282 British Journal of Ophthalmology 1995; 79: 282-289 Ultrastructural study of the comeal epithelium in the recurrent erosion syndrome Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from

Dorothy A Aitken, Zeidoon A Beirouty, William R Lee

Abstract microscopy the corneal epithelium in 23 Background-This study describes the patients who had developed epithelial sliding adhesion systems in the corneal epithe- usually after minor trauma. A number of addi- lium in the recurrent erosion syndrome tional findings were of interest and these and the mechanisms by which binucleate included the presence of binucleate cells, and multinucleate cells are formed within multinucleate giant cells, and polymorpho- the epithelium. nuclear leucocytes within the cytoplasm of the Methods-Twenty five samples of sliding comeal epithelial cells. epithelium were obtained from 23 patients and were examined by conventional light and transmission electron microscopy. Materials and methods Results-The separation of the anchoring system occurred either below the level of CLINICAL OBSERVATIONS the anchoring plaques or at the level ofthe In 17 ofthe 25 cases an abrasion was caused by epithelial cell membrane. Normal and trauma of various types (clinical details are degenerate polymorphonuclear leuco- shown in Table 1) including seven who cytes were found within and between the reported two or even three separate and seem- epithelial cells and within the anchoring ingly unrelated incidents. Of the primary layer. Binucleate and multinucleate cells injuries five were caused by a finger, two were were found within all the layers of the described as scratches, two involved twigs, two epithelium as were cysts containing resulted from minor assault, and the remainder degenerate celiular material. reported injuries caused variously by a key, a Conclusion-The presence of leucocytes napkin, scissors, and a snooker cue. Four cases and degenerate epithelial cells within the were considered to be idiopathic, one was sliding epithelium suggests that these are described as a map dot fingerprint dystrophy, the source of the metalloproteinases and the other reported an unspecified problem

which cleave Bowman's layer below the in one eye. Of the repeat traumas, four http://bjo.bmj.com/ anchoring system. The formation of occurred in the same eye and three reported binucleate and multinucleate giant cells trauma on a separate occasion in the other eye. does not appear to occur by fusion of The appearance of epithelial sliding occurred adjacent cells, but rather by nuclear any time from 2 days to several years after the indentation and cleaving due to an initial trauma. All patients were treated with abnormal microtubular system in the chloramphenicol (Parke Davis, Pontypool)

cytoskeleton. ointment alone or with a combination of on September 29, 2021 by guest. Protected copyright. (BrJ Ophthalmol 1995; 79: 282-289) Table 1 Summary ofclinical details Recurrent epithelial erosion was first described Recurrent in the ophthalmic literature by Hansen in Lab no Age Sex Nature of trauma sliding 18721 since when various authors have 1 113/89 25 M Scratch/finger + reported a series of similar and probably inter- *2 315/89 (see 1) Finger + related disorders of the comeal epithelium 3 135/89 47 M Key + 4 210/89 40 M fb/metal bracket/finger + + under variously named dystrophies.2-8 It has 5 211/89 76 M ?mdf + been suggested that these anterior membrane 6 46/90 44 M ?eye op/finger + 7 149/90 42 M Snooker cue + disorders such as Cogan's microcystic dys- 8 196/90 56 F Finger + trophy, Meesman's corneal dystrophy, map 9 200/90 32 M Scratch/elbow + 10 367/90 37 M Twig + dot fingerprint dystrophy, and recurrent 11 90/439 25 F Twig/finger + epithelial erosion9 10 may have a common 12 12/91 70 M fb sens +++++ 13 25/91 32 F ?/tweezers + + aetiology and anomalies of the basement 14 80/91 31 M Assault ++++ The Tennent Institute membrane are cited as the common factor in 15 81/91 27 F Scissors + of Ophthalmology, 16 97/91 33 M Assault +++ University of Glasgow, these disorders.5-11 Apart from these con- 17 16/92 73 F fb/spectacles +++++ Glasgow genital dystrophies, similar findings have been 18 53/92 57 F fb sens + D A Aitken reported following metaherpetic keratitis,12 19 58/92 64 F fb sens + Z A Beirouty 20 65/92 36 F Napkin + and as a rare complication of both cataract 21 80/92 33 M fb sens + + W R Lee 22 01/92 35 F Finger +++++ surgeryl3 and epikeratoplasty.14 An interesting 23 03/92 40 F Finger + Correspondence to: feature of recurrent erosion is that the epithe- 24 74/92 31 F Abrasion +++++ Dorothy A Aitken, Tennent *25 75/92 (see 24) Institute of Ophthalmology, lium readily separates and slides across the University of Glasgow, Glasgow GIl 6NT. corneal surface and can be easily removed. To + =Episode of recurrent sliding; * =second excision; investigate the adhesion system in corneal fb=unspecified foreign body; fb sens=complained of gritti- Accepted for publication ness: no evidence of foreign body; mdf=map dot fingerprint; 21 November 1994 erosion we have studied by light and electron ?=not specified in clinical notes. Ultrastructural study ofthe corneal epithelium in the recurrent erosion syndrome 283

~NO Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from

Figure 1 Light micrograph of corneal epithelial bopsy Figure 3 hlectron micrograph of a detached epithelium demonstrating binucleate (smaUl arrow) and multinucleate with well organised architecture. Inset: from another cells (large arrow). Haematoxylin and eosin, magnification specimen with attached Bowman's layer and anchoring X530. complexes (arrowheads).

ointment and drops. The age and sex distribu- MORPHOLOGICAL FINDINGS tions are shown in Table 1. Light microscopy In the majority of specimens, sections cut MORPHOLOGICAL OBSERVATIONS transversely across the rolled up specimen After topical anaesthesia with bupivacaine, the revealed the full thickness of the epithelial epithelial samples were easily excised with layers. In the 25 cases examined by light scissors and were fixed in 3% cacodylate microscopy the most notable feature in buffered glutaraldehyde. Small fragments of paraffin sections and toluidine blue stained folded yellowish/white tissue (1 to 8 mm) in semithin sections was the presence of multi- length were processed for paraffin histology nucleate giant cells, binucleate cells, or both using conventional stains (haematoxylin and (Figs 1 and 2). Some of these cells reached a eosin, periodic acid Schiff). Larger specimens large size and contained as many as 16 nuclei were divided and half of the tissue sample was and multinucleate giant cells and binucleate http://bjo.bmj.com/ post-fixed in osmium tetroxide, dehydrated in cells were located in all cell layers. Cysts graded alcohols, and embedded in Araldite for containing cell debris were present in 18 conventional electron microscopy. When there specimens (Fig 2): in many specimens was insufficient material for Araldite embedding polymorphonuclear leucocytes were con- on the initial submission, the tissue used for spicuous. paraffin histology was subsequently cleared in xylol, rehydrated, post-fixed, and reprocessed as on September 29, 2021 by guest. Protected copyright. above for transmission electron microscopy.

Figure 4 Normal control human comeal epithelium for comparison showing single columnar basal layer (B), two Figure 2 Another corneal epithelial biopsy showing to three layers ofwing or polygonal cells (W9, and two to multinucleate cells (small arrow) and encysted cells (large three rows ofsuperficial cells (S). The epithelium isfirmly arrow). Haematoxylin and eosin, magnification X 530. attached to an intact Bowman's layer. 284 Aitken, Beirouty, Lee Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from

Figure S Epithelial cells with numerous desmosomes. Note binucleate cell (large arrow) and a cell with a nuclear cleft (small arrow). Filaments are condensed in the clefts in the nuclei. Degenerate cells (d) are also present. Electron microscopy were numerous and bands of condensed The epithelial cell organelles were preserved surrounded some of these nuclei in each specimen and this was comparable with indentation where the clefts occurred with normal control tissue (Figs 3 and 4). In (Fig 5). At higher magnification fibrillar and most of the pathological specimens it was tubular structures (Figs 6 and 7) were identi- possible to identify the fied in the nuclear clefts and between the of the epithelium and anchoring filaments lobes of the nuclei. Bundles of microfibrils and plaques were persisting in the majority and microtubules could be demonstrated in (Fig 3), but the pattern was variable within an both longitudinal and transverse section individual specimen. In some cases the cell where they occupied 'nuclear holes' (Fig 6). membrane was the limiting layer at the base of In some larger cells the aggregates of fila-

the epithelium. Where the basement mem- ments and tubules appear to cleave the http://bjo.bmj.com/ brane complex was preserved, the outer zone nucleus (Fig 7). Cells apparently containing of Bowman's layer was present and hemi- more than two nuclei also appeared in all desmosomes, anchoring plaques, and fibrils the layers of the epithelium (Figs 8-10) and could be demonstrated (Fig 3, inset). The in some daughter nuclei, dissolution and epithelial cells throughout all layers were dispersion of nuclear chromatin suggested a attached by plentiful desmosomes (Figs 3 and degenerative process. Cells containing up to

5). Occasionally some cells in the superficial as many as eight nuclear profiles were also on September 29, 2021 by guest. Protected copyright. or basal layer were denser and less well identified in all the epithelial layers preserved than normal but this was possibly (Figs 8-10). These 'multinucleate' giant cells an in vivo drying artefact or could have been were, in most instances, firmly attached to produced by handling during the excision the mononuclear neighbouring cells by procedure (Fig 5). Cells with nuclear clefts desmosomes and the cytoplasm had the

-PEMIIJ -,~ owMMOrXM Figure 6 Filaments and tubules in cross section with nuclear holes as shown in Figure 5. Ultrastructural study ofthe corneal epithelium in the recurrent erosion syndrome 285 Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from

Figure 8 Giant cell containingfour apparently separate Figure 10 Part ofa multinucleate giant cell with nuclei each with a prominent nucleolus in the basal layer. condensed nuclear chromatin and cytoplasmic The cytoplasm is rarefied and contains bundles ofcondensed condensations similar to those seen in normal desquamating tonofibrils. cels.

characteristic paucity of organelles that is typical of the corneal epithelium. There was no evidence of desmosomal residues within the cytoplasm of the cells containing numerous nuclear profiles - a feature which could indicate cell fusion. In some areas the giant cells had pale oval nuclei (Fig 9) whereas others showed clumping of nuclear chromatin (Fig 8) even in undisputed multi- nucleate giant cells (Fig 10). Intraepithelial polymorphonuclear leucocytes were observed in many specimens (see Table 2) and were well preserved in general (Fig 11), but a signi- ficant number were degenerate and showed http://bjo.bmj.com/ secondary phagolysosome formation (Fig 12). The morphology suggested that the inflam- matory cells had been phagocytosed by the epithelial cells (Figs 12 and 13) and that this process progressed to encystment of derived from cellular condensed on September 29, 2021 by guest. Protected copyright. degradation (Fig 13). A similar process of Figure 11 Normal (arrows) and degenerate leucocytes phagocytosis of cells was observed in several (arrowheads) within the sliding epithelium. Cystic spaces containing degenerate material are present within the superficial layers.

rigure DYLsegeneratepolymorpnonuclearseucocyres Figure 9 Large cel in the superficial layer with prominent within the epithelium (arrows). It appears that some nuclear segmentation. The nuclear chromatin isfinely epithelial ceUls have endocytosed the leucocytes. Cystic granular and sparse suggesting a degenerative process. spaces (s) contain debris. 286 Aithen, Beirouty, Lee Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from

tigure 16 In a specimen in which Bowman s layer was Figure 13 An epithelial ceU (arrow) contains two retained, the remnants ofa degenerate polymorphonuclear identifiable polymorphonucear leucocytes and some nuclear leucocyte are debris. A similar epithelial cell (arrowheads) contains a (arrowhead) identified. circular mass ofcompact debris.

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Figure 17 A mononuclear cell with a nucleus containing on September 29, 2021 by guest. Protected copyright. Figure 14 Within the basal layer there is a multinucleate two prominent nucleoli and 'atypical' centrioles cell which contains a circular inclusion containing (arrowheads) within a nuclear cleft. Inset: a centriole pair identifiable*,q f * +ecells:<' *note zs,the >Jradjacent 's.*<.r.*smultinucleate P.e * *giant.'*cells + with satellite tubular arrays from another cell. (arrows).fE -/§'*. A--* r;'.5 ffis; ieb rss ?>E w ii lSbWt,,,SW gs iffi ;:> Db: ..... * ,; s > :

Figure 15 A large mass ofcondensedproteinaceous Figure 18 Perinuclear rod-like stnrctures in the epithelium material and cellular debris seemingly within an enlarged (arrows) have a banded crystalline structure at high epithelial cell. magnification (inset). Ultrastructural study ofthe corneal epithelium in the recurrent erosion syndrome 287

Table 2 Comparison ofmorphologicalfeatures mented clinically but only rarely by light and electron microscopy.2 45 6 13 Tonofibrils were Lab no bc mgc pmn Cyst bm prominent in the sliding epithelial cells in our Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from 1 113/89 +++ +++ +++ +++ + material. The appearances were similar to *2 315/89 +++ - +++ - ++ 3 135/89 +++ +++ ++ - +++ those described as abundant in an early report 4 210/89 ++ - +++ + +++ and tonofibrils 5 211/89 ++ - ++ + + of recurrent epithelial erosion16 6 46/90 +++ +++ +++ +++ + are known to be present to a much lesser extent 7 149/90 +++ +++ ++ +++ +++ in normal corneal epithelium.17 A more recent 8196/90 ++ - + - + 9 200/90 +++ Im +++ +++ + +++ significant report on epithelial abnormalities 10 367/90 ++ ++ ++ + - following epikeratoplasty illustrates in two tll 90/439 + + Im + + 12 12/91 ++ - + + ++ cases, an increase in tonofibrils which 13 25/91 ++ Im ++ + + ++ on the nucleus to the extent that 14 80/91 +++ lm + + - ++ impinged 15 81/91 +++ - + + ++ binuclear profiles were formed. 14 In our 16 97/91 +++ Im +++ + ++ + material binuclear profiles were identified in all 17 16/92 +++ +++ +++ +++ ++ 18 53/92 ++ - ++ + +++ the specimens examined by electron micro- 19 58/92 + Im + + + + scopy and were present at all levels in the 20 65/92 ++ +++ - ++ 21 80/92 ++ Im ++ +++ ++ ++ corneal epithelium. While the impingement of 22 101/92 ++ +++ + + ++ tonofibrils on the nucleus has been illustrated 23 103/92 ++ - - - ++ 24 174/92 +++ +++ ++ + - in the normal cornea,17 our demonstration of *25 175/92 +++ +++ ++ + - the presence of microtubular structures within *=Second excision; lm=visualised by light microscopy only; deep indentations in the nuclei suggests that t=not submitted for electron microscopy. this process is of importance in the formation bc=binucleate cell; mgc=multinucleate giant cell; pmn=polymorphonuclear leucocyte; bm=basement of binucleate cells. membrane. The abundance of multinucleate giant cells in the sliding epithelium in recurrent erosions of the multinucleate giant cells and the was an unexpected feature when the specimens spectrum extended from recognisable cellular were originally examined by light microscopy. constituents (Fig 14) to large cystic masses of Multinucleate giant cells were identified in the fibrillogranular debris (Fig 15). Debris sliding epithelium in 17 cases by light micro- derived from polymorphonuclear leucocytes scopy in paraffin sections. In the thinner was located below the level of the anchoring sections used for electron microscopy a system in some specimens (Fig 16). nucleus with numerous indentations could An interesting feature of the sliding appear as multinucleate. Also at the electron epithelium was the presence of epithelial cells microscopic level the section may only pass with atypical nuclear characteristics - for through one of several nuclei present at example, prominent nucleoli, centrioles, different levels within a cell which would have and a coarse nucleolonema (Fig 17). This been identified as multinucleate by light feature was conspicuous in most of the speci- microscopy. This latter feature of microscopy http://bjo.bmj.com/ mens (Figs 3, 5, 6, 8, 11), and centrioles, could explain why multinucleate giant cells assemblies of tubules, and dense aggregations were found only in nine specimens at the offilaments were also common findings in the electron microscopic level. Herpetic giant cells biopsies. In several specimens dark rod-like have been described in the pathology of herpes structures were observed adjacent to the simplex keratoiritis,'8 but the present morpho- nucleus (Fig 18) and at higher magnification logical study did not provide morphological periodicity could be demonstrated: the evidence to indicate a viral infection which was on September 29, 2021 by guest. Protected copyright. nature and significance of this feature are not also excluded by virological analysis. The known. present morphology did, however, resemble The morphological features are summarised the descriptions provided in a single case in Table 2. report of fingerprint dystrophy,7 a familial condition in which the epithelial attachment system is defective and in which there is some Discussion similarity to recurrent corneal erosion. A review by Chandler15 in 1945 gave a com- Brodrick et al 7 illustrated a multinucleate giant prehensive history of the early work dealing cell in the basal layer and multinucleate giant with recurrent epithelial erosion. At this time, cells encysting degenerate cellular material. An investigators considered that the pathogenesis alignment in a columnar configuration in- included a mild form of oedema caused by a dicated that as many as 12 cells had fused to thin layer of fluid under the epithelium, which form this giant cell.7 Some ofthe multinucleate increased at times of relapse. It was suggested giant cells in the examples of epithelial erosion that a defective endothelium was the cause in our series were similar to those described as of the persistent epithelial oedema and the fusing cells by Brodrick et al,7 but the majority aetiology was assumed to be neuropathic. In were dissimilar in architecture and outline 1964 Cogan et al described a microcystic (both circular and elongated) and were not dystrophy of the cornea.2 This and subsequent confined solely to the basal layer. reports3-10 described a variety of anterior The mechanism by which multinucleate corneal dystrophies with a pathology similar in cells are formed is as yet undetermined. It some respects to the intraepithelial cystic has been suggested that multinucleate giant degeneration which we describe in the present cell formation in epithelial cells is due to material. Microcysts containing what appeared biochemical factors produced by degenerating to be cellular debris have been well docu- cells.7 The presence of cysts containing 288 Aitken, Beirouty, Lee

degenerating cells was a common feature in plus the carboxyl terminal domain of type VII

our material and this adds support to the previ- have been located in the anchoring plaques.27 Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from ous suggestion.7 Similarly it has been shown in The epithelium is also thought to require the multinucleate tumour cell formation that adhesive macromolecules fibronectin and chemically induced changes in membrane to mediate attachment of the basal properties allow the close apposition and cells to the type IV and heparan ultimate fusion of cell membranes. 19 However, sulphate of the .29 Fibronectin we were unable to identify intracytoplasmic is also considered necessary for successful desmosomes which would indicate cell epithelial attachment and migration during membrane fusion and incorporation. Alter- resurfacing following minor injury29 and it has natively it is also accepted that where mitosis been shown that the occurs without cell cytokinesis, giant cells may molecules can influence and organise the also form: certain multinucleate giant cells are basal cell surface and also the actin rich cortex thought to form in this fashion - for example, of basal cells.303' The binding sites for the megakaryocytes and some types of neoplastic extracellular matrix molecules are protease cells.20 We cannot discount the possibility sensitive.3' Polymorphonuclear leucocytes, that the multinucleate cells in the comeal which showed a variety of degenerative epithelium were formed by mitosis without changes and were located in all levels of the cytokinesis, but on no occasion were mitotic epithelium, were present in our cases of recur- figures observed either by light or transmission rent erosion. The lysosomal constituents of electron microscopy. Multinucleate cells form- these leucocytes presumably released proteases ing in the absence of cytokinesis have been which caused proteolytic degradation of the shown to contain multiple centrioles20 which stromal5 and basement membrane.3' The are derived from microtubules. importance of metalloproteinases in the degra- In the normal attached comeal epithelium, dation of the epithelial basement membrane microtubules are only present in the mitotic has recently been emphasised and the best spindle.2' Centrioles are present but rarely characterised ofthese is collagenase.32 A 92 kD observed in the basal cell layer and almost (type IV and V) collagenase MMP-9 is syn- never seen in the wing and superficial cell thesised by neutrophils, macrophages, and by layers.22 However, it has been shown that corneal epithelial cells.32 This collagenase is during experimental wound healing the cyto- one of the two gelatinase subtypes of the plasmic extensions contain microtubules.21 In MMPs found in the cornea and is implicated in the present study microtubules were abun- both cellular invasion and degradation of dant (Figs 5, 6, and 7) and centrioles were a epithelial basement membrane before corneal common occurrence in all layers ofthe corneal ulceration.32 33 epithelium (Fig 17). In normal epithelium two Thus there are numerous complicated inter- centrioles are usually visible before mitosis, actions between structural and the http://bjo.bmj.com/ two daughters forming as a rule at right angles enzyme systems which control their synthesis to the parent but in the present material these and degradation and these mechanisms may be structures were not arrayed at right angles and regulated by various mediators such as growth this abnormality is an indication of nuclear factors released from epithelial cells and polyploidy.23 It is known that tubulin assembly keratocytes.34 It is hoped that this description in vitro can be arrested or stimulated by a of the ultrastructural pathology of recurrent variety of drugs and conditions,23 and we can erosion system and its spectrum of morpho- on September 29, 2021 by guest. Protected copyright. only speculate that some similar mechanism logical changes in the corneal epithelium and was triggered during epithelial repair follow- its anchoring system may aid in exposing the ing both the initial trauma and subsequent factors responsible for the susceptibility of this episodes of erosion. Chloramphenicol, the group of patients to an uncomfortable and common therapeutic agent prescribed in this recalcitrant disease. series of patients, has never been suspected of an 1 Hansen E. Intermittirinde keratitis vesiculosa neuralgica af having antimitotic effect and we do not con- traumatisk Oprindelse. Hospitalstid 1872; 201: Aug 15. sider this drug as the aetiological agent. Cited by Chandler'5. 2 Cogan D, Donaldson D, Kuwabara T, Marshall D. The most interesting feature in recurrent Microcystic dystrophy of corneal epithelium. Trans Am corneal erosion is the rapidity with which the Ophthalmol Soc 1964; 62: 213-25. loses 3 Kuwabara T, Ciccarelli EC. Meesmann's corneal dystrophy: epithelium adhesion and slides freely. a pathology study. Arch Ophthalmol 1964; 71: 676-82. The importance of anchoring systems in main- 4 Guerry D. Observations on Cogan's microcystic dystrophy of the corneal epithelium. Am J Ophthalmol 1966; 62: taining epithelial adhesion has long been estab- 65-73. lished24 and defective anchoring systems have 5 Cogan DG, Kuwabara T, Donaldson DD, Collins E. been incriminated in Microcystic dystrophy of the comea: a partial explanation epithelial erosions and for its pathogenesis. Arch Ophthalmol 1974; 92: 470-4. other anterior disorders.2-5 9 12-14 16 24 The 6 Rodrigues MM, Fine BS, Laibson PR, Zimmerman LE. previous Disorders of the corneal epithelium: a clinicopathologic literature must be reconsidered in study of dot, geographic and fingerprint patterns. the light of recent developments in the Arch Ophthalmol 1974; 92: 475-82. of 7 Brodrick JD, Dark AJ, Peace GW. Fingerprint dystrophy of understanding normal corneal adhesion the cornea. Arch Ophthalmol 1974; 92: 483-9. mechanisms. Collagen types I, III, V, VI, and 8 Bron AJ, Brown NA. Some superficial corneal disorders. laminin have been located in the anchoring Trans Ophthalmol Soc UK 1971; 91: 13-30. 9 Tripathi RC, Bron AJ. Ultrastructural study of non- plaques of the subepithelial basement mem- traumatic recurrent corneal erosion. Br J Ophthalmol brane 26 1972; 56: 73-85. complex25 and collagen type VII has 10 Bron AJ, Burgess EP. Inherited recurrent corneal erosion. been identified as a major structural com- Trans Ophthalmol Soc UK 1981; 101: 239-43. in the 28 11 Fogle JA, Kenyon KR, Stark WJ, Green WR. Defective ponent anchoring fibrils.27 Laminin epithelial adhesion in anterior corneal dystrophies. and type VI collagen,25 26 and type IV collagen AmJ Ophthalmol 1975; 79: 925-40. Ultrastructural study ofthe corneal epithelium in the recurrent erosion syndrome 289

12 Kaufman HE. Epithelial erosion syndrome: metaherpetic and laminin. Graefes Arch Clin Ophthalmol 1991; 229: keratitis. AmJ_ Ophthalmol 1984; 56: 983-7. 157-63.

13 Brodrick JD. Anterior membrane dystrophy following 26 Marshall GE, Konstas AG, Lee WR. Immunogold Br J Ophthalmol: first published as 10.1136/bjo.79.3.282 on 1 March 1995. Downloaded from cataract extraction. BrJ Ophthalmol 1979; 63: 331-5. fine structural localization of extracellular matrix 14 Frangieh GT, Kenyon KR, Wagoner MD, Hanninen L, components in aged human cornea. II. Collagen types V John T, Steinart RF. Epithelial abnormalities and sterile and VI. Graefes Arch Clin Ophthalmol 1991; 229: ulceration of epikeratoplasty grafts. Ophthalmology 1988; 164-71. 95: 213-27. 27 Keene DR, Sakai LY, Lunstrum GP, Morris NP, Burgeson 15 Chandler PA. Recurrent erosion of the cornea. Am J RE. Type VII collagen forms an extended network of Ophthalmol 1945; 28: 355-63. anchoring fibrils. J CellBiol 1987; 104: 611-21. 16 Goldman JN, Dohlman CH, Kravitt BA. The basement 28 Gipson IK, Spurr-Michaud SJ, Tisdale AS. Anchoring membrane of the human cornea in recurrent erosion fibrils form a complex network in human and syndrome. Trans Am Acad Ophthalmol Otolaryngol 1969; rabbit cornea. Invest Ophthalmol Vis Sci 1987; 28: 73: 471-81. 212-20. 17 Jakus MA. Ocularfine structure. Boston: Little Brown, 1964: 29 Berman M. The pathogenesis of corneal epithelial defects. 16. Acta Ophthalmol 1989; 67 (suppl 192): 55-64. 18 Hogan MJ, Kimura SJ, Thygeson P. Pathology of herpes 30 Sugrue SP, Hay ED. Response of basal epithelial cell simplex kerato-iritis. Am J Ophthalmol 1964; 57: 551-64. surface and cytoskeleton to solubilised extracellular 19 Chambers TJ. Multinucleate giant cells. JPathol 1978; 126: matrix molecules. J Cell Biol 1981; 91: 45-54. 125-48. 31 Sugrue SP, Hay ED. The identification of extracellular 20 Ghadially FN. Ultrastructural pathology ofthe cell and matrix. matrix (ECM) binding sites on the basal surface of London: Butterworths, 1982: 181-90. embryonic corneal epithelium and the effect of ECM 21 Gipson IK. Cytoplasmic filaments: their role in motility and binding on epithelial collagen production. J Cell Biol cell shape. Invest Ophthalmol Vis Sci 1977; 16: 1081-4. 1986; 102: 1907-16. 22 Hogan MJ, Alvarado JA, Weddell JE. Histology ofthe human 32 Matsubara M, Girard MT, Kublin CL, Cintron C, Fini eye. Toronto: Saunders, 1971: 65-82. ME. Differential roles for two gelatinolytic enzymes ofthe 23 Dustin P. Microtubules. New York: Springer-Verlag, 1984: family in the remodelling 131-41. cornea. Dev Biol 1991; 147: 425-39. 24 Khodadoust AA, Silverstein AM, Kenyon KK, Dowling JE. 33 Fini ME, Girard MT. Expression of collagenolytic/gela- Adhesion of regenerating corneal epithelium: the role of tinolytic metalloproteinases by normal cornea. Invest basement membrane. AmJ' Ophthalmol 1968; 65: 339-48. Ophthalmol Vis Sci 1990; 31: 1779-88. 25 Marshall GE, Konstas AG, Lee WR. Immunogold fine 34 Tervo T, van Settin G-B, Paallysaho T, Tarkkanan A, structural localisation of extracellular matrix com- Tervo K. Wound healing of the ocular surface. Ann Med ponents in aged human cornea. I. Types I-IV collagen 1992; 24: 19-27. http://bjo.bmj.com/ on September 29, 2021 by guest. Protected copyright.