MICROCYSTIC CORNEAL DYSTROPHY* BY Peter R. Laibson, MD INTRODUCTION

THE FIRST TWO REPORTS OF MICROCYSTIC CORNEAL DYSTROPHY WERE PRE-

sented at meetings of the American Ophthalmological Society.1'2 Since then other investigators have described this corneal dystrophy and found it to be more common than is generally realized. This study is an investigation of 78 patients seen over the past eight years, who have corneal changes recognized as part of the spectrum of superficial corneal disease called microcystic corneal dystrophy. Forty-eight of these patients belong to 20 unrelated families. The other 30 are isolated examples of this corneal condition. An analysis of patients for similar corneal changes to determine the incidence of this dystrophy in normal populations has been done prospectively. This work has been subdivided into the following sections: 1. Literature Review 2. Differential Diagnosis 3. Description of Pathology 4. Clinical Materials and Methods A. Analysis of 78 patients B. Pathology C. Prospective Study D. Description of Families 5. Discussion and Conclusions 6. Summary LITERATURE REVIEW MICROCYSTIC CORNEAL DYSTROPHY, (MICROCYST AND MAP CHANGES)

In 1964, Cogan and associates' documented five cases of a keratopathy not previously described. Because of the spontaneous and symmetrical appearance of these changes it was classified as a dystrophy. Clinically there were grayish-white, discrete, but occasionally confluent superficial corneal opacities as large as 1 mm in length but usually smaller *From the Cornea Service, Wills Eye Hospital, 1601 Spring Garden Street, Philadelphia, Pennsylvania. This work was partially supported by Biomedical Research Support Grant #05510 from the National Eye Institute. TR. AM. OPHTH. Soc., vol. LXXIV, 1976

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and variable in size and shape. They were most commonly seen in the pupillary area and sometimes caused slight reduction in visual acuity. Most often these changes were seen fortuitously at routine examination, and rarely caused a foreign body sensation. In one case an annoying blur led the authors to strip the epithelium from the central cornea, thereby providing a basis for the first histologic description of what is now called Cogan's microcystic dystrophy. The main findings were intraepithelial cysts containing pyknotic nuclei with cytoplasmic debris and anomalous basement membrane within the epithelium. The individual opacities varied, spontaneously appearing and diminishing with different distributions in the cornea, but were generally central. No uniform cause such as trauma could be found for these unique corneal changes. Symptoms were mild and transient, with blurred vision noted in three eyes. In one patient the vision was decreased enough to necessitate stripping the central epithelium. Foreign body sensation was present in two eyes and an erosion in another eye. There were no symptoms in three eyes and the last eye had been enucleated thirty years previously for a limbal melanoma. This eye was examined thirty years after enucleation for epithelial changes when the fellow eye developed epithelial cysts similar to those in those in the other four patients. Epithelial changes were not marked but thought to be pathologic and qualitatively similar to the alterations in the stripped epithelium of their first case. Other family members of these patients were not systematically observed. Nine cases were reviewed by Guerry2 in 1965 extending the findings of Cogan and associates. In addition to the microcystic changes previously noted in the corneal epithelium, Guerry found irregular faintly gray configurations varying in size from 1 mm to several millimeters in length, with clear zones between gray patches. The borders of the clear zones were a darker gray color. He called these changes maplike areas and also noted small irregular, putty gray dots (microcysts) similar to the ones described by Cogan and associates. Neither fluorescein nor Bengal rose stained any of these lesions. All of the patients reviewed had map areas, and 8 of the 9 also had microcysts. Symptoms were minimal in this group of patients. Five had no complaints, the corneal changes being recognized on routine but detailed slit lamp examination. One patient had slightly blurred vision and two others a little more blurring with vision varying from 6/12 to 6/18. Corneal curettage was performed on one patient because of blurred vision but it was difficult to tell in this "neurotic" woman whether the marked

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improvement in vision was real. Another patient, number 9 in the series, had corneal epithelial curettage after publication of the paper with improvement in her vision (personal communication, DuPont Guerry 1975). Visual acuity decreased sometime after debridement of the epithelium when similar epithelial pathology recurred. In two other patients contact lenses could not be worn because of considerable irritation with their use. These patients were aphakic. Guerry felt the microcystic epithelial dystrophy precluded use of a methylmethacrylate corneal lens. Other patients in his clinic with the same epithelial involvement have been able to wear soft contact lenses to improve visual acuity. He was unable to determine whether or not there was a hereditary pattern in this dystrophy, as hereditary studies were not performed. Stocker,3 in commenting on Guerry's paper in the Transactions of the American Ophthalmological Society on microcystic dystrophy stated, "The condition certainly is separate from the hereditary epithelial dystrophy described by Dr. L. B. Holt and myself, although there are also changes in the basement membrane of the epithelium observed there." Stocker proposed the term, "dystrophia epithelialis multiformis fugax (Cogan-Guerry)" to describe its location, variable appearance and fleeting nature, but, this descriptive term did not gain acceptance. Since Guerry's paper, 60 more cases have been reported.4-1" The findings in these cases parallel those of Cogan and Guerry and add several clinical aspects to this dystrophy which had not been described. There were more symptomatic patients in some series than in others. Trobe'0 stated that 54% of his patients had discomfort with severe or acute pain noted in 10 of 35 patients. Impairment of vision was noted in five patients, (vision reduced two Snellen lines or more). Bron and Triphathi4 found a few symptomatic patients with Cogan's microcystic dystrophy in their small series. They had symptoms of corneal erosion. These authors mentioned that microcystic dystrophy should not be confused with recurrent erosion. Generally the ocular complaints were minor in patients with microcystic dystrophy. Vision was reduced usually one line and there was no visual loss in many patients. Visual complaints were most prominent when the microcystic and map changes were in the central part of the cornea, over the pupil. Visual acuity in one of Levitt's8 two cases was reduced to 6/21 but vision improved when the microcysts went away. Although the visual loss was not great when recorded in Snellen lines the quality of vision was definitely impaired. Halos around lights and

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blurred second images were the most common complaints.5'9 Stripping the corneal epithelium was done on several eyes with two purposes in mind: first, to remove the cause of visual impairment and second to provide tissue for light and electron microscopic analysis. In eyes where the epithelium was removed the result was usually good to excellent. One patient reported two months afterward, "the operation was an unqualified success. "5 Seven eyes so operated upon achieved better vision and although there were minor relapses in some patients, all eventually had visual improvement and cessation of symptoms. Systemic disease does not play a role in this dystrophy according to several reports.12'10 Investigation of the precorneal tear film by detailed tear analysis including lysoplate test, spectrophotometric assay of lysozyme content and qualitative electrophoretic separation of tear proteins to measure nonlysozyme antibacterial factor (NLAF) revealed no abnormalities in these tear functions.9 The results of the Schirmer tests were inconclusive, but usually were within normal limits. Multiple other corneal lesions were seen in one series of patients. Arcus senilis, anterior crocodile shagreen, Vogt limbal girdle, Hudson-Stahli lines, and fingerprint lines in three patients were present.9 FINGERPRINT LINES

Fingerprint lines in the cornea were described by Vogt in his slit lamp atlas of 1930.12 It was not until 1950 that another report appeared on fingerprint-like lines in the cornea. Guerry13 then published two cases, a 65-year-old man and a 41-year-old woman, with wavy, very fine lines in their corneas. The whorl-like contour of these superficial corneal changes resembled fingerprints to him. This pathology was seen best by retroillumination. Guerry suggested that the lines might be present from birth but were not hereditary since children and three siblings of one of his two patients did not have similar findings. His description of this pathology 26 years ago is as good as any other published to date. "These lines were extremely narrow in width and paralleled each other in much the same fashion as fuirrows in a plowed field. They did not follow a particular curve but rather had a wavy contour simulating fingerprints. In general, the whorls tended to run parallel to the limbus, the convex portion facing peripheralward and the concavity, axially." "An attempt was made to localize these lines as to depth in the cornea but this was not too accurate since the lines were poorly

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seen with direct illumination. As near as could be ascertained, they were located in the basal layers of the epithelium or else in the extreme superficial zone of Bowman's membrane. "13 Curettage and chemical cautery was necessary for the 41-year-old woman when she developed a dendritic ulcer. After epithelial healing the fingerprint lines were no longer seen. She had two recurrences of dendritic ulceration within the next four months and eventually quieted. Her vision was 6/6-2 one year later. The fingerprint lines did not recur in her right eye and remained visible in her left eye. A second patient who was asymptomatic had similar lines in each eye with early bilateral cornea guttata. The differential diagnosis of fingerprint corneal lines was reviewed including a discussion of lines seen in interstitial keratitis, Fuchs' dystrophy and the lines around the base of the cone in keratoconus. Twelve years after Guerry's paper, DeVoe14 reported on fingerprint lines in the cornea, distinguishing them from superficial linear keratitis of Spicer.15 He had seen fingerprint lines on many occasions but felt, as did Guerry, that they were easily overlooked unless the observer is particularly interested in corneal disease. DeVoe thought one mechanism for production of this pathology is injury to Bowman's membrane with subsequent production of tension lines. Why they were only occasionally seen following such injury was not known. Three cases were described with histopathologic study in one case. There was a splitting of Bowman's membrane with the superficial portion thrown into folds that extended into the basal layers of epithelium. The histopathologic changes were suggestive of the changes seen in bullous keratopathy but were not typical of that disease. He referred to this alteration of the cornea as splitting or reduplication of Bowman's membrane. Kaufman and Clower16 described six cases with irregularities in Bowman's membrane. One case had marked fingerprint markings in one eye and minimal changes in the other eye. Because the irregularities in Bowman's membrane seemed to cause pain and loss of vision, the epithelium was removed. Following this, vision in the left eye improved from 6/30 to 6/7.5 without correction. The patient had no recurrence of pain or discomfort. The epithelium of a second patient was curetted and the vision improved from 6/24 to 6/6. This report was illustrated and the picture could be an example of the epithelial changes in microcystic dystrophy. Four other cases were described. In three the changes were present in one eye only. These patients had minimal if any complaints. The fingerprint-type of pathology in these

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corneas is not clear-cut, as the authors stated that the lines in Bowman's membrane had the appearance of fingerprints, but frequently they made circles and small craters suggesting the appearance of a flattened moonscape. Whether these corneas had fingerprint lines alone or a combination of other superficial corneal disorders as described by Bron and Brown17 or by Trobe and Laibson10 is not known. It is evident though that fingerprint changes may be accompanied by other superficial corneal pathology. Bron and Brown17 discussed superficial corneal disorders and included the fingerprint changes with bleb and net changes of the corneal epithelium. Eight patients were observed who had this fingerprint pattern. In six patients they were bilateral and in two unilateral. One of these patients suffered from recurrent corneal erosion. Nineteen other patients had combined findings of blebs, nets, and fingerprints. Fingerprint lines were noted to radiate from a superficial corneal scar in one eye of a patient and in the other eye there were similar fingerprint lines unrelated to any scar. They concluded that fingerprint lines were not a common counterpart of corneal scarring. Two more patients with fingerprint lines were studied by Poohkay and Hassard.18 Complaints were mild and vague in their patients and they did not require curettage. Brodrick, Dark, and Peace19 detailed the clinical and pathologic findings in another case of fingerprint dystrophy of the cornea. This patient had bilateral combined fingerprint and epithelial microcystic changes and suffered from recurrent erosion of the right cornea. Between the fingerprint lines, aggregates of microcysts were noted that appeared optically empty in retroillumination, but appeared grayish in focal illumination. Fingerprint lines were associated with microcysts or map patterns in 5 of 35 patients reported by Trobe and Laibson. 10 None of these patients had preceding trauma. In their study of 35 patients with dystrophic changes of the anterior cornea, 3 patients were included who had only the fingerprint pattern in their corneas. They reasoned that as the fingerprint pattern was associated with typical map and microcystic changes, the fingerprint itself could be a variant of these dystrophic corneal alterations. In another case report,20 a family was described in which one involved member had both the fingerprint and map pathology in each eye.

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Laibson DIFFERENTIAL DIAGNdSIS

Other anterior corneal changes may resemble microcystic corneal dystrophy. The clinical picture, family history, course of disease, and ultimate visual outcome usually distinguish these dystrophies and diseases from the microcystic corneal dystrophy. REIS-BUCKLERS CORNEAL DYSTROPHY

An anterior corneal dystrophy was described by Biicklers21 in 1949. Members of the same family had been reported by Reis22 32 years before. Families with this dominant dystropy or variants of it were more recently described by Rice and associates,23 Hogan and Wood,24 Giffith and Fine,25 de Vicentiis,26 and Smith, Wilson, and Williams.27 The major pathologic change is replacement of Bowman's membrane by a partly cellular, fibrillar material confined for the most part to the superficial cornea. There is no excess, splitting or reduplication of epithelial basement membrane.25 An early appearance in affected individuals, decreased corneal sensitivity, marked scarring in severe cases and need for corneal transplantation differentiates it from the microcystic dystrophy. GRAYSON-WILBRANDT CORNEAL DYSTROPHY

Grayson and Wilbrandt28 reported on a family with three cases resembling Reis-Bucklers dystrophy. Their patients differed in that a PAS-staining material was noted between Bowman's membrane and the epithelium. There were also areas where Bowman's membrane had been destroyed, as in Reis-Bucklers dystrophy. Corneal sensitivity was not decreased. The clinical picture, pathology, and course of their cases also can be distinguished from microcystic dystrophy, where Bowman's membrane is intact, corneal sensitivity is not reduced and vision is normal. STOCKER-HOLT CORNEAL DYSTROPHY

The rare hereditary dystrophy described by Stocker and Holt29 can easily be distinguished from microcystic dystrophy. It occurs only in members of one family descended from Moravian settlers. Corneal changes were seen in all age groups examined. It was felt that all patients with this pathology had the disease to some degree at birth or in early childhood. In most cases there were small whitish dots and serpiginous lines in the superficial cornea and there was superficial punctate corneal staining with fluorescein. The conreal sensitivity was reduced. Lesions located between Bowman's membrane and the epithelium, consisted of a thickened amorphous layer of dark red-stain-

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ing material. This was felt to be a product of diseased epithelial cells. The only treatment recommended for the more severe cases was corneal transplantation, which was successfully performed in one case. MEESMANN CORNEAL DYSTROPHY

Meesmann's epithelial corneal dystrophy is a rare hereditary bilateral disorder of the corneal epithelium which may be seen during the first few months of life.3031 It is a dominantly inherited dystrophy. The earliest corneal changes are tiny epithelial cysts, best viewed by retroillumination with the broad beam of the slit lamp. At first the interpalpebral corneal zone is involved but later all of the epithelium may show similar changes. These cysts, unlike those in Cogan's microcystic dystrophy, are very small, regular in size and shape, and usually spherical (Table I). The putty-like gray appearance and bizarre variable shapes seen in microcystic dystrophy are lacking in Meesmann's dystrophy. The onset of Meesmann's dystrophy is usually in the first year or two of life, as contrasted to a much later onset in microcystic dystrophy. FABRY'S DISEASE

A linear pattern of superficial corneal pathology is also seen in Fabry's disease. In this rare, sex-linked disease caused by an inborn metabolic error, there is a whorl-like picture in the superficial cornea from the formation of subepithelial ridges. The ridges, according to one report, are produced by a thin band of reduplicated basement membrane and are the result of production of amorphous material of unknown origin between basement membrane and Bowman's membrane.32 These ridges were not demonstrated in the carrier state according to another report.33 Since the changes are seen only in the affected male and in the female carrier, the corneal whorl-like pattern and skin changes differentiate it clinically from anterior basement membrane corneal dystrophy. Other whorl patterns in corneal disease were reviewed by Bron34 and readily distinguished from fingerprint changes in the cornea. RECURRENT CORNEAL EROSION

Recurrent epithelial erosion of the cornea is characterized by very small cysts in the corneal epithelium observed during and between episodes of erosion. These cysts can be differentiated from those seen in Cogan's microcystic dystrophy as they are usually smaller, varying from 10 to 100 ,u in diameter, are more uniform than the microcysts in Cogan's dystrophy, and are clear, containing little cellular debris (Table I). Us-

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ing slit lamp retroillumination, they appear as clear microvacuoles, some as small as two or three epithelial cells in width. They usually occur in the lower two-thirds of the cornea in an area where there has been previous traumatic loss of corneal epithelium. This has been referred to as the microform type of corneal erosion by Chandler.35 Recurrent erosion of the cornea may occur spontaneously as well as follow episodes of superficial corneal trauma. It has been described in families,3627 and after herpes simplex keratitis.38 Typical trauma which causes recurrent erosion is characterized by a glancing injury to the corneal epithelium, sometimes produced by a fingernail, the edge of a piece of paper, or by a tree branch, evergreen twig, or piece of string. Whether or not the injury can be recalled by the patient may not be significant, as very minor trauma which is quickly forgotten sometimes can produce recurrent erosion lasting for months to years. The corneal epithelial cysts observed in spontaneous erosions, erosions following trauma, and those occurring in families are similar. All age groups are affected by recurrent erosion, but the age range is different than in microcystic dystrophy. Usually, recurrent erosions following trauma and the typical accompanying epithelial cysts are seen between the ages of 20 and 50 years, whereas the cysts in microcystic dystrophy are noted more commonly after the age of 40. Both sexes are equally involved in recurrent erosion, while women predominate in Cogan's microcystic dystrophy. DESCRIPTION OF PATHOLOGY

MICROCYSTS

In order to recognize the fine corneal changes in this dystrophy, various means of slit lamp illumination must be used. The corneal epithelial microcysts are the most obvious findings. The smallest microcysts are dot-like or oval grayish-white points on the cornea. These pinpoint changes may be missed with focal illumination alone. To see them a broad slit beam should be used, with the slit directed from one side. These dot changes also can be recognized by retroillumination after dilating the pupil. The broad slit is placed directly in front of the examiner's binocular microscope, thereby blocking one ocular. With one eye only, the examiner sees the red reflex filling the enlarged pupillary space. Any fine opacity in the cornea or on the tear film stands out as a dark spot against this red background (Fig. 1). The fine microvacuoles typically seen in patients with healed recurrent erosion are distinguished from microcysts in this dystrophy, as they

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FIGURE 1

Microcyst seen directly in slit bean (A) as well as by retroillumination (B). Map changes are also seen as curving lines or mounded areas. (C)

contain little debris and appear almost clear. They are uniformly small and do not show the varied formation that is seen with microcysts (Fig. 2). The larger microcysts are irregular in shape but have smooth, rounded edges. I have seen microcysts 1 mm in length, but this size is rarely attained (Fig. 3). Microcyst color uniformity does not vary with size and even the largest ones haye a similar color to smaller cysts. MAP-LUKE CHANGES

The map-like corneal pathology is more difficult to recognize. In many cases these map changes are very faint (Fig. 4A). When they are located away from the central cornea the iris serves as a background rather than the black pupil, and map areas are more difficult to recognize. A combination of small maps located in the peripheral cornea challenges the ophthalmologist to detect their presence (Fig. 4B). To best find the map areas, broad and then narrower beams of the slit are directed from one side and then the other while the corneal surface is scanned in each quadrant (Fig. 4C). The fine slit cannot be used to locate these changes. Examination with retroillumination is also performed (Fig.

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FIGURE 2

Patient with recurrent erosion following localized epithelial abrasion by an evergreen tree branch. Very fine clear dots are seen in retroillumination (arrow). There were continued painful symptoms on awakening in the morning which gradually subsided as the dots faded.

4D). When looking at the corneas of family members of patients with microcystic dystrophy or patients with recurrent erosion symptoms but no obvious corneal changes, fluorescein is applied to the tear film and it is closely observed for early breakup. Maps which escape detection by other means can frequently be seen as the fluorescein rapidly flows away from the edge of the maps (Fig. 5). This leaves an outline of the edge of this pathology. One reason for this appearance is the slightly irregular egde of the map which may be minutely elevated, compared to the adjacent normal cornea. FINGERPRINT LINES

Fingerprint lines in the cornea were not considered part of the usual corneal changes in microcystic dystrophy by some authors, as they were not observed. 1'28'9 Other reports included these changes in microcystic dystrophy as part of the spectrum of pathologic corneal epithelial

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FIGURE 3

A: Variation in size of microcysts scattered across the central cornea. This picture was taken by focal illumination and no map changes are evident even though they were visualized with retroillumination. B: Opaque microcysts with wide variations in size stand out in this figure. A small map-like change is seen also (arrow). This picture was obtained by side illumination with the broad slit beam. Note how much brighter these microcysts are compared to Figure 3A even though they appeared

similar by focal illumination.

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FIGURE 4

A: Pinpoint microcysts with many confluent irregular larger ones. Map areas are faint but visible in this high power photograph taken with side illumination of the broad slit. The microcysts usually spare the clear cornea sharply outlined by the aberrant basement membrane but some microcysts are seen in the clear areas (arrows). B: Fine map area near the limbus of the cornea. This patient had no other corneal changes in this eye but had microcysts and map areas in her other eye. c: Obvious map areas seen by side illumination of the broad slit. There were no microcysts in this eye when the photograph was obtained but 6 months before 4 small microcysts were seen. D: Retroillumination photograph of map areas which appear mounded, and several small microcysts with the maps. The maps were seen by focal illumination but their full extent was not appreciated until viewed

by retroillumination.

changes. 10,16.17 Fingerprint lines can be found secondary to other disease processes in the cornea. These fine linear defects occur following trauma,14 corneal edema, herpes simplex keratitis, and recurrent erosion. They are particularly apparent near the wound at the upper limbus following cataract extraction, and are caused by endothelial damage at the wound site with secondary transient corneal edema. Patients who have early epithelial edema from Fuchs' dystrophy sometimes develop fingerprint lines when the corneal epithelium is elevated by

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FIGURE 5

Fluorescein pattern of stain around a map in the peripheral cornea. This map area was not visualized in this patient until studied with fluorescein. She is the mother of a patient with map and microcyst corneal changes.

edema and then flattens, leaving behind fine epithelial lines which look like fingerprints. These fine lines are the most difficult alterations to see. They can only be viewed well by retroillumination or by observation following application of fluorescein (Fig. 6). The examiner has to search the entire surface of the cornea, as they may be discovered in the central or peripheral cornea. An awareness of their possible presence in family members, in patients with the diseases mentioned previously, or in those examined specifically for this pathology is the only way these lines can be found. Other lines in the cornea have to be distinguished. Blood vessels are double contoured, branch and can be traced to the limbus. Ridges in Descemet's membrane are thicker and have shadows when viewed in retroillumination, besides being present in the back of the cornea (Fig. 7). The lines present in lattice dystrophy are easily distinguished by their depth in the cornea and thicker nature.

FIGURE 6

A: Multiple fingerprint lines seen by retroillumination. They appear in the slit beam at the pupillary margin (arrow) and against the red fundus reflex. Fine blebs are present above the fingerprint lines. These blebs are in the epithelium and are not caused by drying of the tear film. B: Fingerprint pattern photographed with retroillumination.

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FIGURE 7

Patient with interstitial keratitis caused by congenital syphilis. Two different linear patterns are present: first fine double contoured lines which are deep blood vessels (A) and thicker lines which are permanent folds in Descemet's membrane. (B)

CLINICAL MATERIALS AND METHODS ANALYSIS OF 78 PATIENTS

Seventy-eight patients with corneal pathology comprise the study group. These patients either had corneal epithelial microcysts, map-like changes, fingerprint-like lines, or combinations of these findings. Many other people were examined who were family members of these patients, but no corneal pathology was evident in their eyes. Bilateral corneal involvement was present in 71 patients and unilateral changes in 7 others. A total of 149 eyes with pathology, therefore, were evaluated. One hundred and thirteen of the 149 eyes had map areas, while microcysts and fingerprints were each noted in 49 eyes. The number of lesions is greater than the total number of eyes as some patients had more than one lesion (Fig. 8A). Sixty-eight

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Distribution of Corneal Patterns in Patients Examined

A Age Distribution of Patients

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0 - 9 10-19 20-29 30-39 40-49

Age in Years FIGURE 8

A: Distribution of corneal patterns in 78 patients with microcystic or epithelial basement membrane corneal dystrophy. B: Age distribution of 78 patients.

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of the 78 patients had corneal changes in at least one eye which were undisputedly the pathology of Cogan's microcystic dystrophy. Map changes alone (63 eyes) or map and microcystic areas (36 eyes) or solitary microcysts (1 eye) were found in these eyes. The other ten patients had fingerprint-like lines alone in each cornea. Five of these ten were discovered to have fingerprint lines only when examined prospectively as family members of patients with known microcystic dystrophy. Thus of the 28 eyes with fingerprint-like lines (Fig. 8A), 10 occurred in patients where at least one, immediate relative had microcystic dystrophy. The age of patients in this series ranged between 5 and 80. There were 27 men whose average age was 49.5 years and 52 women with an average of 52.5 years. In the group of patients with fingerprintlike lines alone, there were eight women and two men whose average age was 49.7. It was unusual to find these changes in the first three decades; only 5 cases of the total of 78 were found to be under 30 years of age. The incidence of pathology peaked in the fifth decade (Fig. 8B). The number of men and women involved in each decade was similar. There were a variety of ocular symptoms in these patients. Blurred vision, pain, and discomfort were the most common complaints, while photophobia and inability to wear contact lenses also were mentioned. Blurred vision was noted in 27 of the 149 eyes (18%). Erosion symptoms usually consisting of pain on awakening in the morning and gradually diminishing, occurred in 24 eyes (16%), while failure to tolerate contact lenses was noted twice and light sensitivity once. Distortion of images, double images, and halos around lights were noted by most of the patients who complained of blurred vision. Usually, vision was reduced only one or two Snellen lines. There were three patients who had significant reduction of vision (6/18 to 6/24). In their eyes, marked microcyst and map changes were present in the central cornea overlying the visual axis. Mechanical debridement of the central epithelium improved the quality and acuity of vision in each eye indicating that the distortion of vision was produced by the map and microcystic changes. The discomfort and pain of corneal erosion was a fairly common complaint occurring in 16% of the 149 eyes. In ten the pain was mild and fleeting, usually occurring in the morning on awakening and lasting only up to one hour. In 14 there was moderate to marked pain following episodes of corneal epithelial erosion. Ten patients with fingerprintlike lines had these problems while 14 with map and microcystic epithelial changes voiced these complaints. The corneal erosion was recurrent in 7 instances and nonrecurrent in 17.

507 Corneal Dystrophy In this study most of the epithelial pathology was discovered in patients referred by ophthalmologists for corneal evaluation following specific complaints such as blurred vision or pain. Examination of their eyes revealed the corneal changes which were considered to be the cause of their symptoms. Other patients found to have similar, but less extensive pathology had no symptoms. They were usually relatives of the patients referred originally. Relatives who were requested to come for screening were much more likely to be asymptomatic although many of them had the epithelial changes of microcystic corneal dystrophy. Examination of the tear film was performed on all patients. This included slit lamp evaluation of the precorneal tear film for excessive mucus and narrowing of the tear meniscus at the junction of the lower lid and the cornea. Schirmer's test strips were used and then fluorescein was placed on the lower bulbar conjunctiva for determination of the tear film break up time. There were no conclusive results from these procedures. The only consistent findings was an early breakup of the tear film over areas of fingerprint-like lines, and map changes. Schirmer's test was decreased in some of the older patients, but not more than would be expected from their ages. Corneal sensitivity was checked in most patients with the aesthesiometer of Cochet and Bonnet. No consistent abnormal patttern of impaired sensitivity was found in any age group. An evaluation of other ocular and systemic diseases was made for each patient. No alteration of other structures either in the eye or in the area of general health was found. The intraocular pressure was normal by applanation. Four patients had endothelial dystrophy in each eye but no sign of stromal or epithelial edema. The state of the endothelium was carefully checked in each eye, particularly those with the fingerprint pattern aldMe as similar lines occur in patients with Fuchs' dystrophy and following cataract extraction. PATHOLOGY

The histopathogenesis and histology of microcystic dystrophy5'39 and fingerprint dystrophy"1 have recently been investigated. Previously, light and electron-microscopic studies12'7'8"0'1 described the pathology of intraepithelial cysts in microcystic dystrophy. In many eyes these cysts were indistinguishable from the cysts seen in recurrent corneal erosion. 40'41 Cogan and associates5 suggested a relationship between aberrant basement membrane and microcyst formation. The microcysts (which are really pseudocysts as they have no walls5'7 are found where maturing epithelial cells are blocked by aberrant basement membrane ma-

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terial within the corneal epithelium. With their path from deep to superficial cornea blocked, the degenerating cells form clusters in the shape of microcysts. In most histologic studies the microcysts are described as being posterior to the abnormally placed basement membrane. The microcysts finally break through to the corneal surface either by rupturing through basement membrane or by migrating around the edges. In the light microscopic inset in Figure 9 aberrant or multilaminar basement membrane is seen (arrows) extending up into the corneal epithelium from the basal layer. A microcyst is seen to one side posterior to the misplaced basement membrane. Bowman's layer is intact, not involved in the process, and the stroma is normal. The intraepithelial cyst is surrounded by a normal appearing epithelial cell with no true cyst wall present. It is really a pseudocyst. The electron micrograph is a view of the cyst contents to show degenerated epithelial cell remnants. This patient had clinical pathology which was clearly microcystic dystrophy with map changes and microcysts in the central cornea. Mechanical debridement which removed the area of pathology and provided the specimen, also cured the patient of the irregular epithelial changes which caused blurred vision. FINGERPRINT LINES

Fingerprint-like corneal lines may accompany map and microcystic corneal changes or may be found alone. They have been seen in one eye without other epithelial pathology while in the opposite eye map changes were also present. These lines were examined by light and electron microscopy following a corneal biopsy. The biopsy was performed in an area of fingerprint-like lines on a patient with maps and fingerprints in one eye and only fingerprint lines in the biopsied cornea. The patient had symptoms of recurrent corneal erosion only in the unbiopsied eye. Normal Bowman's membrane is present indicating that only the epithelium is involved (Fig. lOB). The basement membrane of the corneal epithelium extends into the epithelium with apparent ridges (arrows) of multilaminar basement membrane apposed, but separated by a thin band of presumed collagen fibrils. These ridges of aberrant basement membrane are thought to be the histopathologic equivalent of the fine fingerprint line. Rodrigues and co-workers39 postulated that the most reasonable explanation for the fingerprint lines was very minor. trauma following which epithelial sliding might override to cause one edge to grow

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Patient with map areas and microcysts. Inset shows detached intraepithelial basement membrane (arrows) and epithelial microcyst. Bowman's layer (B) is intact. S indicates normal superficial stroma (toluidine blue, X 160). Electron micrograph shows degenerated epithelial cell remnants (*) in an epithelial microcyst (X5,760).

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FIGURE 10

Patient with fingerprint lines and map changes who had corneal erosion. Inset shows basement membrane excrescences (arrows) in the basal epithelium. Bowman's layer (B) is intact (toluidine blue, X355). Electron micrograph shows markedly thickened multilaminar basement membrane (BM) and associated detached hemidesmosomes (arrows). Collagen (C) separates basement membrane from Bowman's layer (X8,875).

over the everted opposite epithelial edge. They also felt the lines could be caused by minute epithelial looseness from slight edema ofdthe basal cells. The production of multilaminar basement membrane occurred apparently as the result of nonspecific epithelial basal cell activity. Brodrick, Dark, and Peace19 recognized the possible relationship between the fingerprint-like lines, microcystic dystrophy, and recurrent

Corneal Dystrophy

511

corneal erosion. They biopsied a patient's cornea with fingerprint lines who had sharp pain on awakening in the morning. Microcysts were seen by light microscopy but these cysts could be found in recurrent erosion or microcystic dystrophy. The fingerprint lines in their case were described as, "elongated blocks of amorphous material", which in some sections were continuous with basement membrane. This material is similar to the aberrant basement membrane in the epithelium (Fig. 10) of the patient with map and fingerprint changes described above. These authors hypothesized that metabolically disordered cells polymerized a fibrogranular protein that came to lie between basement membrane and Bowman's membrane. Persistence foci of activity resulted in budding processes which produced the fingerprint lines. Since the corneal epithelial basal cell can only function in a limited way to different stimuli, it is reasonable to believe that the production of aberrant multilaminar basement membrane by this cell may occur secondary to trauma, to corneal edema or infection and also may occur as a dystrophic or degenerative alteration. The fingerprint-like line may be as much a part of microcystic dystrophy as the map changes which are also caused by aberrant basement membrane. These lines may also be secondary to corneal erosion which occurs in this dystrophy and in other corneal diseases and therefore may not be a primary finding in microcystic dystrophy. The more accurate term epithelial basement membrane corneal dystrophy, describes the pathogenesis better than microcystic dystrophy. This label encompasses the map and fingerprint pathology and provides a reason for the microcysts first recognized by Cogan and associates. The label microcystic dystrophy probably will be retained, as it points to the major and striking pathology which is the hallmark of this dystrophy. The epithelial microcyst which is seen in this disease is difficult to distinguish from those seen in corneal erosion and recurrent erosion (Fig. 11). Aside from the history and clinical picture, the pathology of epithelial microcysts may provide some information for this distinction. The microcyst in epithelial basement membrane corneal dystrophy usually does not stain with fluorescein but those in recurrent erosion take up the dye later. One reason for the staining may be pooling of the dye in the cysts which break open to the surface following corneal erosion. An open cyst can be seen in two scanning electron micrographs (Fig. 12) of the same corneal tissue removed for electron microscopy in Figure 11.

512

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FIGURE 1 1

Patient with recurrent erosion. Inset shows intraepithelial microcysts of varying size (arrows) (toluidine blue, x 170). Note pale cells in basal zone of epithelium. Basement membrane is not attached to basal layer of epithelium. Electron micrograph shows a desquamated epithelial cell with pyknotic nucleus (N) within a small epithelial cyst (x6,120). PROSPECTIVE STUDIES

A bias for patients with microcystic dystrophy who have symptoms is introduced when the propositus of each family and isolated cases are referred because of their symptoms. The dystrophic corneal changes are only discovered after the examination. Family members who have epithelial basement membrane corneal dystrophy are found when they are asked to come for corneal evaluation rather than for symptoms.

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These patients examined in a prospective study were usually free of symptoms although in some cases corneal changes were as marked as in the propositus. In order to determine the relative frequency of microcystic dystrophy in the general population a prospective study was designed so patients could be evaluated in three separate geographic areas. Two hundred and fifty people were screened for corneal pathology. The examination was performed using a Haag-Streit slit lamp in a darkened room. Each examiner was well acquainted with the technique of finding subtle corneal pathology such as faint fingerprint lines. There were 165 women and 85 men in the study to reflect the sex ratio found in the 78 patients with pathology already discussed. The patients were grouped according to age so that most of those examined were over forty years of age. All patients were healthy and without ocular complaints when they were examined. Six patients were discovered to have fingerprint-like lines in their corneas. Four were women and two men. Two women were relateda 62-year-old mother and her 20-year-old daughter. The mother previously had symptoms of corneal erosion, but was comfortable when seen. There were seven patients with map areas in their cornea, five women and two men. None had symptoms of erosion but one had blurred vision (decreased two Snellen lines) in one eye. Map and fingerprint changes were recognized in two asymptomatic patients, a woman and a man. The fingerprint-like lines and map changes invariably were faint and difficult to detect unless the observer was looking specifically for them. None of the patients had any known eye pathology that could have produced these patterns. Only 1 patient of the 250 had typical microcysts and map changes as originally described in microcystic dystrophy. There were three small microcysts on the cornea of this woman and she was asymptomatic. The microcysts were noted in the mid-peripheral cornea within the map area. She was followed for six months during which time the microcysts disappeared and then reappeared in the same general area but not the same position. There were no symptoms during this time. Unfortunately family studies were impossible to obtain. DESCRIPTION OF FAMILIES

Nine separate representative familes are described of the 20 families found to have microcystic or epithelial basement membrane corneal dystrophy. Seventy-nine direct relatives in these nine families were examined. Twenty-seven had microcystic dystrophy and 52 did not. This dystrophy, which usually appears after the third decade, shows

Corneal Dystrophy

515

a dominant inheritance pattern. Corneal changes were found in only one generation (multiple sibs) in one family. In four families, two generations were involved and in four other families, three generations had the dystrophy. In the 11 families not detailed here there was involvement of two generations in 8 and three generations in 3 families. Five patients 50 years and older, with typical pathology of epithelial basement membrane corneal dystrophy including map areas in five and maps with microcysts in two, had their families examined. All members of these families were not examined for geographic reasons but wherever possible a local ophthalmologist provided the corneal evaluation. No other family members with corneal dystrophic changes were discovered in these five families. Both parents of two patients were deceased and one parent of each of the other three patients had died. CF Family: A 47-year-old woman (CF-6 Fig. 13A) had the onset of pain in her right eye two weeks prior to being seen. She was treated with antibiotics and patches, but when corneal staining with fluorescein persisted and developed a dendritic form, her ophthalmologist thought she had herpes simplex virus infection and started IDU therapy. Ten days later when there was no response she was referred for evaluation. There was slight epithelial fluorescein staining of the right cornea just at the upper margin of the undilated pupil. Map changes were present around this punctate staining, and four microcysts were noted. Her visual acuity was 6/7.5 in both eyes with best correction. Because the configuration of punctate staining was interpreted as a dendritic

lesion, antiviral therapy had been initiated. Idoxuridine was discontinued and 5% sodium chloride was prescribed as drops during the day and ointment at bedtime. One week later her symptoms had abated and visual acuity improved slightly. The map changes persisted in each eye, changing their shape but remaining in approximately the same position. Slight fingerprint lines were noted 3 mm from the limbus in her left eye. The fingerprint lines were seen only by retroillumination. Six months later she had an episode of pain in her left eye, and small corneal erosions could be seen over the map areas. The erosions responded quickly to increased use of sodium chloride drops and ointment and her vision did not decrease. Her 81-year-old father (CF-1 Fig. 13A) had no corneal pathology. Three sisters, ranging in age from 41 to 59 (CF-3,4,5 Fig. 13A) were seen and in one aged 48, paracentral fingerprint lines were found. Vision

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where the propositus is BC-1, a 67-year-old woman.

Corneal Dystrophy

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was normal in each ofthe sisters as was their corneal sensitivity, Schirmer's test, and ocular pressure readings. None had subjective eye complaints. Two daughters of the propositus (CF-8,9 Fig. 13A) were examined. One aged 28 had no symptoms but had an early tear film breakup time with several microcysts in the lower third of her cornea. Early map changes were seen by retroillumination, just below the pupil. This was present in one eye only. The other daughter had microvacuoles in each cornea just below the pupil, but no map or microcystic areas. Corneal sensitivity, tear film studies and applanation tonometry were normal in each eye of the sisters.

JS Family:

A 47-year-old man (JS-3 Fig. 13B) had complained of blurred vision, photophobia and halos around lights in his left eye for 14 months. He had no previous foreign body sensation or erosion symptoms. The past medical history was insignificant. Visual acuity was 6/5 in the right and 6/21 in his left eye with best correction. Corneal sensitivity was normal and the intraocular pressure by applanation was 14 in each eye. The Schirmer's test was within normal limits. In the right cornea map changes were present just below the pupil. Map and microcyst epithelial alterations were present over the optical axis in his left cornea. These changes caused early breakup of the precorneal tear film. He was followed for 18 months and in that time typical Cogan microcysts appeared and disappeared in the right cornea which had only map changes originally. The microcysts in his left cornea diminished and then increased in number but never disappeared. The map changes also varied slightly during the 18 month observation period. His vision fluctuated from 6/12 to 6/7.5+2. He never experienced discomfort. Four of the patient's five sibhngs were examined. His parents who were deceased never had eye problems. Two siblings were without anterior corneal changes (JS-4,5 Fig. 13B) but one had endothelial dystrophy. Two sisters JS-7,8 Fig. 13B) had map changes. They were 58 and 60 years old. The younger sister had many central map changes with early tear film breakup time. Her vision was only correctable to 6/9+2 in the right and 6/9-1 in the left eye although her pinhole vision was 6/6-2 in each eye. No microcysts or fingerprint changes were seen. The older sister's vision was 6/7.5 in the right and 6/9+3 in the left eye. Her vision was not improved by pinhole examination. She had map areas only in the superior third of the cornea and no microcysts. An early endothelial dystrophy was noted in each eye. Neither

518

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sister remembered having erosions, ulcers or foreign body sensation and both had normal corneal sensitivity and Schirmer tear tests. BC Family:

Slightly blurred vision in each eye for two years bothered a 67year-old woman (BC-1 Fig. 13C). She was relieved by artificial tears. The only ocular pathology noted was vitreous floaters until her ophthalmologist discovered corneal microcysts in the superficial cornea on a subsequent examination. Central and paracentral epithelial microcysts were present in each eye, with a background of map changes around the microcysts. Her vision was 6/6-2 in the right eye and 6/6 in the left eye. She did not experience discomfort related to these epithelial changes, such as ocular pain on awakening in the morning, corneal erosions, or even transient foreign body sensation. The remaining ocular examination was normal including intraocular pressure, Schirmer's test, and corneal sensitivity tests. Over the next 2% years, she was examined at four to six month intervals. Vision remained in the range of 6/6 to 6/9 without any subjective changes, except blurred vision from time to time. The microcyst and map changes varied in their appearance in each eye but did not disappear. Her parents were deceased and she did not have siblings. A 43-yearold daughter (BC-3 Fig. 13C) had fingerprint changes in the peripheral cornea 2 to 3 mm from the limbu4 in each eye and fine map changes. She had normal vision and no ocular symptoms. Her 19-year-old son also had no symptoms and normal vision, but map changes centrally in his right eye (BC-9 Fig. 13C). Three other children, aged 13, 17, and 21 years of age, (BC-6,7,8 Fig. 13C), had no corneal pathology. MV Family: MV, a 46-year-old woman, was referred because of recurrent corneal erosions and a "bilateral anterior corneal dystrophy" (MV-5 Fig. 14A). Her symptoms had begun about four months before and were typical of recurrent erosion, with sharp pain on awakening and then intermittent sharp pain continuing for 30 minutes to several hours. She was examined during an acute episode of discomfort. A small central erosion was noted in her right cornea. Fingerprint changes, corneal microcysts, and map changes were all seen in the epithelium in her right eye involving 2/3 of the central cornea. There was edema just beneath Bowman's membrane under the area of corneal erosion. In her left eye, fine microcysts were present in the central cornea with fingerprint lines and slight map changes. The fingerprint lines were con-

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A: VM family where the propositus is MV-5, a 46-year-old woman. B: BA family where the propositus is BA-li. c: SD family where the propositus is SD-6, a 39-year-old woman.

520

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centric with the inferior and nasal limbus and measured 4 mm in each quadrant. She was treated with an antibiotic ointment and an eye patch. In two days the erosion healed and her symptoms abated. The superficial corneal edema resolved when the erosion healed. One week later she was comfortable. Her vision improved from 6/21 to 6/9 after healing. Unfortunately, two weeks later a large area of erosion recurred necessitating debridement of the corneal epithelium from the center of her cornea. Gradually, the epithelium reformed and two weeks afterward she felt comfortable. In the central portion of the left cornea which never had an erosion, fingerprint lines, small map changes, and microcystic areas were seen. There was no history of previous trauma to either eye. She is seen at yearly intervals and complains of an occasional foreign body sensation which is transient, lasting for at most an hour. She has weaned herself from the 5% sodium chloride ointment and uses it only if symptoms return. Her visual acuity is 6/6-3 in the right eye and 6/6 in the left eye. This case illustrates that it is sometimes difficult to find other members of the family involved. Her 85-year-old grandfather was examined and had no corneal changes. Her grandmother was deceased. Her mother, (MV-1 Fig. 14A) had slight map changes in her right cornea but no changes in her left cornea. Three siblings (MV-2,3,4 Fig. 14A) were normal as were her five children who ranged in age from 13 to 20. BA Family:

A 39-year-old female (BA-li Fig. 14B) was referred by her ophthalmologist because of a corneal degeneration in her right cornea. She had blurred vision for six months without preceding trauma in her right eye. Her referring physician described corneal opacities in the central cornea of her right eye which had persisted since he began seeing her four months before. Her visual acuity was decreased to 6/ 24 in the right eye with pinhole improvement to 6/9. Her left eye had vision of 6/6. In the right cornea, there were multiple microcysts typical of the changes in Cogan's microcystic corneal dystrophy. These microcysts were numerous and varied in size from 1 mm to just pinpoint dots which could not be measured. The microcysts were located over areas of map changes in the cornea and usually occurred over the hazy portion of the geographic maps rather than in the central clear area. The density of these changes in the central cornea was responsible for

Corneal Dystrophy

521

her visual loss. In the left cornea, fingerprint changes were present as well as map changes and small microcysts just off the central cornea. The number and distribution of the microcyst and map changes permitted good vision in her left eye. Her ocular pressure, corneal sensitivity, and Schirmer's tear tests were normal. Tear film breakup time was increased over the central cornea where there was irregularity of the epithelial surface. Mechanical debridement of the central cornea removed the microcystic and map changes and although, with re-epithelialization, some map changes persisted, her vision improved to 6/9 in the right eye. In follow up over the past year, her visual acuity has fluctuated between 6/9 and 6/12 with only a few central microcysts returning in the right eye. Her 75-year-old father (BA-1 Fig. 14B) had large map changes in the right cornea but no microcysts. In his left cornea, a small map area was noted superiorly near the limbus with several small surrounding microcysts. His visual acuity was decreased to 6/60 in the right eye because of macular degeneration and was 6/9 in his left eye. The tear film, ocular pressure and Schirmer's tests were normal for his age. He had never had visual complaints or previous ocular injuries. Two siblings (BA-4,9 Fig. 14B) had corneal changes one with map areas and the other, both map and microcystic changes. Visual acuity was normal in each eye with no signs or symptoms of corneal erosion, foreign body sensation, or recognizable blurred vision. Six other siblings were normal. A 25-year-old daughter (BA-16 Fig. 14B) had an early faint map change in the right cornea but had no ocular symptoms. Three other children of the propositus and three children of two involved sisters all were examined and had no corneal changes. These siblings varied in age from 10 to 27. SD Family:

Repeated pain on awakening in the morning had bothered a 47-year-old man (SD-6 Fig. 14C) for three months. Recurrent corneal erosion was diagnosed by his ophthalmologist and when he did not improve with the use of topical tear replacement drops and Lacrilube ointment, he was referred for evaluation. His visual acuity was 6/6 in the right eye and 6/5 in his left eye. The applanation tonometry readings were 14 in each eye, and his corneal sensitivity and Schirmer's test were within normal limits. Map changes were present just below the optical axis in each eye with fine tiny microvacuoles in his left cornea interspersed with some of the map changes.

522

Laibson

These microvacuoles were not the microcyst described by Cogan and associates' but rather fine clear pinpoint epithelial changes which are frequently seen as a remnant of recurrent corneal erosion. Over the next six months with use of 5% sodium chloride drops three to five times a day, and 5% sodium chloride ointment at bedtime the recurrent episodes of erosion on awakening in the morning diminshed, and finally disappeared. His 56-year-old brother had map areas in the upper third of his cornea, but no central pathology and normal visual acuity (SD-4 Fig. 14C). A 54-year-old sister had normal corneas as did their 73-year-old mother. Their 74-year-old father (SD-2 Fig. 14C) had faint map changes around the central portion of his cornea which did not interfere with his vision. Neither the brother nor the father had ocular discomfort or complaints related to corneal erosion or foreign body sensation. Neither had ocular trauma prior to being examined. Four children of the involved brothers wre examined (SD-8,9,10,11 Fig. 14C). They varied in age from 12 years to 27 years and all four had normal corneas. CM Family: CM was five years old when she was first examined because of repeated erosions of her left cornea (CM-7 Fig. 15A). For one year she had had recurrent symptoms with intermittent blurred vision in her right eye. Her referring ophthalmologist thought the recurrences could have been caused by herpes simplex virus, but she did not respond to IDU therapy. Her visual acuity was 6/12 in the right eye and 6/6 in the left eye. The right cornea had fine map changes in the central portion with microvacuoles indicative of past recurrent erosion just below the map changes. In the left eye which was asymptomatic, faint map changes were seen by retroillumination. Examination of her 27-year-old mother's eyes was performed on the same initial visit and small map areas were noted on the left cornea with three typical microcysts. Map changes alone were found in her right eye. The mother had never had symptoms and her vision was 6/6 in each eye (CM-f Fig. 15A). The 63-year-old grandmother (CM-1 Fig 15A) who had normal vision and no symptoms was also seen. Map changes in this patient were much more obvious than in either her daughter or granddaughter. In addition, fingerprint lines were noted around the periphery of the map changes. No microcysts were present. The ocular pressure, Schirmer's test, and corneal sensitivity were normal in all three patients, although the tear film breakup time was shortened over the map changes. Examination of other members of the family showed no corneal changes.

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FIGURE 15 A: CM family where the propositus is CM-7, a 5-year-old who is the youngest of the 78 affected patients in the entire study. B: RP family where the propositus is RP-4, a 30-yearold man with map areas and microcysts. c: HG family where the propositus is a 54-year-old woman, HG-2.

524

Laibson

The 5-year-old daughter with recurrent erosions was the youngest patient seen with either map changes or recurrent erosion. Indeed, she was the only patient under ten years of age in the entire study. Her mother and her grandmother with similar changes did not have symptoms. RP Family:

Foreign body sensations lasting 30 minutes to several hours developed in both eyes, of a 30-year-old man five months before being examined (RP-4 Fig. 15B). In addition to the discomfort, he noted halos around lights in the evening and on awakening in the morning. These symptoms occurred about once every second month. Occasionally the irritation was so severe he had to lie down for several hours before relief was evident. He said the pain was similar to "applying alcohol to a raw surface." The first ophthalmologist who saw him described dots on the surface of his cornea which did not stain, and one episode of corneal erosion in his right eye. His visual acuity was 6/6 in the right eye and 6/9 in his left eye with best correction. There were map areas in the center of his right cornea which extended for about half the corneal surface. Three microcysts were located in the area of the map changes. In his left eye, similar map changes, but in a different distribution, were noted centrally. There were eight typical microcysts present in that eye. He was treated with 40% glucose ointment at bedtime and did well for about six months, using the ointment regularly at first and then intermittently. During that period, he had four episodes of halos around lights in the evening followed by foreign body sensation in his eyes in the morning. Examination six months later showed a different distribution of map changes and fewer microcysts in each eye. His last examination, 2% years after the initial one, found him asymptomatic with 6/6-1 vision in each eye without correction. The map changes had diminished significantly in each eye and there were no microcysts in either cornea. There was no corneal staining and the tear film breakup time was shortened in each eye. The patient's 62-year-old father (RP-2 Fig. 15B) had no previous eye complaints and his visual acuity was 6/6 in each eye. Map changes were present in each cornea between the upper limbus and the pupil, but did not affect his central cornea. There were no microcysts seen. His 60-year-old mother was normal. He had no siblings. His grandparents were deceased, but a brother of his grandfather had map changes in each eye which did not alter his vision. The propositus presently uses no medication and has no visual complaints since his last examination. He is seen at yearly intervals.

Corneal Dystrophy

525

HG Family: A 54-year-old woman (HG-2 Fig. 15C) with blurred vision in her right eye of six months duration, was first seen in May of 1968. She had no tearing, redness, or foreign body sensation. Her visual acuity was 6/15+2 in the right eye, and 6/6 in the left eye with best correction. There were ten microcysts in the central portion of her right cornea, in an area of map changes. Four microcysts were present in her left cornea, with fewer map changes in that eye. Cogan's microcystic dystrophy was diagnosed. The remaining eye examination was within normal limits, including intraocular pressure, Schirmer's test, and corneal

sensitivity. She returned periodically during the next three years, during which time the microcysts varied from visit to visit, but the general background of map changes remained the same. Her vision fluctuated in the right eye from 6/7.5 to 6/18. There was no foreign body sensation, irritation, nor were there symptoms of recurrent corneal erosion. By 1972, her vision had stabilized to 6/9 and has remained in that range. Slight visual blurring in the right eye does not annoy her, and only if the two eyes are compared by covering one alternately, is there any noticeable difference. The decrease in vision in her right eye is probably related to the irregular surface of the cornea epithelium. When a plano soft contact lens is placed on the right eye, visual acuity improves. The soft lens eliminates surface irregularity but is not needed for full time use. The patient's 80-year-old mother (HG-1 Fig. 15C) was examined, and found to have map changes in the central cornea of each eye, but no microcysts. Her visual acuity was 6/18 in the right eye and 6/7 in the left eye with best correction. Her visual loss in the right eye was due to an incipient cataract. A 47-year-old sister (HF-3 Fig. 15C) also had map changes in the upper third of her right cornea. Her visual acuity was normal in each eye, and neither the mother nor the sister had any ocular complaints related to these corneal changes. Their corneal sensitivities and Schirmer's tests were normal, but the tear film breakup time was shortened. Three other siblings (HG-4,5,6 Fig. 15C) were examined and no corneal epithelial alterations were noted. DISCUSSION AND CONCLUSIONS

In the original papers of Cogan and associates1 and Guerry,2 the basic clinical and pathological findings in epithelial basement membrane corneal dystrophy (microcystic dystrophy) were detailed. Figure 16 is a schematic drawing of the corneal epithelium in this dystrophy. Sub-

526

Laibson

FIGURE 16

Schematic drawing to illustrate some aspect of map and microcystic epithelial alterations. The map changes appear as broad gray areas with central lacunae, the other edges gradually fading into normal corneal epithelium. Epithelial microcysts are usually within the map region beneath aberrant basement membrane which produces the map picture. Occasionally the microcysts can be seen in or at the edge of a lacunae.

sequent publications broadened the spectrum of this entity by describing the symptoms, electron microscopy, associated findings, and familial nature of the disease. From the additional studies it is apparent that these corneal changes are more common than previously realized. The investigation of patients in a prospective study indicates that map and fingerprint-like alterations are not rare and can be found in asymptomatic people without past history of trauma or ocular disease. Microcysts are less common but also occur more frequently than was thought. The observation of these changes depends upon a thorough knowledge of how to look for them and a careful, complete slit lamp study of the corneal epithelium in patients with the onset of minimal blurred vision and ocular irritation. Patients with obvious large microcysts and map changes in the visual, axis will have considerable blurred vision, but this is not very common. Symptoms related to recurrent corneal erosion and blurred vision are the two major complaints heard from patients with epithelial basement membrane corneal dystrophy. In this study they were documented in 51 of 149 eyes (34%). Most of the symptoms were minor with vision reduced

Corneal Dystrophy

527

only one or two Snellen lines and the erosion symptoms were brief and self limited. Some patients though, with continued recurrent erosion, were first examined through referral by other ophthalmologists when they could not relieve the erosion problem. Failure to recognize that the symptoms were caused by a corneal dystrophy resulted in treating many symptomatic patients with antiviral drugs, corticosteroids, and antibiotics without significant short or long term success. Patients with mild erosion symptoms were most often comforted by using 2 or 5% sodium chloride drops in the day and 5% sodium chloride or Lacrilube ointment at bedtime. This is the treatment usually recommended for mild recurrent erosion.42 Eventually each person established a regimen of drug use which was felt to control symptoms best. This might involve using medication only when symptoms recurred, or in some instances, application was necessary daily until the symptoms abated. Where medical therapy failed, mechanical debridement of the involved corneal epithelium followed by pressure patching, was effective. To prevent repeated erosions in patients with epithelial basement membrane corneal dystrophy, a soft lens was fitted. In four patients the lens was worn continuously for two to four months and then removed. There were no recurrences in three of the four patients. In two others where the lens could not be worn all the time, it was removed at night. These patients also did well. The inclusion of fingerprint-like lines in the spectrum of epithelial changes along with microcysts and maps in microcystic dystrophy was done for two reasons. First, fingerprint-like lines were seen together with maps and microcysts in some eyes. They were also found in the opposite eye of patients who had map changes and microcysts in their other eye. These patients did not have previous trauma, erosion or ocular disease in the eye in which the fingerprint lines were found. The lines were present too often for chance in family members of patients with typical findings of epithelial basement membrane corneal dystrophy. Secondly, the pathology of the fingerprint line is apparently similar to the map change. Both appear to be caused by aberrant or multilaminar basement membrane. 19,39 Whether the fingerprint line was an early stage of the map change, could not be determined, but this was unlikely, as far too many patients had very faint maps and no fingerprint lines. Similar fingerprint-like lines can be found in patients with Fuchs' dystrophy, herpes simplex keratitis, corneal edema secondary to cataract

528

Laibson

extraction, and trauma. These are all conditions where there may be repeated loosening of the epithelium and a recurrent erosion-like clinical picture. It is likely that the corneal epithelial basal cell produced the multilaminar basement membrane in response to nonspecific stimuli such as epithelial edema and loosening of the corneal epithelium brought on by these diseases. The basal cell of the epithelium functioning in only a limited way in response to varied stimuli, could produce similar aberrant, multilaminar basement membrane in corneal dystrophies like microcystic dystrophy. Defective ep'ithelial adhesion is responsible for erosion of the corneal epithelium.434'" Normal adherence of corneal epithelium is a function of proper basement membrane complexes including production of normal basement membrane, associated hemidesmosomes and anchoring fibrils.45 The erosions encountered in 24 eyes (16%) in this study therefore were not unexpected as there is abnormal basement membrane production in microcystic dystrophy. Production of incompetent basement membrane was also found in other corneal dystrophies with recurrent epithelial erosion.46 The hereditary pattern appeared to be dominant with variable penetrance in different families. Why two-thirds of the patients were women is unexplained, but perhaps suggests some linkage to the X chromosome. SUMMARY

Seventy-eight patients with corneal epithelial changes found in microcystic dystrophy (epithelial basement membrane corneal dystrophy) form the basis of this study. These patients had epithelial microcysts, and/or map changes (68) and fingerprint-like lines (10) in their cornea, either alone or in combination. Bilateral changes were found in 71 patients and unilateral changes in 7. Symptoms were present in 34% of the 149 eyes involved. In a prospective study of 250 asymptomatic normal patients matched for age and sex with the 78 patients with microcystic dystrophy, all 3 patterns of epithelial change were found. Microcysts were noted in only 1 patient. Examination of asymptomatic family members revealed the familial nature of this dystrophy. Two or more members in 20 kinships were discovered to have microcystic dystrophy but other family members were not involved in all cases. A dominant pattern of inheritance was seen with a possible X chromosome link, as women were involved twice as often as men. This dystrophy is differentiated from other anterior

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corneal dystrophies and diseases of the anterior cornea with similar fingerprint-like lines. The pathology of microcystic dystrophy is apparently related to production of faulty multilaminar basement membrane which insinuates into the corneal epithelium from beneath the basal epithelial cells where it is usually produced. The maturing epithelial cells may be blocked from surfacing by this layer and form microcysts (pseudocyst). The aberrant basement membrane appears clinically as the more common map change or a fingerprint-like line in the cornea. Because the underlying change is related to abnormal corneal epithelial basement membrane, a more general term for this dystrophy would be epithelial basement membrane corneal dystrophy rather than microcystic dystrophy. ACKNOWLEDGEMENTS

I gratefully acknowledge the assistance of Merlyn Rodrigues, MD for her expertise in light and electron microscopy and Diane Van Horn PhD for help with scanning electron microscopy. Jay Krachmer, MD and George Waring, MD participated in the prospective studies. David Silva and Karen Albert aided illustration immeasurably. REFERENCES 1. Cogan DG, Donaldson DD, Kuwabara T, et al: Microcystic dystrophy of the corneal epithelium. Trans Am Ophthalmol Soc 63:213-235, 1964. 2. Guerry D: Observations on Cogan's microcystic dystrophy of the corneal epithelium.

Trans Am Ophthalmol Soc 62:320-334, 1965

3. Stocker FW: Discussion of paper, Observations on Cogan's microcystic dystrophy of the corneal epithelium. Trans Am Ophthalmol Soc 62:332-333, 1964. 4. Bron AJ, Tripathi RC: Cystic disorders of the corneal epithelium. I Clinical Aspects. Br J Ophthalmol 57:361-375, 1973. 5. Cogan DG, Kuwabara T, Donaldson DD, et al: Microcystic dystrophy of the cornea. Arch Ophthalmol 92:470474, 1974. 6. Donaldson DD: Corneal degenerations, in: Atlas of External Disease of the Eye: Cornea and Sclera. St. Louis, CV Mosby Co., 1971, Vol 3, part 1 pp 213-215. 7. King RG Jr, Geeraets R: Cogan-Guerry microcystic corneal epithelial dystrophy: A clinical and electron microscopic study. Med Coll Va Qrtly 8:241-246, 1972. 8. Levitt JM: Microcystic dystrophy of the corneal epithelium. Amj Ophthalmol 72:381382, 1971. 9. Luxenberg MN, Friedland BR: Superficial microcystic corneal dystrophy. Arch Ophthalmol 93:107-110, 1975. 10. Trobe JD, Laibson PR: Dystrophic changes in the anterior cornea. Arch Ophthalmol 87:378-382, 1972. 11. Wolter JR, Fralick FB: Microcystic dystrophy ofcorneal epithelium. Arch Ophthalmol 75:380-383, 1966.

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12. VogtA: Lehrbuchund Atlas Spaltlampenmikroskopie des LebendenAuges. Berlin, Julius Springer 1:264-265, 1930. 13. Guerry D: Fingerprint lines in the cornea. Am J Ophthalmol 33:724-726, 1950. 14. DeVoe A: Certain abnormalities in Bowman's membrane with particular reference to fingerprint lines in the cornea. Trans Am Ophthalmol Soc 60:195-201, 1962. 15. Spicer WTH, Greeves RA: On superficial linear keratitis together with an account of the pathological examination of two affected eyes. Ophthalmoscope 14:116-127, 1916. 16. Kaufman HE, Clower JW: Irregularities of Bowman's membrane. Am J Ophthalmol 61:227-230, 1966. 17. Bron AJ, Brown NA: Some superficial corneal disorders. Trans Ophthalmol Soc UK 91:13-29, 1971. 18. Poohkay ME, Hassard DTR: Fingerprint dystrophy of the cornea. Can J Ophthalmol 8:54-58, 1973. 19. Broderick JD, Dark AJ, Peace GW: Fingerprint dystrophy of the cornea. Arch Ophthalmol 92:483-489, 1974. 20. Laibson PR, Krachmer JH: Familial occurrence of dot (microcystic), map, fingerprint dystrophy of the cornea. Invest Ophthalmol 14:397-399, 1975. 21. Bucklers M: Ueber eine weitere familiare Hornhautdystrophie (Reis). Klin Monatsbl, Augenheilkd 114:386-397, 1949. 22. Reis W: Familiare fleckige hornhaut entartung. Deutsch Med Wchschr 43:575, 1917. 23. Rice NSC, Ashton N, Jay B, et al: Reis-Bucklers dystrophy: A clinicopathologic study. Br J Ophthalmol 52:577-603, 1968. 24. Hogan MJ, Wood I: Reis-Bucklers' corneal dystrophy. Trans Ophthalmol Soc UK 91:41-57, 1971. 25. Griffith DG, Fine BS: Light and electron microscopic observations in a superficial corneal dystrophy. Am J Ophthalmol 63:1659-1666, 1967. 26. DeVincentiis M: Bilateral symmetrical dystrophy of Bowman's membrane. Arch Ophthalmol 48:636-638, 1952. 27. Smith EL, Wilson WMG, Williams DK: A possibly new familial superficial corneal dystrophy. Can J Ophthalmol 6:30-37, 1971. 28. Grayson M, Wilbrandt H: Dystrophy of the anterior limiting membrane of the cornea (Reis-Bucklers type). Am J Ophthalmol 61:345-349, 1966. 29. Stocker FW, Holt LB: Rare form of hereditary epithelial dystrophy (genetic, clinical and pathologic study). Arch Ophthalmol 53:536-541, 1955. 30. Meesmann A, Wilke F: Klinische und anatomische untersuchunger uber eine bisher unbekannte, dominant vererbte epithel dystrophie der hornhaut. Klin Monatsbl Augenheulkd 103:361-391, 1939. 31. Bums R: Meesmann's corneal dystrophy. Trans Am Ophthalmol Soc 66:530-635, 1968. 32. Weingeist TA, Blodi FC: Fabry's disease: Ocular findings in a female carrier. Arch Ophthalmol 85:169-176, 1971. 33. Font RL, Fine BS: Ocular pathology in Fabry's disease. Histochemical and electron microscopic observations. Am J Ophthalmol 73:419-430, 1972. 34. Bron AJ: Vortex patterns of the corneal epithelium. Trans Opthalmol Soc UK 93:455-472, 1973. 35. Chandler PA: Recurrent erosion of the cornea. Am J Ophthalmol 28:355-363, 1945. 36. Franceschetti A: Hereditare rezidivierende erosion der hornhaut. Zschr Augenheilkld 66:309-314, 1928. 37. Wales JH: A family history of corneal erosions. Trans Ophthalmol Soc NZ 8:7778, 1955. 38. Kaufman HE: Epithelial erosion syndrome: Metaherpetic keratitis. Am J Ophthalmol 57:983-987, 1964.

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39. Rocrigues MM, Fine BS, Laibson PR, Zimmerman LE: Disorders of the corneal epithehum. A clinicopathologic study of dot, geographic, and fingerprint patterns. Arch Ophthalmol 92:475-482, 1974. 40. Tripathi RC, Bron AJ: Ultrastructural study of nontraumatic recurrent corneal erosion. Br J Ophthalmol 56:73-85, 1972. 41. Tripathi RC, Bron AJ: Cystic disorders of the corneal epithelium II. Pathogenesis. Br J Ophthalmol 57:367-390, 1973. 42. Trobe JD: Recurrent corneal erosion. Int Ophthalmol Clinics 13: No. 4, 155-165, 1973. 43. Khodadoust AA, Silverstein AM, Kenyon KR, et al: Adhesion of regenerating corneal epithelium. The role of basement membrane. Am J Ophthalmol 65:339348, 1968. 44. Goldman JN, Dohlman CH, Kravitt BA: The basement membrane of the human cornea in recurrent epithelial erosion syndrome. Trans Am Acad Ophthalmol Otolaryngol 73:471481, 1969. 45. Pulhorn G, Thiel HJ: Ultrastructural investigations of basal membrane regeneration of corneal epithelium. Albrecht von Graefes Arch Klin Ophthalmol 189:21-32, 1974. 46. Fogle JA, Kenyon KR, Stark WJ, Green WR: Defective epithelial adhesion in anterior corneal dystrophies. Am J Ophthalmol 79:925-940, 1975.