Woman with corneal crystals undergoes evaluation

The patient previously had a renal transplant. Her family members also had similar ocular and renal problems.

Mark E. Patron

Andre J. Witkin

A 59-year-old woman was referred for corneal evaluation. The patient denied any recent changes in vision, pain or discomfort. She reported some mild glare and photophobia, which she had had for several years without recent change.

Ocular history was significant for diabetes without retinopathy. She had also long been told she had “crystals in her corneas.” She had no previous intraocular surgery or trauma. Her medical history was significant for hypertension, diabetes, renal transplant, hypercholesterolemia and hypothyroidism. Family history was remarkable for five of six siblings with similar ocular and renal problems.

Examination

On examination, the patient’s visual acuity without correction was 20/20-1 in the right eye and 20/30 in the left, with pinhole improvement to 20/25. IOPs were 12 mm Hg and 10 mm Hg, respectively. Both pupils were equal and reactive without afferent pupillary defect. Extraocular movements were full in both eyes and produced no pain. On slit lamp examination, there were diffuse fine corneal crystals from limbus to limbus, with bilateral diffuse patchy stromal scars and stromal vessels temporally in both corneas, as well as 1+ nuclear sclerotic cataracts (Figure 1). The vitreous was quiet in both eyes, and the retinal exam was remarkable for a congenital hypertrophic retinal pigment epithelium lesion in the right eye, without evidence of diabetic retinopathy in either eye.

Figure 1. Diffuse bilateral crystals from limbus to limbus with stromal scars and stromal vessels. Image: Goren JF, Duker JS, Goldstein M

What is your diagnosis?

Bilateral corneal crystals

The differential diagnosis of bilateral corneal crystals includes four broad categories: stromal dystrophy, medication toxicity, corneal infection and systemic disease.

Corneal dystrophies include macular, granular, lattice, Bietti’s and Schnyder’s. They are all typically symmetric, bilateral and hereditary. Macular dystrophy is an autosomal recessive disorder, often presenting in the first decade of life with ground-glass haze throughout the stroma leading to decreased vision and photophobia. The appearance is distinct from what is observed in our patient. Lattice dystrophy is a diagnosis made based on clinical appearance and does not match the crystals found in our patient. Similarly, granular dystrophy, which is also autosomal dominant and may cause recurrent erosions, is characterized by the presence of discrete opacities with clear areas in the intervening stroma. The appearance is typically different than that observed in our patient. Schnyder’s crystalline corneal dystrophy is an autosomal dominant, slowly progressive dystrophy most common in persons of Swedish or Finnish descent that typically presents with central and midperipheral corneal opacification, dense arcus and decreased corneal sensation. Systemic associations include hypercholesterolemia, but it is not typically associated with renal failure as seen in our patient. Bietti’s crystalline dystrophy is an autosomal recessive dystrophy characterized by progressive night blindness and visual field loss. Clinically, this dystrophy presents with sparkling yellow-white crystalline deposits in the peripheral cornea at the level of the superficial stroma and subepithelial layers, distinct from that seen in our patient.

Topical fluoroquinolones can cause the formation of corneal crystals; however there was no recent use of topical medications in our patient. Corneal infections may also cause crystal formation, with Streptococcus viridans being the most common causative organism. Infection is much more common after procedures such as penetrating keratoplasty or refractive surgery, and our patient had no history of ocular surgery. In addition, the eyes in our patient were white and quiet.

Systemic diseases such as cystinosis and myeloproliferative disorders can also cause corneal crystals. Multiple myeloma or monoclonal gammopathy of unknown significance may present clinically with ophthalmic findings such as bilateral eyelid ecchymoses and corneal crystals in the absence of widespread signs of disease. The ocular findings may be the first manifestations of disease. Typically, if there are no other clues to the diagnosis, these patients should undergo workup including urine and bone marrow analyses. In our patient, however, this is very unlikely given the presence of corneal crystals throughout the patient’s lifetime. Cystinosis would be highest on the differential diagnosis given the positive family history, onset in childhood and associated renal failure.

Discussion

Cystinosis is a rare, autosomal recessive disorder that is due to a defect in the lysosomal cysteine transport protein, leading to the intracellular accumulation of cysteine. The defect is localized to chromosome 17p13. When cystine cannot be transported out of the lysosome, it forms crystals that concentrate in the kidneys, bone marrow, pancreas, muscle, brain, testis and eyes.

The most severe form of cystinosis is infantile nephropathic cystinosis, which is also the most common. These patients typically present in infancy by 6 to 12 months of age, with growth retardation, renal tubular acidosis (Fanconi syndrome) and hypothyroidism, and they typically die early on from renal failure. Milder variants include late-onset nephropathic cystinosis, which has both renal and corneal manifestations that are milder than the infantile form. There is also an ocular variant that presents in adulthood with corneal crystals without renal involvement.

The typical ocular presentation of cystinosis includes conjunctival and corneal crystal deposits. The crystals are needle-shaped, refractile and polychromatic, and they typically extend throughout the full thickness of the cornea, initially starting in the corneal periphery and then spreading more centrally. There may also be associated band keratopathy. Symptoms include photophobia, glare, corneal erosions, decreased corneal sensation and a mild decrease in visual acuity. Posterior segment abnormalities include retinal crystals, hypopigmentation of the retinal pigment epithelium in the periphery with pigment stippling, and mild to severe visual field abnormalities.

Patients who have cystinosis are treated with oral cysteamine, which promotes growth, maintains glomerular filtration rate and preserves thyroid function. Cysteamine works by traversing the lysosomal membrane and interacting with cystine in a disulfide interchange reaction to produce cysteine, which then exits the lysosome via the lysine transport system, causing a decrease in the systemic crystal burden. Oral therapy, however, does not prevent the formation of corneal crystals. Currently, there is an ongoing clinical trial sponsored by the National Eye Institute involving the use of topical cysteamine drops to treat ocular cystinosis. Although topical therapy appears to decrease crystal density, topical cysteamine is readily oxidized and has to be maintained by freezing or packaging in argon, and because of this, it has not yet been approved by the U.S. Food and Drug Administration. Other treatment options for patients with significant symptoms include penetrating keratoplasty and phototherapeutic keratectomy.

Our patient had a previous diagnosis of cystinosis, confirmed with genetic testing. She had previously been a part of the National Eye Institute study described above, but had not felt that there was a significant improvement in her vision or quality of life, and so she had withdrawn from the study. The patient continues to be happy with her vision and experiences mild symptoms of glare and photophobia that do not affect her quality of life. We will continue to observe her.

References:

• Cantani A, Giardini O, Ciarnella Cantani A. Nephropathic cystinosis: ineffectiveness of cysteamine therapy for ocular changes. Am J Ophthalmol. 1983;95(5):713-714.
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• Gahl WA, Reed GF, Thoene JG, et al. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med. 1987;316(16):971-977.
• Goldstein DA, Schteingart MT, Birnbaum AD, Tessler HH. Bilateral eyelid ecchymoses and corneal crystals: an unusual presentation of multiple myeloma. Cornea. 2005;24(6):757-758.
• Iwata F, Kuehl EM, Reed GF, McCain LM, Gahl WA, Kaiser-Kupfer MI. A randomized clinical trial of topical cysteamine disulfide (cystamine) versus free thiol (cysteamine) in the treatment of corneal cystine crystals in cystinosis. Mol Genet Metab. 1998;64(4):237-242.
• Jean G, Fuchshuber A, Town MM, et al. High-resolution mapping of the gene for cystinosis, using combined biochemical and linkage analysis. Am J Hum Genet. 1996;58(3):535-543.
• Kaiser-Kupfer MI, Caruso RC, Minkler DS, Gahl WA. Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol. 1986;104(5):706-711.
• Yanoff M, Duker JS. Ophthalmology. Elsevier; 2009.

• Jordana F. Goren, MD, MS, Jay S. Duker, MD, and Michael Goldstein, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; website: www.neec.com.

• Edited by Mark E. Patron, MD, and Andre J. Witkin, MD. Drs. Patron and Witkin can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; website: www.neec.com.