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

Abstract

IMPORTANCECorrelates 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 PARTICIPANTSA 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 MEASURESObserved 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. RESULTSOf 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 RELEVANCEIn 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.

AI-based structure-function correlation in age-related macular degeneration

“…Finally, image acquisition for inferred sensitivity can be performed in centres without the expertise for psychophysical testing. So far inferred sensitivity has been explored in macular telangiectasia type 2, Leber congenital amaurosis (LCA), blue cone monochromasy, pseudoxanthoma elasticum as well as MNV and GA secondary to AMD, demonstrating that mesopic sensitivity can be inferred with an accuracy of 3.36–4.64 decibel (dB) MAE cross those diseases [ 24 , 25 , 44 – 47 ].…”

“…11.9 dB (a) 10.8 dB (b) LCA 1. 4.6–17.6 dB Sumaroka et al [ 45 ] Foveal therapy in blue cone monochromacy: predictions of visual potential from artificial intelligence Blue Cone Monochromacy • Random forest (a) Layer thickness (b) reflectivity • Fundus-controlled Perimetry (a) Mesopic • Root mean squared error (RMSE) (a) 2.91 dB (b) 2.69 dB Heß et al [ 47 ] Mesopic and scotopic light sensitivity and its microstructural correlates in pseudoxanthoma elasticum Pseudoxanthoma Elasticum • Random forest (LOO-CV) • Fundus-controlled perimetry: (a) Mesopic (b) DA Cyan (c) DA Red • Mean absolute error (MAE) (a) 4.91 dB (b) 5.44 dB (c) 4.99 dB

Fig. 1 Inferred sensitivity mapping.

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“…Studies using ML algorithms further analysed feature importance of inferred sensitivity and demonstrated that layer thicknesses proved more indicative for predictions than layer intensities [ 24 , 25 , 45 – 47 ]. Hereby, the results of the analysis of retinal thickness seemed biological plausible, as ONL thickness proofed to be the most important imaging feature in all types of testing and cross disease stage.…”

The complexity of visual dysfunction in patients with pseudoxanthoma elasticum

“…Exudation and/or subretinal hemorrhages may eventually lead to subretinal fibrosis with atrophy of the overlying photoreceptors. However, it is possible that not all CNVs are detrimental: non-exudative (quiescent) occult CNVs might play a role in ensuring metabolic support for the RPE and outer retina when this is not sufficiently provided anymore by the choroid due to an increased BrM barrier [ 6 , 9 ], possibly slowing down development of atrophy [ 10 , 11 ].…”

Scotopic microperimetry: evolution, applications and future directions

“…1 Reduced scotopic vision is an early symptom in many conditions, including rod-cone degenerations, 2,3 chorioretinal degenerations and maculopathies. 4,5 With promising new therapies on the horizon, it is important to have appropriate visual function markers to identify suitable patients and to monitor localised treatment effects. Traditional methods for investigating scotopic retinal function include dark adaptometry, which is performed at pre-determined loci.…”