Copyright 2002 American Medical Association. All Rights Reserved.
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We report a case of nephropathic cystinosis, with corneal crystals,
imaged and analyzed by in vivo confocal microscopy. The subject had a visual
acuity of 6/6 OU. Slitlamp biomicroscopy revealed dense, hyperreflective cysteine
crystals corresponding to a "Gahl score" of 2.75 to 3.00 in both eyes. In
vivo confocal microscopy highlighted dense, polyhedral crystals throughout
the posterior stroma and crisscrossing crystals of similar density throughout
the anterior stroma. Quantitative assessment suggested that crystal density
was lowest in the middle stroma. The longitudinal and transverse diameters
of a total of 100 crystals for anterior and posterior stromal layers were
measured and analyzed. The advantages of in vivo confocal microscopy for microstructural
analysis of a living human cornea might provide useful information about the
natural history of crystal deposition and growth throughout the stromal layers
in subjects with cystinosis.
Infantile nephropathic cystinosis may affect vision due to corneal disease,
retinopathy, or glaucoma.1 Of these 3 complications,
glaucoma is the one most commonly associated with significant visual loss
in adult subjects.2 Corneal crystals may
be observed as early as age 1 year, but they generally have a benign course
and rarely cause severe visual loss, although photophobia is a common symptom.3 Recently, corneal crystals have been successfully
treated with cysteamine drops.3,4
A 24-year-old man received a diagnosis of cystinosis at the age of 14
months and underwent renal transplantation at the age of 22 years. From the
age of 1 year he was treated with oral cysteamine hydrochloride that was changed
to oral cysteamine bitartrate because of a manufacturer's change in 1999.
He has always been aware of having photophobia but reported a worsening of
his symptoms following the change in his systemic medication; however, because
of serious life-threatening problems, his eye symptoms have been considered
less important. Unfortunately, the subject cannot be offered treatment with
topical cysteamine drops because the medication is currently not registered
in New Zealand.
The subject's examination in our unit included photobiomicroscopy, in
vivo confocal microscopy, tonometry, and fundus dilatation. The subject had
a visual acuity of 6/6 OU. Slitlamp biomicroscopy revealed dense, hyperreflective
cysteine crystals corresponding to a score of 2.75 to 3.00 in both eyes based
on the library published by Gahl et al.3 Careful
examination of the optical section revealed a random distribution of the crystals
throughout the corneal thickness; however, there was apparently greater density
toward the limbus (Figure 1).
Slitlamp biomicroscopy of the
cornea demonstrating dense hyperreflective cysteine crystals distributed throughout
the entire cornea of the right (A) and left (B) eyes. Careful examination
of the optical section reveals random distribution of the crystals throughout
corneal thickness (C and D).
Crystals were also identified over the anterior surface of the iris.
Intraocular pressures were 12 and 13 mm Hg, OD and OS, respectively, and there
were no signs of posterior segment involvement.
The methodology for in vivo confocal examination has been published
previously.5 In the case reported herein,
4 passes at a 900-µm working distance were used. To minimize image glare
and reflections from the hyperreflective crystals, the intensity of the light
was decreased to approximately half the usual intensity for human subjects.
The bright reflections prevented visualization of the cellular elements of
the stroma, but the endothelial mosaic and superficial epithelial layers were
clearly recognizable. Only the central cornea was examined because the reflections
from the peripheral cornea were very bright. Two acquisitions were performed
for each eye and a total of 900 images were saved onto a hard disk drive.
Despite being very photophobic the subject had no difficulties undergoing
In vivo confocal microscopy visualized the crystals in detail and their
appearance in both eyes was very similar. Immediately in front of Descemet
membrane the crystals were dense and polyhedral, the longitudinal and transverse
diameters measuring 85 ± 37 µm to 43 ± 29 µm (mean
± SD) (n = 50 measurements), respectively. Anteriorly, a few larger
crystals were highlighted; however, most of the smaller crystals were needle
shaped. Crystals in the anterior fifth of the stroma appeared to be crisscrossing
and of similar density, with longitudinal and transverse diameters measuring
57 ± 41 µm to 21 ± 17 µm (mean ± SD) (n =
50 measurements), respectively. However, quantitative assessment suggested
that crystal density was lowest in the middle stroma (Figure 2). The corneal endothelium and epithelium appeared to be
normal in respect to structure and cell density; however, stromal keratocytes
were shadowed by the crystals thus making evaluation impossible.
In vivo confocal microscopy demonstrated
dense, polyhedral crystals in the region in front of Descemet membrane (A).
Anteriorly, a few larger crystals were highlighted, and most of the smaller
crystals were needle shaped (B-D). Crystals in the anterior fifth of the stroma
were more crisscrossing and less bright than the crystals in the posterior
stroma (E and F).
The cornea has been called "the window to cystinosis"; however, the
cause for the severity and progression of the corneal presentation is still
not clear.3 It has been proven that cysteamine
drops may have a beneficial effect in up to 62% of symptomatic patients and
patients with recurrent erosion syndrome.3 However,
the effect of the medication has been evaluated "semiquantitatively" on the
basis of clinical photography.3
We report the application of in vivo confocal microscopy for imaging
both corneas of a subject who has nephropathic cystinosis. By careful modulation
of the confocal settings, the crystals can be visualized in detail, providing
an excellent opportunity for qualitative and quantitative analysis. We found
the central cornea to be best for analysis in our subject, but we believe
that this site may be beneficial for several reasons: the central cornea is
thinner with fewer crystals, providing easier structural discrimination and
measurement, the examination can be repeated using the pupillary margin as
a landmark, and, finally, the dynamics of the central cornea may be more closely
associated with the patient's symptoms such as photophobia and glare. In addition,
the examination by in vivo confocal microscopy is relatively quick (2-5 minutes)
and in this report our subject coped well with the procedure with no unusual
An alternative method of examination in these subjects is ultrasound
biomicroscopy (UBM).2 The advantage of this
technique is visualization of a larger area of the cornea and adjacent structures
including the conjunctiva, iris, anterior chamber angle, and lens.2 However, owing to low magnification, comparable
to the conventional slitlamp, UBM provides only a semiquantitative analysis
of the corneal crystals.2 Our report demonstrates
the advantage of in vivo confocal microscopy, not only in visualizing the
crystals but also in accurately measuring their dimensions. In vivo confocal
microscopy will equally cover the same age groups as previously examined by
UBM (>16 years); however, it might provide better follow-up of the corneal
changes especially following application of cysteamine eyedrops.2
Our in vivo confocal observations of the distribution of the corneal
crystals throughout the corneal thickness (z-dimension) did not concur with
the slitlamp observations. In the latter the crystals appeared to be evenly
distributed throughout the optical slice, whereas, confocal microscopy highlighted
greater density anteriorly and posteriorly, with least crystal density in
the middle stroma. By isolating the area of interest, confocal microscopy
offers the advantage of minimizing the effect of adjacent regions and in the
future might provide useful information about the natural history of crystal
deposition and growth throughout the stromal layers in subjects with cystinosis.
The study was supported in part by an unrestricted grant from the Maurice
and Phyllis Paykel Trust.
The authors have no financial interest to declare.
Corresponding author: Charles McGhee, PhD, FRCOphth, Discipline of
Ophthalmology, University of Auckland, Private Bag 92019, Auckland, New Zealand
Grupcheva CN, Ormonde SE, McGhee C. In Vivo Confocal Microscopy of the Cornea in Nephropathic Cystinosis. Arch Ophthalmol. 2002;120(12):1742-1745. doi: