A Morphologic Study of Fuchs Dystrophy and Bullous Keratopathy · A Morphologic Study of Fuchs...

BASIC INVESTIGATIONS

A Morphologic Study of Fuchs Dystrophy andBullous Keratopathy

Hunter K. L. Yuen, MRCSEd,* Charles E. Rassier, MD,* Maria Stephanie R. Jardeleza, MD,*

W. Richard Green, MD,* Zenaida de la Cruz, BS,* Walter J. Stark, MD,†

and John D. Gottsch, MD†

Purpose: To describe the morphologic features of Fuchs corneal

dystrophy and compare them with those of bullous keratopathy.

Methods: This was an observational case series. The study group

consisted of 32 corneal buttons with a diagnosis of Fuchs dystrophy

and the comparison group consisted of 22 corneal buttons with

bullous keratopathy. Morphologic analysis was performed of corneal

buttons from patients with the clinical diagnosis of Fuchs dystrophy

or bullous keratopathy by light and electron microscopy.

Results: The main outcome measure was identification of degen-

erated keratocytes, granular material in and around keratocytes, and

lipid keratopathy. The overall morphologic features of Fuchs dys-

trophy and bullous keratopathy are similar to those described in

previous literature. A high proportion of keratocytes exhibited de-

generative changes (78.9% in Fuchs dystrophy versus 50.5% in

bullous keratopathy). Granular material was identified in and around

variably degenerated keratocytes in all cases of Fuchs dystrophy and

in 14 of 22 (64%) of the corneas with bullous keratopathy. The

percentage of keratocytes with granular deposits was higher in Fuchs

dystrophy corneas as compared with corneas with bullous keratopathy

(51.7% versus 14.1%, P, 0.0005). Lipid keratopathy was a common

occurrence in both Fuchs dystrophy and bullous keratopathy (23/32

[72%] versus 12/22 [55%]).

Conclusions: Histopathologic changes in the corneal stroma and

keratocytes occur in Fuchs dystrophy. Secondary lipid keratopathy

ensues and may contribute to corneal haze. A higher proportion of

keratocytes in Fuchs dystrophy have granular deposit than in bullous

keratopathy. That a high proportion of keratocytes had degenerative

changes in both Fuchs dystrophy and bullous keratopathy suggests

that keratocytes may degenerate secondary to altered stromal micro-

environment because of endothelial cell loss.

Key Words: Fuchs dystrophy, bullous keratopathy, stroma, granular

deposit, keratocyte degeneration, lipid keratopathy

(Cornea 2005;24:319–327)

I t was almost a century ago when Fuchs1 first described thedisorder ‘‘dystrophia epithelialis corneae’’ in 1910, which is

now known as Fuchs endothelial dystrophy. Much work hasbeen done on the histologic and ultrastructural changes,pathophysiology, inheritance, and treatment. Although it isusually described as a dystrophy, it may be argued that itbehaves more like degeneration than a dystrophy.

Fuchs dystrophy is more common in females and isusually manifest after 40 years. Patients are usually asymp-tomatic in the early stage as the remaining endothelial cells canundergo polymegethism and compensate for endothelial cellloss. In the second stage, the cornea decompensates when thefluid entering the cornea increases, causing visual impairmentdue to corneal edema. In the third stage, patients may havepain due to formation of epithelial bullae and the vision dete-riorates further. In the final stage, subepithelial scarring oc-curs, and there may be profound visual loss but pain may beabsent.2–5

Information regarding the ultrastructural changes ofthe stroma and keratocytes in Fuchs corneal dystrophy islimited.2,6–10 We examined 32 cases of Fuchs cornealdystrophy by light and electron microscopy and comparedthese with a group of 22 corneas with bullous keratopathy.

METHODSThirty-two corneal buttons submitted to the Eye

Pathology Laboratory of the Wilmer Eye Institute witha clinical diagnosis of Fuchs dystrophy were examined bylight and electron microscopy. The corneal buttons were fixedin a buffered solution of 1% glutaraldehyde and 4%formaldehyde and bisected; half of each was processed forlight or electron microscopy. In cases in which only half of thecorneal button was submitted, a 1-mm sliver was transectedand processed for electron microscopy. Staining for lightmicroscopy included hematoxylin and eosin, periodic acid–Schiff, Perls’ iron stain, Alcian blue, colloidal iron, oil red O,and Sudan black B. Thin sections for electron microscopywere doubly stained with tannic acid and lead citrate. Ul-trastructural features of the stroma, keratocytes, Descemet

Received for publication December 23, 2002; Revision received July 14,2004; accepted July 17, 2004.

From the *Eye Pathology Laboratory, Department of Pathology, The JohnsHopkins Medical Institutions, Baltimore, MD; and †Cornea Service,Wilmer Institute, The Johns Hopkins Medical Institutions, Baltimore, MD.

Supported in part by The Sir Robert Black Trust Fund and the Hong Kong EyeHospital (Dr. Yuen), the Wilmer Institute Shupiro Fund (Dr. Rassier), andthe Independent Order of Odd Fellows, Winston-Salem, NC (Dr. Green).

Reprints: W. Richard Green, MD, The Johns Hopkins Hospital, Eye PathologyLaboratory/Maumenee Building 427, 600 N. Wolfe Street, Baltimore, MD21287-9248 (e-mail: [email protected]).

Copyright � 2005 by Lippincott Williams & Wilkins

Cornea � Volume 24, Number 3, April 2005 319

membrane, and endothelium were noted. At least 3 keratocyteswere sampled, each in the anterior, mid-, and posterior centralstroma. The thickness and number and character of layers ofDescemet membrane were determined. The number of pos-terior nodules and endothelial cells were quantitated (averagein 5 central high-power fields) by light microscopy. The com-parison group of 22 cases of bullous keratopathy (20 cases ofpseudophakic bullous keratopathy, 1 case of aphakic bullouskeratopathy, and 1 case of bullous keratopathy occurringremote after angle closure glaucoma) was collected fromthe same time period as the Fuchs corneas and processed in thesame manner. Statistical analysis was conducted using thePearson x2 test, Fisher exact test, Student t test, and Mann-Whitney U test where appropriate.

RESULTS

Fuchs DystrophyThe mean age of the 32 patients was 70.1 (range, 53–92).

Eleven were male and 21 were female.

Light MicroscopyThe histologic features of the 32 cases of Fuchs

dystrophy were similar and included variable degrees ofintracellular epithelial edema and bullous separation, stromalthickening, Descemet membrane thickening with posteriornodules, and endothelial loss. Intracellular epithelial edemawas quantitated as mild in 21, moderate in 5, marked in 1, andnot present in 1; no epithelium was present in 4. Bullousseparation was mild in 9, moderate in 6, marked in 0 and nobullae were present in 13.

Bowman membrane was intact except in 2 cases inwhich localized superficial scars were present. The meanstromal thickness was 405 mm (range, 90–570). The meanDescemet membrane thickness was 17.6 mm (range, 7.5–30).Posterior nodules of Descemet membrane were present in allcases, and the average number of posterior nodules per high-power field (403) was 4.0 (range, 0.8–6.4). Most of theposterior nodules were observed under light microscopy. Aposterior fibrous layer partially obscured some of the posteriornodules in 6 cases. Four additional cases had buried nodulesthat were evident by electron microscopy, making a total of 10cases with buried nodules.

The average number of endothelial cells per high-powerfield was 3.5 (range, 0–5.6). Rare large, round, melanin pig-ment granules were present in the endothelium in 5 cases. Noinflammatory cell infiltrate or blood vessels were observed inany of the cases.

Electron MicroscopyWe observed lipid keratopathy and degenerated kerato-

cytes in the stroma. Degenerated keratocytes exhibited loss ofintracellular organelles, dissolution of cytoplasm, presence ofintracellular spaces and vacuoles, and minor peripheral nuclearchromatin clumping (Fig. 1). These were present in all Fuchsdystrophy cases. Some keratocytes had intracellular (Figs. 2Aand 3A, B) and extracellular (Figs. 2B and 3C) granularmaterial.

Lipid keratopathy was present in 72% of Fuchsdystrophy (Fig. 4) and was characterized by minute spacesin the stroma, some of which contain electron-dense material.The spaces measured up to 1.2 mm in diameter.

There was a discrepancy in the thickness of Descemetmembrane as measured by light and electron microscopy in allthe cases, which is likely due to greater tissue shrinkage duringprocessing for light microscopy. Descemet membrane wascomposed of up to 4 layers (Figs. 5 and 6). The layers weredescribed on a morphologic basis only, and the distinction oflayers was not clearly evident in all cases. The first layer, theanterior fetal banded layer, was present and relatively uniformin all cases, was characterized by the presence of wide-spacedcollagen with a periodicity of 110–120 nm, and ranged from1.9–4.2 mm in thickness (mean, 3.2). The second layer wasnonbanded, homogeneous, and less osmophilic than the ante-rior fetal layer and was present in 20 of 32 cases and absent in12. The thickness of this second nonbanded layer ranged from2–4.0 mm in thickness except in one case, in which thethickness was 9.5 mm (mean, 3.2, where present). The thirdlayer was banded, present in all the cases, and ranged inthickness from 5.8–32.1 mm (mean, 15.9). This layer had anosmophilia similar to that of the anterior fetal layer and hadwide-spaced collagen with a periodicity of 110 to 120 nm,which was especially concentrated in the posterior aspect. In 8cases, an additional type of wide-spaced collagen with aperiodicity of about 60 nm was present. The characteristicposterior nodules in Fuchs dystrophy were contiguous with

FIGURE 1. Fuchs dystrophy. Examples of partially degeneratedkeratocytes with variable dissolution of cytoplasm, loss oforganelles, and presence of intracellular spaces (A,312,000; B,320,100; C, 330,000).

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this posterior banded layer in all the cases. The mean maximalwidth of posterior nodules was 15.1 mm (range, 4.3–33.3), andthe mean maximal height was 4.6 mm (range, 0.5–9.5). Thefourth layer was fibrillar and present in 19 of 32 (59%) casesand absent in 13 of 32 (41%) cases and ranged in thicknessfrom 0.5 to 19.8 mm (mean, 7.8, where present). This layer wascomposed of a loose matrix of collagen with a fibril diameterof 20–40 nm. In 10 cases, some of the posterior nodules wereburied within this layer (Figs. 7 and 8). In 7 cases, multiplewaves of basal lamina were present in the fibrillar layer, and allthese cases had foci of wide-spaced collagen with a periodicityof around 60 nm in the posterior aspect of the posterior bandedlayer and anterior aspect of the fibrillar layer (Fig. 9).

The endothelium was attenuated to atrophic and wasespecially attenuated over the posterior nodules. Individualendothelial cells sampled were unremarkable or exhibitedvariable degrees of degeneration (Fig. 10). The degree of de-generation was classified as none (4), mild (12), moderate(12), and severe (4). Endothelial cells had myoblastic featureswith subplasmalemmal aggregates of microfilaments withfusiform densities in 5 cases (15.6%) (Fig. 11A). Overlappingof intact endothelial cells with junctional complexes waspresent in 1 case (Fig. 11B). Large, round, melanin pigment

granules were present in the endothelium in 7 cases (trace in 3,mild in 2, and moderate in 2).

Bullous KeratopathyThe mean age of 22 patients with bullous keratopathy

was 73.4 (range, 54–89). Twelve were male and 10 werefemale. The light microscopic features of bullous keratopathyincluded variable degrees of intracellular epithelial edema andbullous separation, stromal thickening, and endothelial loss.Intracellular epithelial edema was mild in 14 and moderate in 2;no epithelium was present in 6. Bullous separation was mild in9 and moderate in 2; no bullae were present in 5. The meanstromal thickness was 423 mm. The mean Descemet mem-brane thickness was 9.0 mm, much less than that of Fuchsdystrophy cases. No posterior nodules were present. The aver-age number of endothelial cells per high-power field was 2.7.

Electron MicroscopyGranular material in and around keratocytes was

observed in 14.1% and lipid keratopathy (Fig. 12) in 55%of the bullous keratopathy cases. Descemet membrane mayhave up to 4 layers in bullous keratopathy, including theanterior fetal banded layer, posterior nonbanded layer, pos-terior banded layer, and the forth fibrillar layer (Fig. 13). Theanterior fetal banded layer was similar to that in Fuchsdystrophy with the thickness ranging from 1.9–5.2 mm (mean,3.1). The second posterior nonbanded layer was present in 18of 22 (81.8%) and absent in 4 of 22 (18.2%) cases and ranged

FIGURE 2. Fuchs dystrophy. Examples of granular material(asterisk) within (A) and adjacent (B) to otherwise normal kera-tocytes (A and B, 330,000).

FIGURE 3. Fuchs dystrophy. Granular material within (A and B)and adjacent (C) to variably degenerated keratocytes (A,38100; B, 330,000; C, 315,000).

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in thickness from 1.19–6.8 mm (mean, 3.3, where present) Theposterior banded layer thickness ranged from 1.3–16.8 mm(mean, 8.1, where present). Wide-spaced collagen witha periodicity of about 110 nm was present, especially in theposterior aspect. No posterior nodules were present. A fourthfibrillar layer was present in 13 of 22 (59%) cases, with thethickness ranging from 0.4–10.1 mm (mean, 2.6, wherepresent). Multiple waves of basal lamina were present in thefibrillar layer in 2 cases.

The endothelial cells disclosed similar degenerativechanges as described in Fuchs dystrophy. Endothelial celldegeneration was classified as none in 3 (14%), mild in 5(23%), moderate in 5 (23%), and marked in 4 (18%) cases.The endothelium was atrophic in 5 (23%) of the cases.

DISCUSSIONComparison of the light (Table 1) and electron

microscopic features (Table 2) of Fuchs dystrophy and bul-lous keratopathy are summarized in the tables. The bullouskeratopathy group is chronic corneal edema associated withaphakia, pseudophakia, and remote after angle-closureglaucoma.

The primary defect of Fuchs dystrophy is believed to bein the endothelium because of endothelial cell loss, thickenedDescemet membrane and presence of posterior nodules. Moststudies have concentrated on the endothelial cells and variousmechanisms of endothelial loss,3–5 including hormonal changes,inflammation, fibrinolytic system defects, mechanical or toxicinjury to the endothelium, mitochondrial mutation,11 and geneticmutation.12 Although an intrinsic endothelial loss seems to bemore dominant and receives more attention, extrinsic factorsmay also be possible.

Disturbance in the regulation of apoptosis may beimportant in the pathogenesis of Fuchs corneal dystrophy. Byusing in situ, end-labeling of double-strand DNA break,Li et al13 identified apoptosis in corneal epithelium, keratocytes,and endothelium but little or no apoptosis in normal corneas.In a study using transmission electron microscopy, nucleuslabeling, and TUNEL (terminal deoxynucleotidyl transferase[TdT]–mediated dUTP-biotin nick end labeling) essay,Borderie et al14 demonstrated that the average percentage ofapoptotic endothelial cells was significantly higher in Fuchsdystrophy compared with a control group. They, however, didnot observe any evidence of apoptosis in keratocytes, and thekeratocyte morphology was reported as normal. Using se-rial analysis of gene expression (SAGE), Gottsch et al15

demonstrated the abnormal expression of apoptosis-relatedgenes in the endothelium of Fuchs dystrophy as compared

FIGURE 5. Fuchs dystrophy. Descemet membrane has 4 layers:anterior fetal banded layer (1), posterior nonbanded layer (2),posterior banded layer (3), and a fibrillar layer (4). A posteriornodule (asterisk) arising from the posterior banded layer iscovered by attenuated endothelium (arrow) (34200).

FIGURE 4. Fuchs dystrophy. Lipid keratopathy with numerousdropout spaces. Some of these contain electron dense material(arrows) (A, 321,000; B, 360,000).



with normal endothelium. Whether keratocytes in Fuchs dys-trophy are undergoing apoptosis and play a role in the path-ogenesis of Fuchs dystrophy is still unresolved.

Some evidence suggests that keratocytes are metabol-ically active cells involved in the turnover of the extracellularmatrix and corneal transparency. Senoo et al16 demonstratedthat corneal stromal cells secrete factors that stimulate cornealendothelial cell proliferation. Other studies also support theidea that a strong interplay exists between keratocytes and theendothelium.17–19 For example, endothelial loss normally doesnot occur after LASIK.20,21 In one reported case of a 55-year-old woman with Fuchs dystrophy who underwent LASIK,however, corneal decompensation developed afterward, sug-gesting that a disturbance in the corneal stroma may haveprecipitated compromise of the endothelium.22

The presence of posterior nodules in the central corneawith Descemet membrane thickening characterizes Fuchsdystrophy. The exact mechanism(s) responsible for posteriornodule formation has not been resolved. Posterior nodules mayalso be seen in other conditions such as interstitial keratitis,23–25

posterior polymorphous dystrophy,26,27 and macular cornealdystrophy.28 Severe keratitis can cause the formation of

FIGURE 6. Fuchs dystrophy. Another example of 4 layers ofDescemet membrane including anterior fetal banded layer (1),posterior nonbanded layer (2), posterior banded layer (3), andfibrillar layer (4) (33000).

FIGURE 7. Fuchs dystrophy. Four layers of Descemet mem-brane. A 17.6 3 7-mm posterior nodule is buried by the fourth(fibrillar) layer (35000).

FIGURE 8. Fuchs dystrophy. Another example delineates the4 layers of Descemet membrane and posterior nodules buriedby the fourth (fibrillar) layer. The endothelium (arrow) isextremely attenuated (34200).



temporary ‘‘pseudoguttata,’’ which disappear with subsidenceof the inflammation.29 Posterior nodules are not observed inpseudophakic or aphakic bullous keratopathy unassociatedwith Fuchs dystrophy. It is possible that factors in the stromacontribute to the formation of Descemet membrane excrescences.

FIGURE 9. Fuchs dystrophy. A, Higher power view of 2 types ofwide-spaced collagen in the fourth (fibrillar) layer in a collagenmatrix with a fibril diameter of 25 nm (330,000). B, Higherpower view of posterior aspect of the posterior fibrillar layerwith collagen with a fibril diameter of 25 nm and multiplewaves of basal lamina (arrowheads). The endothelium is intactand has a prominent junctional complex (330,000).

FIGURE 10. Fuchs dystrophy. Examples of partially degen-erated endothelial cells (asterisks) that are covered by intactendothelium (arrows) (A, 38100; B, 315,000).

FIGURE 11. Fuchs dystrophy. Example of an endothelial cellwith subplasmalemmal aggregates of microfilaments withfusiform densities (A, arrow) and overlapping of endothelialcells with a prominent junctional complex (B, arrowhead) (A,330,000; B, 360,000).

FIGURE 12. Bullous keratopathy. Lipid keratopathy in bullouskeratopathy with numerous dropout spaces, some of whichcontain electron-dense material (arrows) (A, 330,000; B,360,000).



Except for thickening, the stroma in Fuchs dystrophyappears unremarkable by light microscopy. Yet it has beendemonstrated that the stroma of Fuchs dystrophy containcollagen with altered biochemical properties.30 We found thepresence of degenerated keratocytes and granular material inand around the keratocytes in our study that were evident onlyby electron microscopy. Iwamoto and DeVoe7,8 described thisgranular material previously, but not much attention has beenpaid to its distribution and occurrence. Moreover, they alsodescribed the presence of ‘‘activated’’ rather than degeneratedkeratocytes. We observed ‘‘degenerated’’ keratocytes through-out the superficial, mid- and deep stroma, and these were notconcentrated in one particular area. The distribution anddensity of keratocytes were unremarkable. The morphologic

changes suggest that keratocytes are undergoing apoptosis ordegenerative changes. However, the typical apoptotic bodieswith eosinophilic cytoplasm and dense nuclear chromatin werenot observed under light microscopy.31 We observed a highproportion of degenerated keratocytes and a higher occurrenceof intra- and extrakeratocytic granular material in Fuchsdystrophy as compared with the bullous keratopathy. Thegreater incidence of granular material and lipid keratopathy inFuchs may be related to a greater chronicity of edema in Fuchsdystrophy as compared with bullous keratopathy. Thesefeatures suggest the possibility of a primary pathologic ora secondary response to microenvironment changes in theFuchs dystrophy stroma. The granular material is somewhatsimilar to the ultrastructural appearance of mucopolysaccha-ride deposition in macular dystrophy.28 However, the depositsin Fuchs dystrophy did not stain with Alcian blue or colloidaliron. The exact nature of these deposits is yet to be determined.Similar granular material has also been observed around thekeratocytes in keratoconus with epikeratoplasty, both in thedonor and host cornea.32,33 Other authors report the presenceof fibrillogranular material around keratocytes in keratoconusand interpreted it as a possible indication of metabolic dys-function of the keratocytes in keratoconus.34–36

We observed dropout spaces compatible with lipidwithin and outside keratocytes in the stroma of Fuchsdystrophy by electron microscopy. These were similar to lipiddeposits described in primary lipid keratopathy,37–39 LCATdisease,40,41 and icthyosis.42 These microscopic lipid deposi-tions were not evident by light microscopy, even with the useof oil red O or Sudan black B stain (in paraffin-fixedspecimens, not in fresh tissue). This may be explained by theminute nature of these deposits and dissolution duringprocessing. Although the systemic lipid profile and the lipidconcentration in the eye were not measured, we believe thatthis lipid keratopathy is a localized corneal problem rather thanrelated to systemic hyperlipidemia since the latter is morecommonly associated with corneal arcus. Corneal lipid de-position is more commonly associated with prior vasculari-zation secondary to trauma or inflammation.38 The corneas inour series were all avascular. It is possible that the lipidkeratopathy is primary in nature and related to keratocytedegeneration. Cogan and Kuwabara43 proposed that fat might

FIGURE 13. Bullous keratopathy. Four layers of Descemetmembrane included anterior fetal banded layer (1), posteriornonbanded layer (2), posterior banded layer (3), and fibrillarlayer (4). No posterior nodule is present (34200).

TABLE 1. Comparison of the Demographic and Light Microscopic Features of FuchsDystrophy and Bullous Keratopathy

Fuchs Dystrophy(Total No., 32)

Bullous Keratopathy(Total No., 22) P Value

Age (mean 6 SD) 70.1 6 8.86 73.4 6 9.9 0.208*

Sex distribution (male:female) 11:21 12:10

Stromal thickness, mm (mean 6 SD) 405 6 99.9 423 6 85.7 0.483*

Descement membrane thickness, mm (mean 6 SD) 17.6 6 5.2 9.0 6 3.6 ,0.0005†

No. of posterior nodules inhigh-power field (mean 6 SD) 4.01 6 1.98 0 ,0.0005†

No. of endothelial cells inhigh-power field (mean 6 SD) 3.46 6 2.19 2.71 6 2.54 0.253*

*Student t test.†Mann-Whitney U test.



be formed in substantial quantities by all deranged native cellsof the cornea, including keratocytes. These lipid depositionswere initially intracellular and appeared as nonmembranedroplets within the keratocytes. As the intracellular lipidmetabolism mechanisms became insufficient, lipid accumu-lated and, with subsequent cell death, was released into thestroma.39,44 Similar lipid keratopathy was observed in thecomparison group, suggesting that these changes are likelysecondary to an altered microenvironment.

Bahn et al45 postulated that Fuchs corneal dystrophyoccurs as a result of abnormal neural crest cell terminal in-duction. The recently described EDICT syndrome, which alsoincludes endothelial dystrophy and iris atrophy as part of itsmanifestations, is also a neurocrest defect that has beenmapped to chromosome 15.46 Keratocytes and endothelialcells are of neural crest origin. If keratocyte and stroma in-volvement in Fuchs dystrophy is primary in nature, Fuchs dys-trophy should possibly be classified as a stromal-endothelialdystrophy rather than an endothelial dystrophy.

The pattern of Descemet membrane changes is similar tothose described in the previous studies and may consist of upto 4 layers including an anterior banded layer, posteriornonbanded layer, posterior banded layer, and a fibrillarlayer.2,7–10,47 The anterior banded layer is relatively constantand represents the fetal portion of Descemet membrane. It waspresent and appeared unremarkable in all the cases, and themean thickness was similar in both groups. The banding of thislayer is due to the presence of wide-spaced collagen. Theposterior nonbanded layer is usually present in an otherwisenormal cornea and thickens with age.2 This layer is eithervariably thin or even absent in some cases in Fuchs dystrophy.It has been suggested that this may reflect abnormal en-dothelial function early in life with production of the abnormalposterior banded layer rather than the normal posteriornonbanded layer.2,10,47 The periodicity of the wide-spacedcollagen of in posterior banded layer is about 110 nm, similarto that in the anterior fetal banded layer and is believed to becomposed of type VIII collagen.48 Although wide-spacedcollagen is quite characteristic in Fuchs dystrophy, it is notpathognomonic as it is also present in bullous keratopathy, asillustrated in our studies and reported elsewhere.47,49 A loosefibrillar layer is present between the posterior banded layer and

the endothelium in more than half of the cases. This layer wasshown to contain oxytalan fibers.50 A possible explanation forthe formation of this layer is that the decompensated en-dothelium allows increased fluid leakage into Descemetmembrane, thereby causing the formation of a loose fibrillarlayer rather than a compact collagenous layer.10,49 Waring et al2

suggested that the formation of the posterior banded layer andthe fibrillar layer represents a nonspecific endothelial responseto disease or injury. Multiple waves of basal lamina werepresent in the fibrillar layer in 7 corneas with Fuchs dystrophy.

Descemet membrane is produced by endothelium and iscomposed of only 2 layers in normal human subjects.51 Themorphologic changes in Descemet membrane in Fuchsdystrophy are presumably reflective of endothelial status,and it has been suggested the morphology would remain thesame once formed.2,10,47,49 However, our observation may notsupport this contention. If Descemet membrane morphologydoes not change once formed, we would have expected to seea much thicker posterior nonbanded layer in all the cases ofbullous keratopathy because the endothelium would pre-sumably be healthy before cataract surgery. Yet we observeda variably thinned, nonbanded layer in 14 cases and none in4 Fuchs dystrophy cases. Although it can be argued that therecould have been preexisting abnormalities in these cor-neas,2,10,47,49 it may be more reasonable to suggest that themorphology of Descemet membrane may change in variousdiseases. Moreover, the posterior banded layer and fibrillarlayers are not pathognomonic for Fuchs dystrophy and are alsopresent in the bullous keratopathy group. This is similar tothose reported in aphakic bullous keratopathy and othercorneal conditions.47,49

The endothelium is attenuated in all the cases of Fuchsdystrophy, and the remaining endothelial cells may havedegenerative changes. It should be noted that only a small areais examined by electron microscopy, and the endothelial cellcount under light microscopy is a more useful means ofquantitation of endothelium. The significance of myoblasticfeatures in the endothelial cells in 5 cases is not known.

In summary, we observed ultrastructural changes inFuchs dystrophy similar to those described in previous studies.We also observed granular deposits in and around variablydegenerated keratocytes together with lipid keratopathy in the

TABLE 2. Comparison of the Keratocyte Changes and Lipid Keratopathy in FuchsDystrophy and Bullous Keratopathy

KeratocytesFuchs Dystrophy(Total No., 32)

Bullous Keratopathy(Total No., 22) P Value

Mean no. sampled (range) 12.3 (7–23) 12.4 (8–30)

% of cases with degenerated keratocytes 100 (32/32) 95 (21/22) 0.41*

Mean % of degenerated keratocytes (range) 78.9 (46–100) 50.5 (0–100) 0.001†

% of cases with granular material 100 (32/32) 64 (14/22) ,0.0005*

Mean % of keratocytes with granularmaterial/total sampled (range) 51.7 (9–100) 14.1 (0–36) ,0.0005†

% of cases with at least mildlipid keratopathy (range) 72 (23/32) 55 (12/22) 0.19‡

*Fisher exact test.†Mann-Whitney U test.‡Pearson x2 test.



stroma of Fuchs corneal dystrophy. These changes could besecondary to chronic endothelial loss and altered stromalmicroenvironment. Whether there is any additional element ofintrinsic keratocytes change is yet to be determined. Thehistopathologic changes observed in the keratocytes in Fuchsdystrophy support the idea that keratocytes may be involved inthe pathophysiology of Fuchs dystrophy.

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A Morphologic Study of Fuchs Dystrophy and Bullous Keratopathy · A Morphologic Study of Fuchs...

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