British Journal of Ophthalmology, 1978, 62, 821-830
Cogan's microcystic dystrophy of the cornea:ultrastructure and photomicroscopyANTHONY J. DARKFrom the Veterans Administration Hospital, and State University ofNew York Upstate Medical Center,Syracuse, New York, USA
SUMMARY Corneal biopsy specimens from 3 patients with Cogan's microcystic corneal dystrophywere examined by light and electron microscopy. Specimens were taken from corneas showingmicrocysts, geographic or map-like areas, and refractile striae. In all samples there is a bilaminatesubepithelial layer of fibrogranular material, the friability of which is probably the basis forrecurrent erosions in this disorder. Histochemical and ultrastructural findings provide furtherevidence that Cogan's dystrophy, the finger print/bleb dystrophy, and Meesmann's dystrophyshould be regarded as separate entities.
In their original account of microcystic dystrophyCogan et al. (1964) noted bilateral white dots, about0-1 to 0 05 mm wide, within the corneal epitheliumof 5 unrelated patients. The presumably spontaneousappearance of these dots in adult life, together withthe absence of inflammatory signs, naturally sug-gested an abiotrophic basis for the disorder. In thefollowing year Guerry (1965) supplemented Coganand colleagues' description by noting that the dotswere accompanied by relucent, often subtle, map-like or 'geographic' nebulae which lay anterior toBowman's membrane. These map-like patches arein fact the essential biomicroscopic feature of thiscondition, since they are often present withoutmicrocysts. In the same year Bietti's (1965) 'lacunardystrophy' was apparently an independent accountof the same disorder. There is general agreementthat the dots, and to some extent the map areas, arein a constant state of flux, disappearing or new onesspontaneously appearing often within a few days.Support for a dystrophic aetiology was provided byLaibson and Krachmer (1975), whose studies showfamilial incidences suggesting autosomal dominance.Although many patients with this disorder areasymptomatic, others experience annoying symp-toms either of epithelial breakdown or, if theopacities lie in the central cornea, of irregularastigmatism and diffraction.The pathological basis of the map areas seems to
Address for reprints: Dr Anthony J. Dark, Department ofOphthalmology, Veterans Administration Hospital, Syracuse,New York 13210, USA
be the deposition of an abnormal sheet of fibro-granular material which lies at the epithelial level.The microcysts were shown by Cogan and hisco-workers (1964) to represent degenerating cellswhich are surrounded but not engulfed by theirneighbours. In these and other respects there areundoubted resemblances between Cogan's dystrophyand the fingerprint/bleb dystrophy described byBron and Brown (1971). Hence Laibson (1976)considered that the two conditions are essentiallyvariants, though ultrastructural evidence of thiscontention is fragmentary.The fine structure of the corneal epithelium in 3
patients with Cogan's microcystic dystrophy is thebasis of the present study, in which its pathogenesisand relationship to other superficial dystrophiesfeaturing epithelial microcysts is discussed.
Case reports
CASE 1A white woman aged 58 years was found to haveimpaired vision in both eyes associated with bilateralposterior subcapsular cataracts. An intermittentsensation as of a foreign body had been present inboth eyes for several months. Irritation of one orother eye accompanied by watering and photo-phobia would occur at any time of the day and lastseveral hours. The slit-lamp microscope revealedmap-like areas in the epithelial layer of both corneas.They were associated with numerous white micro-cysts on the left side. The map areas were best seenin the oblique broad beam as greyish relucent
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Fig. 1 Biomicroscopic appearance of 'map' nebulae in pupillary zone. Illumination by oblique light andfrom iris, I.Lacuna, L, and rolled edges of map material are displayed. x 3. Inset, drawing of optical section of this area,E, epithelium; S, stroma x 70
patches irregular in shape and often perforated byround holes a millimetre or so wide (Fig. 1). Detailsof such a hiatus shown in Fig. 1 underwent nophotographically documented change over a 4-month period. The edges of these lacunae weresharply defined and in places seemed rolled over, anappearance which, as noted by Laibson (1976), isreminiscent of the capsular dehiscences seen in'pseudoexfoliative' disease of the lens. The curlededge was refractile in retroillumination both fromthe iris and if viewed with the ophthalmoscopeagainst the fundal reflex, when it appeared as ablack line. In optical section a bright seam underliesthe epithelium and coincides with the map areas.Near the lacunae this seam enters the epithelialband obliquely and terminates, becoming thicker atits free end, where it corresponds with the rollededge (Fig. 1, inset). In both corneas fine refractilelines were seen by retroillumination from the iris.They differed from those seen in fingerprint dys-trophy in that they could also be seen in the director focal slit-lamp beam, wherein they were visibleas greyish lines. None of these features showed anystaining with fluorescein, rose bengal, alcian blue,or iodonitrotetrazolium. The fluorescein-stained tearfilm rapidly broke up over the refractile striae andover the rolled edge of the geographic patches,probably indicating relative elevation of the cornealsurface at these points. Moreover, massaging thecornea through the closed lid resulted in well-
defined pools of fluorescein corresponding withthese structures. The anterior corneal mosaic wasintact. Corneal sensation to No. 7 nylon wasunimpaired.
Since removal of the left cataract was indicated,preliminary debridement of the affected cornealepithelium was undertaken 2 months before opera-tion. The regenerated epithelium, although showingnew map areas, was free of microcysts, and symp-toms of irritation improved. An uneventful leftcataract extraction was performed with resultant20/20 vision. The ablated corneal epithelium andthe cataractous lens were placed in fixatives appro-priate for subsequent microscopy.
CASE 2A 40-year-old white woman developed familialcataracts which 3 years ago had advanced to thepoint when left lens extraction was successfullyundertaken. Since then a soft contact lens had beencomfortably worn and provided her with 20/20vision. For the past few years, however, recurrentirritation of the right eye had been accompanied byredness and photophobia. Slit-lamp examination ofboth corneas showed geographic patches withrolled edges characteristic of Cogan's microcysticdystrophy and with staining characteristics similarto those in Case 1. One or two microcysts werefound sporadically in both corneas. A few grey linesresembling those seen in fingerprint dystrophy were
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Cogan's microcystic dystrophy of the cornea: ultrastructure and photomicroscopy
Fig. 2 Corneal epithelium.Microcysts, M, lie near rollededge of midepithelial lamina, L.Epithelial cells in this regionappear distorted by the laminaledge. Toluidine blue x 760
present in each cornea; they were visible in bothfocal and reversed light. Irritation of the right eyecontinued in spite of the liberal use of bland oint-ments, so that limited curettage of the cornealepithelium was undertaken. This was followed byless frequent attacks. The ablated epithelium waspreserved for microscopy.
CASE 3A white woman aged 60 was found to have correctedvisual acuities of OD = 20/30 and OS = 20/20.There had been no symptoms suggestive of recurrentepithelial breakdown. Geographic patches ofCogan's microcystic dystrophy as described abovewere present in both corneas. There were no micro-cysts but 1 or 2 sheaves of fine grey lines were seenin focal light. A 2-mm trephine was used to obtainan epithelial biopsy from the pupillary zone of theright cornea. Recovery was uneventful, and visionon the right side improved by 1 line.
Methods
Corneal epithelial biopsies from Cases 1 and 2 werefixed in 10% neutral formalin, dehydrated, and theninfiltrated with paraffin wax. Paraffin sections weretreated with various staining techniques to bementioned alongside the results.
Other corneal epithelial specimens from all 3patients were fixed in 2j% cold glutaraldehyde priorto osmification and embedding in epoxy resin.Pieces of the cataractous lens obtained from Case 1were fixed in 10% neutral formalin, osmified, andembedded in epoxy resin. Orientational sectionswere stained with toluidine blue and examined withthe light microscope while suitably thin sections
were stained with uranyl acetate and lead citratebefore being submitted to transmission electronmicroscopy with a Phillips 300 electron microscope.
Observations
LIGHT MICROSCOPYThe lens from Case 1 showed changes consistentwith posterior subcapsular cataract. There were noabnormal periodic acid Schiff (PAS) positiveaccumulations in relation to the lens capsule.Corneal specimens from the 3 patients consisted ofepithelium basement membrane and a subepitheliallayer of 'hyaline' material. Vacuolar degeneration ofthe epithelial cells together with acantholytic isola-tion of individual cells was seen in some sections.The subepithelial seam was lightly stained pink
in haematoxylin and eosin, and although otherwisestructureless consisted of a more densely stainedsuperficial layer and a paler deep layer. In placesthe superficial layer of this seam was insinuatedbetween the epithelial cells and lay at a variabledepth as a horizontal lamina between the surfaceand basal cells. In some areas this lamina wasapparently ruptured. The broken ends, which werecoiled, suggesting elasticity (Fig. 2), apparentlycorresponded with the rolled edges of the lacunaeseen with the slit lamp (Fig. 1 inset). There wassome distortion of the epithelial cells near therolled edges (Fig. 2), giving the impression that itwas conditioning their forward migration. Else-where continuity of the midepithelial lamina wasmaintained until it finally rejoined the subepithelialseam; the epithelial enclave thus isolated containedthe majority of the microcysts.The subepithelial and midepithelial seams were
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Fig. 3 Corneal epithelium.Microcyst, M, surface squames(arrowed), and nearby cellinterfaces are stained with alcianblue x 1070
a~~~~~~~~~~~~~~~~~~~-x ? b..........Fig.4Cornea! epithelium to show possiblepathogenesis.of.rfratil stie.().iiml.digofb.aiasueihla ebae. ()Olqeivgntoo.iia odit h epithelium (c.oizna.xtnin correspond...withstriae,theirduality is still evident. Toluidine~~~~....bluex..1100...
strongly PAS positive but did not stain with alcianblue or Gomori's reticulin stain. They were mono-
refringent in polarised light and did not exhibitautofluorescence in ultraviolet light.
Microcysts contained fragmented cell debriswhich was often PAS positive and invariablystained with alcian blue at pH 2-5 (Fig. 3) and withcolloidal iron. The lining surface of the microcystswas regularly stained with alcian blue, colloidal iron,and with Gomori's method for alkaline phosphatasein a manner similar to the anterior corneal surface.Cell borders in the vicinity of the microcysts were
often sharply outlined with alcian blue and colloidaliron. Pretreatment of paraffin sections with hyal-uronidase or diastase did not prevent or diminish
colouration with PAS, alcian blue, or colloidal ironin any of the above structures. In general, themicrocysts lay posterior to the midepithelial lamina,but a few lay close to the surface near the rupturedcurled-up ends of this structure.The refractile striae were apparently produced by
invagination of the subepithelial seam, a process inwhich both layers were involved (Fig. 4).
TRANSMISSION ELECTRON MICROSCOPYEpithelial cells for the most part appeared to behealthy but in places, especially posterior to themidepithelial lamina, varying degrees of hydropicdegeneration were seen to result in cytoplasmicpallor. This change was accompanied by acantholy-
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Fig. 5 Corneal epithelium, 'pale'cells, showing acantholysis, A,with intercellular accumulation ofgranular material x 3600
sis (Fig. 5) with the formation of amorphousgranules in the widened interspace, and was pre-sumably followed by cell shrinkage and microcystformation. Occasionally the basal cells showed finecytoplasmic processes extending into the sub-epithelial seam.
Microcysts contained a variety of cell fragmentsincluding myelin figures and cell membranes, butorganelles were rarely recognisable (Fig. 6). Thecell membranes surrounding these cysts were thrown
7- o- -wFig.6 Corneal epithelium.Microcyst separated by attenuatedsquames from tear film. Thesurface lining of cysts is throwninto microvilli. Cyst contentsinclude cell membranes, myelinfigures, granules, and vacuolatedcystoplasmic remnants. Montage
ON F ^; ,<- x 2100
into microvilhi similar to those of the surfacesquames. The midepithelial lamina (Fig. 7) consistedmainly of irregularly banded fibres embedded ingranular material similar to the superficial layer ofthe subepithelial seam with which it was continuous.Basement membrane and hemidesmosomes weresparse. The refractile striae were seen as inter-epithelial protrusions of both layers of the sub-epithelial layer and appeared to be produced byfolding of this membrane. Basement membrane and
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Fig. 7 Corneal epithelium, E, contains midepitheliallamina, L, composed of irregularly bandedfibres, embeddedin granular matrix producing a dappled effect. Basallamina and hemidesmosomes sparsely present. Occasionalcollagen-like fibrils (arrowed) lie alongside L x 4270
hemidesmosomes were sporadically present in theseinfoldings.The subepithelial seam in all specimens as noted
in light microscopy was bilaminate (Fig. 8). Abasement membrane was often present and appearedto have its normal complement of hemidesmosomes,but there were places where both elements wereabsent. The superficial layer consisted of granularmaterial which was intimately connected to thehemidesmosomes (Fig. 9). This material formed ahoneycomb-like system of compartments in whichlay fibres, some 50 nm long. They were composedof laterally aggregated fibrils 8 nm wide whichfanned out in three dimensions at both ends (Figs.10, 11). The deeper layer was mostly composed ofrandomly orientated fibrils banded at 28 nm (Fig.12). They had a dense outer rim and rarefied corewhen seen in cross-section. Coarser fibrils bandedat 66 nm like typical collagen were occasionallyinterspersed among the finer fibrils (Fig. 13). Insome places the deep layer was composed partly ofgranules measuring about 7 nm.
Discussion
The pathogenesis of Cogan's microcystic dystrophyhas recently been discussed by Cogan et al. (1974)and by Rodrigues et al. (1974). Both groups considerthat the microcysts, which are usually foundposterior to a midepithelial lamina of presumedaberrant basement membrane material, developbecause the forward migration of epithelial cells isnow mechanically inhibited by this lamina. Thustrapped, the deeper cells undergo changes in situ
Fig. 8 Bilaminate seam liesunderneath epithelium, E, andconsists of 2 layers: a superficialstratum, S, in which darklystained fibres are embedded infinely granular matrix, whichitself is in continuity withhemidesmosomes; and deep layer,D, which is less densely packedand contains finer randomlyorientated fibrils x 3780
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Fig. 9 Illustrates continuity oJbasement membrane-like granularmaterial of the superficiallayer with hemidesmosomes(arrowed) x 46 500
.-.,2>E j Eo
which fit them for their normal role as surfacesquames. Thereafter their programmed death isfollowed by autolysis and subsequent seclusion asmicrocysts. The microcysts move forward, probablythrough lacunae in the midepithelial lamina, andfinally their contents erupt into the tear film. Themorphological findings of the present study do notcontradict this view of the pathogenesis of themicrocysts, but it is equally possible that some otherfactor such as permeability characteristics of theintraepithelial lamina (which are unknown) mayresult in impaired metabolism of the deeper cellsand so contribute to their premature death. Phago-cytosis is not involved in the process of microcystformation, the walls of the cysts being formed byadjacent cells which flatten and surround withoutengulfing the dying cells. Tripathi and Bron (1973)observed acantholysis of the pale cells as the firstdiscernible sign of cell death, a finding confirmedhere. Histochemical findings in the present studysuggest that intercellular and surface accumulationof acid mucopolysaccharides may be an early signof cell upset which precedes microcyst formation.It is of interest in this connection that Skerrow andMatoltsy (1974) found significant quantities of PASpositive glycoproteins in their chemical analysis ofisolated desmosomes. These changes are suggestiveof a metabolic lesion rather than simply a vicariousmaturation due to impaired forward migration.Encystment is apparently followed by dehydrationshrinkage and finally autophagic breakdown. Similarmorphological observations on the formation ofmicrocysts were made by Broderick et al. (1974) intheir study of fingerprint dystrophy. A midepithelialsheet of basement-like material is not, however, a
feature of fingerprint dystrophy or of the otherconditions in which microcysts occur.
Subepithelial basement membrane material wasseen in all sections studied and it is presumablypresent over most of the cornea. It consists of two
W...?~Fi.10 Sapl efndjucio fsuefiil S ndeep~~~~lae,Dfsueihla atra 447
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microcysts to erupt into the tear film. Thus in placesthis layer is ruptured and the free ends curled backin a scroll doubtless corresponding with the bio-microscopic appearances of lacunae with rollededges (Fig. 1).
Fine refractile lines resembling those seen infingerprint dystrophy also lie at the midepitheliallayer. They are apparently produced by invaginationof the subepithelial seam and hence have a multi-
y~4 e fl ;>$
Fig. 11 Irregularly bandedfibre in superficial part ofsubepithelial seam contains numerous laterally aggregatedfibrils 8 nm wide embedded in fine granules x 88 500
layers. The first is a superficial zone containing finegranular material which is seemingly being synthe-sised in the vicinity of the hemidesmosomes. Thismaterial is compartmented like a sponge, in thecells of which lie peculiar banded fibrils reminiscentof those found by McTigue and Fine (1966) at theperiphery of the normal cornea. In places villousprojections extend from the basal cells into this layer.The deeper layer consists of banded fibrils which arepresumably abnormal type IV collagens. Friabilityof the abnormal material lying beneath the cornealepithelium appears to be responsible for the easewith which epithelium may be surgically removed inthis condition and it is probably the basis forrecurrent erosions.
Aberrant basement membrane at the midepitheliallevel is continuous with the more superficial laminaof the two subepithelial layers and has a similarstructure. Cells adjacent to this sheet of fibro-granular material are not otherwise identifiable asbasal cells; moreover, hemidesmosomes and normalbasement membrane are rarely discernible. Thislamina of fibrogranular material appears to be thehistological counterpart of the map-like nebulaeseen with the slit lamp. The midepithelial extensionsof the superficial layer of this basal seam may resultfrom tangential forces causing buckling. Epithelialcells insinuating posterior to this layer go on dividinguntil the lamina breaks, allowing these cells and the
Fig. 12 Randomly orientated fibrils banded at 28 nmoccupy the deep layer of the subepithelial seam x 120 400
Fig. 13 Occasional b-undles of collagen-like fibres, C,banded at 66 nm lie at the junction of the superficial, S,and deep, D, zones of subepithelial seam x 52 500
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Table 1 Corneal epithelial diseases with microcysts andabnormal basement membrane production
'Primary' 'Secondary'
Cogan's microcystic dystrophy H. simplex (Broderick and Dark,1976)
Meesmann's dystrophy Trauma (Laibson, 1976)
Fingerprint/bleb dystrophy Fuchs's corneal dystrophy (Bronand Tripathi, 1973)
Dysplasia of corneal epithelium(Dark and Streeten, 1978,unpublished observations)
laminar appearance in section. Laibson (1976) notedthat they may be the sole manifestation of thisdisorder in members of some affected kinships.Moreover, since microcysts may occur in fingerprintdystrophy as observed by Broderick et al. (1974),Laibson (1976) was led to postulate that map
nebulae, microcysts, and refractile striae are a
spectral expression of the same fundamentaldisorder.
In contrast to this view of a continuum the presentstudy serves to emphasise the differences betweenfingerprint and Cogan's dystrophy. Thus, the sub-epithelial seam and refractile striae in microcysticdystrophy consist of irregularly banded fibrilsembedded in a fine granular matrix, in contrast tothe granular ultrastructure of the striae and sub-epithelial seam seen in fingerprint dystrophy as
described by Broderick et al. (1974) and the sub-epithelial seam in bleb dystrophy by Dark (1977).Biomicroscopically the striae in Cogan's dystrophy
are visible in focal illumination as fine grey linesunlike those of the fingerprint disorder, which arevisible only in retroillumination. Moreover, thelarge 'putty' cysts of Cogan's dystrophy, as pointedout by Bron and Tripathi (1973), have distinctivemorphological and tinctorial properties which setthem apart clinically from microcysts seen in a
variety of other superficial disorders of the corneaof which Table 1 is an incomplete classification.A consideration of the histological and cyto-
logical findings also serves to delineate the 'primary'disorders of this group. From the present study ofCogan's dystrophy the basic ultrastructural cellchange appears to be hydropic cell degeneration,followed by shrinkage with intercellular accumula-tion of acid mucopolysaccharide (AMP). Fine andhis co-workers (1977) have shown that in Mees-mann's dystrophy autofluorescent AMP accumu-
lates within both the cell and the abnormal sub-epithelial seam; moreover, the ultrastructuralfinding of a 'peculiar' fibrillogranular material inthe cytoplasm is diagnostic of this disease. Infingerprint dystrophy Broderick et al. (1974) des-cribed cell shrinkage and the formation of multi-nucleated epithelial giant cells as the salient cyto-logical changes. There is thus increasing evidence(Table 2) for tentatively regarding these 3 disordersas separate diseases.
It is a pleasure to acknowledge Miss Sharon Edward'sresponsibility for the technical aspects of electron microscopyin this study.
This study was supported by a grant from the ResearchService of the Veterans Administration.
Table 2 Comparison of Cogan's, fingerprint/bleb, and Meesmann's dystrophies
Cogan Fingerprint/Bleb Meesmann
Epithelial cytology Intracellular oedema, acantholysis, Acantholysis, cell shrinkage, Diagnostic accumulation of fibrillo-intercellular accummulation of epithelial cell fusion granular material within cytoplasmAMP
MicrocystsBiomicroscopy Large (20 ,um to 1 mm) opaque Translucent or clear (10 to 100 ,m) Small stained with fluorescein (10 to
unstained with fluorescein staining with fluorescein 50,m)
Histochemistry AMP positive. No autofluorescence. AMP positive.* No auto- AMP positive. Autofluorescence. PASPAS positive fluorescence.* PAS positive positive
Ultrastructure Loosely packed amorphous debris Electron-dense masses Homogeneous vacuolated substance
Abnormal basementmembrane
Biomicroscopy Visible direct and retro beam as Visible only in retroillumination as Not observedmap nebulae and refractile striae fingerprint striae
Histochemistry AMP negative. PAS positive AMP negative. PAS positive AMP positive. PAS positive
Ultrastructure Fibrogranular Granular Fibrogranular and granular
* Dark, A. J.. unpublished observations
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