Ocular Features of Pseudoxanthoma Elasticum Observed by Multispectral Imaging

doi:10.21203/rs.3.rs-3216125/v1

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Case Report

Ocular Features of Pseudoxanthoma Elasticum Observed by Multispectral Imaging

https://doi.org/10.21203/rs.3.rs-3216125/v1

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Clinically there are controversies on the nature of peau d'orange change in pseudoxanthoma elasticum (PXE). It was originally described as pigmentary changes due to the dark spots under funduscopic examination, but later other features by infra-red image, autofluorescence and spectral-domain OCT indicated the lack of pigment clumping activity in the outer retina. We recently developed light-emitting-diode-based multispectral imaging system for investigation of ocular pigment changes and, in this study, we enrolled PXE chorioretinopathy as a pilot case to demonstrate its ability of revealing spectrum-sensitive imaging features of MSI.

pseudoxanthoma elasticum (PXE)

peau d'orange

multispectral imaging

Pseudoxanthoma elasticum (PXE) is characterized by systemic calcification involving the cardiovascular system, skin and the retina due to mutations in ABCC6 gene.¹ In retina, it presents as angioid streaks (AS), optic nerve drusen, choroidal neovascularization, and peau d’ orange appearance, typically in the temporal macula resembling the skin of an orange². The diffuse calcification of PRE-Bruch membrane complex is an early event in PXE patients even decades before the presence of AS. The increasing brittleness formed by the calcification will finally result in the formation of AS described as irregular elevated, yellowish white to orangish red lesion, usually juxta-or peripapillary in location with well‐defined geographic borders.² Histopathological documentation of the PXE chorioretinal pathology in literature is very scarce. In 1977, Jensen found heavy calcification of the membrane outside the ruptures stained by alizarin red in a 43 year old PXE female.³ In patients with PXE, the optical coherence tomography (OCT) of Bruch's membrane showed higher reflectivity by quanitified measurement, which was proposed to the first biomarker for Bruch's membrane calcification by Risseeuw.⁴

Multimodal imaging has been applied greatly into the funds features of PXE including fundus autofluorescence ⁵, OCT⁶and infra-red imaging.⁷ While multi-modal imaging has been used in AS and peau d’ orange in PXE patients, in this study, we explored the added value of multispectral imaging (MSI) to investigate the spectral characteristic of a patient with PXE. This technique uses a multi-spectrum-based emitting light imaging system, which integrates seven discontinuous narrow band spectrum light source and Complementary Metal Oxide Semiconductor (CMOS) device to generate a series of structure-based grey scale images that are based on the absorption and reflection of anatomical and pathological structure of the posterior segment. ^8,9 This allows multilayered en-face visualization from the vitreoretinal interface to the deep choroid.

Clinical

A 45-year-old Chinese female with no significant medical history was referred to the retina clinic for decreased vision for 2 months. Initial visual acuity was 3/50 in the right eye and 20/20 in the left eye. Anterior segment examination in both eyes was unremarkable. The ophthalmoscopy showed bilateral typical angioid streaks around the optic disc, peau d’ orange, and right macular neovascular (MNV) membrane with hemorrhages temporal to the macular area (Fig. 1A). Systemic review revealed symmetrical orange-reddish linear streaks on the dorsal sides of both arms and legs. No gastrointestinal or cardiovascular abnormalities were detected. The diagnosis was made for pseudoxanthoma elasticum with right MNV. Anti-VEGF intravitreal treatment was initiated in the right eye for MNV and she was scheduled for further follow-up.

Imaging

A series of multispectral imaging scans (MSI C2000, Thondar, China) showed dense ‘pigment clumping’, which presented as hyporeflective dots scattered in a hyperreflective background starting from 550nm (Fig. 1, B) and the interlaced pattern abnormality which got more prominent in 680nm slab (Fig. 1C). It dwindled down and blurred out in infrared wavelength slabs from 780nm to 850nm indicating presence of the lesion in deeper retina(Fig. 1D). This feature corresponded with the pattern seen in the infrared photo (Fig. 1E) but with less prominence and clarity in autofluorescence (Fig. 1F). The peau d’orange features seen in MSI are also manifested in the left eye (Fig. 2A-F). The swept-source optical coherence tomography (SS-OCT, VG200D, SVision Imaging, Ltd, China) showed that there was actually a lack of ‘pigment clumping’ in the peau d’orange area, but instead a discontinous hyperrefletive signals in the outer layers of RPE-Bruch membrane complex (Fig. 1I-K and Fig. 2I-K).

Angioid streaks on MSI are characterized by the hyporeflective radial lines around the optic nerve and hyperreflective sheath around the streaks (Fig. 1B). The borders of the AS merged with the background in longer wavelength slabs due to more penetration of the longer waves which could reach behind the Bruch’s membrane. The one distinctive feature of AS in 550nm, where the streaks were most defined, was that the hyporeflectivity was not homogenous in the streak itself (Fig. 3). The absolute hyporeflective area (Fig. 3A) indicated both the break in RPE and Bruch membrane (Fig. 3C, red arrow) while the medium hyporeflective area (Fig. 3D) indicated only the break of Bruch membrane with the remaining of RPE (Fig. 3F) as confirmed with OCT scan. Infrared (IR) mode is not optimal to observe AS but fundus autofluorescence (FAF) is able to show that the RPE-affected area was actually wider than the AS itself (Fig. 3B&E). However, it failed to differentiate between BM break only or RPE-BM break.

A linear MNV scar extended from the 9:00 o’clock angioid streak cleft all the way to the macular area. This was confirmed with fluorescein angiography (FFA) indicating an active leakage in the early phase (Fig. 1G) and late staining in the late phase (Fig. 1H). No MNV lesion was observed in the left eye (Fig. 2G-H). SS-OCT showed thickened, hyperreflective subretinal MNV lesion with minimal subretinal fluid (Fig. 3H&J). Retinal and choroidal vasculature was evaluated with optical coherence tomography angiography (OCTA) showing subfoveal MNV in multiple layers involving the avascular outer retina and choriocapillaris. It presented as densely branched fan-shaped MNV membrane, with apparent peri-MNV dark halo in the choriocapillaris (Fig. 3J).

The current imaging techniques in evaluation of the PXE chorioretinal changes involve the fluorescence angiography and OCT and OCTA for the presence and activity of MNV, near infra-red (NIR) for outer retinal changes including the pigment changes, and fundus autofluorescence (FAF) for the widespread and heterogeneous pigment disturbances located mostly adjacent to AS or MNV.

Peau d’orange is best seen in color fundus photography (CFP) and NIR but is hardly detectable on FAF.⁷ Issa et al. have used multimodal imaging for the investigation of the nature of PXE chorioretinal changes indicating that the bright spots of peau d’orange on IR seem to show higher intensity of the RPE-BM band. In our study, this sign was even more visible and much more widespread with infrared slab of MSI. It extended from the posterior pole towards the whole midperiphery, exhibiting as intertwined dark and bright reflectance in the area of peau d’orange that correlated with dark and light patterns seen on CFP and NIR. The natural course of peau d’orange has been retrospectively reviewed in 158 patients diagnosed in PXE in a 9 year course.¹⁰ It was found that the peau d’orange (55.6%) was the first fundus feature observed in younger patients which may disappear with age. The peau d’orange lesion observed by using multispectral imaging technique showed more prominace under infrared wavelengths, which provide a sensitive tool for the detection of peau d’orange sign.

There is inconsistency for the ‘pigment change’ observed 550nm in MSI and in OCT: very prominent hyporeflective dots with very minimal OCT change (a lack of proof for morphological PRE change) and hardly any signs on FAF (a lack of proof for functional RPE pathology) in the corresponding area. This controversial phenomenon is an alert as to whether the ‘hyporeflective dots’ were actually the uncalcified BM ‘fishnet’ spots that appears to be ‘darker’ than the actual calcified area. Both pathology study¹¹ and clinical OCT scan indicated that there was an extensive calcification of in the BM complex, which will accordingly enhance the total fundus background. OCT scan in our case also demonstrated the same feature of increased reflectivity on the level of outer retinal pigment epithelium-Bruch membrane complex (Fig. 3). Similar hyperreflective patterns have been observed from previous studies.^2,12,13

Second, the different degree of hyporeflectivity in 550nm in angioid streaks is a characteristic demonstration that RPE and Bruch membrane can act as a mirror of reflection for imaging lights. In the absence of Bruch membrane in areas of angiod streaks, the imaging light would be directly reaching the underlying tissue. The choroid and the melanin in deeper tissue is able to absorb the lights that present the AS as hyporeflective. And the more losses of reflective layers the darker is its corresponding area. The hyperreflective lines in OCT which work on the basis of scanning laser also present in the same way for diode emitting light in multispectral imaging. And MSI, by presenting dark, grey signal with different grey-scales, provides lesion information of different layers.

In summary, after conducting a literature review utilizing PubMed and Google Scholar, we did not find any prior reports of multispectral imaging in PXE chorioretinopathy. MSI is valuable in differentiating the spectrum features of different components of confusing ocular pathologies such as pigmentary changes and BM calcification, as well as differentiating BM break with or without RPE break. MSI, in combination of multimodal imaging, is valuable in evaluating patients with PXE.

• Ethics approval and consent to participate: The study protocol was approved by the Second Hospital of Hebei Medical University (Approval No. 2023-R100) and conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants prior to their inclusion in the study.

• Consent for publication: Written consent for publication was obtained from all participants involved in this study. We have taken the necessary steps to ensure the privacy and confidentiality of the participants' personal information, and all data presented in this manuscript are anonymized.

• Availability of data and materials: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. The raw data, including imaging files and measurement data, will be made available to researchers for the purpose of replication and further analysis.

• Competing interests: The authors declare that they have no competing interests in relation to this work. There are no financial or non-financial conflicts of interest that could influence the interpretation of the findings or the presentation of the results.

• Funding: This study was supported by Hebei Province Medical Science Research Key Project (No.20200069). The funding source had no role in the design of the study, data collection, analysis, interpretation of results, or manuscript preparation.

• Authors' contributions: Dr.Feiyan Ma contributed to the conception and design of the study, image acquisition as well as drafting of the manuscript. Dr.Hong Wang and Jing Yuan contributed to revision of the manuscript. Dr.Congrong Guo contributed to the image analysis, and Dr.Igor Kozak critical revision of the manuscript. All authors have read and approved the final version of the manuscript.

• Acknowledgements: We would like to express our gratitude to all the participants who took part in this study. We would also like to thank the staff members of the Ophthalmology Department of the Second Hospital of Hebei for their assistance during data collection and analysis. Additionally, we acknowledge the support and guidance provided by our colleagues and the valuable feedback from the reviewers, which greatly contributed to improving the quality of this manuscript.

Financial Disclosure Statement: None of the authors have any relevant financial disclosure.

Funding: 1. Precision medicine project of Hebei Natural Science (Grant No. 2022206571)

Disclosure Statement: All authors have no conflict of interest to disclose.

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No competing interests reported.

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Ocular Features of Pseudoxanthoma Elasticum Observed by Multispectral Imaging

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