The Extent of Retinal Involvement of Canthaxanthin Crystalline Retinopathy Demonstrated by Multimodal Imaging

Introduction

Canthaxanthin is a naturally occurring carotenoid used for artificial food-coloring, for the treatment of photosensitivity disorders such as erythropoietic protoporphyria, and as a tanning agent.¹ Once ingested, it accumulates in the dermis and subcutaneous tissues.^1,2 Previous studies have shown the deleterious effects of these golden canthaxanthin crystals on the retina.^3,4 The extent of retinopathy has been suggested to affect the inner retina,⁵ but a complete analysis of the retinal layers involved has not been reported. We present a case of a middle-aged woman with crystalline retinopathy due to canthaxanthin characterized using multi-modal imaging, including swept-source optical coherence tomography (SS-OCT).

Case Report

A 51-year-old woman from Bolivia had been experiencing progressive blurry vision of her left eye for 2 years prior to presentation. She had no past medical history or relevant surgical history. She was previously taking a skin-tanning medication called Broncearte for 7 years but stopped 3 years prior to presentation. She smokes half a pack of cigarettes daily.

On presentation, her vision was 20/20 in the right eye and 20/30 in the left. The fundus examination revealed a circinate pattern of crystalline deposits mainly in the left macula; however, there were a few scattered crystals seen in the right macula (Figures 1A and 1B). OCT imaging of both eyes revealed a normal macular contour with tiny deposits corresponding to the crystals scattered diffusely in the left more than right macula (Figure 2). In addition, when scanning the superior macula of the left eye, not only were there crystals in various layers of the retina, but also a loss of the outer retinal layers (Figure 2D). She was asked not to restart the canthaxanthin-based medication and to continue close follow-up with her local ophthalmologist in Bolivia.

Figure 1. Fundus photography at presentation (A, B) showed a few crystals (blue arrows) in the right eye (A). However, the left eye had a circinate pattern of crystalline retinopathy limited to the macula (B). Fundus photography 4 years later (C, D) revealed that although the right eye had significantly improved, the cathaxanthin crystalline retinopathy (blue arrow) was persistent but the number of crystals had decreased in the left eye (D) compared to presentation.

Figure 2. Optical coherence tomography at the time of presentation. The right eye (A, B) and left eye (C, D) at different areas of the macula demonstrated pinpoint hyperreflective material throughout the various layers of the retina representing the canthaxanthin crystals (blue arrows). In addition, (D) also had outer retinal subsidence and atrophy of the left superior macula.

The patient was lost to follow-up in our clinic but continued her routine follow-up with her local ophthalmologist in Bolivia. The patient returned to our clinic 4 years later, and her vision had improved to 20/20 in both eyes. Fundus examination of the left eye showed persistent but decreased crystalline deposits (Figures 1C and 1D). Although the right eye findings had improved, OCT of the left eye still showed persistent crystalline deposits in several retinal layers, and a scan of the superior macula of the left eye revealed new intraretinal fluid, persistent subsidence and atrophy of the outer retina, and a new retinal pigmented epithelial detachment (RPED) (Figure 3). SS-OCT (PLEX Elite 9000, Carl Zeiss Meditec, Dublin, CA) imaging revealed the multi-layer involvement of the crystalline retinopathy in the inner, middle, and outer retina of left eye (Figure 4). SS-OCT was able to detect both large and subtle pigmented epithelial detachments thought to be caused by crystalline retinopathy, that may have been missed by other imaging modalities. SS-OCT angiography did not reveal any exudative lesions (Figure 5). Therefore, these retinal changes were related to the crystalline retinopathy. The patient continues to be monitored closely.

Figure 3. Optical coherence tomography of the left macula 4 years after presentation continued to have canthaxanthin crystals (blue arrows) at various parts of the retina. New intraretinal cysts (yellow arrow) (B), disruption of the retinal pigment epithelium (B, C), outer retinal atrophy, and a pigmented retinal detachment (orange arrow) (C) were all detected at this visit.

Figure 4. Swept-source optical coherence tomography structural imaging using both en face and b-scans to look at different levels of the left macula using a 10-μm slab. (A) looked at the inner retina, (B) looked the middle retina, and (C) looked at the outer retina. At each level, canthaxanthin crystals could be seen (blue arrows and yellow boxes).

Figure 5. Swept-source optical coherence tomography (OCT) angiographic imaging using a slab between the retinal pigment epithelium (RPE) and Bruchs' membrane of the left eye. (A) OCT angiography en face flow image with a slab between the RPE and Bruchs' membrane of the left eye did not reveal any choroidal neovascularization. The pink navigation line cuts through an area of the retina with a pigment epithelial detachment (PED) (B, C). (C) Flow signal was not present underneath the PED. The blue navigation line cuts through an area of the retina with a subtle PED (D, E). (E) Flow signal was not present underneath this PED, either.

Discussion

Canthaxantin retinal toxicity was first described by Cortin in 1982.⁶ These highly reflective, golden crystalline deposits in the macula can cause a retinopathy with a dose-dependent incidence estimated of between 12% to 14%.^7–9 Carotenoids are believed to deposit in the lipid membranes, affecting permeability and fluidity of cells.^2,10 In vitro studies have shown that carotenoids can demonstrate pro-oxidant effects in high concentrations. In theory, vascular dysfunction may occur due to canthaxantin aggregated complexes disrupting the lipid membrane properties in vessels.^2,10,11

The extent of canthaxantin toxicity on all the retinal layers has not been reported. Daicker et al. described canthaxantin crystals affecting the inner layers of the retina using light and electron microscopy in an autopsy specimen from one patient.⁵ Ultra-high-resolution OCT by Duker et al. expanded on prior theories by suggesting that canthaxantin crystals could be found in the outer plexiform layers, as well.¹² To our knowledge, our current report is the first demonstration of canthaxanthin crystals being visualized in all layers of the retina, from inner to outer retina and the retinal pigment epithelium (Figure 4). Moreover, using SS-OCT en face structural imaging, we can correlate the crystals in different layers of the B-scan with the en face structural images, which allows for easier recognition of the crystals. In addition, we show that canthaxanthin retinopathy can cause outer retinal atrophy, as well as RPE disruptions leading to multiple RPEDs (Figure 5).

In patients with canthaxanthin crystalline retinopathy, prognosis is usually favorable with observation after cessation of this agent.¹³ Improvement in visual acuity can occur in many patients as it did in ours. However, crystals can remain many years after cessation of canthaxanthin and resolution of these crystals can take up to 20 years.^13,14 Although the actual number of crystalline deposits decreased with time in our patient, the retinal damaged caused by the crystalline retinopathy is permanent leading to retinal atrophy and RPE disruptions. Our patient is fortunate that these retinal changes occurred away from the fovea. However, close observation with SS-OCT angiography will be required to detect neovascularization that may form under the RPEDs.