Crystalline Keratopathy: Spectrum of Disease,

Diagnosis and Treatment

By Preeya K. Gupta, MD, Bhairavi V. Kharod, MD, and Natalie
A. Afshari, MD
Edited by Ingrid U. Scott, MD, MPH, Sharon Fekrat, MD, and
Woodford S. Van Meter, MD
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.

Infection

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.

Corneal Dystrophy
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

Systemic Disease
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 ophthalmologists 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

Medication
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.

Conclusion
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. ___________________________
1
2
3
4
5
6
7

Osakabe, Y. et al. Cornea 2006;25:12271230.

Weiss, J. S. et al. Cornea 1992;11:93101.
Gaynor, P. M. et al. Arterioscler Thromb Vasc Biol 1996;16:992999.
Jiao, X. et al. Am J Hum Genet 2000;67: 13091313.
Gahl, W. A. et al. N Engl J Med 2002;347: 111121.
Garibaldi, D. C. et al. Surv Ophthalmol 2005;50:6180.
Awwad, S. T. et al. Eye Contact Lens 2004; 30:169172.