RESEARCH
ARTICLE
Photoreceptor Layer Thinning in Idiopathic Parkinson’s Disease Nicolas M. Roth, MD,1 Shiv Saidha, MD,2,5 Hanna Zimmermann, MEng,1 Alexander U. Brandt, MD,1 €hn, MD,1,3 Justine Isensee,1 Agnieszka Benkhellouf-Rutkowska,1 Matthias Dornauer,1 Andrea A. Ku 4 5¶ 1,3,6 ,¶ €ller, MD, Peter A. Calabresi, MD, and Friedemann Paul, MD Thomas Mu * 1
—Universita €tsmedizin Berlin, Germany NeuroCure Clinical Research Center, Charite 2 Department of Neurology, Beaumont University Hospital, Republic of Ireland 3 —Universita €tsmedizin Berlin, Germany Department of Neurology, Charite 4 Department of Neurology, St. Joseph Hospital, Berlin, Germany 5 Department of Neurology, John Hopkins School of Medicine, Baltimore, Maryland, USA 6 —Universita €tsmedizin Berlin and Max-Delbru €ck-Center for Experimental and Clinical Research Center, Charite Molecular Medicine, Berlin, Germany
ABSTRACT:
This study was undertaken to quantify retinal and intra-retinal layer thicknesses in Parkinson’s disease (PD), and to evaluate whether retinal structural changes may be related to altered discrimination of color vision and to severity and duration of PD disease. We examined 97 PD patients and 32 healthy controls (HC) with spectral-domain optical coherence tomography (OCT), including intra-retinal layer segmentation. In total, we compared 111 retinal nerve fiber layer (RNFL)-scans and 114 macula scans from 68 PD patients with 62 RNFL and 63 macula scans from 32 HC. For clinical evaluation of disease severity, we used the Unified Parkinson’s Disease Rating Scale (UPDRS) motor examination. To determine color discrimination, we performed the Farnsworth Munsell 100 Hue Test (FMT) in a subgroup of PD patients. We found significant combined outer nuclear and photoreceptor layer thinning in PD versus HC (118.6 vs. 123.5 mm, P 5 0.001). Differ-
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Although the predominant clinical presentation is with
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*Correspondence to: Dr. Friedemann Paul, NeuroCure Clinical Research Universitaetsmedizin Berlin, Charite platz 1, 10117 Berlin, Center, Charite Germany, E-mail: [email protected] Funding agencies: This study was supported by the German Research Council (DFG Exc 257 to F.P.). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. ¶
Equally contributing senior authors in alphabetical order.
Received: 27 August 2013; Revised: 20 February 2014; Accepted: 3 March 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25896
ences in RNFL, total macular volume, or the other retinal layer thicknesses were not detected. The OCT measures were not associated with disease severity, duration, or color vision. By showing photoreceptor cell layer thinning, our findings support previous in vivo and autopsy studies demonstrating retinal alterations in PD. Optical coherence tomography may help to assess morphological retinal changes in PD patients; however, the utility of OCT in routine clinical practice may be limited because many PD patients have difficulties complying with OCT investigation because of disease-related symptoms such C 2014 as tremor, axial rigidity, or cognitive impairment. V International Parkinson and Movement Disorder Society
K e y W o r d s : optical coherence tomography; retina, photoreceptor dysfunction
layer;
Parkinson’s
disease;
visual
motor symptoms, both sensory and visual symptoms are widely reported.1-3 Dopamine (DA) plays an important role not only in synaptic transmission in the brain but also as a neurotransmitter for visual processing in the retina.4 Dopaminergic neurons (amacrine cells) have been described in the human retina’s inner nuclear and plexiform layers.5 Retinal DA deficiency is considered responsible for impaired vision in PD, because it contributes to visual processing by modulating the (center-surround) organization of the receptive field of ganglion cells.4,6 Clinical symptoms of visual impairment in PD include altered visual acuity, spatial contrast sensitivity, temporal sensitivity, and color vision.6-9 The importance of retinal DA deficiency in PD is underscored by a post-mortem study that showed lower
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retinal DA concentrations in patients who had not been treated with levodopa (L-dopa)10 and an in vivo study suggesting improvement of contrast sensitivity after L-dopa treatment.11 Pattern electroretinogram (PERG) also demonstrated retinal involvement in PD,12-14 and alterations of visual evoked potentials were shown to be stimulus dependent.15,16 Pattern electroretinogram reflects retinal activity, in particular of the retinal ganglion cells.17 In addition to electrophysiology that provides information about the functional state of the retina and the visual pathway, optical coherence tomography (OCT) may serve as a tool to investigate retinal morphology in PD. Optical coherence tomography has been performed in numerous neurological diseases, and associations of retinal neuroaxonal damage with functional visual outcomes have been reported.18-20 Applying these observations to PD, one could hypothesize that retinal DA deficiency may be responsible for visual dysfunction and also could cause structural damage to the retina. However, previous OCT studies in PD have shown inconsistent results: Significant reductions in retinal nerve fiber layer (RNFL) thickness as well as alterations in the inner and outer retina or the total macula volume (TMV) have been reported.21-26 Recently, in a study additionally employing manual intra-retinal layer segmentation techniques, a thicker inner nuclear layer in PD patients versus healthy controls (HC) was observed; differences in other OCT parameters were not described.27 In accordance with this, other studies failed to show differences in RNFL and macular volume between PD patients and HC.28,29 Another recent study using retinal single-layer analysis also could not show any significant alterations in retinal layers in PD patients,30 whereas others reported parafoveal inner nuclear layer thinning31 and association of neuroaxonal retinal damage with disease severity and duration.32,33 In another recently published, Jimenez and colleagues suggest that RNFL can be used as a predictor for disease severity.34 Against the background of these discrepant findings, the aim of our study was to investigate structural changes in the different retinal layers in PD versus HC by applying intra-retinal segmentation and to relate OCT measures to clinical parameters and functional parameters of color vision. We chose the FarnsworthMunsell color discrimination test (FMT), which has been previously established in PD patients.35
Patients and Methods Patients Ninety-seven patients (Table 1) who met the United Kingdom brain bank criteria for idiopathic PD36 and 32 HCs were recruited at Charite-Universit€atsmedizin
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TABLE 1. Cohort overview
Sex Age at visit UPDRS Disease duration (mo)
Male/female Mean 6 SD Range Mean 6 SD Range Mean 6 SD Range
PD n 5 68
HC n 5 32
37/31 68.8 6 8.1a 43.0-90.0 19 6 10 1-49 86.7 6 72.2 0.1-291.3
20/12 64.7 6 7.5 53.0-82.0
a Significantly different between PD and HC (p 5 0.001). Abbreviations: PD, Parkinson’s disease; HC, healthy controls; UPDRS, Unified Parkinson’s Disease Rating Scale; SD, standard deviation.
Berlin and at the Department of Neurology of the St. Joseph Hospital Berlin-Weissensee. Diagnosis was based on patients’ history, neurological examination, and dopaminergic response. Patients were seen during regular follow-up. The HCs were selected and matched for age and sex. All subjects were interviewed for a comprehensive medical history, and their medical records were reviewed when applicable. No additional ophthalmologic examination was performed other than OCT and color vision testing. Each OCT was carefully analyzed by experts in the field for confounding pathological conditions. The Unified Parkinson’s Disease Rating Scale (UPDRS) motor part III37 was used for clinical assessment while patients were receiving their usual dopaminergic treatment. Exclusion criteria for PD patients and HCs were insufficient scan quality according to current quality criteria,38 a signal strength of less than 7/10, technical artifacts leading to incorrect layer segmentation, and a diagnosis of glaucoma, Alzheimer’s, or any other retinal pathological condition. Because of the exclusion criteria, we had to exclude 83 RNFL scans (61 because of scan quality; 22 for medical reasons: retinal pathological conditions, n 5 8; Alzheimer’s disease, n 5 2; glaucoma, n 5 12) and 80 macula scans (58 because of scan quality, 22 for medical reasons: see earlier list) from PD patients and two RNFL scans (scan quality, n 5 1; retinal pathological conditions, n 5 1) and one macula scan (retinal pathological conditions) from HCs. Three macula scans from HCs and 93 macula scans from PD patients had to be excluded from intra-retinal segmentation. In total we included 111 RNFLs and 114 macula scans from 68 PD patients and 62 RNFLs and 63 macula scans from 32 HCs (Table 1). Clinical evaluation data, expressed by the UPDRS— part III, were available for 57 of 68 patients (84%). Data on disease duration were available for 67 patients. The PD patients were sex-matched with HCs (P 5 0.173, Pearson’s v2), but they differed in age (P 5 0.001, Mann-Whitney U).
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TABLE 2. OCT results PD
pRNFL (mm) TMV (mm3) GCIP (mm) GCIP 1 mRNFL (mm) INL/OPL (mm) ONL/PRL (mm)
HC
Mean 6 SD
Range
Mean 6 SD
Range
p-Values (GEE)
92.6 6 8.8 8.0 6 0.4 78.1 6 8.0 111.2 6 10.8 65.1 6 4.6 118.6 6 6.0
70.8-112.8 7.0-9.2 54.7-94.9 77.6-140.7 54.2-76.8 106.1-130.7
91.5 6 10.7 8.2 6 0.4 79.2 6 7.4 112.0 6 9.9 64.7 6 3.9 123.5 6 6.3
70.5-127.0 7.2-9.4 63.0-106.2 90.4-146.1 55.9-73.4 108.3-136.5
0.704 0.126 0.656 0.769 0.681 0.001
Comparison between PD patients and HC. p-values are from generalized estimating equation models corrected for age and sex. Abbreviations: pRNFL, peripapillary retinal nerve fiber layer; TMV, total macular volume; GCIP, ganglion cell layer/ inner plexiform layer; mRNFL, macular retinal nerve fiber layer; INL/OPL, inner nuclear layer/ outer plexiform layer; ONL/PRL, outer nuclear layer/inner and outer photoreceptor segments; PD, Parkinson’s disease; HC, healthy controls; SD, standard deviation; GEE, generalized estimating equation models.
Ethics The local ethics committee approved the study, and all participants gave informed written consent according to the 1964 Declaration of Helsinki.
Optical Coherence Tomography All OCT scans were carried out with a spectral domain OCT (Cirrus HD-OCT Version 5.0, Carl Zeiss Meditec, Dublin, CA, USA).39 Peripapillary RNFL (pRNFL) was measured with the “Optic Disc Cube 200 3 200” scan, a 6 3 6-mm square–based spatial cube surrounding the optic disc, including 200 3 200 A-scans. From the optic disc scan, the device measures pRNFL thickness throughout the data cube, determines the optic nerve head center, and then extracts measurements from a peripapillary ring with a diameter of 3.4 mm around that center location. Macular measurements were performed using the “Macular Cube 200 3 200” setting, which obtains a 6 3 6-mm square–based cube around the fovea centralis using 200 3 200 Ascans. The TMV is then defined as the volume between inner limiting membrane and the inner boundary of the retinal pigment epithelium within a 6-mm diameter circle around the fovea.
Intra-retinal Segmentation Macular scans were further analyzed in a blinded fashion using segmentation software at John Hopkins University, as described in detail elsewhere (Fig. 1).18 Briefly, segmentation performed in three dimensions yields the thicknesses of the following macular layers: ganglion cell layer 1 inner plexiform layer (GCIP), inner nuclear layer 1 outer plexiform layer (INL/OPL), and outer nuclear layer including inner and outer photoreceptor segments (ONL/PRL). This segmentation protocol has been shown to be reproducible in multiple sclerosis and HCs.40
Color Vision Testing We performed the FMT in a binocular fashion in a subset of 29 PD patients. The PD patients arranged a
series of colored discs in sequence between pairs of reference discs. The higher the number of misplacements is, the larger the total error score (TES). The TES was determined as previously proposed.41 To evaluate the existence of a color axis, the total error score was separated into blue–yellow and red–green partial scores.42
Statistical Analysis Differences between PD patients and HC were analyzed using Pearson’s v2 test for sex and MannWhitney U test for age. To account for minor differences in the subgroup analyses, all tests were corrected for sex and age. Group differences in OCT measures were analyzed using general estimation equation models (GEE) accounting for inter-eye/intra-patient effects. Influences of disease severity or disease duration were analyzed in a similar fashion using GEE. The OCT-derived measures were used as dependent variable and UPDRS III or disease duration were used as independent variables. Additionally, we divided the patients into groups with low UPDRS III (mild disease severity) and high UPDRS III (severe disease severity) or short time diseased and long time diseased using the median as group divider, and applied a group-wise comparison using GEE. All models were carefully investigated for possible nonlinear effects. Associations between retinal layers were analyzed using linear regression models after excluding measurements in which the independent value was below the 5th percentile or above the 95th percentile to minimize a potential influence of outliers. All statistical tests were performed using SPSS 20 (IBM, New York, NY, USA). A P-value less than 0.05 was considered significant.
Results Neither pRNFL nor TMV differed between PD patients and HC (Table 2). In contrast, intra-retinal segmentation indicated a significant reduction of the
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combined ONL/PRL in PD versus HC (118.6 vs. 123.5 mm, P 5 0.001, Table 2), whereas no differences were seen in any other of the segmented layers (Table 2 and Fig. 2A). To investigate a potential influence of dopaminergic amacrine cells in the INL and GCIP on ONL/PRL thickness, we performed linear regression analyses. Here, INL/OPL and GCIP were weakly associated with ONL/PRL thickness in PD patients but not in HC. This association was only significant for GCIP (beta 5 0.278, P 5 0.007) and not for INL1OPL (beta 5 0.159, P 5 0.129) (Fig. 2B).
OCT Measures and UPDRS III Next we investigated whether OCT measures differed between patients with high and low disease scores and stratified patients according to UPDRS III scores in two groups (high vs. low disability) along the group median of 18. This subgroup analysis showed no differences regarding any of the OCT parameters between patients with high and those with low disability (Table 3). Likewise, no correlation was found of UPDRS III scores with OCT measures (GEE, corrected for age and sex; not shown).
OCT Measures and Disease Duration Using a median divider (median disease duration 5 70.3 mo), we stratified patients into short and long disease duration subgroups. No differences in any of the OCT parameters were evident between patients with short and those with long disease duration (Table 3). Likewise, no correlation was seen of disease duration with OCT measures (GEE, corrected for age and sex; not shown).
OCT Measures and Color Vision No correlation was found between OCT parameters and the TES or partial error scores for blue–yellow and red–green pathways in PD patients (not shown).
Discussion This large OCT study with intra-retinal segmentation is the first to show a significant thinning of the photoreceptor and the outer nuclear layer in patients with idiopathic PD versus HC, but no differences in the pRNFL, TMV, or other retinal layers. A pathophysiological explanation for the selective changes of the combined ONL/PRL while the other OCT measures were found unaltered, is challenging and fuels the discussion on how retinal DA deficiency may cause structural retinal damage detectable by OCT. Our findings are in line with previous data on retinal damage in PD derived from electrophysiological and psychophysical tests. The photoreceptor layer con-
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FIG. 1. During segmentation of the optical coherence tomography (OCT) image, the segmentation software identifies the inner limiting membrane (A), and the outer boundaries of the macular retinal nerve fiber layer (RNFL; B), inner plexiform layer (IPL; C) and outer plexiform layer (OPL; D), as well as the inner boundary of the retinal pigment epithelium (E), which, similar to the ILM, is identified by the conventional Cirrus HD-OCT algorithm. The segmentation of these boundaries within examined and neighboring B-scans is peformed in three dimensions, across the macular volume cube generated by Cirrus HD-OCT, thereby enabling the determination of the thicknesses of the macularRNFL, ganglion cell layer 1 IPL (GCIP), the inner nuclear layer 1 OPL, and the outer nuclear layer (ONL), including the inner and outer photoreceptor segments.
tains rods and cones that receive input from dopaminergic cells.43,44 Interestingly, the blue cone system seems to be preferentially affected in PD and other retinal diseases.45 Given their longer distance, short wavelength–sensitive cones may be more vulnerable to dopaminergic deficiency, as has been demonstrated in post-mortem retinas from PD patients.10 In line with this, luminance contrast sensitivity data show that the blue cone axis is predominantly impaired in PD,45 and Sartucci et al.46 demonstrated that the PERG latency is significantly delayed for blue–yellow stimuli. Thus, one could assume a process of transsynaptic degeneration of ONL neurons as a consequence of impaired synaptic input from dopaminergic neurons via D2 family receptors on both rod and cone photoreceptors.47 This is supported by the weak correlations between dopaminergic cell–bearing layers in PD patients but not in HCs in our study. Moreover, the close mutual interaction of photoreceptors and DA neurons, which is crucial for the diurnal rhythm of DA production47 and for the normal functioning of the retina as a whole, is likely to be impaired in PD, presumably contributing to photoreceptor layer thinning. The weak effect size and the absence of overall RNFL and GCL thinning in our and some of the previous studies may be explained by lack of synapses between dopaminergic axon terminals and ganglion cells, as has been investigated by autoradiography.5 Here, dopaminergic amacrine cells were localized in the inner nuclear and the inner plexiform layers and formed synaptic contacts mostly within these. Although dopaminergic cell processes considerably contribute to the INL thickness,48 dopaminergic cells account for fewer than 10% of the INL’s cell bodies. Even a massive degeneration of dopaminergic cells may be too subtle to cause measurable changes in OCT.5 Additionally, multiple factors beyond loss of
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FIG. 2. (A) Scatter plots showing retinal layer group differences between PD patients and HC. Error bars indicate the 95% confidence interval. (B) Scatter plots showing the association between GCIP and ONL/PRL (on the left) and INL/OPL and ONL/PRL (on the right). Black dots indicate data from PD patients, white dots from healthy controls. Solid lines are from a linear regression including PD patients’ data, dashed lines are from healthy control data.
neurons and axons, such as inflammation, edema, and gliosis, may influence the backscatter of light used in OCT. Thus, retinal layer thinning as quantified by OCT may not exclusively reflect impaired neuroaxonal integrity.
None of the OCT parameters showed any association with clinical measures. One could assume that degeneration in the retina may be discordant with that in other structures or that retinal damage occurs early and does not progress further as the disease advances.
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TABLE 3. OCT correlation with UPDRS and disease duration Grouping according to UPDRS III
pRNFL (mm) TMV (mm3) GCIP (mm) GCIP 1 mRNFL (mm) INL/OPL (mm) ONL/PRL (mm)
Grouping according to disease duration
Mild PD (UPDRS < 18)
Severe PD (UPDRS 18)
p-Values
Short disease duration (< 70.3 mo)
Long disease duration (70.3 mo)
p-Values
91.1 6 8.9 8.0 6 0.4 78.4 6 7.6 110.9 6 10.5 65.3 6 4.7 119.1 6 5.4
94.2 6 8.6 8.0 6 0.5 77.1 6 9.1 110.3 6 11.5 64.7 6 5.1 118.3 6 6.0
0.258 0.503 0.401 0.597 0.303 0.171
91.8 6 7.6 8.0 6 0.4 79.0 6 7.6 112.6 6 10.5 65.4 6 4.8 118.7 6 6.3
93.7 6 9.8 8.0 6 0.4 77.5 6 8.3 110.3 6 11.0 64.9 6 4.6 119.0 6 5.5
0.288 0.868 0.652 0.494 0.605 0.258
To evaluate whether OCT parameters correlate with disease severity, we separated patients according to UPDRS scores in a mild and a severe (according to median UPDRS III 18) PD group and according to disease duration in a short time diseased and a long time (according to median duration 70.3 months) diseased group. Finally, we did directly correlate OCT parameters with the UPDRS and the disease duration (see above the p-values). Values expressed as means 6 standard deviation. The p-values are from generalized estimating equation models. Abbreviations: pRNFL, peripapillary retinal nerve fiber layer; TMV, total macular volume; GCIP, ganglion cell layer/inner plexiform layer; mRNFL, macular retinal nerve fiber layer; INL/OPL, inner nuclear layer/ outer plexiform layer; ONL/PRL, outer nuclear layer/inner and outer photoreceptor segments, UPDRS 5 Unified Parkinson’s disease rating scale, part III (motor examination).
But we must also consider that long-term dopaminergic treatment may have negative effects on retinal neurons and axons.49,50 Another very likely explanation for the missing association of OCT measures with UPDRS III scores is that ratings were performed while patients were on their dopaminergic drug regimen, which is a methodological weakness of our study. At first glance, the fact that the substantial photoreceptor and outer nuclear layer damage in PD was not related to functional visual deficits in color discrimination seems surprising. However, several explanations may resolve this seeming contradiction: 1) we could perform the color discrimination test in a subset of our patients only; thus the sample size may have been too small to yield significant correlations between structural and functional visual parameters, 2) FMT performance may be influenced not only by retinal pathological conditions but also by cerebral changes in PD; 3) FMT performance is prone to various confounders, because it requires different kinds of movements in a complex sequence in combination with visuospatial cognition, self-elaboration of internal strategies, sorting, and planning51; 4) motor impairment was shown to influence FMT error scores52; and 5) the mean loss of roughly 5 mm in PRL/ONL thickness in PD from controls may not have been severe enough to cause measurable deficits in color discrimination. In line with our findings, Adam et al.53 reported a lack of correlation between inner retinal layer thickness and contrast sensitivity in PD and suggested a dissociation of functional deficits and anatomic structural changes. We found no RNFL thinning or TMV reduction. This is in contrast to some older and smaller studies that reported RNFL thinning using time domain OCT technology.21,22,54 One of these also found an inverse correlation between foveal retinal thickness and the UPDRS.21 On the contrary, another time domain OCT study did not find altered RNFL thickness and TMV in 37 PD patients.28
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Time domain OCT has a lower resolution than spectral domain OCT technology used in our and other more recent studies. Several smaller recent studies applied spectral domain OCT but with different devices and no automatic intra-retinal segmentation: One study demonstrated a significant thinning of the inner retinal layer in 24 PD patients.23 Another study did not detect RNFL or inner retinal layer (a composite measure of pRNFL, GCL, inner plexiform layer [IPL], and INL) reductions in nine PD patients versus 16 controls but differences in macular thickness (both thinning and thickening) in three of nine subfields.55 A subsequent study with a larger sample size of 40 PD patients versus 35 controls reported no difference in pRNFL or TMV.27 Additional manual intra-retinal segmentation was performed, which showed a thicker INL in PD versus controls but otherwise similar layer measurements. Another recent study found differences in macular volume between 23 PD patients and 18 controls.56 These discrepant and equivocal data on OCT measures of retinal damage in PD are likely to be explained by differences in the applied OCT devices and technologies, patient selection, and the limited sample size in most works that makes it difficult to draw firm conclusions from these data. By contrast, our study has a much larger sample size and the additional advantage of employing highly reproducible and automated intraretinal segmentation, decreasing the chances of a technical error.18,40 Fortunately, other OCT studies have overcome some of the limitations of previous works by including larger numbers of patients and controls and by applying modern SD technology with intra-retinal segmentation in some. Despite these improvements, the discrepancies between cohorts regarding RNFL and GCO thinning and the correlation of OCT measures with clinical disease severity and duration have not been finally resolved.30-33,57-59 One limitation of our study is that the HC group was slightly younger than the PD group. Because no
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correlation was found of ONL/PRL measures with age in either group and we included age as covariate in all statistical analyses, we believe that this age difference is negligible. Noteworthy is the high number of scans that had to be excluded in the PD but not in the HC group. This was caused by the high number of patients that had difficulties complying with the OCT examination because of head or neck tremor, axial rigidity, or cognitive impairment, all of which may have impaired the ability to hold the head still on the chin rest of the OCT device. This has to be taken into account for design and sample size calculation of future OCT studies in PD. Moreover, the comparably small control group limits the interpretation of negative RNFL findings. Possibly, in combination with the difficulties the more severely impaired PD patients had with the examination, this led to an underestimation of a potential RNFL and GCIP thinning. Conversely, studies reporting RNFL thinning in severely impaired patients might overestimate RNFL loss by not rigorously excluding low-quality images. Finally, sector thicknesses for the different regions of the macula are not yet derived with the segmentation technique used in this study. Therefore, determining whether photoreceptor thinning was localized to the fovea was not possible. In summary, we have found significant thinning of the photoreceptor layer in PD, the pathophysiological mechanisms of which warrant further elucidation. Although our data show that OCT is adequate to detect neurodegeneration in PD, some disease-specific features that may have a negative impact on patient compliance during OCT examinations have to be considered for future studies. Acknowledgments: F.P. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We thank Scott Meyer and his team from Carl Zeiss Meditec, Dublin, CA, USA, for their technical support.
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Albrecht P, M€ uller A-K, S€ udmeyer M, et al. Optical coherence tomography in parkinsonian syndromes. PLoS ONE. 2012;7: e34891. doi: 10.1371/journal.pone.0034891.
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Archibald NK, Clarke MP, Mosimann UP, Burn DJ. Retinal thickness in Parkinson’s disease. Parkinsonism Relat Disord. 2011;17: 431-436. doi: 10.1016/j.parkreldis.2011.03.004.
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Lee J-Y, Kim JM, Ahn J, Kim H-J, Jeon BS, Kim TW. Retinal nerve fiber layer thickness and visual hallucinations in Parkinson’s disease. Mov Disord 2013. doi: 10.1002/mds.25543.
Sartucci F, Orlandi G, Lucetti C, et al. Changes in pattern electroretinograms to equiluminant red-green and blue-yellow gratings in patients with early Parkinson’s disease. J Clin Neurophysiol 2003; 20:375-381.
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Witkovsky P. Dopamine and retinal function. Doc Ophthalmol 2004;108:17-40.
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Garcia-Martin E, Larrosa JM, Polo V, et al. Distribution of retinal layer atrophy in patients with Parkinson disease and association with disease severity and duration. Am J Ophthalmol 2013. doi: 10.1016/j.ajo.2013.09.028.
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Witkovsky P, G abriel R, Krizaj D. Anatomical and neurochemical characterization of dopaminergic interplexiform processes in mouse and rat retinas. J Comp Neurol 2008;510:158-174. doi: 10.1002/cne.21784.
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M€ uller T, van Laar T, Cornblath DR, et al. Peripheral neuropathy in Parkinson’s disease: levodopa exposure and implications for duodenal delivery. Parkinsonism Relat Disord 2013;19:501-507; discussion, 501. doi:10.1016/j.parkreldis.2013.02.006.
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M€ uller T, Przuntek H, Kuhlmann A. Loss of color vision during long-term treatment with pramipexole. J Neurol. 2003;250:101102. doi:10.1007/s00415-003-0915-5.
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Adam CR, Shrier E, Ding Y, Glazman S, Bodis-Wollner I. Correlation of inner retinal thickness evaluated by spectral-domain optical coherence tomography and contrast sensitivity in Parkinson disease. J Neuroophthalmol 2013;33:137-142. doi: 10.1097/ WNO.0b013e31828c4e1a.
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Cubo E, Tedejo RP, Rodriguez Mendez V, L opez Pe~ na MJ, Trejo Gabriel Y, Gal an JM. Retina thickness in Parkinson’s disease and essential tremor. Mov Disord. 2010;25:2461-2462. doi:10.1002/ mds.23215.
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Aaker GD, Myung JS, Ehrlich JR, Mohammed M, Henchcliffe C, Kiss S. Detection of retinal changes in Parkinson’s disease with spectral-domain optical coherence tomography. Clin Ophthalmol 2010;4:1427-1432. doi: 10.2147/OPTH.S15136.
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Kirbas S, Turkyilmaz K, Anlar O, Tufekci A, Durmus M. Retinal nerve fiber layer thickness in patients with Alzheimer disease. J Neuroophthalmol 2013;33:58-61. doi: 10.1097/WNO.0b013e318267fd5f.
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ARTICLE
Photoreceptor Layer Thinning in Idiopathic Parkinson’s Disease Nicolas M. Roth, MD,1 Shiv Saidha, MD,2,5 Hanna Zimmermann, MEng,1 Alexander U. Brandt, MD,1 €hn, MD,1,3 Justine Isensee,1 Agnieszka Benkhellouf-Rutkowska,1 Matthias Dornauer,1 Andrea A. Ku 4 5¶ 1,3,6 ,¶ €ller, MD, Peter A. Calabresi, MD, and Friedemann Paul, MD Thomas Mu * 1
—Universita €tsmedizin Berlin, Germany NeuroCure Clinical Research Center, Charite 2 Department of Neurology, Beaumont University Hospital, Republic of Ireland 3 —Universita €tsmedizin Berlin, Germany Department of Neurology, Charite 4 Department of Neurology, St. Joseph Hospital, Berlin, Germany 5 Department of Neurology, John Hopkins School of Medicine, Baltimore, Maryland, USA 6 —Universita €tsmedizin Berlin and Max-Delbru €ck-Center for Experimental and Clinical Research Center, Charite Molecular Medicine, Berlin, Germany
ABSTRACT:
This study was undertaken to quantify retinal and intra-retinal layer thicknesses in Parkinson’s disease (PD), and to evaluate whether retinal structural changes may be related to altered discrimination of color vision and to severity and duration of PD disease. We examined 97 PD patients and 32 healthy controls (HC) with spectral-domain optical coherence tomography (OCT), including intra-retinal layer segmentation. In total, we compared 111 retinal nerve fiber layer (RNFL)-scans and 114 macula scans from 68 PD patients with 62 RNFL and 63 macula scans from 32 HC. For clinical evaluation of disease severity, we used the Unified Parkinson’s Disease Rating Scale (UPDRS) motor examination. To determine color discrimination, we performed the Farnsworth Munsell 100 Hue Test (FMT) in a subgroup of PD patients. We found significant combined outer nuclear and photoreceptor layer thinning in PD versus HC (118.6 vs. 123.5 mm, P 5 0.001). Differ-
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Although the predominant clinical presentation is with
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*Correspondence to: Dr. Friedemann Paul, NeuroCure Clinical Research Universitaetsmedizin Berlin, Charite platz 1, 10117 Berlin, Center, Charite Germany, E-mail: [email protected] Funding agencies: This study was supported by the German Research Council (DFG Exc 257 to F.P.). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. ¶
Equally contributing senior authors in alphabetical order.
Received: 27 August 2013; Revised: 20 February 2014; Accepted: 3 March 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25896
ences in RNFL, total macular volume, or the other retinal layer thicknesses were not detected. The OCT measures were not associated with disease severity, duration, or color vision. By showing photoreceptor cell layer thinning, our findings support previous in vivo and autopsy studies demonstrating retinal alterations in PD. Optical coherence tomography may help to assess morphological retinal changes in PD patients; however, the utility of OCT in routine clinical practice may be limited because many PD patients have difficulties complying with OCT investigation because of disease-related symptoms such C 2014 as tremor, axial rigidity, or cognitive impairment. V International Parkinson and Movement Disorder Society
K e y W o r d s : optical coherence tomography; retina, photoreceptor dysfunction
layer;
Parkinson’s
disease;
visual
motor symptoms, both sensory and visual symptoms are widely reported.1-3 Dopamine (DA) plays an important role not only in synaptic transmission in the brain but also as a neurotransmitter for visual processing in the retina.4 Dopaminergic neurons (amacrine cells) have been described in the human retina’s inner nuclear and plexiform layers.5 Retinal DA deficiency is considered responsible for impaired vision in PD, because it contributes to visual processing by modulating the (center-surround) organization of the receptive field of ganglion cells.4,6 Clinical symptoms of visual impairment in PD include altered visual acuity, spatial contrast sensitivity, temporal sensitivity, and color vision.6-9 The importance of retinal DA deficiency in PD is underscored by a post-mortem study that showed lower
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retinal DA concentrations in patients who had not been treated with levodopa (L-dopa)10 and an in vivo study suggesting improvement of contrast sensitivity after L-dopa treatment.11 Pattern electroretinogram (PERG) also demonstrated retinal involvement in PD,12-14 and alterations of visual evoked potentials were shown to be stimulus dependent.15,16 Pattern electroretinogram reflects retinal activity, in particular of the retinal ganglion cells.17 In addition to electrophysiology that provides information about the functional state of the retina and the visual pathway, optical coherence tomography (OCT) may serve as a tool to investigate retinal morphology in PD. Optical coherence tomography has been performed in numerous neurological diseases, and associations of retinal neuroaxonal damage with functional visual outcomes have been reported.18-20 Applying these observations to PD, one could hypothesize that retinal DA deficiency may be responsible for visual dysfunction and also could cause structural damage to the retina. However, previous OCT studies in PD have shown inconsistent results: Significant reductions in retinal nerve fiber layer (RNFL) thickness as well as alterations in the inner and outer retina or the total macula volume (TMV) have been reported.21-26 Recently, in a study additionally employing manual intra-retinal layer segmentation techniques, a thicker inner nuclear layer in PD patients versus healthy controls (HC) was observed; differences in other OCT parameters were not described.27 In accordance with this, other studies failed to show differences in RNFL and macular volume between PD patients and HC.28,29 Another recent study using retinal single-layer analysis also could not show any significant alterations in retinal layers in PD patients,30 whereas others reported parafoveal inner nuclear layer thinning31 and association of neuroaxonal retinal damage with disease severity and duration.32,33 In another recently published, Jimenez and colleagues suggest that RNFL can be used as a predictor for disease severity.34 Against the background of these discrepant findings, the aim of our study was to investigate structural changes in the different retinal layers in PD versus HC by applying intra-retinal segmentation and to relate OCT measures to clinical parameters and functional parameters of color vision. We chose the FarnsworthMunsell color discrimination test (FMT), which has been previously established in PD patients.35
Patients and Methods Patients Ninety-seven patients (Table 1) who met the United Kingdom brain bank criteria for idiopathic PD36 and 32 HCs were recruited at Charite-Universit€atsmedizin
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TABLE 1. Cohort overview
Sex Age at visit UPDRS Disease duration (mo)
Male/female Mean 6 SD Range Mean 6 SD Range Mean 6 SD Range
PD n 5 68
HC n 5 32
37/31 68.8 6 8.1a 43.0-90.0 19 6 10 1-49 86.7 6 72.2 0.1-291.3
20/12 64.7 6 7.5 53.0-82.0
a Significantly different between PD and HC (p 5 0.001). Abbreviations: PD, Parkinson’s disease; HC, healthy controls; UPDRS, Unified Parkinson’s Disease Rating Scale; SD, standard deviation.
Berlin and at the Department of Neurology of the St. Joseph Hospital Berlin-Weissensee. Diagnosis was based on patients’ history, neurological examination, and dopaminergic response. Patients were seen during regular follow-up. The HCs were selected and matched for age and sex. All subjects were interviewed for a comprehensive medical history, and their medical records were reviewed when applicable. No additional ophthalmologic examination was performed other than OCT and color vision testing. Each OCT was carefully analyzed by experts in the field for confounding pathological conditions. The Unified Parkinson’s Disease Rating Scale (UPDRS) motor part III37 was used for clinical assessment while patients were receiving their usual dopaminergic treatment. Exclusion criteria for PD patients and HCs were insufficient scan quality according to current quality criteria,38 a signal strength of less than 7/10, technical artifacts leading to incorrect layer segmentation, and a diagnosis of glaucoma, Alzheimer’s, or any other retinal pathological condition. Because of the exclusion criteria, we had to exclude 83 RNFL scans (61 because of scan quality; 22 for medical reasons: retinal pathological conditions, n 5 8; Alzheimer’s disease, n 5 2; glaucoma, n 5 12) and 80 macula scans (58 because of scan quality, 22 for medical reasons: see earlier list) from PD patients and two RNFL scans (scan quality, n 5 1; retinal pathological conditions, n 5 1) and one macula scan (retinal pathological conditions) from HCs. Three macula scans from HCs and 93 macula scans from PD patients had to be excluded from intra-retinal segmentation. In total we included 111 RNFLs and 114 macula scans from 68 PD patients and 62 RNFLs and 63 macula scans from 32 HCs (Table 1). Clinical evaluation data, expressed by the UPDRS— part III, were available for 57 of 68 patients (84%). Data on disease duration were available for 67 patients. The PD patients were sex-matched with HCs (P 5 0.173, Pearson’s v2), but they differed in age (P 5 0.001, Mann-Whitney U).
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TABLE 2. OCT results PD
pRNFL (mm) TMV (mm3) GCIP (mm) GCIP 1 mRNFL (mm) INL/OPL (mm) ONL/PRL (mm)
HC
Mean 6 SD
Range
Mean 6 SD
Range
p-Values (GEE)
92.6 6 8.8 8.0 6 0.4 78.1 6 8.0 111.2 6 10.8 65.1 6 4.6 118.6 6 6.0
70.8-112.8 7.0-9.2 54.7-94.9 77.6-140.7 54.2-76.8 106.1-130.7
91.5 6 10.7 8.2 6 0.4 79.2 6 7.4 112.0 6 9.9 64.7 6 3.9 123.5 6 6.3
70.5-127.0 7.2-9.4 63.0-106.2 90.4-146.1 55.9-73.4 108.3-136.5
0.704 0.126 0.656 0.769 0.681 0.001
Comparison between PD patients and HC. p-values are from generalized estimating equation models corrected for age and sex. Abbreviations: pRNFL, peripapillary retinal nerve fiber layer; TMV, total macular volume; GCIP, ganglion cell layer/ inner plexiform layer; mRNFL, macular retinal nerve fiber layer; INL/OPL, inner nuclear layer/ outer plexiform layer; ONL/PRL, outer nuclear layer/inner and outer photoreceptor segments; PD, Parkinson’s disease; HC, healthy controls; SD, standard deviation; GEE, generalized estimating equation models.
Ethics The local ethics committee approved the study, and all participants gave informed written consent according to the 1964 Declaration of Helsinki.
Optical Coherence Tomography All OCT scans were carried out with a spectral domain OCT (Cirrus HD-OCT Version 5.0, Carl Zeiss Meditec, Dublin, CA, USA).39 Peripapillary RNFL (pRNFL) was measured with the “Optic Disc Cube 200 3 200” scan, a 6 3 6-mm square–based spatial cube surrounding the optic disc, including 200 3 200 A-scans. From the optic disc scan, the device measures pRNFL thickness throughout the data cube, determines the optic nerve head center, and then extracts measurements from a peripapillary ring with a diameter of 3.4 mm around that center location. Macular measurements were performed using the “Macular Cube 200 3 200” setting, which obtains a 6 3 6-mm square–based cube around the fovea centralis using 200 3 200 Ascans. The TMV is then defined as the volume between inner limiting membrane and the inner boundary of the retinal pigment epithelium within a 6-mm diameter circle around the fovea.
Intra-retinal Segmentation Macular scans were further analyzed in a blinded fashion using segmentation software at John Hopkins University, as described in detail elsewhere (Fig. 1).18 Briefly, segmentation performed in three dimensions yields the thicknesses of the following macular layers: ganglion cell layer 1 inner plexiform layer (GCIP), inner nuclear layer 1 outer plexiform layer (INL/OPL), and outer nuclear layer including inner and outer photoreceptor segments (ONL/PRL). This segmentation protocol has been shown to be reproducible in multiple sclerosis and HCs.40
Color Vision Testing We performed the FMT in a binocular fashion in a subset of 29 PD patients. The PD patients arranged a
series of colored discs in sequence between pairs of reference discs. The higher the number of misplacements is, the larger the total error score (TES). The TES was determined as previously proposed.41 To evaluate the existence of a color axis, the total error score was separated into blue–yellow and red–green partial scores.42
Statistical Analysis Differences between PD patients and HC were analyzed using Pearson’s v2 test for sex and MannWhitney U test for age. To account for minor differences in the subgroup analyses, all tests were corrected for sex and age. Group differences in OCT measures were analyzed using general estimation equation models (GEE) accounting for inter-eye/intra-patient effects. Influences of disease severity or disease duration were analyzed in a similar fashion using GEE. The OCT-derived measures were used as dependent variable and UPDRS III or disease duration were used as independent variables. Additionally, we divided the patients into groups with low UPDRS III (mild disease severity) and high UPDRS III (severe disease severity) or short time diseased and long time diseased using the median as group divider, and applied a group-wise comparison using GEE. All models were carefully investigated for possible nonlinear effects. Associations between retinal layers were analyzed using linear regression models after excluding measurements in which the independent value was below the 5th percentile or above the 95th percentile to minimize a potential influence of outliers. All statistical tests were performed using SPSS 20 (IBM, New York, NY, USA). A P-value less than 0.05 was considered significant.
Results Neither pRNFL nor TMV differed between PD patients and HC (Table 2). In contrast, intra-retinal segmentation indicated a significant reduction of the
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combined ONL/PRL in PD versus HC (118.6 vs. 123.5 mm, P 5 0.001, Table 2), whereas no differences were seen in any other of the segmented layers (Table 2 and Fig. 2A). To investigate a potential influence of dopaminergic amacrine cells in the INL and GCIP on ONL/PRL thickness, we performed linear regression analyses. Here, INL/OPL and GCIP were weakly associated with ONL/PRL thickness in PD patients but not in HC. This association was only significant for GCIP (beta 5 0.278, P 5 0.007) and not for INL1OPL (beta 5 0.159, P 5 0.129) (Fig. 2B).
OCT Measures and UPDRS III Next we investigated whether OCT measures differed between patients with high and low disease scores and stratified patients according to UPDRS III scores in two groups (high vs. low disability) along the group median of 18. This subgroup analysis showed no differences regarding any of the OCT parameters between patients with high and those with low disability (Table 3). Likewise, no correlation was found of UPDRS III scores with OCT measures (GEE, corrected for age and sex; not shown).
OCT Measures and Disease Duration Using a median divider (median disease duration 5 70.3 mo), we stratified patients into short and long disease duration subgroups. No differences in any of the OCT parameters were evident between patients with short and those with long disease duration (Table 3). Likewise, no correlation was seen of disease duration with OCT measures (GEE, corrected for age and sex; not shown).
OCT Measures and Color Vision No correlation was found between OCT parameters and the TES or partial error scores for blue–yellow and red–green pathways in PD patients (not shown).
Discussion This large OCT study with intra-retinal segmentation is the first to show a significant thinning of the photoreceptor and the outer nuclear layer in patients with idiopathic PD versus HC, but no differences in the pRNFL, TMV, or other retinal layers. A pathophysiological explanation for the selective changes of the combined ONL/PRL while the other OCT measures were found unaltered, is challenging and fuels the discussion on how retinal DA deficiency may cause structural retinal damage detectable by OCT. Our findings are in line with previous data on retinal damage in PD derived from electrophysiological and psychophysical tests. The photoreceptor layer con-
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FIG. 1. During segmentation of the optical coherence tomography (OCT) image, the segmentation software identifies the inner limiting membrane (A), and the outer boundaries of the macular retinal nerve fiber layer (RNFL; B), inner plexiform layer (IPL; C) and outer plexiform layer (OPL; D), as well as the inner boundary of the retinal pigment epithelium (E), which, similar to the ILM, is identified by the conventional Cirrus HD-OCT algorithm. The segmentation of these boundaries within examined and neighboring B-scans is peformed in three dimensions, across the macular volume cube generated by Cirrus HD-OCT, thereby enabling the determination of the thicknesses of the macularRNFL, ganglion cell layer 1 IPL (GCIP), the inner nuclear layer 1 OPL, and the outer nuclear layer (ONL), including the inner and outer photoreceptor segments.
tains rods and cones that receive input from dopaminergic cells.43,44 Interestingly, the blue cone system seems to be preferentially affected in PD and other retinal diseases.45 Given their longer distance, short wavelength–sensitive cones may be more vulnerable to dopaminergic deficiency, as has been demonstrated in post-mortem retinas from PD patients.10 In line with this, luminance contrast sensitivity data show that the blue cone axis is predominantly impaired in PD,45 and Sartucci et al.46 demonstrated that the PERG latency is significantly delayed for blue–yellow stimuli. Thus, one could assume a process of transsynaptic degeneration of ONL neurons as a consequence of impaired synaptic input from dopaminergic neurons via D2 family receptors on both rod and cone photoreceptors.47 This is supported by the weak correlations between dopaminergic cell–bearing layers in PD patients but not in HCs in our study. Moreover, the close mutual interaction of photoreceptors and DA neurons, which is crucial for the diurnal rhythm of DA production47 and for the normal functioning of the retina as a whole, is likely to be impaired in PD, presumably contributing to photoreceptor layer thinning. The weak effect size and the absence of overall RNFL and GCL thinning in our and some of the previous studies may be explained by lack of synapses between dopaminergic axon terminals and ganglion cells, as has been investigated by autoradiography.5 Here, dopaminergic amacrine cells were localized in the inner nuclear and the inner plexiform layers and formed synaptic contacts mostly within these. Although dopaminergic cell processes considerably contribute to the INL thickness,48 dopaminergic cells account for fewer than 10% of the INL’s cell bodies. Even a massive degeneration of dopaminergic cells may be too subtle to cause measurable changes in OCT.5 Additionally, multiple factors beyond loss of
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FIG. 2. (A) Scatter plots showing retinal layer group differences between PD patients and HC. Error bars indicate the 95% confidence interval. (B) Scatter plots showing the association between GCIP and ONL/PRL (on the left) and INL/OPL and ONL/PRL (on the right). Black dots indicate data from PD patients, white dots from healthy controls. Solid lines are from a linear regression including PD patients’ data, dashed lines are from healthy control data.
neurons and axons, such as inflammation, edema, and gliosis, may influence the backscatter of light used in OCT. Thus, retinal layer thinning as quantified by OCT may not exclusively reflect impaired neuroaxonal integrity.
None of the OCT parameters showed any association with clinical measures. One could assume that degeneration in the retina may be discordant with that in other structures or that retinal damage occurs early and does not progress further as the disease advances.
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TABLE 3. OCT correlation with UPDRS and disease duration Grouping according to UPDRS III
pRNFL (mm) TMV (mm3) GCIP (mm) GCIP 1 mRNFL (mm) INL/OPL (mm) ONL/PRL (mm)
Grouping according to disease duration
Mild PD (UPDRS < 18)
Severe PD (UPDRS 18)
p-Values
Short disease duration (< 70.3 mo)
Long disease duration (70.3 mo)
p-Values
91.1 6 8.9 8.0 6 0.4 78.4 6 7.6 110.9 6 10.5 65.3 6 4.7 119.1 6 5.4
94.2 6 8.6 8.0 6 0.5 77.1 6 9.1 110.3 6 11.5 64.7 6 5.1 118.3 6 6.0
0.258 0.503 0.401 0.597 0.303 0.171
91.8 6 7.6 8.0 6 0.4 79.0 6 7.6 112.6 6 10.5 65.4 6 4.8 118.7 6 6.3
93.7 6 9.8 8.0 6 0.4 77.5 6 8.3 110.3 6 11.0 64.9 6 4.6 119.0 6 5.5
0.288 0.868 0.652 0.494 0.605 0.258
To evaluate whether OCT parameters correlate with disease severity, we separated patients according to UPDRS scores in a mild and a severe (according to median UPDRS III 18) PD group and according to disease duration in a short time diseased and a long time (according to median duration 70.3 months) diseased group. Finally, we did directly correlate OCT parameters with the UPDRS and the disease duration (see above the p-values). Values expressed as means 6 standard deviation. The p-values are from generalized estimating equation models. Abbreviations: pRNFL, peripapillary retinal nerve fiber layer; TMV, total macular volume; GCIP, ganglion cell layer/inner plexiform layer; mRNFL, macular retinal nerve fiber layer; INL/OPL, inner nuclear layer/ outer plexiform layer; ONL/PRL, outer nuclear layer/inner and outer photoreceptor segments, UPDRS 5 Unified Parkinson’s disease rating scale, part III (motor examination).
But we must also consider that long-term dopaminergic treatment may have negative effects on retinal neurons and axons.49,50 Another very likely explanation for the missing association of OCT measures with UPDRS III scores is that ratings were performed while patients were on their dopaminergic drug regimen, which is a methodological weakness of our study. At first glance, the fact that the substantial photoreceptor and outer nuclear layer damage in PD was not related to functional visual deficits in color discrimination seems surprising. However, several explanations may resolve this seeming contradiction: 1) we could perform the color discrimination test in a subset of our patients only; thus the sample size may have been too small to yield significant correlations between structural and functional visual parameters, 2) FMT performance may be influenced not only by retinal pathological conditions but also by cerebral changes in PD; 3) FMT performance is prone to various confounders, because it requires different kinds of movements in a complex sequence in combination with visuospatial cognition, self-elaboration of internal strategies, sorting, and planning51; 4) motor impairment was shown to influence FMT error scores52; and 5) the mean loss of roughly 5 mm in PRL/ONL thickness in PD from controls may not have been severe enough to cause measurable deficits in color discrimination. In line with our findings, Adam et al.53 reported a lack of correlation between inner retinal layer thickness and contrast sensitivity in PD and suggested a dissociation of functional deficits and anatomic structural changes. We found no RNFL thinning or TMV reduction. This is in contrast to some older and smaller studies that reported RNFL thinning using time domain OCT technology.21,22,54 One of these also found an inverse correlation between foveal retinal thickness and the UPDRS.21 On the contrary, another time domain OCT study did not find altered RNFL thickness and TMV in 37 PD patients.28
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Time domain OCT has a lower resolution than spectral domain OCT technology used in our and other more recent studies. Several smaller recent studies applied spectral domain OCT but with different devices and no automatic intra-retinal segmentation: One study demonstrated a significant thinning of the inner retinal layer in 24 PD patients.23 Another study did not detect RNFL or inner retinal layer (a composite measure of pRNFL, GCL, inner plexiform layer [IPL], and INL) reductions in nine PD patients versus 16 controls but differences in macular thickness (both thinning and thickening) in three of nine subfields.55 A subsequent study with a larger sample size of 40 PD patients versus 35 controls reported no difference in pRNFL or TMV.27 Additional manual intra-retinal segmentation was performed, which showed a thicker INL in PD versus controls but otherwise similar layer measurements. Another recent study found differences in macular volume between 23 PD patients and 18 controls.56 These discrepant and equivocal data on OCT measures of retinal damage in PD are likely to be explained by differences in the applied OCT devices and technologies, patient selection, and the limited sample size in most works that makes it difficult to draw firm conclusions from these data. By contrast, our study has a much larger sample size and the additional advantage of employing highly reproducible and automated intraretinal segmentation, decreasing the chances of a technical error.18,40 Fortunately, other OCT studies have overcome some of the limitations of previous works by including larger numbers of patients and controls and by applying modern SD technology with intra-retinal segmentation in some. Despite these improvements, the discrepancies between cohorts regarding RNFL and GCO thinning and the correlation of OCT measures with clinical disease severity and duration have not been finally resolved.30-33,57-59 One limitation of our study is that the HC group was slightly younger than the PD group. Because no
P H O T O R E C E P T O R S
correlation was found of ONL/PRL measures with age in either group and we included age as covariate in all statistical analyses, we believe that this age difference is negligible. Noteworthy is the high number of scans that had to be excluded in the PD but not in the HC group. This was caused by the high number of patients that had difficulties complying with the OCT examination because of head or neck tremor, axial rigidity, or cognitive impairment, all of which may have impaired the ability to hold the head still on the chin rest of the OCT device. This has to be taken into account for design and sample size calculation of future OCT studies in PD. Moreover, the comparably small control group limits the interpretation of negative RNFL findings. Possibly, in combination with the difficulties the more severely impaired PD patients had with the examination, this led to an underestimation of a potential RNFL and GCIP thinning. Conversely, studies reporting RNFL thinning in severely impaired patients might overestimate RNFL loss by not rigorously excluding low-quality images. Finally, sector thicknesses for the different regions of the macula are not yet derived with the segmentation technique used in this study. Therefore, determining whether photoreceptor thinning was localized to the fovea was not possible. In summary, we have found significant thinning of the photoreceptor layer in PD, the pathophysiological mechanisms of which warrant further elucidation. Although our data show that OCT is adequate to detect neurodegeneration in PD, some disease-specific features that may have a negative impact on patient compliance during OCT examinations have to be considered for future studies. Acknowledgments: F.P. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We thank Scott Meyer and his team from Carl Zeiss Meditec, Dublin, CA, USA, for their technical support.
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