Eye care practitionrs are intimately familiar with the ocular manifestations of systemic diseases. However, some diseases like cystinosis are so rare that we may have never seen a presentation in our office.
What is Cystinosis?
Cystinosis is an inherited, autosomal recessive metabolic disorder of chromosome 17, in which the amino acid cystine is improperly transported out of the body’s lysozyme cells. This causes cystine deposition in multiple organs, including the eye. The symptoms of cystinosis may present at any age, and the condition affects both genders and all ethnic backgrounds. There are only about 2,000 known individuals with cystinosis in the world—600 of those live in the U.S.1
If left untreated, children with cystinosis undergo kidney failure and die before age 10.2 So, how can you make the diagnosis? Slit lamp biomicroscopy reveals refractile, polychromatic corneal deposits, along with subjective symptoms of glare, photophobia, blepharospasm and recurrent corneal erosion.3 Visual acuity usually remains good.4 Rui Tavares, MD, and colleagues performed confocal microscopy on a 20-year-old female with infantile cystinosis and described the corneal crystals, found primarily in the anterior stroma, as hexagonal, needle-shaped and hyper-reflective. Cystine crystals can also be found in the iris, conjunctiva and the retina.5
Oral cysteamine, Cystagon (cysteamine bitartrate, Mylan), was FDA approved in 1994 for the management of nephropathic cystinosis in children and adults. Cysteamine works by converting cystine to cysteine and cysteine-cysteamine mixed disulfides, which are able to cleave lysozmes, thus reducing corneal cystine crystal accumulation. However, it is unable to prevent crystal formations in the cornea due to poor penetration.
In October 2012, the FDA approved Cystaran 0.44% (cysteamine ophthalmic solution, Sigma-Tau Pharmaceuticals), a topical ophthalmic drop for the treatment of patients suffering from corneal cystine crystal accumulation secondary to cystinosis. Cystaran has been manufactured since 1995 under the FDA’s orphan drug provision for pharmaceuticals developed specifically for a rare condition.6
From 1986 through 2012, the clinical safety and efficacy of Cystaran was evaluated in 300 patients who were enrolled in controlled clinical trials at the National Institutes of Health. Patients underwent an eye exam that included tests of retinal function and evaluation of visual acuity, night vision and color vision, age permitting. They were prescribed cysteamine eye drops in both eyes for every waking hour.
Patients were seen daily for the first week, and yearly therafter.Slit lamp photos were taken and a corneal cystine crystal score (CCCS) was calculated to assess the effects of treatment—absent or minimal corneal crystals were graded 0.0 to 0.25, while visible crystals were graded up to 3.00.7
The primary clinical efficacy endpoint was the response rate of eyes that had a reduction of at least one unit in the photo-rated CCCS when baseline CCCS ≥1, or a lack of an increase of more than one unit in CCCS when the baseline CCCS <1. Study 1 combined the data from three smaller studies: Eyes with a baseline of CCCS <1 had a 13% response rate and eyes with a baseline of CCCS ≥1 had a 32% response rate. Study 2 found a 62% response rate in ocular cystinosis patients who had a baseline of CCCS ≥1. Study 3 found a 33% response rate for ocular cystinosis patient eyes with a baseline of CCCS ≥1.7
The most frequent ocular adverse reactions include sensitivity to light, redness, ocular pain/irritation, headache and visual field defects.
Cystaran is dosed one drop in each eye, every waking hour. Because it contains benzalkonium chloride, contact lenses should be removed prior to application and reinserted 15 minutes after use. Cystaran is supplied in a 15mL opaque bottle. Unopened bottles must be kept frozen and then thawed for 24 hours prior to use. All bottles must be discarded after one week of use. Currently, Cystaran is available only through specialty pharmacy distribution channels.8
With the recent approval of topical Cystaran, patients suffering from cystinosis can effectively reduce or eliminate the deposition of corneal crystals and ease some of the ocular symptoms.
1. Kugler M. Cystinosis. About.com: rare disease. 2006 Apr 23. Available at:
rarediseases.about.com/od/rarediseasesc/a/cystinosis.htm. Accessed December 2012.
2. MacDougall R. FDA approves crystal-dissolving eye drops, a major milestone for NIH rare disease researchers. National Human Genome Research Institute. 2012 Oct 5. Available at: www.genome.gov/27550938. Accessed December 2012.
3. Cornea and external diseases. Digital Ref Ophthalmol. Available at: http://dro.hs.columbia.edu/cystinosis.htm. Accessed December 2012.
4. Tavares R, Coelho D, Macario MC, et al. Evaluation of treatment with cysteamine eyedrops for cystinosis with confocal microscopy. Cornea. 2009 Sep;28(8):938-40.
5. Tsilou ET, Rubin BI, Reed GF, et al. Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis. Cornea. 2002 Mar;21(2):173-6.
6. U.S. Food & Drug Administration. Available at: www.fda.gov. Accessed December 2012.
7. Gahl WA, Kuehl EM, Iwata F, et al. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops. Mol Genet Metab. 2000 Sep-Oct;71(1-2):100-20.
8. Crystaran: highlights of prescribing information. Sigmatau. 2012 Oct. Available at: www.sigmatau.com/products/CYSTARANPI.pdf. Accessed December 2012.