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Retinal thinning and correlation with functional disability in patients with Parkinson's disease
  1. M Satue1,2,
  2. M Seral3,
  3. S Otin1,2,
  4. R Alarcia3,
  5. R Herrero1,2,
  6. M P Bambo1,2,
  7. M I Fuertes1,2,
  8. L E Pablo1,2,
  9. E Garcia-Martin1,2
  1. 1Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain
  2. 2Aragones Institute of Health Sciences, Zaragoza, Spain
  3. 3Neurology Department, Miguel Servet University Hospital, Zaragoza, Spain
  1. Correspondence to Dr Maria Satue, Ophthalmology Department, Miguel Servet University Hospital, C/ Padre Arrupe. Consultas Externas de Oftalmología, Zaragoza 50009, Spain; mariasatue{at}


Aims To determine whether there is an association between retinal thinning and functional rating scales in patients with Parkinson's disease (PD).

Materials and methods Patients with PD (n=153) and controls (n=242) underwent evaluations of the macula and retinal nerve fibre layer (RNFL) using two new-generation Fourier domain optical coherence tomography (OCT) devices (Cirrus, Carl Zeiss Meditec, Dublin, California, USA; Spectralis, Heidelberg Engineering, Heidelberg, Germany). PD severity was assessed using the Schwab-England Activities of Daily Living scale, the Unified Parkinson Disease Rating Scale, the Hoehn and Yahr (HY) scale. Retinal and RNFL thicknesses were compared between patients and controls. Correlations between structural parameters and the scores of the neurologic scales were evaluated.

Results RNFL parameters were significantly reduced in patients with PD, especially when using the Spectralis OCT device. All macular parameters, except for foveal thickness, differed significantly between controls and patients with PD (p<0.001). HY scores were significantly and inversely correlated with all macular parameters when measured with the Spectralis OCT device (p<0.05) and with RNFL thickness when measured with the Cirrus OCT device (nasal quadrant, sectors 2 and 5).

Conclusions The neurodegeneration caused by PD can be detected using Fourier domain OCT. RNFL and macular thicknesses correlate with PD severity.

  • Optic Nerve
  • Retina
  • Pathology
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Clinical manifestations of Parkinson's disease (PD) include movement alterations as well as non-motor symptoms, such as dementia, depression and autonomic dysfunction.1 Dopaminergic drugs are typically used to alleviate symptoms of PD; however, insights into the pathophysiology of PD and an increasing awareness of factors that contribute to levodopa-induced motor complications have stimulated the development of new drugs as well as very promising surgical techniques.2–4 The increasing number of therapeutic interventions in PD has highlighted the importance of measuring clinical outcomes. Impairment, disability, disease progression and neurologic effects are evaluated using validated scales that analyse motor and non-motor symptoms, including mentation, mood and activities of daily life.5

Vision is one of the non-motor systems altered in PD, especially the visual field corresponding to the fovea.6 Recent studies demonstrated retinal thinning in different macular sectors in PD patients compared with healthy persons,7 ,8 and alterations in mean retinal nerve fibre layer (RNFL) peripapillary thickness using spectral-domain optical coherence tomography (OCT).9 ,10 To our knowledge, however, there have been no previous analyses of the possible correlations between neurologic progression (evaluated using PD rating scales) and macular and RNFL structural alterations in PD.

Three validated scales were used in this study: the Hoehn and Yahr (HY) scale, the Schwab-England Activities of Daily Living (ADL) scale, and the Unified Parkinson Disease Rating Scale (UPDRS). The HY scale is a commonly used diagnostic for quantifying the progression of PD symptoms.11 Stages range from 0 (no signs of disease) to 5 (requiring a wheelchair, or bedridden unless assisted).

The Schwab-England ADL scale assesses the ability to perform daily activities in terms of speed and independence, and this is reflected through a percentage figure (100% indicates total independence).

Clinicians and researchers most commonly use the UPDRS and the motor section in particular, for following the longitudinal course of PD in clinical studies.5 The scale has three sections that evaluate the key areas of disability, and a fourth section that evaluates treatment complications.

Two Fourier-domain OCT devices were used in the present study: the Cirrus (Carl Zeiss Meditec, Dublin, California, USA) and the Spectralis (Heidelberg Engineering, Heidelberg, Germany). The Spectralis OCT device offers two applications for analysis of the RNFL: the classic software (glaucoma application) and new software for neuro-ophthalmology evaluation (Nsite Axonal Analytics), which was specifically designed for studying neurodegenerative diseases.

The purpose of the present study was to examine whether there is an association in PD patients between macular and RNFL defects and PD severity measured by the HY scale, the UPDRS and the Schwab-England ADL scale.

Material and methods

Patients with PD and healthy individuals were included in the study. All procedures adhered to the tenets of the Declaration of Helsinki, and the experimental protocol was approved by the local ethics committee. All participants provided informed consent to participate in the study.

Diagnosis of PD was based on UK Brain Bank Criteria, which included, in the first stage, bradykinesia and one additional symptom, that is, rigidity, 4–6 Hz resting tremor, or postural instability.12 ,13

Inclusion criteria were a confirmed diagnosis of PD, best-corrected visual acuity (BCVA) of 20/30 or higher (using a Snellen chart) in each eye for protocol performance to be assessed, anterior chamber depth of Schaffer grades III and IV using indirect gonioscopy, and an intraocular pressure less than 21 mmHg to rule out RNFL thinning due to other processes, such as open-angle chronic glaucoma.14 All patients with PD included in the study had current ON state. Exclusion criteria were the presence of significant refractive errors (>5 dioptres of spherical equivalent refraction or 3 dioptres of astigmatism), media opacifications, systemic conditions that could affect the visual system (eg, diabetes or ischaemic cardiopathy), a history of ocular trauma or concomitant ocular disease (including a previous history of retinal pathology, glaucoma, or laser therapy), ocular pathologies affecting the cornea, optic nerve, or retina (including macular alterations), and any other neurologic diseases, such as dementia or multiple sclerosis. Controls had no history of ocular or neurologic disease, and their BCVA was 20/30 or better, according to the Snellen scale.

All patients underwent a neuro-ophthalmologic examination, which included assessment of BCVA, eye movement, pupillary, anterior segment and funduscopic examinations, Goldmann applanation tonometry, and OCT examinations using the Cirrus high definition (HD) OCT device and the Spectralis OCT device (the RNFL protocol of the glaucoma application, and the RNFL-N protocol of the Axonal Analytics application). Each eye was considered separately, and one eye from each patient was randomly selected for analysis.

OCT evaluation

OCT was performed to obtain measurements of the peripapillary RNFL using the Cirrus and Spectralis OCT devices, which were used in random order to prevent fatigue bias. All scans were performed by the same experienced operator. An internal fixation target was used because it provides the highest reproducibility.15 The quality of the scans was assessed prior to the analysis, and poor quality scans were rejected.

The Cirrus OCT optic disc protocol analyses a 6 mm-wide cube around the optic nerve. In each series of scans, mean RNFL thickness, quadrant RNFL thickness (superior, inferior, temporal and nasal), and thickness at the 12 clock hours for each 30° of the RNFL were analysed. The hour sectors were assigned a number from position C1 to C12 in the clockwise direction for the right eye and in the anticlockwise direction for the left eye.

The Cirrus Macular Cube 200×200 protocol provides retinal thickness values for nine areas that correspond to the Early Treatment Diabetic Retinopathy Study (ETDRS) (16). ETDRS areas include a central 1 mm circle representing the fovea, and inner and outer rings measuring 3 mm and 6 mm in diameter, respectively. The inner and outer rings are divided into four quadrants each: superior, nasal, inferior and temporal. Central foveal thickness was also calculated. Mean retinal thickness and total macular volume in the 6 mm diameter ETDRS ring were calculated based on the proportional contribution of the regional macular thickness.16 The mean of all points within the inner circle of 1 mm radius was defined as the central foveal subfield thickness. The nine areas were analysed using Cirrus software (V.3.0).

The new Nsite Axonal Analytics application of the Spectralis OCT device has fovea-to-disc technology that correctly orients the anatomy for papillomacular bundle (PMB) measurement accuracy and minimises variability due to patient head orientation. The RNFL-N system places the temporal region of the scan in the centre of the viewing window for better analysis of axonal loss in the PMB, which occurs in patients with neurologic diseases such as multiple sclerosis. The RNFL thickness graph for the RNFL-N scans displays the scan results in the order of nasal, inferior, temporal, superior and nasal sectors. This protocol also provides two new neuro-ophthalmologic parameters: the PMB thickness and the nasal/temporal ratio. The nasal/temporal ratio is defined as the mean RNFL thickness in the nasal quadrant divided by the mean RNFL thickness in the temporal quadrant. The additional PMB protocol focuses on the PMB and the nerve fibres surrounding the macula, performing an isotropic scanning of 20 different sectors. This protocol provides a vast amount of information about the thickness of the main bundle, which transmits the stimuli collected in the macula photoreceptors.

The Fast macular protocol of the Spectralis OCT device (glaucoma application) uses an internal fixation source and centres on the patient's fovea. The operator independently monitors the stability of fixation with the incorporated infrared camera. The retinal thickness map analysis protocol represents the nine subfields, as defined by the ETDRS, in a similar manner to the Cirrus OCT device.16 RNFL and retinal acquisitions were obtained by the same observer using TruTrack eye-tracking technology that recognises, locks onto and follows the patient's retina during scanning. Spectralis software (V.5.2b) was used.

Neurologic evaluation

The stage and severity of PD were determined based on three different rating scales: the HY scale, the Schwab-England ADL scale, and the UPDRS. One neurologist tested all patients on all scales. The neurologist who was trained on how to apply the scales, was blind to the OCT results. For the HY scale, increasing parkinsonian motor impairment was charted from unilateral (Stage 1) to bilateral disease (Stage 2) without balance difficulties, to the presence of postural instability (Stage 3), loss of physical independence (Stage 4), and being wheelchair-bound or bed-bound (Stage 5). The Schwab-England ADL rating was determined by the neurologist according to the established criteria, with 100% indicating total independence, and 0% indicating a state of complete dependence. The UPDRS score was calculated using three sections that analysed the key areas of disability, together with a fourth section that evaluated any treatment complications.

Disease duration was also recorded, setting the appearance of the first symptoms as the onset time of the disease.

Statistical analysis

All variables were recorded in a database created with the FileMaker Pro 8.5 program. A cross-sectional analysis was performed: the independent variable was ‘diagnosed with PD’ or ‘not diagnosed with PD’, and dependent variables were the parameters obtained by the different diagnosis techniques included in the protocol. Age, sex and intraocular pressure were modifying variables.

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS V.20.0; SPSS, Chicago, Illinois, USA). The Kolmogorov–Smirnov test was used to assess sample distribution. Because the data were parametrically distributed, differences between patients and healthy controls were compared using Student t test, and correlations were examined by Pearson's test. Values of p<0.05 indicated statistically significant differences.

Linear agreement between RNFL and macular thickness, and the three neurologic scales (HY, UPDRS and Schwab-England ADL) was sought using Pearson's correlation coefficient.


One hundred and fifty-three patients with PD, and 242 healthy controls, were included in the study. Mean age of the patients with PD was 68 years (range: 59–77 years), and mean age of the healthy controls was 66 years (range: 52–80 years). Mean time from diagnosis was 5.25 years (range: 2.85–7.65 years). Age (p=0.114), sex (p=0.237), and intraocular pressure (p=0.559) did not differ significantly between healthy controls and patients with PD. The median HY stage was 2.5, and the IQR was 1.0. The frequency of the HY scale was distributed as follows: 1 patient on 1.0 stage, 4 patients on 1.5 stage, 22 patients on 2.0 stage, 24 patients on 2.5, 36 patients on 3.0 stage, 11 patients on 4.0 stage and 2 patients on 5.0 stage. The stage of PD based on the UPDRS was 25.06 (range: 16.82–33.30). The mean Schwab-England score was 67.40 (range: 47.50–87.30). BCVA was significantly different between groups (0.94, healthy controls; 0.78, PD patients; p<0.001).

The differences in RNFL thickness between healthy controls and patients with PD are shown in table 1 (Spectralis OCT measurements), and table 2 (Cirrus OCT measurements). The Spectralis OCT measurements revealed significant differences in most of the RNFL sectors using the classic glaucoma application, and in the mean thickness, the inferior quadrant, the inferonasal and the inferotemporal RNFL sectors using the axonal application. Thinning occurred in other structures in patients with PD, but these differences were not statistically significant (table 1). PMB thickness was not significantly different between patients with PD and healthy controls (p>0.05), although there was a tendency toward thinning in patients with PD (figure 1). The Cirrus OCT measurements revealed significant RNFL differences in mean thickness, thickness of superior, inferior, and temporal quadrants, and thickness of sectors 1, 6, 7, 10 and 11 (table 2).

Table 1

Mean (SD) of retinal nerve fibre layer and macular thicknesses obtained with the Spectralis optical coherence tomography device using the glaucoma classic application, Axonal Nsite Analytics application, and retinal (macular) application in healthy controls and patients with Parkinson's disease

Table 2

Mean (SD) of retinal nerve fibre layer and macular thicknesses obtained with the Cirrus optical coherence tomography device in healthy controls and patients with Parkinson's disease

Figure 1

Structural parameter means of PMB thickness obtained with the Nsite Axonal Analytics software of the Spectralis optical coherence tomography device, comparing healthy controls and patients with Parkinson's disease. There was a tendency toward retinal thinning in patients with Parkinson's disease. PMB, papillomacular bundle; PD, Parkinson's disease.

Macular thickness was also significantly reduced in patients with PD for all values of the 3 mm (inner) and the 6 mm (outer) ring using the Spectralis OCT device; and for the 1 mm central ring (fovea thickness) and the nasal and inferior quadrants of the 6 mm (outer) ring measured with the Cirrus OCT device (tables 1 and 2).

Correlation analyses revealed inverse correlations between macular thickness measured by Spectralis OCT and scores on the HY scale (table 3, figure 2).

Table 3

Correlation between macular structural measurements and severity of disease measured by the Hoehn and Yahr scale in patients with Parkinson's disease.

Figure 2

(A) Correlation between the inferior inner macular thickness and severity of disease measured by the Hoehn and Yahr scale in patients with Parkinson's disease. (B) Correlation between the superior inner macular thickness and severity of disease measured by the Hoehn and Yahr scale in patients with Parkinson's disease.

There was a significant correlation between the Schwab-England ADL scores and the outer temporal macular thickness measured with the Cirrus OCT device (r=0.284, p=0.010); and between the Schwab-England ADL scores and the inner inferior macular thickness measured with the Spectralis OCT device (r=0.217, p=0.039).The UPDRS scores were significantly correlated with the inner inferior macular thickness, measured using the Cirrus OCT device (r=−0.331, p=0.032).

Disease duration was correlated with RNFL thickness measured by the Spectralis OCT device (nasal quadrant using glaucoma application, p=0.036; nasal quadrant and mean thickness using axonal application, p=0.016 and p=0.038, respectively). There was no correlation between disease duration and Cirrus OCT values.


Dopamine in the human retina is released by a unique set of amacrine cells.17 These dopaminergic cells are located in the proximal inner nuclear layer, and send long (0.5 mm) processes laterally in sublamina 1 of the inner plexiform layer and into the outer plexiform layer. Dopamine in the mammalian retina modulates colour vision and contrast sensitivity through D1 and D2 receptors, which are differentially located in the retinal layers. A complete lack of D1 and D2 receptor activation leads to signal dispersion and alterations in colour vision and contrast sensitivity.7 Dopamine also has multiple trophic roles in retinal function related to circadian rhythm, cell survival and eye growth.17

Our results revealed macular thinning of all areas in patients with PD compared with controls, an inverse correlation with HY and UPDRS severity, and a positive correlation with the Schwab-England ADL scale. Therefore, increased neurologic effects and severity of PD progression are linked to thinning of macular tissue. The degree of correlation is usually classified as low (<0.30), moderate (0.30–0.70), or significant (>0.70). Our results were statistically significant (p<0.005) and showed a low and moderate degree of correlation. These results are consistent with findings in other neurodegenerative diseases.18

Our results also showed a relative conservation of the foveal structures and the PMB thickness. These findings do not correspond with previous reports in which foveal three-dimensional structures demonstrated changes in the foveal pit in patients with PD compared to controls.6 The OCT devices used in our study differed from those used in the Bodis–Wollner study, however, and therefore the results might not be comparable. Measures corresponding to the PMB thickness showed a tendency towards retinal thinning in patients with PD, although the results were not statistically significant. A larger sample size may be needed to reach significant results.

RNFL effects in PD were first demonstrated in 2004.19 The number of published studies analysing alterations in retinal measurements provided by OCT in PD has recently increased.10 ,11 ,20 ,21 To our knowledge, however, there are no published studies correlating RNFL and macular thinning with neurologic effects and disease progression in patients with PD. Only one study analysing treatment with levodopa versus dopamine agonists demonstrated a protective effect of levodopa in RNFL neurodegeneration in patients with PD compared with dopamine agonists; however, disease progression and neurologic effects were not analysed.22 In most patients with PD, the degree of dopaminergic axon degeneration in the substantia nigra target region, the striatum, exceeds substantia nigra cell body loss, suggesting a ‘dying back’ model, whereby the axonal compartment is the first target of degenerative alterations.23 Patients treated with levodopa show less RNFL loss than patients treated with dopamine agonists.22 This could be interpreted as a neuroprotective and trophic role of levodopa. The correlation demonstrated in our study between retinal thinning and neurologic effects in PD may be due to low dopamine levels producing axonal degeneration and, as in the ‘dying back’ model,23 a decrease of the inner retinal layers (including the ganglion cells and the amacrine cells). It is not known whether low dopamine levels directly affect amacrine retinal cells. Currently available OCT software cannot differentiate the thickness of the individual retinal layers, so the correlation between the dopaminergic cells and RNFL loss is not clear.

The quality of the data obtained by the imaging devices is influenced by media opacity, retinal pigment epithelium status, instrument variability, and positioning and centring of the images. Also, patient collaboration is necessary to perform the scans. In our study, we selected only good quality scans, and we tried to eliminate possible bias by establishing inclusion criteria. If PD symptoms were severe and this affected the quality of the scans, the patient was excluded from the study. The final number of patients was not altered. In clinical practice, however, this is not always possible. These limitations must be taken into account when interpreting the OCT results.

Recent studies demonstrated the ability of OCT to provide biomarkers of progression and diagnosis in other neurodegenerative processes, such as multiple sclerosis.24 Imaging techniques, such as OCT are non-invasive, inexpensive and fast, and may be useful for monitoring treatment effectiveness, detecting progressive neurodegeneration, and improving diagnostic procedures in neurologic diseases (such as making a differential diagnosis between PD and essential tremor).9

In conclusion, neurodegeneration caused by PD can be detected using Fourier domain OCT, and macular and RNFL thickness are correlated with PD severity. Longitudinal studies with a larger sample are needed to corroborate these results, and to evaluate the usefulness of macular and RNFL measurements as biomarkers of disease progression and treatment effectiveness in PD.


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  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval All individuals gave detailed consent to participate in this study, which was conducted in accordance with the guidelines established by the Ethics Committee of the Miguel Servet Hospital, and based on the principles of the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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