer thickness 267.00 (16.9) 263.05 (17.9) <0.001
 Temporal outer 265.00 (16.6) 266.00 (20.2) 0.058
Spectralis OCT parameters (SD)
 Foveal thickness 270.80 (24.2) 276.63 (24.5) <0.001
 Superior inner thickness 331.95 (16.4) 335.89 (15.6) 0.015
 Nasal inner thickness 335.42 (17.4) 339.35 (15.8) 0.008
 Inferior inner thickness 327.68 (16.6) 329.80 (18.2) 0.020
 Temporal inner thickness 320.95 (15.3) 325.35 (17.8) 0.001
 Superior outer thickness 287.55 (16.8) 289.63 (20.7) 0.032
 Nasal outer thickness 302.41 (17.7) 307.20 (20.4) <0.001
 Inferior outer thickness 278.30 (21.1) 279.08 (16.4) 0.099
 Temporal outer 277.00 (15.9) 278.00 (13.7) 0.125
Table 4
 
Correlation Between Structural and Functional Ophthalmologic Measurements in PD Patients and Disease Duration, Severity, and QOL Parameters
Table 4
 
Correlation Between Structural and Functional Ophthalmologic Measurements in PD Patients and Disease Duration, Severity, and QOL Parameters
Disease Duration, y Hoehn and Yahr Scale, PD Severity SE-ADL Scale, QOL
Functional parameters
 BCVA 0.061 0.189 −0.049
 MD of visual field −0.452 0.328 −0.028
 VEP latency 0.566 0.132 −0.187
 VEP amplitude −0.476 −0.020 −0.067
 PERG P50 latency 0.161 0.486 −0.496
 PERG P50 amplitude 0.224 0.395 −0.324
 PERG N95 latency 0.395 −0.138 0.136
 PERG N95 amplitude 0.216 0.295 −0.212
 PERG N95/P50 ratio −0.080 −0.490 0.491
Structural parameters: RNFL thicknesses
 Cirrus OCT
  Average −0.104 0.031 0.016
  Superior −0.085 0.398 −0.312
  Nasal −0.144 −0.266 0.057
  Inferior −0.181 0.220 0.402
  Temporal 0.217 −0.251 −0.335
 Spectralis OCT
  Average −0.020 −0.324 0.304
  Superonasal 0.057 −0.192 0.383
  Nasal 0.000 −0.634 0.125
  Inferonasal −0.032 −0.085 0.187
  Inferotemporal −0.189 −0.539 0.569
  Temporal 0.215 −0.524 0.335
  Superotemporal −0.138 −0.236 0.076
  PMB sector −0.406 −0.744 0.610
  N/T index −0.101 0.731 −0.625
Structural parameters: retinal thicknesses
 Cirrus OCT
  Foveal −0.049 −0.510 0.404
  Superior inner 0.054 −0.704 0.581
  Nasal inner 0.219 −0.619 0.609
  Inferior inner 0.050 −0.579 0.253
  Temporal inner −0.118 −0.281 −0.280
  Superior outer −0.112 −0.404 0.098
  Nasal outer −0.109 −0.675 0.336
  Inferior outer −0.056 −0.204 0.515
  Temporal outer −0.212 −0.138 −0.033
 Spectralis OCT
  Foveal −0.197 −0.714 0.639
  Superior inner −0.032 −0.898 0.831
  Nasal inner 0.129 −0.925 0.875
  Inferior inner 0.049 −0.904 0.842
  Temporal inner −0.089 −0.785 0.718
  Superior outer 0.021 0.317 −0.360
  Nasal outer 0.132 −0.507 0.425
  Inferior outer 0.001 −0.570 0.526
  Temporal outer −0.090 −0.376 0.338
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