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- 1. 264 INTRODUCTION The effects of external trauma and of ophthalmic and systemic disease on human corneal endothelium are best understood by rst reviewing the anatomy and physiology of the adult human endothelium. A com- prehensive review of this material can be found in Chapter 4-1. FUCHS DYSTROPHY Introduction Fuchs endothelial corneal dystrophy (FD) is a bilateral, non- inammatory, progressive loss of endothelial cells that results in cor- neal edema and reduction of vision. Its key features include the presence of central guttae, folds in Descemets membrane, stromal edema, and microcystic epithelial edema. Corneal endothelial degen- eration is the primary defect that leads to the development of corneal edema. Associated features include prominent corneal nerves, stromal opacication, recurrent corneal erosions, female gender and familial predisposition. Epidemiology and Pathogenesis FD is the most common corneal dystrophy to require keratoplasty, accounting for approximately 3.9% of all penetrating keratoplasties and 47.7% of all endothelial keratoplasties in the United States in 2011.1 Pedigree analysis suggests that FD is an inherited dystrophy with an autosomal dominant inheritance pattern, although the exact mode of inheritance in many cases remains unknown.2 FD is likely to be com- plex in etiology, with genetic as well as environmental factors playing a role in its pathogenesis.3 A signicant variation occurs in expressivity between males and females, with a 4:1 femalemale ratio recorded at the time of keratoplasty.4 It is equally common among whites and blacks who undergo keratoplasty, but is relatively rare in Asians.5 Development of guttae and the onset of symptoms are more com- mon in middle age.2 A variant of early-onset FD, which presents with corneal changes within the rst few years of life, has been described.6 FD patients are believed to have an increased incidence of open-angle glaucoma.7 Short axial length, shallow anterior chamber, and angle-closure glaucoma also have been seen in conjunction with FD.8 FD has been associated with keratoconus.911 The progressive loss of endothelial cell function is primary in nature rather than secondary to any alteration in aqueous humor ow rate12 or constituency.13 Endothe- lial dysfunction is mainly a result of a reduction in Na+ ,K+ -ATPase pump activity,14 which leads to a reduction in ion ux across the endothelium.11 Molecular biological studies of corneal buttons from patients with FD suggest that apoptosis may play an important role in endothelial cell degeneration.15 Recent studies have demonstrated an oxidantantioxidant imbalance in FD cells, which in turn leads to oxi- dative DNA damage and apoptosis.16 Mutations in the gene COL8A2 in chromosome 1p34.3-p32 that codes for the alpha2 chain of type VIII collagen have been reported in patients with early onset FD and in families with posterior polymor- phous corneal dystrophy.6,17 Several genetic loci have been identied in late-onset FD patients.3 The rst genetic locus was mapped to chromo- some 13, called Fuchs corneal dystrophy locus 1 (FCD1).18 Subse- quently, two other loci, FCD219 and FCD3,20 were mapped to chromosomes 18 and 5 respectively. Additionally, other reports have provided evidence for potential linkage to chromosomes 1, 7, 15, 17 and X by genome-wide linkage analysis.21 Mutations in the Borate Cotransporter encoded by the SLC4A11 gene, also associated with congenital hereditary endothelial dystrophy, have been linked to the development of late-onset FD.22,23 Additionally, mutations in the TCF8 gene, associated with posterior polymorphous corneal dystrophy, have been identied in patients with late-onset FD.24 Recently, a strong association has been discovered between late- onset FD and sequence variants in the transcription factor 4 (TCF4) gene in chromosome 18.2527 This gene encodes the E2-2 transcription factor which is involved in cellular growth and differentiation.25 Ocular Manifestations The earliest slit-lamp nding in FD is the presence of focal excres- cences of extracellular matrix in Descemets membrane, called guttae (cornea guttata). In the earliest stages of this disease, the guttae rst emerge in the central corneal endothelium (Fig. 4-21-1). Guttae are not Noel Rosado-Adames, Natalie A. Afshari 4.21Corneal Endothelium SECTION 6 Corneal Diseases PART 4 CORNEA AND OCULAR SURFACE DISEASES Associated feature A delicate tissue subject to alteration from age, trauma, systemic or ocular disease, contact lens wear, surgery, intraocular solutions, and unique dystrophic conditions Key feature A tissue containing large quantities of membrane-bound Na+ ,K+ -ATPases with specialized intercellular junctions that establish a pumpleak process integral to the maintenance of corneal deturgescence Definition: Hexagonal nonreplicating monolayer of neural crest- derived tissue that regulates the hydration state of corneal stroma. Fig. 4-21-1 Slit-lamp view of FD. Note the guttae on the specularly reflected image of the endothelium.
- 2. CornealEndothelium 4.21 265 Pathology Light microscopy ndings include a thickened Descemets membrane, which may be laminated in appearance with buried guttae, guttae on the surface, or devoid of guttae but thickened (Fig. 4-21-3).4 The endothelial layer is attenuated. Histological comparison of normal, early-onset FD and late onset FD corneas have shown distinct histo- logical patterns, demonstrated by electron microscopy.3 Early-onset FD shows a markedly thickened Descemets membrane anterior banded layer (ABL). ABL is presumed to develop during early fetal life, thus suggesting that these changes in ABL may represent pathological pro- cesses that start in utero and continue to develop later during specic to FD, and they may be seen in asymptomatic patients and in the setting of both uveitis and nonspecic supercial keratopathies. Up to 11% of eyes in patients older than 50 years of age have guttae.28 Pathologically identical lesions in peripheral Descemets membrane are known as HassallHenle warts and are part of the normal aging process (see Chapter 4-22). The guttae initially appear on specular reection as scattered, dis- crete, isolated dark structures, smaller than an individual endothelial cell.29 An associated ne pigment dusting may be observed within the central endothelium. At this stage, referred to as stage 1, the patients vision is usually normal, and the stroma and epithelium are unin- volved.3,28 Over time, these individual excrescences increase in number, enlarge, and fuse with adjacent guttae to disrupt the normal endothelial monolayers specular reection.29 This produces a roughened surface with a specular reection similar to beaten metal in appearance. Even- tually, this process expands from the center of the cornea to involve the corneal periphery as well. As the disorder progresses, the endothelial monolayer becomes attenuated in thickness, with an increase in aver- age cell size (polymegathism), a decrease in the percentage of hexagonal shaped cells and an increase in the coefcient of variation in cell size (pleomorphism). In the last stages of the dystrophy, effacement of the endothelium results in overlying stromal edema. At this point, the endothelium becomes more difcult to observe using conventional specular microscopy, but it may still be visualized using confocal microscopy.29 As endothelial function progressively declines, the uid accumulat- ed in the stroma during night-time lid closure is removed at a reduced rate, which results in signicant stromal edema upon awakening.30 This heralds the onset of stage 2.3,28 Patients note blurred vision, glare, and colored halos around lights. Initially, the stromal edema is local- ized in front of Descemets and behind Bowmans membrane.31 Eventu- ally the entire stroma swells, taking on a ground-glass appearance. With the increase in corneal thickness, the posterior stroma and Descemets membrane are thrown into folds. Vision at this time is variable. With progressive endothelial dysfunction, bulk uid ow across the cornea results in microcystic and bullous epithelial edema. This devel- opment represents stage 3 of the disease.3,28 With involvement of the epithelial layer, the optical quality of the tearair interface is severely degraded, which produces a profound reduction in vision. With the onset of epithelial edema, basal adhesion complexes become disrupted to produce recurrent corneal erosions. As a slit-lamp marker of recur- rent epithelial sloughing, duplication of basement layers occurs, which creates ngerprint and map changes. If erosions are prominent, a vascular pannus between epithelium and Bowmans membrane may be induced and results in an anterior stromal haze, with further reduction in vision, representing stage 4 of the disease.3 However, the associated secondary brotic layer produced within the pannus often reduces or eliminates the painful recurrent epithelial erosions experienced by the patient. With the increase in stromal edema, glycosaminoglycans elute from the stroma,32 causing disorganization of the collagen brils, which contributes to additional stromal opacication. Diagnosis and Ancillary Testing The earliest observable change suggestive of FD is the presence of gut- tae on slit-lamp examination (see Fig. 4-21-1). Specular microscopy provides endothelial cell counts, as well as a photographic record that can be a useful educational aid for the patient (Fig. 4-21-2). Subtle stro- mal edema can be observed using sclerotic scatter techniques. Corneal pachymetry documents increased corneal thickness. As the disease progresses, more obvious signs may develop, which include folds in Descemets membrane, stromal haze, microcystic and bullous epithe- lial edema, subepithelial brosis, and pannus formation. When corneal opacication precludes specular microscopy, confocal microscopy can be used to image the endothelium and obtain reliable endothelial cell counts.2
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