To report in vivo corneal confocal microscopic findings of patientswith central cloudy dystrophy of François.
Two unrelated patients, a 78-year-old man and a 75-year-old woman, withcentral cloudy dystrophy of François were examined using routine slitlampbiomicroscopy and confocal microscopy.
In both cases, slitlamp biomicroscopy showed bilateral polygonal opacitiesseparated by clear spaces. The corneal opacities were most prominent centrallyand were located in the deeper stromal layer immediately anterior to the Descemetmembrane. By confocal microscopy, normal superficial and basal epitheliallayers, midstromal layers, and endothelial layers were noted in both cases.However, small highly refractile granules and deposits were observed in theanterior stromal layer in both cases. Also, multiple dark striae among theextracellular matrix with increased intensities were observed in the posteriorstroma adjacent to the corneal endothelial layer in both cases.
Abnormal stromal deposits and multiple dark striae were observed incentral cloudy dystrophy of François using in vivo corneal confocalmicroscopy. Use of confocal microscopy to investigate these abnormal stromalopacities may be helpful in differentiating various corneal stromal pathologicfeatures.
Central cloudy dystrophy of François (CCDF) is characterizedby polygonal, cloudy gray stromal opacities separated by relatively clearlines, which creates a leatherlike crocodile appearance in the central cornea.1 This condition is presumably autosomal dominant andusually bilateral. In contrast, similar corneal opacities located at eitherthe central or peripheral cornea in the deep stromal layer are known as “posteriorcrocodile shagreen” and are usually considered to be age-related cornealdegenerations.2 Other than the hereditary pattern,the central corneal opacities in both conditions are typically located inthe axial two thirds of the cornea, are most dense posteriorly, and may extendinto the anterior one third of the stroma. To date, the knowledge regardingthe pathology of CCDF or posterior crocodile shagreen3- 5 hasbeen limited. This may be owing to the difficulty in obtaining diseased corneassince the corneal opacities in CCDF or posterior corneal shagreen do not interferewith vision and the corneal opacities or corneal shagreen are usually asymptomatic.Herein, we report the in vivo confocal microscopic findings of 2 cases ofCCDF.
Two unrelated patients having the diagnosis of CCDF were examined. Thisstudy was approved by the ethical committee of the Kanazawa University GraduateSchool of Medical Science, Kanazawa, Japan. Informed consents were obtainedfrom both patients after a detailed explanation of corneal confocal microscopy.Prior to the confocal microscopy, topical 0.4% oxybuprocaine hydrochloride(Benoxil; Santen Pharmaceutical Co, Osaka, Japan) was instilled in each eye.A corneal confocal microscope (ConfoScan 2; Nidek Technologies, Vigonza, Italy)was used to perform layer-by-layer analyses of the central corneas. Beforealigning the lens with the patient’s eye, 1 drop of 0.2% polyacrylicacid (Viscotirs; CIBA Vision Ophthalmics, Rome, Italy) was placed on the objectivelens of the microscope to protect the patient’s cornea in accord withthe manufacturer’s instructions. The objective lens was an ×40Achroplan (Zeiss, Oberkochen, Germany) water-immersion lens, with a numericaperture of 0.75 and a working distance of 1.92 mm. The center of the corneawas aligned to obtain tangential optical sections of the cornea; the z-axiswas controlled by a manual joystick. Each corneal confocal microscopic examinationwas completed within 2 minutes and encompassed 350 serial digital images.No software was used to enhance contrast of the images obtained by confocalmicroscopy.
A 78-year-old man was noted to have bilateral deep stromal corneal opacitiesduring the preoperative evaluation for cataract surgery. Postoperatively,he was referred to us for further evaluation of the corneal opacities. Hehad well-controlled type 2 diabetes mellitus. Both eyes were pseudophakicand the best-corrected visual acuity was 20/20 OD and 20/16 OS. Intraocularpressure was within normal limits in both eyes. Results of an external examinationand a dilated fundal examination were unremarkable in both eyes. On slitlampbiomicroscopy, polygonal stromal opacities separated by clear cracklike lineswere observed in the both eyes (Figure 1A).The corneal opacities were most prominent centrally and were located in thedeeper stromal layer immediately anterior to the Descemet membrane (Figure 1B). The distribution of the corneal opacitieswas symmetric in both eyes, and they were best detected by retroillumination.A clinical diagnosis of CCDF was made. Corneal endothelial cell density measuredby specular microscopy was 2364 cells/mm2 OD and 2109 cells/mm2 OS. No other abnormalities were detected in the corneal endothelium.Medical and family histories were noncontributory. There was no clinical evidenceof ichthyosis. Both corneas of the patient’s 52-year-old son were completelynormal, without any evident corneal opacity.
Slitlamp views of the left corneain case 1. A, Central corneal opacities with polygonal pattern separated byclear spaces were observed with broad beams. B, The opacities were more prominentcentrally and were located in the deep corneal layers anterior to the Descemetmembrane (arrows).
Confocal microscopy in the central cornea of both eyes revealed normal-appearingsuperficial epithelial layers with typical dark and light cells and basalepithelial layers with polygonal cells. However, in the superficial stromallayer adjacent to the corneal epithelium, small highly refractile granulesand deposits were observed (Figure 2A).The midstromal layers showed normal nuclei of keratocytes with a characteristiccoffee bean–like appearance (Figure 2B).Most notably, in the deep stroma adjacent to the corneal endothelial layer,multiple dark acellular striae among extracellular matrices with increasedintensities were observed (Figure 2C).The width of these striae varied from 10 to 20 μm. The directions of thesemicrostriae were highly variable, as they appeared as vertical, horizontal,oblique, or reticular lines. The corneal endothelial layer was normal.
Confocal microscopic images of theleft cornea in case 1. A, Small highly refractile granules and deposits wereobserved in the superficial stromal layer beneath the corneal epithelium.B, The midstromal layers showed a typical appearance of keratocytic nuclei.C, In the deep stroma anterior to the corneal endothelium, multiple dark acellularstriae among extracellular matrices with increased intensities were noted.Some small refractile granules were also noted in the posterior stroma. Barindicates 50 μm.
An otherwise healthy 75-year-old woman was referred to us for furtherevaluation of bilateral corneal opacity. She had been complaining of photophobiafor a few years. Her uncorrected visual acuity was 20/40 OD and 20/25 OS.Intraocular pressure was within normal limits in both eyes. Findings froma dilated fundal examination showed mild preretinal membrane in the righteye. By slitlamp biomicroscopy, gray polygonal central corneal opacities separatedby thin clear spaces in deep corneal stroma anterior to the Descemet membranewere observed in both corneas symmetrically. A clinical diagnosis of CCDFwas made. Corneal endothelial cell density by specular microscopy was 2090cells/mm2 OD and 2014 cells/mm2 OS. No other abnormalitieswere detected in the corneal endothelium. Medical and family histories werenoncontributory. No evident ichthyosis was noted. The 70-year-old sister ofthis patient had faint peripheral mosaic opacities without any central cloudiness,and the 50-year-old son of the patient had no discernible corneal opacities.
Confocal microscopy in the central corneas revealed normal-appearingsuperficial and basal epithelial layers. In the anterior stromal layer, however,small highly refractile granules were observed. Keratocytic nuclei with atypical coffee bean–like appearance were noted in the midstromal layers.In the deep stromal layer, multiple dark striae with increased intensitiesof the keratocytes and extracellular matrices were noted (Figure 3). The width of the microstriae varied from 15 to 25 μm.These microstriae also oriented toward various directions. The corneal endotheliallayer was normal.
Confocal microscopic images of theleft cornea in case 2. In the deep stroma anterior to the corneal endothelium,multiple dark striae among dense extracellular matrices and keratocytes werenoted. Some small refractile granules were also noted. Bar indicates 50 μm.
The typical findings of CCDF consist of gray-white, polygonal opacitiesseparated by relatively clear thin spaces with indistinct edges in the centralcornea.1,6 The condition was firstdescribed as faint, deep central stromal opacifications occurring in 2 siblingsand 6 additional unrelated patients.1 Two otherinvestigators subsequently described families with multiple affected membersand presumed an autosomal dominant inheritance mode.6- 7 Othershave also noted similar clinical appearances of CCDF, arcus senilis, and anterioror posterior crocodile shagreen.8- 9 Arcussenilis and anterior or posterior crocodile shagreen are usually seen in theperipheral cornea and are considered to be age-related corneal degenerations.Ichthyosis is also known to cause bilateral cloudy cornea10;however, in our patients this possibility was ruled out by a dermatologist.
Karp et al5 reported histological findingsof CCDF. By light microscopy, they noted a faint undulating appearance ofthe deep stromal lamella with the entire corneal stroma stained positive foracid mucopolysaccharide, most notably in the epithelial basement membraneand in the pre-Descemet stroma. By transmission electron microscopy, thickenedepithelial basement membrane intermingled with fibrillogranular materialswas observed. Also, numerous extracellular vacuoles with diameters of 250nm to 6 μm were present throughout the stroma but were most notable inthe mid and deep stroma. They noted that the keratocytes contained or weresurrounded by fibrillogranular materials. On the other hand, Krachmer et al3 reported histological findings of concurrent posteriorcrocodile shagreen and polymorphic amyloid degeneration. Transmission electronmicroscopy revealed distinctive irregular vertical and unique sawtoothlikeconfigurations of the stromal collagen lamellae, interspersed with patchesof 100-nm, widely spaced collagen, corresponding to the central cloudy opacitiesseen clinically.3 They did not find extracellularfibrillogranular vacuoles or the presence of acid mucopolysaccharide. Meyeret al4 also reported a similar sawtoothed patternof collagen lamellae in a patient with a full-thickness, mosaic pattern, centralcorneal cloudiness sharing features of CCDF, and posterior crocodile shagreen.However, their sawtooth structures are more prevalent in the anterior onethird of the stroma and they also noted numerous lacunae (0.5-2.0 μm indiameter) in the corneal stroma, similar to those reported by Karp et al.5 The significance of these sawtoothlike collagen lamellaeor fibrillogranular vacuoles or lacunae remains unclear.
In vivo corneal confocal microscopy allows better lateral resolutionand image contrast of the corneal layers than conventional imaging devicessuch as slitlamp biomicroscopy and specular microscopy.11 Italso allows a noninvasive, real-time, spatial sectioning of living tissuesat the cellular level. Consequently, confocal microscopy has been used successfullyto obtain and to differentiate images of normal and abnormal human corneas.11 We reported herein the findings of in vivo white-lightconfocal microscopic analysis of 2 unrelated patients withCCDF. To our bestknowledge, this is the first confocal microscopic analysis of CDDF. We foundthat both cases showed subepithelial and anterior stromal granules with highreflectivities. These granules might correspond to the fibrillogranular materialsor localized aggregates of acid mucopolysaccharide beneath the basement membraneof the epithelium, as previously observed by Karp et al.5 Toour best understanding, these pathological findings of subepithelial or anteriorstromal deposits have never been observed or reported in posterior crocodileshagreen.3 We also noted by confocal microscopythat similar refractile granules were present in the posterior stroma as well,but to a lesser extent (Figure 2C and Figure 3). Corneal stromal microdeposits canalso be observed by confocal microscopy in long-term contact lens wearers12; however, both patients reported herein had no historyof contact lens use.
Another striking feature noted in our patients on confocal microscopywas multiple microstriae (10 to 20-μm microstriae in patient1 and 15 to 25-μm microstriae in patient 2) among extracellularmatrices with increased intensities in the deep stromal layer. The increasedintensity of the extracellular matrices may correspond to the clinical cornealopacities, caused by extracellular accumulation of mucopolysaccharide andlipidlike materials.5 However, the etiologyof the microstriae in the deep stroma is unclear. These may correspond tothe histological findings of an undulating appearance of the deep lamella.3,5 We suspect that some microstriae mayreflect the clear spaces interspersed between the opacities, as they are acellularand with optical lucency by confocal microscopy. The presence of similar striaeon confocal images has been reported in other conditions such as keratoconusand after penetrating keratoplasty.13 Therefore,these findings may represent a common morphological alteration of the stromallamellae, induced by either a mechanical (such as surgery) or a nonmechanical(such as a degenerative process or abnormal stromal deposits) process.
The cause of corneal mosaic pattern remains unknown, but Bron and Tripathi14- 15 have proposed that anterior mosaicshagreen might result from relaxation of the normal tension of the Bowmanlayer. They surmise that when tension on the Bowman layer is released, a reproduciblepolygonal ridge pattern (as clear spaces between the mosaics) can manifestowing to the collagen lamellae inserting obliquely into the Bowman layer andsupporting the layer in ridges. A similar anterior mosaic can be seen in thesuperficial cornea by fluorescein staining after pressure patching of theeye. It can also be observed in a cornea with ocular hypotony, or in a keratoconiccornea that has been flattened by a hard contact lens.16 Itis also possible that the multiple microstriae we observed in both patientsusing confocal microscopy may represent microfolds caused by reduced tensionof the Descemet membrane similar to that proposed by Bron and Tripathi14- 15 in the case of anterior crocodileshagreen.
Further studies are necessary to correlate these confocal microscopicfindings with relevant histopathological findings. However, using confocalmicroscopy to investigate posterior stromal opacities may prove useful indifferentiating various corneal conditions with primary deep stromal involvements.
Correspondence: Akira Kobayashi, MD, PhD,Department of Ophthalmology, Kanazawa University Graduate School of MedicalScience, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan (firstname.lastname@example.org).
Financial Disclosure: None.
Submitted for Publication: October 22, 2003;final revision received March 9, 2004; accepted April 22, 2004.
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