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Ophthalmic Pearls: Cornea
Crystalline Keratopathy: Spectrum of Disease, Diagnosis and Treatment
Crystalline keratopathy is a condition in which crystals are deposited in the corneal epithelium and/or anterior stroma. Affected individuals frequently present to the ophthalmologist with symptoms of pain, decreased vision or photophobia. This condition may arise from a multitude of causes, such as infection, corneal dystrophy or systemic disease, that result in a buildup of metabolic products in the cornea.
Infectious crystalline keratopathy may occur with a bacterial infection. The infection can arise de novo or as a sequela of surgical procedures, such as refractive surgery and corneal transplants, if the cornea is traumatized chemically or mechanically. Streptococcus viridans is the most common organism to cause crystal deposits in the cornea, however, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus, Enterococcus, and Candida have also been reported as causative organisms.1 Eyes undergoing refractive surgery are at higher risk for infections with atypical organisms such as mycobacteria (acid-fast bacteria) and Alternaria (fungi). With the increasing number of patients undergoing refractive surgery and the relevance of early intervention, it is important to recognize infectious crystalline keratopathy. It may also be seen in corneal grafts of eyes that have undergone penetrating keratoplasty and in those eyes that have an otherwise immunocompromised cornea (e.g., chronic corticosteroid use and topical anesthetic abuse).1
Infection-related crystalline deposits have a fine branchlike shape, develop over time and may be associated with inflammation. Diagnostic testing such as gram stains, acid-fast stains, routine bacterial and fungal cultures, as well as mycobacterial cultures, should be obtained. It is important to realize, however, that culture yield may be low.1
First-line treatment of infectious crystalline keratopathy is with intensive topical antibiotics. Most corneal surgeons use “fortified” antibiotics such as cefazolin 50 mg/cc or vancomycin 50 mg/cc. When the organism has not been identified, a broad-spectrum antibiotic should be used. The antibiotic coverage should be tailored once the organism and antibiotic sensitivities have been obtained. If symptoms do not resolve, it is reasonable to expand coverage or to start systemic antibiotics. It is common for treatment of infectious crystalline keratopathy to be necessary for weeks or even months. In cases that do not resolve after penetrating keratoplasty, the ophthalmologist may consider repeat surgical intervention as a last resort. However, the ophthalmologist must be careful since an active infection can lead to the spread of the organism into the anterior chamber with endophthalmitis.
Several corneal dystrophies are associated with crystal deposits in the cornea. Corneal dystrophies are usually bilateral, symmetric and hereditary.
Schnyder crystalline corneal dystrophy. This is a slowly progressive, autosomal dominant dystrophy that is most common in persons of Swedish or Finnish descent.2 This condition is associated with central and midperipheral corneal opacification, dense arcus and decreased corneal sensation. Microscopic subepithelial corneal crystals of cholesterol and phospholipid are increased 10-fold and fivefold, respectively, in eyes with Schnyder crystalline corneal dystrophy3 and can cause discomfort with recurrent corneal erosion syndrome. Upon diagnosis of Schnyder corneal dystrophy, patients should be sent for a lipid profile because genetic alterations in lipid metabolism have been associated with corneal lipid deposition.3 Symptomatic patients with Schnyder corneal dystrophy are treated with phototherapeutic keratectomy for subepithelial crystals. Penetrating keratoplasty is reserved for severe cases with panstromal involvement. Lifestyle modifications and/or medications are recommended for treating elevated cholesterol.
Bietti crystalline corneoretinal dystrophy. This is an autosomal recessive dystrophy characterized by progressive night blindness and visual field loss. Clinically, this dystrophy manifests as tiny, yellowish, glistening retinal crystals; choroidal atrophy and sclerosis; and sparkling yellow-white crystalline deposits in the peripheral cornea at the level of the superficial stroma and subepithelial layers. No treatment is currently available for this disease.
Bietti crystalline corneoretinal dystrophy is associated with certain genetic mutations; therefore, family members of patients with this dystrophy also should be evaluated.4
Cystinosis. This is an autosomal recessive disorder of lysosomal membrane transport. There are two types of cystinosis: nephropathic and nonnephropathic. The latter is a benign variant of cystinosis in which crystals are absent from the kidney. Nephropathic cystinosis typically presents in the first year of life with polyuria, polydipsia, dehydration, failure to thrive and renal failure (Fanconi syndrome), with progressive systemic involvement if left untreated.5 In general, a later onset of disease expresses less severe systemic involvement.
Diagnosis is made by the presence of an elevated leukocyte cystine level (a standardized laboratory test) and/or evidence of cystine crystal formation in the cornea.5 This is critical because in the nonnephropathic variant, initial diagnosis will often be made by the ophthalmologist since these patients do not present early on with renal failure. The diagnosis can be made using careful slit-lamp examination. Polychromatic cystine crystals can be seen in the conjunctiva, corneal stroma (densest in the peripheral cornea but present throughout the anterior stroma) and trabecular meshwork.5
Early diagnosis and treatment is critical in nephropathic cystinosis as patients can suffer progressive renal problems in advanced stages of the disease. Oral cysteamine (an aminothiol drug that facilitates membrane transport of cystine out of lysosomes) should be administered to treat systemic manifestations. The oral form, however, is not needed to treat related eye disease. Topical cysteamine eyedrops are used to dissolve corneal crystals and relieve ocular symptoms.5 Patients should be referred to a primary care physician and to a geneticist if available.
Lymphoproliferative disorders. Monoclonal gammopathy and multiple myeloma have been reported as rare causes of crystalline keratopathy,6 and the ophthalmologist should entertain the possibility of a lymphoproliferative disorder in a patient who does not fit the clinical pattern of other causes of crystalline keratopathy. Corneal deposits may be in the epithelium or stroma and are variably symptomatic.6 A thorough history and physical examination may reveal a patient complaining of “bone pain,” frequent bruising and even a history of multiple fractures. A conjunctival biopsy and blood/bone marrow smear can be obtained to aid in the diagnosis of a lymphoproliferative disorder. The patient should be referred to a primary care physician and a hematologist/oncologist for further workup and management. The ophthalmologist’s role in treating patients with crystalline keratopathy secondary to any lymphoproliferative disorder is to provide symptomatic care while the hematologist/oncologist provides treatment for the underlying systemic disorder.
Topical fluoroquinolone medications have been reported as a cause of crystalline keratopathy. Ciprofloxacin has been noted to cause diffuse crystal deposition in the cornea.7 The diagnosis is made clinically since crystalline keratopathy follows the initiation of the medication in an otherwise healthy cornea. These crystals are usually precipitations of the medications; therefore, crystalline keratopathy secondary to a fluoroquinolone resolves without any residual effects once the medication is discontinued.
Crystalline keratopathy is an important clinical entity that can occur secondary to a variety of causes ranging from topical medications to systemic disease. Once the diagnosis is made, the ophthalmologist should pursue a workup based on clinical evidence and history and establish the etiology of the crystals in order to implement timely and appropriate therapy.
2 Weiss, J. S. et al. Cornea 1992;11:93–101.
3 Gaynor, P. M. et al. Arterioscler Thromb Vasc Biol 1996;16:992–999.
4 Jiao, X. et al. Am J Hum Genet 2000;67: 1309–1313.
5 Gahl, W. A. et al. N Engl J Med 2002;347: 111–121.
6 Garibaldi, D. C. et al. Surv Ophthalmol 2005;50:61–80.
7 Awwad, S. T. et al. Eye Contact Lens 2004; 30:169–172.
Dr. Gupta is a resident in ophthalmology, and Dr. Afshari is an associate professor of ophthalmology. Both are at Duke University. Dr. Kharod is an assistant professor of ophthalmology at University of Arkansas Medical Center. Dr. Afshari has a research award from Research to Prevent Blindness.