Clinical background
Fuchs’ endothelial corneal dystrophy (FECD) is a bilateral, asymmetric, slowly progressive disorder specific to the corneal endothelium, resulting in decreased visual function and in some cases pain, secondary microbial infection, and corneal neovascularization ( Figure 5.1A ). The disease was first described in 1910 by Ernst Fuchs, an Austrian ophthalmologist. FECD is an age-related disorder that affects 4% of the population over 40 years of age and its typical symptomatic onset is in the fifth or sixth decade of life ; however, an early form of the disease does exist. Women are predominantly affected and familial clustering is commonly seen with this disease, which suggests an autosomal-dominant inheritance with incomplete penetrance.
The two different forms of FECD are mainly distinguished by the time of onset of disease. The more typical form presents in the fourth or fifth decade and is known as late-onset FECD. Rare cases have been reported of early-onset FECD that demonstrate disease as early as the first decade with diffuse corneal edema by the third or fourth decades without prior guttae formation. The two forms of FECD also vary in terms of histopathology ( Figure 5.2 ), Descemet’s membrane electron micrography, immunohistochemistry, distribution of various proteins in Descemet’s membrane, corneal slit-lamp photography, specular microscopy, and genetic inheritance. These differences will be discussed further in the following sections of this chapter.
The underlying defect in FECD is believed to be a programmed decline in the number of functional endothelial cells. This causes a dysfunction of this layer which leads to a progressive sequence of stromal and epithelial edema, eventually resulting in structural alterations to the other corneal layers. The endothelial dysfunction is thought to lead to a thickening of Descemet’s membrane along with stromal and epithelial edema which, if extensive enough, can produce subepithelial bullae. The edema results in decreased vision and the bullae cause the pain associated with FECD.
FECD overlaps with other conditions sharing endothelial attenuation, such as pseudophakic corneal edema (PCE), but is typically distinguished from these other corneal disorders by the presence of refractile endothelial excrescences called guttae. A nonguttate form of FECD does exist and is thought to be a variant. In addition several other conditions can cause pseudoguttae in the setting of inflammation and infection (e.g., luetic keratitis).
Pathology and pathophysiology
Overview of the structure and function of the cornea
To understand the functional impact of FECD on the cornea, a brief discussion of normal corneal physiology is important, in particular understanding the function of each layer and comparing normal cornea to corneas affected by FECD, beginning with the endothelium and progressing anteriorly. The cornea is a thin, highly specialized tissue that faces the challenge of being an interface between the outside environment and the inside of the body while maintaining tissue clarity at a level which allows sharp visual acuity. This is achieved via the efficacy of specialized layers as thin as monolayers, in maintaining corneal health. The two main functions of the cornea are maintaining the structural integrity of the eye and clarity. Corneal clarity is most universally related to it, being maintained in a state of deturgescence. The endothelial monolayer function, supplemented by epithelial evaporation and augmented by the cornea’s avascularity, is responsible for corneal deturgescence. Endothelial deturgescence is accomplished in two ways: (1) by acting as a barrier to the movement of salt and metabolites into the stroma; and (2) by actively pumping bicarbonate ions from the stroma to the aqueous humor. Active transport is achieved as a result of the gradient of the Na-K-ATPase pump in the lateral cell membrane of endothelial cells. Endothelial dysfunction has been observed in corneas where ATPase inhibitors such as ouabain and carbonic anhydrase inhibitors such as acetazolamide have been used topically or intracamerally.
The endothelium
The endothelial monolayer is composed of cells with hexagonal plate-like shape with nuclei that are round and spaced roughly 2–4 nuclear diameters from their neighbors. Cell thickness equals that of the nuclei. With endothelial attenuation, the number of cells first decreases, then the cytoplasm thins, and finally the nuclei thin to adopt a progressively flattened shape.
In FECD, several factors may contribute to corneal edema, though the primary cause of this endothelial dysfunction is unknown. Homeostasis of fluid across the posterior surface of the cornea is thought to occur as a result of the pump leak model. A decreased number of endothelial cells may result in fewer sites of pump action. In addition, the attenuation of cell cytoplasm as cells spread and enlarge horizontally to cover Descemet’s membrane may decrease the barrier function of the endothelium. Decreased pump activity within the endothelium has been identified ( Figure 5.3 ). Recent studies have shown advanced glycation end products (AGEs) in corneal endothelium, suggesting a possible role for oxidative stress and AGEs in FECD pathogenesis. Keratin expression not normally seen in endothelium has been noted in patients with FECD as well as other conditions of endothelial stress, though this may represent an epiphenomenon of the endothelial pathology. Studies of aquaporins, a family of transport molecules, show a decreased expression of aquaporin 1 in both FECD and PCE corneas but increased aquaporin 3 and 4 in PCE alone, suggesting a role for these molecules in FECD which differs from that in PCE. Similar findings occurred in thermally induced endothelial dysfunction in mice. Most recently, ultrastructural studies of three cases of early-onset FECD showed swollen mitochondria, a sign of cell stress.
Guttae formation and progression can be identified with slit-lamp biomicroscopy, specular microscopy, and confocal microscopy ( Box 5.1 ; stage 1). Pachymetry can document the increased corneal thickness due to edema and fluorophotometry can demonstrate the loss of barrier and pump function. Histopathologically, the edema fluid separates the corneal lamellae and forms “fluid lakes.” The separation of collagen fibrils leads to loss of corneal transparency. As the disease progresses, the edema fluid enters the epithelium, resulting in an irregular epithelial surface. The edema varies from slight bedewing to frank bullae formation ( Box 5.1 ; stage 2). Mild-to-moderate corneal guttae can remain as such for years without affecting vision. As the disease advances, vascular connective tissue is formed under and in the epithelium ( Box 5.1 ; stage 3). This condition is followed by extremely limited visual acuity ( Box 5.1 ; stage 4) and secondary complications (e.g., epithelial erosions, microbial keratitis, corneal vascularization).
Stage 1
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This stage is defined by the presence of corneal guttae in the central or paracentral area of the endothelium
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It occurs in the fourth or fifth decade of life
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The excrescences of corneal guttae increase in number and may become confluent, resulting in a beaten-metal appearance of the endothelial surface
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The patient usually has no complaints at this stage
Stage 2
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This stage is characterized by confluent guttae in the central and/or paracentral area of the corneal endothelium associated with stromal edema
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Increasing visual and associated problems develop, caused by incipient edema of the corneal stroma initially and later the epithelium
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The patient sees halos around lights and also experiences blurred vision and glare along with foreign-body sensation and pain
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With progression microcystic epithelial edema develops and ultimately macrobullae form that may rupture and expose the cornea to the danger of infectious keratitis
Stage 3
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In this stage, subepithelial connective tissue and pannus formation along the epithelial basement membrane are present
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The periphery of the cornea becomes vascularized and a reduction in bullae formation occurs
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Epithelial edema is reduced, so that the patient is more comfortable
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Stromal edema remains
Stage 4
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Visual acuity may be reduced to hand motions, but the patient does not experience painful attacks
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Subepithelial scar tissue forms, limiting vision, but bullae formation decreases
Descemet’s membrane in FECD
Descemet’s membrane is divided into two layers: an anterior banded layer (ABL) laid down during embryogenesis, and a posterior nonbanded layer (PNBL) which represents the progressively thickening basement membrane of the endothelium throughout life. At birth, the thickness of the ABL averages 3 µm and stays relatively constant throughout life. It acquires an intricate laminar structure formed from the extracellular matrix secreted by endothelial cells. The ABL contains large, regularly spaced bands of collagen VIII. In contrast to the ABL, the PNBL continues to thicken throughout life, averaging 2 µm at 10 years and 10 µm at 80 years. In prenatal development, the expression of short filaments is observed perpendicular to the plane of the anterior layer of Descemet’s membrane. Transmission electron microscopy has shown these filaments to have a striated or banded pattern forming the ABL. The deposition of nonstriated material continues with age and forms the PNBL.
The structure of Descemet’s membrane is adversely affected by the FECD disease process ( Figure 5.4 ). The ABL thickness in both normal corneas and those affected by late-onset FECD ranges from 3 to 4 µm. However, in early-onset FECD, the ABL can be as thick as 38 µm. The PBNL of Descemet’s membrane is the most prominent structure affected in late-onset FECD, accounting for the majority of the increase in thickness along with the corneal guttae. Unlike late-onset FECD, the PNBL in early-onset disease is similar to normal corneas, except for the presence of rare strips of widely spaced collagen. This layer is accompanied by a unique 2-µm internal collagenous layer (ICL) characterized by widely spaced collagen strips and a 12-µm posterior striated layer. Wide-spaced type VIII collagen was found to be the major structural component to Descemet’s membrane in both the ABL and PBNL of normal, early-onset FECD, and late-onset FECD corneas. A loose fibrillar layer can also be found between the PNBL and the endothelial cells. The fibrillar layer seems to be thicker in corneas with more decompensation as there is presumably more fluid accumulation through diseased endothelial tight junctions.
