This retrospective study of ophthalmological data of 12 cystinosis patients treated at the University Hospitals Leuven showed that, despite receiving treatment with a compounded preparation of aqueous 0.5% cysteamine eye drops combined with oral cysteamine, patients developed progressive corneal cystine deposition and keratopathy.
Corneal cystine crystals in patients with cystinosis appear as highly reflective needles in the epithelium, stroma and endothelium . These crystals can be identified as early as at 12 months of age in patients with INC and are clearly visible by 18 months of age . The crystals tend to accumulate first in the peripheral anterior corneal layers and later progress to the posterior cornea and towards the center, eventually filling the whole cornea with cystine crystals. These crystals are visible with the naked eye as a hazy layer once the entire cornea is affected . The crystals typically cause progressive photophobia and subsequent blepharospasm, impairing daily activities. Corneal punctate epithelial erosions, filamentary keratopathy, erosions, peripheral vascularization, band keratopathy, decreased corneal sensitivity, increased corneal thickness and glare have also been reported [8,9,10,11,12,13,14,15,16,17,18,19,20]. Corneal crystals do not necessarily cause a decrease in visual acuity; however, pigmentary retinopathy can be associated with the accumulation of these crystals in the cornea . All patients included in this case study showed a higher CCCS (≥ 2) at the end of the study, indicating progressive cystine depositions in the cornea despite treatment with aqueous 0.5% cysteamine eye drops. No improvement was observed in the degree of photophobia, blepharospasm and anterior segment complications. These results indicate that treatment with a compounded preparation of aqueous 0.5% cysteamine eye drops was not effective in this patient population in reducing the ocular symptoms of cystinosis at the doses used.
While corneal crystals can be found in all patients with cystinosis, retinal pathology, in contrast, is not always present . Bilateral and relatively symmetrical peripheral patches of depigmentation and mottling can be detected in the temporal quadrants; these progress to the posterior pole with macular edema, resulting in a decrease in visual acuity [8, 20]. Oral cysteamine treatment has a favorable effect on the retinal complications, whereas topical therapy is not effective in preventing them. In our case series, retinal dystrophy and retinal hemorrhages were observed in one patient.
Cysteamine eye drops have been reported to be beneficial in the treatment of corneal cystine accumulation and symptoms of keratopathy [7, 14] and are recommended to be used frequently, preferably every waking hour . The compounded preparation used in our study is comparable to the standard formulation described in the study by Tsilou et al. . The difference in efficacy could be explained by the suboptimal dosage regimen in our patients. Other formulations with comparable or lower concentrations of cysteamine have also been described to be successful at an hourly regimen [12,13,14,15]. Consequently, hourly instillation would seem to be more important than the concentration of cysteamine. However, this recommended dosage is not useful in real-life situations. Furthermore, treatment with cysteamine eye drops is reported to be associated with a burning and stinging sensation [3, 11], which might explain the reduced compliance (< 6 times/day) observed in patients included in this study.
Although cysteamine eye drops are the only available topical treatment in ocular cystinosis, these eye drops are not commercially available in Belgium, in contrast to most European countries. To counter this problem, hospital pharmacies usually prepare and dispense these off-licensed drops. However, these compounded cysteamine eye drops are not stable at different storage conditions. Compounded cysteamine eye drops can be easily oxidized to a less effective cystamine when stored at temperatures above − 20 °C [22, 23], which may negatively affect the efficacy of cysteamine eye drops. This instability may provide an explanation of why we found limited evidence of effectiveness in the patients included in this retrospective case study. However, since the stability of our formulation was not tested in this study, we cannot confirm this hypothesis at this time.
Cystadrops® (Recordati Rare Diseases, Milan, Italy) is a recently approved gel-like viscous commercial preparation of cysteamine that is indicated for the treatment of corneal cystine crystals in patients with cystinosis who are older than 2 years . Clinical trials have confirmed its efficacy and safety in this target patient population [25, 26]. The recommended dose of Cystadrops® is four times a day during waking hours  compared with once every waking hour for compounded cysteamine eye drops. Cystadrops® is also a more stable preparation of cysteamine and can be stored at room temperature for 7 days after opening . The decreased dosing frequency and improved stability of Cystadrops® may favor its use in the treatment of ocular cystinosis.
The main limitation of the present study is that it is a retrospective review of patients attending a single multidisciplinary clinic; consequently, it is subject to selection bias. In addition, some parameters reported by patients (e.g. pain, photophobia) were subjective assessments, and there was no quantification of corneal cystine deposition by means of in vivo confocal microscopy due to this procedure not being availability to the investigators during the study period. No control group was included, so the therapeutic impact of cysteamine drops could not be assessed. Also, the lack of efficacy of cysteamine eye drops seen in the study patients may be due to the low frequency of instillation and the relatively short duration of follow-up.