3 Clinical Investigations and Diagnosis of Endothelial Cell Dysfunction The corneal endothelium is a transparent single cell layer lining the posterior cornea. It plays an essential role in maintaining stromal fluid balance and transparency. A minimum number of endothelial cells is required to provide adequate endothelial function; endothelial cell density decreases from approximately 3000 to 4000 cells/mm2 at birth to 2500 cells/mm2 in late adulthood.1 Tight junctions among endothelial cells and pump function association with Na + /K + -ATPase and bicarbonate-dependent Mg2 + -ATPase are necessary for endothelial functioning.1 The currently accepted paradigm is that corneal endothelial cells have limited proliferative potential. Various pathological conditions can lead to damage of the endothelial cells. Neighboring residual cells migrate and spread over the area of endothelial cell injury; they compensate for the endothelial cell loss and maintain corneal deturgescence and corneal transparency. However further endothelial loss will ultimately lead to decompensation of the corneal endothelium, associated with progressive visual impairment.2 It has been shown that the density of the corneal endothelial cells is strongly heritable, with an 82% heredity contribution compared to 18% unique environmental contribution.3 These genetic and environmental factors may trigger endothelial dysfunction and dystrophies. This chapter reviews the clinical findings and investigations needed for various conditions leading to endothelial cell dysfunction, including Fuchs dystrophy, and posterior polymorphous corneal dystrophy and pseudophakic bullous keratopathy (PBK). Corneal dystrophies are noninflammatory corneal diseases that affect the cornea, leading to progressive loss of transparency. They have long been clinically classified into three groups: superficial corneal dystrophy, stromal corneal dystrophy, and posterior corneal dystrophy.4 In 2008, an International Committee for Classification of Corneal Dystrophies classified dystrophies into four groups based on clinical features, pathological exams, and genetic data5: (1) epithelial and subepithelial dystrophies, (2) epithelial–stromal transforming growth factor beta induced (TGFBI) dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies.4 Fuchs endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy, congenital hereditary endothelial dystrophy, and X-linked endothelial corneal dystrophy are characterized as endothelial dystrophies. FECD is a slowly noninflammatory progressive disease characterized by loss of endothelial cells that results in edema and loss of vision. Its key features include the presence of central guttae, folds in Descemet’s membrane, stromal edema, and microcystic epithelial edema6 (► Fig. 3.1). Fuchs endothelial dystrophy is the most common endothelial dystrophy, with a prevalence ranging between 4 and 9% in various populations.7,8,9 A 10-year review from 2005 to 2014 showed that FECD accounted for 22% of corneal transplantations in the United States.10 It is also more prevalent in females than in males, where females are predisposed to Fuchs dystrophy and develop corneal guttae 2.5 times more frequently than males, progressing to corneal edema 5.7 times more often than males.11 All layers of the cornea may be affected by FECD. It is characterized by loss of endothelial cells, with thickening and excrescences of the Descemet membrane (guttae) in the central cornea.4 Development of guttae and the onset of symptoms are more common in the fifth through seventh decades in life. Studies have demonstrated that Fuchs corneas exhibit a 45 to 59% reduction in endothelial cell density compared to healthy corneas.12,13 Most of the corneal dystrophies are inherited with an autosomal dominant pattern. Posterior polymorphous dystrophy has been associated with mutations in VSX1, COL8A2, and ZEB1 genes.4 There is some genetic basis for Fuchs dystrophy. Coding mutations in four genes have been identified to be causal for the FECD phenotype: TCF8, SLC4A11, LOXHD1, and AGBL1.1 Mutations in two transcription factors (TCF4/E2–2 and TCF8/ZEB-1), one collagen subunit (COL8A2), and two membrane proteins (LOXHD1 and SLC4A11/NaBC1) have been found in Fuchs dystrophy.9 Except LOXHD1, these mutations appear to converge on the collagen secretion and water pump functions of corneal endothelium. L450W14 and Q455K15 in the COL8A2 are two autosomal dominant mutations reported in early-onset Fuchs dystrophy. COL8A2 is the gene encoding the a2 chain of type VIII collagen. Missense mutations attributing to loss of function in TCF8, a gene encoding the ZEB1 protein, are sufficient to cause late-onset of Fuchs.16 Additionally single-nucleotide polymorphisms in the TCF4 gene, encoding the E2–2 protein, are thought to result in decreased expression of the protein.17 E2–2 is a transcription factor known to upregulate TCF8,18 suggesting that both TCF4 and TCF8 are involved in the same pathway in Fuchs dystrophy development. Additional mutations in SLC4A11 were also identified. Posterior polymorphous corneal dystrophy (PPCD) encompasses a broad spectrum of corneal and anterior segment abnormalities.19 This rare dystrophy has a clinical spectrum that ranges from congenital corneal edema to late-onset corneal edema in middle age. PPCD is a bilateral autosomal dominant disease. It has been linked to three chromosomal loci: PPCD1 on chromosome 20p11.2-q11.2, PPCD2 on 1p34.3-p32.3, and PCD3 on 10p11.2. The gene for PPCD1 is unknown, the gene for PPCD2 is collagen type VIII alpha 2 (COL8A2), and the gene for PPCD3 is zinc finger E-box binding homeobox 1 (ZEB1).19,20,21,22 Fig. 3.1 (a) Slit lamp photography showed corneal guttae (OD). Specular microscopy was unable to provide an image of the eye due to corneal edema. (b) Specular microscopy of the left eye (OS) captured multiple guttae, with inability to perform cell counts. (Adapted from Jurkunas U, Azar DT. Potential complications of ocular surgery in patients with coexistent keratoconus and Fuchs’ endothelial dystrophy. Ophthalmology 2006;113(12):2187–97.) The hallmark of PPCD is a vesicular lesion. Examination of the posterior corneal surface will show any or all of isolated grouped vesicles; geographic-shaped, discrete, gray lesions; and broad bands with scalloped edges. On slit lamp examination the vesicular lesions appear as transparent cysts surrounded by a gray halo at the level of the Descemet membrane. By specular microscopy, the vesicular lesions range in diameter from 0.10 to 1.00 mm.20,21 The endothelial cells between the involved areas may have three appearances: normal-sized cells with a typical mosaic pattern, cells smaller than normal and crowded together, or enlarged pleomorphic cells.20,21 Diffuse opacities are also observed, and they may be either small, macular, gray-white lesions or larger sinous lesions at the level of the Descemet membrane.19 Various degrees of stomal edema, corectopia, and broad iridocorneal adhesions may also be seen.22 PBK and aphakic bullous keratopathy (ABK) are corneal diseases caused by endothelial decompensation following cataract surgery in the presence (PBK) or absence (ABK) of intraocular lenses (IOLs). The endothelial density is reduced and a compromised endothelial cell pump leads to overhydration of the cornea.23 PBK is more likely to occur after anterior chamber IOLs than after posterior chamber IOLs. The incidence of bullous keratopathy induced by anterior chamber IOLs may be up to 10%.23,24 Other than Fuchs dystrophy, failed corneal grafts, penetrating or blunt trauma, and refractory glaucoma are listed as secondary causes.23 Visual acuity is reduced in almost all cases. This is due to increased corneal thickness and Descemet membrane folds. Patients may experience discomfort and severe pain following the formation, and rupturing, of epithelial layer bullae. PBK and ABK also predispose to corneal infection and scarring. Modern techniques of posterior keratoplasty have supplanted corneal transplantation as the gold standard treatment for patients with PBK. Other (historical) alternatives that are rarely used today include anterior stromal puncture, phototherapeutic keratectomy, amniotic membrane transplantation, conjunctival flap, bandage contact lens, and collagen cross-linking. Corneal guttae are the first sign of Fuchs dystrophy and develop centrally and spread toward the periphery.22 The guttae initially appear as scattered, discrete, isolated structures, smaller than an individual endothelial cell. Patients at this early stage are not symptomatic. Over time the guttae spread peripherally, the Descemet membrane becomes thickened and irregular, and folds develop secondary to stromal edema. Additional to swelling, blurred vision, foreign body sensation, photophobia, and halo perception may develop. A more advanced FECD may have “buried guttae” centrally.25 The epithelium is generally intact in early stages of classic Fuchs dystrophy; however, in severe FECD loss of pump function in the edematous cornea results in anterior migration of fluid through the corneal stroma and the formation of painful epithelial bullae.1 Microcystic epithelial edema may follow, characterized as a stippled pattern that stands out in sclerotic scatter.19 An abnormal Bowman layer with diffuse bright reflection and a paucity or absence of nerves are revealed in approximately half of the patients with FECD.1 An increased center-to-peripheral thickness ratio in the stroma of FECD-affected corneas has been observed versus that in controls.26 The Descemet membrane in FECD is marked by the presence of a thick posterior banded layer, a posteriormost layer in which collagen fibrils approximately 10 to 20 µm in diameter with 110 µm banding are deposited by the endothelium.1 This posterior banded layer is approximately 16 µm thick and correlates directly with the clinical severity of FECD.27 Additionally, a fibrillary layer may be present in corneas with severe edemas, described as a posterior collagenous layer.28,29 Transmission electron microscopy of FCD corneas demonstrates some endothelial cells with cytoplasmic filaments, increased rough endoplasmic reticulum, and cytoplasmic processes, bearing similarity to fibroblasts; intercellular vacuoles remain in areas associated with loss of cells.29 In end-stage disease, avascular subepithelial fibrous scarring occurs between the epithelium and the Bowman membrane. Peripheral superficial corneal neovascularization can also occur. Irregularity of the surface and loss of transparency further decrease vision.19
3.1 Introduction
3.2 Endothelial Cell Dysfunction
3.2.1 Endothelial Dystrophies
Fuchs Endothelial Corneal Dystrophy
Posterior Polymorphous Corneal Dystrophy
3.2.2 Pseudophakic and Aphakic Bullous Keratopathy
3.3 Clinical Examination
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