Fuchs' Corneal Dystrophy

A Clinicopathologic Study of the Variation in Corneal Edema

MERLYN M. RODRIGUES, MD, JAY H. KRACHMER, MD, JOSEPH HACKETT, BS, REGINALD GASKINS, ANASTASIOS HALKIAS, MD

Abstract: Corneal buttons from six patients with Fuchs' dystrophy had varying degrees of clinical edema measured in most cases by preoperative optical or ultrasonic pachyrnetry. These were sectioned in the operating room so that histologic correlations could be made. Histologically, marked thickening of Des­cemet's membrane and abnormal corneal endothelium corresponded to areas of severe clinical edema and were usually located in the central and paracentral regions. Descemet's membrane displayed multiple prominent guttata of varying size and shape, either facing the anterior chamber, or buried within multilaminar Descemet's membrane. In some corneas, aggregates of 10 nm fibrils were seen at the edges of guttata, corresponding to areas that stained for oxytalan fibrils. The endothelium was attenuated underlying the guttata. Clinical edema was not present unless accompanied by marked thickening of Descemet's membrane with multiple guttata and attenuation of corneal endothelium. The peripheral cornea was relatively clear clinically and showed minimal histologic changes. [Key words: corneal dystrophy, electron microscopy, Fuchs' dystro­phy, oxytalan, pachymetry.] Ophthalmology 93:789-796, 1986

MATERIALS AND METHODS

CLINICAL

Clinical and electron microscopic studies of Fuch's dystrophy have shown that epithelial and stromal edema are secondary to the primary endothelial dysfunction. However, clinical and histopathologic correlation of varying stages of edema in different portions of the cornea in patients with Fuchs' dystrophy has not been reported previously.

We describe clinical and histopathologic changes in edematous and nonedematous portions of the cornea in six patients with Fuchs' dystrophy who required pene­trating keratoplasty because of visual deterioration.

From the Laboratory of Ophthalmic Pathology, National Eye Institute, Na­tional Institutes of Health, Bethesda, and the Corneal Service, Department of Ophthalmology, University of Iowa City, Iowa City.

From 1977 until 1985, six corneal buttons (8 mm in diameter) removed at the time of penetrating keratoplasty from patients with Fuchs' dystrophy were studied histo­logically. Preoperatively, each cornea was carefully studied by slit lamp examination, drawn to indicate edematous and nonedematous areas, and in most cases measured with optical or ultrasonic pachymetry. Photographic doc­umentation of edematous areas was performed preoper­atively in each case.

Presented at an Annual Meeting of the American Academy of Ophthal­mology.

Reprint requests to Merlyn M. Rodrigues, MD, National Eye Institute, Na­tional Institutes of Health, Building 10, Room 1 ON112, Bethesda, MD 20205.

After removal of the corneal button in the operating room the tissue was sectioned according to preoperative drawings so that edematous and nonedematous areas could be isolated. Each small piece of tissue was then placed in vials containing glutaraldehyde or buffered for­malin. A corneal button from a patient with pseudophakic

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Fig I. Case I. A and B, central location of opacification. C, nonedematous peripheral cornea.

RODRIGUES, et al • FUCHS' CORNEAL DYSTROPHY

Fig 2. Case 2. A disciform area of corneal edema just temporal to and including the visual axis.

bullous keratopathy was processed in a similar manner as a control.

HISTOPATHOLOGY

For light microscopy, portions of some corneas were fixed in buffered formalin and embedded in paraffin. Spe­cial stains included periodic acid-Schiff (PAS), orcein, Verhoeff-van Gieson and aldehyde fuchsin with prior ox­idation in potassium permanganate for five minutes.

For electron microscopy, tissues fixed in buffered glu­taraldehyde were developed in ascending concentrations of alcohol and embedded in epon. Sections ( 1 ~m thick) were stained with toluidine blue. Thin sections were stained with uranyl acetate and lead citrate and examined in a Philips 400 electron microscope.

CASE REPORTS

Case 1. An 82-year-old white woman underwent penetrating keratoplasty in her right eye on March 22, 1978. She had bilateral Fuchs' corneal dystrophy with visual acuity of 20/400 in the right eye and 20/70 in the left. Confluent cornea guttata were noted in the central three-quarters of both corneas. The central one-third ofthe right cornea showed the cicatricial stage of Fuchs' dystrophy with stromal edema, subepithelial fibrosis, and non­bullous epithelial edema (Fig 1 A, B). The midperipheral corneas showed only slight edema and the area peripheral to the confluent cornea guttata showed no stromal edema (Fig 1 C). There was an iron line demarcating the extent of the subepithelial fibrosis. The central corneal thickness was 0.64 mm by optical pachy­metry.

Fig 3. Case 4. Slit-lamp photo demonstrates stromal edema centrally. Midperipheral and peripheral cornea is nonedematous.

Case 2. A 50-year-old white woman had undergone pene­trating keratoplasty for Fuchs' dystrophy in her left eye with resultant visual acuity of 20/20. With a visual acuity of 20/70 in the right eye, she underwent penetrating keratoplasty on Feb­ruary 22, 1985. Slit-lamp findings included confluent cornea guttata to the midperiphery in the right eye and disciform stromal and epithelial edema, located slightly to the temporal side of the center of the cornea (Fig 2). Ultrasonic pachymetry of the right eye indicated the following thicknesses: central 0.617 mm; 12, 3, 6 and 9 o'clock peripheral readings of0.593 mm, 0.589 mm, 0.601 mm, and 0.605 mm; 0.620 mm midway between the center and 3 o'clock (temporal) peripheral area.

Case 3. A 66-year-old white woman with bilateral Fuchs' dys­trophy underwent a penetrating keratoplasty in the right eye on October 28, 1977. Preoperative slit-lamp examination revealed stromal and epithelial edema in a localized disciform area, which split the visual axis and extended inferotemporally. Optical pa­chymetry with the Haag-Streit instrument indicated a midpe­ripheral superior nonedematous area with a thickness of 0.65 mm, a central thickness of 0.64 mm, and a thickness of 0.68 mmjust below the visual axis in the edematous area. Her visual acuity was 20/70 in that eye. The fellow eye demonstrated similar but less pronounced edema.

Case 4. A 63-year-old white woman with bilateral Fuchs' dys­trophy had a visual acuity of 20/300 in her right eye when she underwent penetrating keratoplasty on January 21, 1978. Both eyes revealed stromal and epithelial edema in a localized central area (Fig 3). Midperipheral areas could be identified showing confluent cornea guttata without stromal or epithelial edema.

Case 5. A 66-year-old white woman with a visual acuity of 20/200 in the left eye underwent penetrating keratoplasty on June 21, 1978. The central 4 mm of her cornea demonstrated stromal and epithelial edema. Confluent guttata extended beyond this area but toward the periphery there was no overlying stromal or epithelial edema.

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Fig 4. Case 7. Pseudophakic bullous keratopathy. Slit-lamp photo shows extensive edema and iris plane intraocular lens.

Case 6. A 78-year-old white woman with a visual acuity of 20/80 had a penetrating keratoplasty of the right eye on Septem­ber 20, 1978. Preoperative slit-lamp examination revealed bi­lateral Fuchs' corneal dystrophy. The edematous area extended from the edge ofthe visual axis inferiorly to the limbus. Inferiorly, there was bullous keratopathy and stromal vascularization.

Case 7. A 74-year-old white woman with pseudophakic bul­lous keratopathy underwent penetrating keratoplasty on May 22, 1978 in her right eye. She did not have Fuchs' dystrophy but was used as a control. Six months prior to corneal surgery she had undergone a cataract extraction with the insertion of an iris plane lens in her right eye. Even though the surgery seemed uneventful, she developed stromal and epithelial edema which progressed postoperatively. The edema was disciform and was

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located centrally with some extension superiorly (Fig 4). The peripheral cornea was nonedematous. Visual acuity was finger counting at one foot in the right eye. Slit-lamp examination of the left eye demonstrated mild nonconfluent cornea guttata. There was no stromal or epithelial edema in the left eye.

HISTOPATHOLOGY

Clinically, areas of edema measured by ultrasonic pachymetry corresponded to histological areas of mark­edly thickened Descemet's membrane (DM) and abnor­mally absent endothelium. In clinically nonedematous areas, DM and endothelium were relatively normal and mildly involved.

LIGHT MICROSCOPY

There was variation in corneal edema and involvement of endothelium and Descemet's membrane that corre­sponded to areas of clinical edema. Central and paracen­tral cornea showed most severe changes (Fig 5). Epithelial and stromal edema was also more marked centrally. His­tologic examination of edematous areas revealed marked thickening of Descemet's membrane up to almost three times the normal width, with multiple guttata and atten­uated endothelial cells. In one case, the guttata were buried with multilaminar Descemet's membrane (Fig 5), con­sisting oflighter stained material that separated them from the endothelium. In the other corneas, the anvil-shaped guttata were exposed to the anterior chamber (Fig 6). Corneas from two patients showed oxytalan fibrils that stained with aldehyde fuchsin and with orcein after prior oxidation. These fibrils were located at the edges of the guttate excrescences, and were not observed in other layers of the cornea.

ELECTRON MICROSCOPY

Transmission electron microscopy confirmed the oc­currence of marked involvement of endothelium and Descemet's membrane corresponding to clinical corneal

Fig 5. Case I. A, centrally, Descemet's membrane is markedly thickened and multilaminar (arrow) and considerable stromal edema is present. More peripherally, Descemet's membrane is almost normal in thickness (curved arrow) (periodic acid-Schiff, Xl07). B, higher magnification of Descemet's membrane centrally. Multiple guttata (arrows) are buried in lighter stained material (periodic acid-Schiff, X330).

RODRIGUES, et al • FUCHS' CORNEAL DYSTROPHY

edema. In the central edematous cornea, Descemet's membrane showed normal anterior 110 nm banding (ap­proximately 3 ~m thick) and a thinned posterior granular portion (Fig 7 A, B). The adjacent posterior collagenous layer varied in thickness from 16 to 38 ~m and showed abnormal 110 nm banding, spindle shaped 10 to 15 nm fibrils and homogenous material. Some extremely large guttata displayed a laminar configuration with foci of pig­ment phagocytosis (Fig 7B).

In nonedematous areas, endothelial cells were present and Descemet's membrane was normal to slightly thick­ened, measuring 12 to 14 ~m with occasional guttata to­wards the periphery (Fig 7C). Endothelial cells displayed a more normal appearance. Electron microscopy showed less 110 nm banding compared with edematous areas, and guttata were usually lacking.

Cases of Fuchs' dystrophy displayed considerable vari­ation in the configuration of guttata. Some were relatively small in size with focal areas of 100 to 110 nm banding (Fig 8). Other anvil-shaped guttata displayed fusiform bundles of 10 to 12 nm banding, more pronounced at the edges (Fig 9). These banded areas corresponded to the same zones that stained for oxytalan fibrils with aldehyde fuchsin and orcein in paraffin sections. Endothelial cells were mostly attenuated with normal or loosened junc­tional complexes or were degenerated in some areas, par­ticularly at the edges of guttata. Endothelial cells showed moderately decreased numbers of mitochondria and oc­casional pigment phagocytosis.

In contrast, a case of aphakic bullous keratopathy showed no evidence of guttata in any of its extent, al­though Descemet's membrane was moderately thickened. A thin fibrillar layer was present between the posterior non banded portion of Descemet's membrane and endo­thelium (Fig 10). Some endothelial cells displayed prom­inent rough endoplasmic reticulum.

DISCUSSION

Since Descemet's membrane is synthesized by the cor­neal endothelium throughout life, a study of its layers can provide useful clues related to the approximate age of the onset of endothelial dysfunction.

Electron microscopic studies of the endothelium and Descemet's membrane have provided a framework for evaluating changes that occur with aging and disease. 1

-6

Morphometric studies have shown that Descemet's membrane consists of an anterior prenatal layer measuring approximately 3 ~m at birth and a posterior nonbanded layer that thickens with age. 3•

4 The new layers of mem­brane are synthesized by corneal endothelium.4

•5 In the

postnatal cornea, a decrease in endothelial cellularity ap­pears to be associated with cellular enlargements. 5

In Fuchs' dystrophy, the anterior prenatal portion of Descemet's membrane is normal; Descemet's membrane is considerably thickened by additional layers in the pos­terior collagenous portion,4

•6

•7 which commences in early

life, and antecedes the clinical manifestation of the dis-

Fig 6. Case 2. Guttata are present centrally (box) and absent in peripheral cornea (toluidine blue, XJ30).

ease.4•6 We confirmed this observation in the present study. In aphakic bullous keratopathy, however, the ab­normal membrane appears to be produced much later in life,4•8 most likely after cataract surgery. In ABK there is a prominent fibrillar layer adjacent to the endothelium and guttata are infrequent.

We observed an interesting clinicopathologic correla­tion between clinical edema and the occurrence of marked alteration in the endothelium and Descemet's membrane. Clinical edema and thickness measured by pachymetry and histopathologic thickness of Descemet's membrane was more pronounced in the central and paracentral cor­nea; the peripheral nonedematous cornea had minimal changes in Descemet's membrane and endothelium. This type of correlation has not been previously described. Bourne et al observed no difference between central and peripheral cornea,6 though these may have been more severe cases of Fuchs' dystrophy than those that we ex­amined. It is uncertain why the central cornea appears to be most severely affected. Histopathologic changes in the corneas of our patients with Fuchs' dystrophy confirmed findings reported by others.4

•6-10 Thickening ofDescemet's

membrane and endothelial attenuation was accompanied by secondary stromal and epithelial edema. Clinical edema occurred only when there were severe histologic changes including marked thickening of Descemet's membrane, multiple guttata, and attenuated endothelium.

In a few cases we noted aggregates of 10 to 12 nm fibrils in the posterior cornea, at the edges of guttata excres­cences. These resembled oxytalan fibrils described by Al­exander and associates and stained positive with aldehyde fuchsin after prior oxidation. 11 We did not find these fibrils elsewhere in the cornea, although they have occasionally been noted beneath the epithelium and Bowman's layer. Oxytalan fibers, part of the normal elastic fibers in mam­malian connective tissue have been described only in pathologic corneal conditions, including keratoconus, corneal scarring, staphyloma and sclerocornea, as well as in posterior keratoconus by Streeten et al. 11

•12

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D M ( .....___

Fig 7. Case I. A, central edematous areas micrograph showing normal II 0 nm banding of anterior Descemet's membrane (I) (0.3 11 thick), and a thin nonbanded layer (2). The remainder of Descemet's membrane is a thick posterior collagenous layer with guttata (G) and abnormal banded and fusiform bundles (X5850). B, central edematous area showing con­centric multilaminar Descemet's membrane containing a few pigment granules (arrow) in a large guttate excrescence (X5850). Inset: same area by light microscopy. Descemet's membrane is indicated (DM) and shows guttata lined by attenuated endothelium (arrows) (toluidine blue, X330). C, nonedematous peripheral cornea showing occasional abnormal ILO nm banding (arrow) and 10 to II nm microfibrils (•) corresponding to oxytalan fibers. Endothelial cells are flattened (X45,000).

RODRIGUES, et al • FUCHS' CORNEAL DYSTROPHY

Fig 8. Case 2. Edematous central cornea showing guttata in Descemet's membrane with scattered 110 nm banded material (arrow). Endothelium (E) is thinned (X 15,200).

Fig 9. Case 4. Electron mi­crograph of edematous cen­tral cornea showing guttata (G) separated by fusiform material. Endothelium is at­tenuated (X7500). Inset: same area by light micros­copy (toluidine blue, X330).

The primary function of the corneal endothelium is the control of corneal hydration by the maintenance of the metabolic A TPase pump that also permits the passage of nutrients. 13

-16 The ATPase pump is located in the lateral

plasma membrane of endothelial cells. 14 In disease states, the leak of fluid into the stroma exceeds its removal by the pump, producing corneal edema. The earliest defect in Fuchs' dystrophy appears to be a breakdown in barrier function, resulting in increased permeability and corneal thicknessP In some of our cases, junctional complexes appeared to be loosened. A recent study of tritiated oua­bain binding to endothelial Na/K ATpase quantitated the density of pump sites in human corneal endothelium of 26 eye bank eyes. Among these eyes, 20 with normal en­dothelia had a constant pump site density; six with mod­erate guttata had significantly increased pump site den­sity. 17 These results indicate that guttata associated with increased endothelial permeability can cause a compen­satory increase in pump function. Such compensatory mechanisms could occur in early Fuchs' dystrophyP However, in late Fuchs' dystrophy, when this reserve ca­pacity is exceeded, corneal decompensation and edema occur.

Differential diagnoses of Fuchs' dystrophy include aphakic bullous keratopathy and a unilateral nonguttate corneal endothelial degeneration. 18 The latter may be a variant of Fuchs' dystrophy. In aphakic bullous keratopa­thy, the posterior nonbanded Descemet's membrane is often wider than in cases of Fuchs' dystrophy and there is a prominent fibrillar layer adjacent to endothelium changes in endothelium. Changes in endothelium occur at a later age than in Fuchs' dystrophy.6•8 Cornea pseu­doguttata have been observed during transient episodes of iritis and keratitis. 19 These pseudo guttata appear clin-

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Fig 10. Case 7. Pseudophakic bullous keratopathy. Electron micrograph shows the normal anterior banded layer (AB). Instead of the normal posterior nonbanded layer, there is a wide posterior zone with abnormal focal banding (arrows) and a fibrillar layer (F) adjacent to the endothelium (E) (X9900). Inset: same area by light microscopy (toluidine blue, X330).

ically as dark spots that interrupt the normal corneal en­dothelial mosaic and disappear with resolution ofinflam­mation.19

Recent biochemical characterization of the Descemet's membrane/posterior collagenous layer from Fuchs' dys­trophy corneas has shown collagen types similar to age­matched controls.20 However, immunofluorescent stain­ing showed fibrinogen/fibrin in the posterior collagenous layer in Fuchs' dystrophy, but not in normal OM. In Fuchs' dystrophy altered assembly of collagen molecules and a possible defect in the fibrinolytic system has been postulated.20·21 An antifibrinolytic drug, tranexamic acid was observed to decrease corneal edema in patients with Fuchs' dystrophy.21

The etiology ofFuchs' dystrophy is unknown. However, several electron microscopic reports, including the present study, have shown that production of the banded posterior collagenous layer begins within the first two decades of life, but shows much later clinical involvement. Corneal edema occurs with progressive decrease in endothelial barrier function.

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