Mesopic and Scotopic Light Sensitivity and Its Microstructural Correlates in Pseudoxanthoma Elasticum

Abstract

Importance: Correlates for Bruch membrane alterations are needed for interventional trials targeting the Bruch membrane in pseudoxanthoma elasticum (PXE).

Objectives: To quantify mesopic and scotopic light sensitivity and identify its microstructural correlates associated with a diseased Bruch membrane in patients with PXE.

Design, setting, and participants: A prospective, single-center, cross-sectional case-control study was conducted at a tertiary referral center from January 31, 2018, to February 20, 2020. Twenty-two eyes of 22 patients with PXE and 40 eyes of 40 healthy individuals were included. Data analysis was completed March 15, 2020.

Exposures: Mesopic and dark-adapted 2-color fundus-controlled perimetry (microperimetry) and multimodal retinal imaging including spectral-domain optical coherence tomography (SD-OCT) and OCT angiography were performed. Perimetry thresholds were analyzed using mixed models, and structure-function correlation with SD-OCT data was performed using machine learning.

Main outcomes and measures: Observed dark-adapted cyan sensitivity loss as measure of rod photoreceptor dysfunction, as well as mean absolute error between predicted and observed retinal sensitivity to assess the accuracy of structure-function correlation.

Results: Of the 22 patients with PXE included in this study, 15 were women (68%); median age was 56.5 years (interquartile range, 50.4-61.2). These patients exhibited mesopic (estimate, 5.13 dB; 95% CI, 2.89-7.38 dB), dark-adapted cyan (estimate, 9.08 dB; 95% CI, 6.34-11.82 dB), and dark-adapted red (estimate, 7.05 dB; 95% CI, 4.83-9.27 dB) sensitivity losses. This sensitivity loss was also evident in 9 eyes with nonneovascular PXE (mesopic: estimate, 3.21 dB; 95% CI, 1.28-5.14 dB; dark-adapted cyan: 5.93 dB; 95% CI, 3.59-8.27 dB; and dark-adapted red testing: 4.84 dB; 95% CI, 2.88-6.80 dB), showing a distinct centrifugal pattern of sensitivity loss with preserved function toward the periphery. Retinal function could be predicted from microstructure with high accuracy (mean absolute errors, of 4.91 dB for mesopic, 5.44 dB for dark-adapted cyan, and 4.99 dB for dark-adapted red). The machine learning-based analysis highlighted an association of a thinned inner retina and putative separation of the pigment-epithelium-photoreceptor complex with sensitivity loss.

Conclusions and relevance: In this study, among 22 patients with PXE, those with and without choroidal neovascularization exhibited reductions of retinal sensitivity being most pronounced in dark-adapted cyan testing. This finding suggests that pathologic characteristics of this Bruch membrane disease may be dominated by rod photoreceptor degeneration and/or dysfunction. A putative pigment-epithelium-photoreceptor separation may further impair rod function, while inner retinal abnormalities appear to be correlated with overall dysfunction.

Conflict of interest statement

Conflict of Interest Disclosures: The Department of Ophthalmology, University of Bonn, received technical support from Heidelberg Engineering, Heidelberg, Germany, Carl Zeiss Meditec, Jena, Germany, and Centervue, Padova, Italy. Dr Gliem is employee and equity owner of F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Figures

Figure 1.. Microperimetry Testing, Image Segmentation, and Multimodal Registration

Spectral-domain optical coherence tomography (SD-OCT) images were segmented in a semiautomated manner. A, The segmentation included the inner retina (internal limiting membrane to outer plexiform layer/outer nuclear layer [OPL/ONL] boundary), outer nuclear layer (OPL/ONL boundary to external limiting membrane), photoreceptor inner segments (external limiting membrane to ellipsoid zone), outer segments (ellipsoid zone to retinal pigment epithelium drusen complex [RPEDC]). The RPEDC encompassed subretinal drusenoid deposits and RPE, as well as sub-RPE type 1 choroidal neovascularization. B, Microperimetry data were registered to the SD-OCT data subsequently to extract thickness and reflectivity values corresponding precisely to stimulus diameter (0.43°) and location. DA indicates dark adapted.

Figure 2.. Spatial Pattern of Sensitivity Loss in Nonneovascular Eyes

The columns show the sensitivity in eyes with nonneovascular pseudoxanthoma elasticum (PXE) and the topography of sensitivity loss for mesopic (A) and dark-adapted (DA) cyan (B) testing. The position 0°/0° refers to the foveal center. The color gradient for mesopic sensitivity is identical to the color gradient of the device manufacturer. For dark-adapted cyan testing, a custom color gradient was applied owing to the lack of contrast with the preset color gradient. The contour lines in the sensitivity loss plot denote 1-dB increments. Inf indicates inferior; Sup, superior; and Temp, temporal.

Figure 3.. Association of Dark-Adapted (DA) Red and DA Cyan Sensitivity Loss With Mesopic Sensitivity Loss

A, The association of DA red sensitivity loss with mesopic sensitivity loss, which represents a linear relationship. B, The association of DA cyan sensitivity loss with mesopic sensitivity loss. A curvilinear relationship is evident. Specifically, DA cyan sensitivity losses of up to 17 dB were mostly associated with no or only minor losses of mesopic sensitivity. More severe losses of mesopic sensitivity were predominantly observed in conjunction with DA cyan sensitivity losses greater than 17 dB. Points were plotted semitransparently to compensate for overplotting. There was a floor effect evident in panel B, possibly affecting associations between mesopic and scotopic functions.

Figure 4.. Feature Importance

A, The permutation importance of the features for the prediction of mesopic sensitivity loss. B, The feature contribution plot for the outer nuclear layer (ONL) thickness. C, The analogous permutation importance of the features for the prediction of dark-adapted cyan sensitivity loss. D, The feature contribution plot for the ONL. The vertical dashed lines label the normative range. The y-axes of the feature contribution plots are inverted (ie, more severe degrees of sensitivity loss are plotted downwards). Points were plotted semitransparently to compensate for overplotting. An extended version of this figure with feature contribution plots for all retinal layers is shown in eFigure 3 in the Supplement. %IncMSE indicates percentage of increase in mean squared error; IRET, inner retina; IS, photoreceptor inner segments; max, maximum; min, minimum; OS, photoreceptor outer segments; and RPEDC, retinal pigment epithelium-drusen complex.