THE NORMAL CORNEA

The cornea has three primary functions. These are:

To achieve these functions the cornea has evolved as an avascular structure with metabolic requirements supplied by diffusion. The main supply of oxygen to the epithelium and stroma is provided by atmospheric oxygen dissolved in the tear film with a small contribution from the limbal vessels peripherally; the endothelium obtains oxygen primarily from the aqueous. Glucose is similarly supplied from the tear film and aqueous. Aerobic metabolism produces carbon dioxide, which either diffuses away through cell membranes or is converted to bicarbonate and pumped into the aqueous by a carbonic anhydrase-dependent pump at the endothelial cell surface. Lactic acid, produced by anaerobic metabolism, cannot easily diffuse through the epithelial cell barrier and most diffuses posteriorly into the aqueous; corneal hypoxia leads to an accumulation of lactic acid and metabolic acidosis which contributes to corneal oedema.

The corneal epithelium is derived from surface ectoderm but the other corneal structures are formed from neural crest. After invagination of the lens vesicle, a layer of loose collagen fibrils between the ectoderm and the lens represents the corneal stroma. Mesenchymal cells from the perilimbic cell mass begin to form endothelium, and the stroma is invaded by perilimbic fibroblasts (future keratocytes) at about 6 weeks of gestation. At birth the cornea is relatively large compared to the rest of the globe and adult size is attained by about 2 years of age.

The cornea has a horizontal diameter of 11–12 mm that is reduced to 9–11 mm vertically by encroachment of the limbus. The central corneal thickness is 0.52 mm (normal range 0.49–0.56 mm) increasing to 0.7 mm peripherally. The central cornea has an anterior radius of curvature of 7.8 mm (43.5d) (normal range 7.0–8.5 mm, 39.5–48d) and a posterior radius of curvature of 6.8 mm (49.5d). The posterior surface faces the aqueous, which has a lower refractive index (1.336) so that the refractive power of this surface is about –6D. The average refractive index of the cornea is 1.376 and the axial refractive power is approximately 43D, which is about 74 per cent of the total dioptric power of the human eye.

Fig. 6.1 The cornea has five distinct histological layers. The epithelium supports the precorneal tear film and consists of a stratified squamous cellular layer attached to an underlying basement membrane. Bowman’s layer is an acellular condensation of superficial stroma approximately 10–20 μm thick that lies immediately beneath the epithelial basement membrane. The stroma forms over 90 per cent of the corneal thickness and consists of regularly spaced collagen lamellae (layers) in a proteoglycan matrix interspersed with keratocytes. Descemet’s membrane is composed of a lattice of collagen fibrils that is 3 μm thick at birth and increases in thickness with age. The endothelium is a monolayer of hexagonal cells.

By courtesy of Professor J Marshall.

Fig. 6.2 The precorneal tear film must be smooth and stable for regular refraction. The epithelial surface is thrown into multiple folds (microvilli and microplicae) which produce a glycocalyx (a branching mucoprotein layer) that renders the surface hydrophilic. The precorneal tear film is about 40 μm thick and is composed of mucus derived from the conjunctival epithelial cells, conjunctival goblet cells and the lacrimal glands. The aqueous component is secreted by the lacrimal glands and the superficial lipid layer from the meibomian glands. Atmospheric oxygen, metabolites and antimicrobial agents (e.g. IgA, lysosyme, lactoferrin) are dissolved in the tear film.

By courtesy of Professor J Marshall.

Fig. 6.3 The epithelium is about five cells thick and separated from Bowman’s layer by the epithelial basement membrane. The morphology of the basal cells changes as they migrate anteriorly to become intermediate wing cells and then elongated superficial cells with flattened nuclei that finally desquamate from the surface into the tear film. Macrophages (dendritic cells) are found in the epithelium having migrated from the limbus although they may be absent in the central zone. These have an antigen-presenting function. The epithelium has zonula occludens junctions between cells which make the healthy epithelium a virtually impermeable barrier.

By courtesy of Professor J Marshall.

Fig. 6.4 Cells from the corneal limbus continuously replace cells lost from the corneal epithelium. A population of stem cells is thought to be located in the basal epithelial cells of the folds of the palisades of Vogt. The stem cells divide to form ‘transient amplifying cells’ that move toward the centre of the cornea. Postmitotic daughter cells then migrate anteriorly from the basal layer to become terminally differentiated cells that are eventually lost from the anterior surface of the epithelium into the tear film.

Fig. 6.5 The mechanical strength of the cornea is provided by the stroma, which is formed predominantly of collagen fibrils (mainly type 1) maintained in a proteoglycan matrix. The stromal fibrils are continuous from limbus to limbus and are arranged into about 200 layers or ‘lamellae’ with a small degree of interdigitation. The superficial Bowman’s layer is acellular and the collagen fibrils are finer and more densely packed. Transmission of light depends on the collagen fibrils regular size and spacing with small changes of refractive index. A relative dehydration of the stromal proteoglycans is required which is achieved because the epithelium is impermeable and by the endothelial pump which removes water from the stroma. Light transmission is maximal at 700 nm (98 per cent) and decreases to 80 per cent at 400 nm. Ultraviolet light with a wavelength below 310 nm is strongly absorbed by the stroma. By contrast, the cornea transmits infrared radiation up to 2400 nm.

By courtesy of Professor K Meek.

Fig. 6.6 Using in vivo confocal microscopy high-resolution images can be obtained in real-time at different depths within the intact living cornea without the need for staining or processing, giving a direct view of living cells. Shown here is the cellular morphology of a normal human cornea. Each image represents an optical volume with approximately 450 × 340 × 9 μm. a, Superficial epithelial cells; b, wing epithelial cells; c, basal epithelial cells; d, subepithelial nerves (on Bowman’s layer); e, first layer of keratocyte nuclei; f, nerve branch and keratocytes in the mid-stroma; g, keratocytes in front of Descemet’s membrane; h, endothelial cells.

By courtesy of Dr T Moller-Pedersen.

Fig. 6.7 Descemet’s membrane, which consists of type IV collagen, is secreted by the endothelium. It is composed of a lattice of collagen fibrils that is 3 μm thick at birth (top), when the entire layer appears striated or ‘banded’. A posterior ‘nonbanded’ layer is continuously laid down throughout life so that Descemet’s membrane increases in thickness with age to reach 30–40 μm in the elderly (bottom). Notice the decrease in endothelial cell population.

By courtesy of Professor J Marshall.

Fig. 6.8 The endothelium can be examined by specular or confocal microscopy. The endothelium does not replicate after birth and cell counts reduce from 3500–4000/mm² at birth to approximately 2000–2500/mm² in the adult cornea. Corneal decompensation is likely with cell counts of less than 500/mm². Cell density is a good guide to function, which can be complemented by other parameters such as variation in cell size and morphology (polymegathism and polymorphism). These specular photographs show the endothelium of an 18-month-old infant (top) and a normal 74-year-old man (middle). Notice the decreasing cell count and larger cell size with age. Larger cells with variation in morphology are seen in the endothelium of a patient after traumatic cataract surgery (bottom).

NORMAL CORNEAL TOPOGRAPHY

The central 4 mm of the corneal surface is spherical but progressively flattens towards the periphery (prolate curvature). Keratometry measures the average curvature of the central 3 mm along its two principal meridians. Topography, which can be performed by reflection, projection or interference based systems, measures the shape (curvature, power or elevation) of the whole cornea.

Fig. 6.9 With topography (see Ch. 1) a series of concentric rings is projected on to the surface of the corneal tear film. A difference in the relative distances between these rings compared to a calibrated spherical surface allows the corneal curvature to be measured from the visual axis to the periphery; this is then converted to dioptric power and displayed as a colour-coded topographical map in which colours towards the red end of the spectrum represent increasingly steep dioptric powers. A small range of dioptric powers can be seen on this normal cornea with flattening toward the periphery.

Fig. 6.10 Astigmatism is seen on topography as distortion of the circular projections into oval reflections. Topography of regular astigmatism appears as a ‘bow tie’ due to progressive peripheral flattening with axes at 90° to each other with mirror image symmetry between the two eyes. Irregular astigmatism, as in keratoconus, appears as steepening below the visual axis (see Fig. 6.33).

AGE-RELATED DEGENERATION

Involutional changes as a result of ageing must be distinguished from pathological changes.

Fig. 6.11 The white limbal girdle of Vogt is a common ageing change at the interpalpebral limbus which appears as a semilunar opacity with a clear zone of separation from the limbus; it is best seen by sclerotic scatter. The nasal cornea is affected nearly twice as often as the temporal side. There may be clear patches in the opacity, which may then resemble a mild form of band keratopathy. Histological examination shows subepithelial hyaline degeneration at the level of Bowman’s layer.

Fig. 6.12 Anterior crocodile shagreen is a pattern of polygonal opacities with intervening clear zones at the level of Bowman’s layer. It is best seen by wide-slit oblique illumination. Histological examination shows folding of Bowman’s layer. Although the superficial variant is an ageing change, a pre-Descemet’s form may be familial and related to the central cloudy corneal dystrophy (of François). Neither produces visual symptoms.

Fig. 6.13 Corneal arcus is due to the deposition of cholesterol and other lipids in the peripheral cornea, particularly adjacent to Bowman’s layer and Descemet’s membrane. It is a common ageing phenomenon and is almost universal by the eighth decade. A sharp clear zone lies between the limbus and the hazy inner border of the arcus. The condition is usually of no significance unless seen in patients under 40 years of age in whom it may be familial (arcus juvenilis); these patients require investigation for hyperlipidaemia. A lucent subepithelial zone with mild thinning may appear within the arcus in elderly people (senile furrow degeneration).

CONGENITAL CORNEAL ANOMALIES

Congenital abnormalities of corneal diameter that are not associated with abnormality of thickness are rare and usually inherited. A small-diameter cornea (microcornea) may be associated with a small anterior segment of a small eye (nanophthalmos). A large-diameter cornea (megalocornea) is normally X-linked and must be distinguished from buphthalmos. Associated ocular and systemic abnormalities are common.

Anterior segment dysgenesis produces a spectrum of anomalies. The current clinical classification does not reflect the underlying genetic defect. Both the Axenfeld–Rieger and Peter’s anomalies can be caused by abnormalities of at least four different genes. Posterior embryotoxon, the mildest expression, represents a centrally displaced Schwalbe ring. It is commonly a normal variant and not associated with glaucoma. The Axenfeld–Rieger syndrome (see Ch. 8) consists of posterior embryotoxon with anterior iris adhesions, corectopia and iris hypoplasia, probably due to arrest of neural crest development. Peter’s anomaly does not usually have posterior embryotoxon or peripheral anterior iris adhesions but there is a central iris to cornea adhesion with a defect of the endothelium and posterior stroma. The significance of the Axenfeld–Rieger syndrome and Peter’s anomaly lies in their association with childhood glaucoma, buphthalmos, corneal oedema and blindness. They may also be associated with systemic defects such as dental and cranial anomalies and malformations of the upper limbs and spine. Posterior keratoconus causes thinning of the posterior stroma with overlying haze and may be congenital; it has therefore been classified as a dysgenesis although many cases are thought to result from trauma. Congenital absence of the limbus is often associated with flattening of the cornea, as is seen in sclerocornea and cornea plana.

Fig. 6.14 Peter’s anomaly is characterized by a central corneal opacity with defects in the posterior stroma, Descemet’s membrane and endothelium and adhesions of the iris collarette to the posterior cornea, making it difficult to see the lens. There may be an anterior cataract or adhesions between the lens and cornea. Secondary glaucoma is common. Associated cardiac defects, cleft palate, craniofacial dysplasia and skeletal abnormalities may also occur (Peter’s-plus syndrome). The defects can be explained by abnormal separation of lens vesicle from surface ectoderm, and the heterogeneity by organs being affected that differentiate at same gestational age. The condition is usually bilateral with a sporadic incidence (80 per cent), although inherited cases occur.

By courtesy of Professor P Khaw.

Fig. 6.15 Sclerocornea is a congenital nonprogressive scleralization of the cornea. Either the peripheral cornea or the entire cornea may be involved; the limbus cannot be identified and the radius of curvature is flattened. There is overgrowth of conjunctival and episcleral vessels on to the cornea. Opacification of the cornea is due to a similar organization of the corneal stromal collagen fibrils to those of normal sclera. The condition is usually bilateral with an equal sex incidence and is usually sporadic, although dominantly and recessively inherited forms have been described. Cornea plana is an inherited abnormality most commonly described in Finnish populations; the cornea is flat with a radius of curvature similar to that of the sclera. The cornea is not opaque unless associated with sclerocornea. Extreme hyperopia, abnormalities of the angle and secondary glaucoma are common.

CORNEAL DYSTROPHIES

The corneal dystrophies are inherited corneal diseases that exhibit a remarkable degree of phenotypic and genetic heterogeneity (Table 6.1). Molecular biology has given new insights into the pathogenesis of these diseases. While at present they are classified clinically or histopathologically, their future classification is likely to be genotypic. It is evident, however, that the distinction between some dystrophies is not as clear as had been thought as apparently different clinical appearances can be caused by mutations in the same gene. Conversely, clinically similar dystrophies can result from different genes on separate chromosomes determining different protein products.

Table 6.1 Inheritance of corneal dystrophies

Many dystrophies are extremely rare and only the more common types are illustrated here. Dystrophies that involve the epithelium and anterior stroma may present with painful recurrent epithelial erosions and reduced vision from scarring; those involving the deeper cornea present only with loss of acuity. Endothelial dystrophies may progress to cause corneal oedema. Early or subclinical cases are sometimes found on routine examination or by examining family members.

EPITHELIAL DYSTROPHIES

Fig. 6.16 The commonest corneal dystrophy is epithelial basement membrane dystrophy. This is bilateral, more frequent in women and its severity increases toward middle age. The clinical signs are variable and there may be grey subepithelial patches (top), dots or microcysts (middle), and concentric fine whorls of fingerprint lines best seen with retroillumination or broad-beam oblique illumination (bottom). The term Cogan’s dystrophy can be used if large grey dots are the prominent feature. Visual symptoms are uncommon but intensely painful recurrent erosions may occur following minor trauma. Symptoms are especially common on waking and can be relieved by using artificial tears during the day and lubricating ointment just before sleep. Severe cases may be helped by debridement of the epithelium, puncture of Bowman’s membrane with a needle or a bandage contact lens. Epithelial debridement followed by superficial excimer laser keratectomy can be useful in recurrent disease.

Fig. 6.17 Histological examination shows thickening and reduplication of the basement membrane and cyst formation.

Fig. 6.18 Meesman’s dystrophy is characterized by epithelial cysts spreading from limbus to limbus. These contain mucopolysaccharide.

Fig. 6.19 Type I Bowman’s membrane dystrophy (Reis–Bückler’s) predominantly affects Bowman’s layer and the superficial stroma (left). It is dominantly inherited and has been linked to the same region of chromosome 5q31 as granular, lattice, and Avellino dystrophies. Patients usually present during the first or second decade of life with painful recurrent erosions; subsequent scarring and surface irregularity blur vision. Disease is bilateral and symmetrical with grey reticular opacities seen mainly in the central cornea.(Right) Type II Bowman’s membrane dystrophy (Thiel–Benhke dystrophy), a histologically distinct subgroup with a honeycomb pattern, has been linked to chromosome 10q24. Excimer laser superficial keratectomy or lamellar keratectomy is the initial treatment of choice but the disease usually recurs with time. Penetrating keratoplasty is rarely indicated.