Electronic Supplementary Material (ESM) to: Remodeling of the Fovea in Parkinson Disease
Journal of Neurotransmission
Authors:
Spund, B3, Ding, Y4, Liu, T4, Selesnick, I4, Glazman, S3, Shrier, EM1,2, Bodis-Wollner, I 3,2,1*
1 Department of Ophthalmology, State University of New York (SUNY)- Downstate Medical Center (DMC), Brooklyn, NY 11203
2 SUNY Eye Institute, Brooklyn, NY 11203
3 Department of Neurology, SUNY- DMC, Brooklyn, NY 11203
4 Department of Electrical and Computer Engineering, Polytechnic Institute of New York University, Brooklyn, NY 11203
*Correspondence: Ivan Bodis-Wollner, MD, DSc; phone number: 718-270-7371; fax number: 718-270-2172;
I.Subject selection for PD and healthy controls:
Criteria for critical selection of the healthy control group
Eye exam:
All subjects (PD subjects and controls) received the same comprehensive ophthalmic examination. Eye movements and blinking rate were established clinically. Vision was assessed with Snellen Visual Acuity and Pelli-Robson Contrast Sensitivity. Intraocular pressure was measured by applanation tonometry. The adnexa, external and internal media were examined, and a dilated fundus exam was performed. Optic nerve and macular examinations were conducted with 90- or 78-D lens at the slit-lamp biomicroscope, cup-to-disc ratio, RNFL, macula, foveal and peripheral retinal assessment examination.
Neurological exclusion criteria:
Neurodegenerative disease of any kind except PD; early-onset PD (<40 years old); Mini Mental State score below 27; brain imaging abnormalities suggestive of other cause for parkinsonism; unusual or atypical risk factors, exposure, or past history (e.g., drug exposure, acute or chronic toxic exposure, infection preceding parkinsonism, repeated head trauma); family history of PD; CVA within the last 2 years; history of temporal (cranial) arteritis.
Ophthalmologic exclusion criteria for ALL subjects (healthy and PD subjects)
History or presence of optic neuropathy, glaucoma, or glaucoma suspicion, visual acuity worse than 20/40, intraocular pressure above 20 mm Hg, intraocular injection, intraocular laser or photodynamic therapy, excluding capsulotomy within the past 90 days, family history of a retinal degeneration/dystrophy, optic neuropathy or atrophy; history of optic neuritis (retro-bulbar optic neuritis as well as papillitis), inability to undergo a dilated fundus exam, intraocular inflammation, acute or chronic ischemic optic neuropathy, pathologic myopic maculopathy, optic nerve head drusen. Age-related macular degeneration, macular drusen or atrophy, macular epiretinal membrane or macular scarring or degeneration. Presence of hypertensive or diabetic retinopathy, of inflammatory, degenerative and vascular pathologies. Based on our previous studies about 15 % of the enrolled subjects may have diabetes as comorbidity with PD.
Post-hoc criteria, discovered on the OCT after having passed the questions, enrollment and examination): unsuspected macular drusen underlying the central 5 mm area of the retina even without evidence of maculopathy, diabetic macular changes (e.g., macular edema by OCT criteria) and presence of a macular epiretinal membrane.
The composition of the healthy control and PD groups.
One may wonder how good is the quantification of the foveal shape, if we excluded nearly 30% of controls? This exclusion was necessary in order to build a gold standard since in the age group of PD, eye (Archibald et al. 2009) and neurological disease are not infrequent. In order to develop the “cleanest” quantification of the foveal pit, to have a “gold standard template,” we excluded many presumably healthy controls (i.e. diabetic patients without evident retinopathy). In all, for the purposes of defining the “pure” PD retinopathy we excluded from this study nearly 30% of subjects, including both “healthy” controls and PD patients. Reasons for exclusions are listed in the Methods. Besides age related eye diseases we additionally excluded as controls subjects with early, subtle signs of PD and potential Alzheimer’s disease which are also associated with retinal changes (Guo et al. 2010). However, we would like to point out that the extremely strict in- and exclusionary criteria we used for the purposes of this study to build a “gold standard”. For a clinical application of OCT we recommend including well defined common co-morbid factors and evaluating the results using multivariate analysis.
II. SD-OCT Methods using the RT-VUE 100
OCT. (ESM Fig 1) Properly centered SD-OCT scans that were of sufficient quality (signal strength intensity >75% of maximal strength) and absent of imaging artifacts or distortions were accepted. Artifacts are visible on the OCT images as spatial irregularities not attributable to localized pathology such as drusen or local distortions due to epiretinal membrane or significant vitreo-macular traction with cystoid retinal changes. Imaging artifacts are usually due to dropped sampling points, visible in the color-coded OCT maps of the OCT equipment. Using the same equipment, retinal thickness measurements have been shown to have a low coefficient of variation between measurements, with no significant difference noted in retinal thickness measurements. As defined by the makers of the OCT software, the measurements for the Inner Retinal Layer (IRL) thickness include the internal limiting membrane, ganglion cell layer, and the inner plexiform layer. The Outer Retinal Layer (ORL) includes layers from the inner nuclear layer to the retinal pigment epithelium. The Full Retinal Thickness (FRT) measurements are measured from the internal limiting membrane to the retinal pigment epithelium.
III. Discriminating PD and Healthy Controls
Variability of the “healthy fovea”.
Race, gender, axial length and variability of the foveal pit.
A number of studies showed that foveal morphology in the healthy population may depend on a number of factors. They do not explain the changes we have quantified in PD. Our results also show that central foveal thickness (foveola) was not statistically different amongst groups. It has been reported in some but not in all studies (Asefzadeh et al. 2007; Kelty et al. 2008; Huang et al. 2009; Ooto et al. 2011; Wagner-Schumann et al. 2011) that race, gender and axial length of the eye may influence foveal thickness. We did find that Caucasians had greater average foveal thickness, but the effect was not significant. Axial length of the eye also includes the distance from the front of the eye through the inner and outer retinal layers to the choroid. The axis goes through the foveola and includes the thickness of the layers below the foveal pit. Axial length is an important parameter in highly myopic individuals, who were excluded as subjects in our study. Lastly, using a best-fit algorithm, we found that the correlation between axial length (range 21.5 to 25.5 mm) and inner retinal thickness is flat (coefficient -0.1124).
Tick et al. (2011) observed remarkable variation in foveal morphology across clinically normal individuals with some (about 10 %) showing remarkably widened foveal pits. We also observed a widened fovea on PD. However, we do not think that the results we obtained in PD can be attributed to normal variability. In subjects with widened pits, central foveal thickness (CFT) and pit width co-varies, unlike in PD. Dubis et al. (2012) created a model of the contour of the fovea in healthy subjects based on automated data acquisition, using relatively coarsely sampled measurements. They defined foveal slope as the maximum slope of the foveal contour and their measures reflect - as they state - “the subjectivity of defining various morphological features” such as the avascular zone or rod-free region. Hammer et al. (2008) defined depth arbitrarily as the distances from base of the pit to the point where the radius is 0.73 mm. Dubis et al. (2012) state that “making the same measurement on our (their) data we found no difference between the data sets, supporting the idea that any differences between our data and those of others rests solely on the definition of the foveal metrics used.” We found that retinal thinning occurs predominantly in the inner plexiform layer and the ganglion cell layer at the edge of the pit. The ganglion cells and retinal nerve fiber layer (NFL) contribute 30% to 35% of retinal thickness in the macula, but not in the foveal pit. Thus, inner retinal thinning between 0.75 and 1.25 mm radial distance by raw data and ROC suggest that the dominant actor in foveal remodeling is neither CFT nor complete ganglion cell loss, but a loss of perhaps select ganglion cells and the preceding organization pertaining to these ganglion cells.
Loduca et al. (2010) used automated segmentation of all retinal layers in one eye of 15 subjects. We have recreated the foveal pit shape based on their data and found small discrepancies but acceptable agreement in the actual perifoveolar thickness of their and our mean values. However, inter-subject variability was considerably higher in their study using an automated retinal segmentation method.
Chui et al (2011) suggested that there is remarkable variability in the size of the healthy FAZ. Dubis et al. (2012) suggested that some foveal pit variability may be linked to a heterogeneity of the Foveal Avascular Zone (FAZ) (Provis and Hendrickson 2008).
We also found that there are differences in the shape of the foveal pit in PD itself, but our result show that they are statistically distinguishable from “normal” variability. The NFL and receptor free portion of the pit we studied contains a large plexus of dopaminergic amacrine cell processes. DA amacrine cells modulate retinal output of the ganglion cells through lateral interactions with other amacrine cells and interactions with horizontal cells (outer plexiform layer) and photoreceptor coupling (Witkowsky 2004) were shown previously to be affected in the PD retina (Djamgoz 1997, NguyelLegros 1998) but do not directly affect ganglion cells. We restricted our study to the comparison of this layer and not all layers of the retina.
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