Dysgeneses of the cornea are developmental disorders, sometimes inherited, resulting in congenital malformations. Corneal dysgeneses may be unilateral or bilateral and are nonprogressive. The central, peripheral, or entire cornea as well as other ocular structures may be affected and, occasionally, associated systemic abnormalities are present.

A corneal dystrophy generally exhibits a familial pattern, is bilateral if not symmetric, and does not appear to be secondary to any environmental or systemic factor. Dystrophies tend to be manifest relatively early in life and are variably progressive. Abnormalities generally affect the central cornea and are noninflammatory in origin. Senescence may encourage deterioration of the dystrophic cornea but is not a primary cause of the disorder. Each unique dystrophy exhibits characteristic histopathologic features.

Corneal degenerations, in contrast to dysgeneses and dystrophies, seem to have no developmental or hereditary pattern and may be unilateral or bilateral. A degeneration is often a manifestation of aging, inflammation, or environmental insult and, therefore, usually occurs later in life than a dystrophy. Degenerations most often begin in the peripheral cornea, although central vision may eventually be affected. Inflammation is sometimes involved early in the degenerative process and may be accompanied by corneal vascularization. In some instances, such inflammatory processes may be associated with systemic disease (e.g., collagen-vascular disease).

ABNORMALITIES OF SIZE AND CURVATURE

Absence of Cornea

Complete absence of the cornea is rare. In such cases, there is variable absence of other anterior ocular structures derived from surface ectoderm, and the eye consists of a scleralike enclosure lined with neural ectoderm.¹ Ultrasonography should aid in differentiating this entity from cryptophthalmos.

Microcornea

The term microcornea implies a corneal diameter of less than 10 mm. Microcornea may occur either unilaterally or bilaterally and is thought to occur secondary to an arrest in corneal growth after the fifth month of fetal development. The eye may be otherwise normal, but often other ocular abnormalities such as colobomas may be present. Just as megalocornea is occasionally associated with anterior megalophthalmos, microcornea often accompanies anterior microphthalmos, with crowding of the anterior segment structures frequently resulting in angle-closure glaucoma.² Microcornea can also be seen in nanophthalmos and as part of other anterior segment dysgeneses.

The microcornea is generally clear with normal histologic architecture and, in the absence of other ocular abnormalities, vision may be good. Certain somatic abnormalities have been described in conjunction with microcornea and anterior microphthalmos, including dwarfism and Ehlers-Danlos syndrome.³

Simple Megalocornea

Simple megalocornea (Fig. 1) is a nonprogressive, usually symmetric, inherited condition in which the cornea and limbus are enlarged without evidence of previous or concurrent ocular hypertension. The diameter of the cornea is greater than 12mm, but the corneal thickness and histologic anatomy are normal. Although X-linked recessive inheritance is most common, all modes of inheritance have been reported. Female carriers may have slightly enlarged corneas.⁴

Simple megalocornea can be differentiated from congenital glaucoma by the clarity of the cornea and by a normal intraocular pressure and optic nerve in the former. Moreover, the megalocornea demonstrates normal endothelial cell population densities on specular microscopy whereas, in congenital glaucoma, these are diminished, ostensibly due to corneal distention.⁵Although some authors suspect that megalocornea may represent arrested congenital glaucoma, a single case reporting the histopathology of megalocornea did not disclose any of the characteristic angle abnormalities of congenital glaucoma. However, both conditions have been reported in the same family and in the same individual.^6,7 Simple megalocornea must also be differentiated from keratoglobus (see discussion later in chapter on ectatic corneal dystrophies).

Anterior Megalophthalmos

In comparison to simple megalocornea, eyes with anterior megalophthalmos have enlargement of the lens-iris diaphragm and ciliary ring in addition to the cornea.⁸ A large myopic astigmatic refractive error often results from the abnormal optical architecture. The iris may exhibit transillumination defects as a result of attenuation of the dilator muscle.

Because of the abnormal spatial relationships of structures in the anterior segment and stretching of the zonules, iridodonesis, phakodonesis, and lens subluxation or dislocation may occur; the latter may result in secondary lens-induced glaucoma. The lens, furthermore, may become prematurely cataractous.

Marfan's syndrome,⁹ Apert's syndrome,¹⁰ and mucolipidosis type II¹¹ have been found in association with this disorder.

Cornea Plana

In cornea plana, the corneal curvature is flatter than normal, often reaching levels as low as 20 to 30 D, with a radius of curvature similar to the sclera.^12,13 Peripheral scleralization of the cornea is almost always present, and the condition is indistinguishable clinically from peripheral sclerocornea. The limbal landmarks are also obscured, simulating microcornea.

In cornea plana, the anterior chamber is shallow by virtue of the low corneal dome. Refractive abnormalities vary from hyperopia of 7 D to myopia of 9 D, depending on the globe dimensions and corneal curvature.¹⁴ This condition also features concurrent anterior segment abnormalities,¹⁵ including iris colobomas, congenital cataract, and occasional posterior segment colobomas. The distortion of the cornea along with concomitant sclerocornea leads to a decrease in corneal transparency. Both dominant and recessive inheritance have been reported for this rare developmental condition.

MESENCHYMAL DYSGENESES

The spectrum of congenital eye findings that the term mesenchymal dysgenesis subsumes has historically been known by a variety of names including mesodermal dysgenesis and anterior segment cleavage syndrome. A number of pathogenetic theories have been advanced to describe this group of congenital abnormalities, all based on concepts of anterior segment embryogenesis. The term anterior segment cleavage syndrome, for instance, implies abnormal separation of developing tissues¹⁶ (for instance, the lens vesicle), a concept that has been placed in question with increased knowledge of ocular embryology. Rather, the more contemporary notion of mesenchymal dysgenesis has been devised to reflect a developmental arrest and incomplete central migration of neural crest cells and corneogenic mesoderm.¹⁷

Neural crest cells migrate into the developing anterior segment in three waves, contributing to the corneal endothelium¹⁸ and trabecular meshwork, stromal keratocytes, and iris, respectively. Arrest at any of these stages may bring about the recognized clinical dysgenesis syndromes. In addition to this developmental arrest, secondary anterior displacement of the lens-iris diaphragm may account for some of the congential abnormalities encountered.^19,20

Whatever the exact pathogenesis, since corneal and iris tissues are likely derived at least in part from the neural crest²¹ rather than from mesoderm, and tissues of other origin (e.g., the ectoderm-derived lens) may also be involved, this heterogeneous group of congenital anomalies may be best described by the broader term mesenchymal dysgeneses.²²

The mesenchymal dysgeneses may affect the periphery of the anterior segment, manifest only central pathologic changes, or affect the entire anterior segment. For simplicity, the spectrum of mesenchymal dysgeneses may be categorized in a stepladder classification scheme as suggested by Waring (Fig. 2).²³ Rarely, however, does a case specifically conform to only one of these entities.

Posterior Embryotoxon

The simplest dysgenesis of the anterior segment periphery is anterior displacement and enlargement of Schwalbe's line, called posterior embryotoxon. Schwalbe's line appears as an irregular, circumferential ridge on the posterior surface of the cornea just inside the limbus. Gonioscopy shows it to jut into the anterior chamber, and the adjacent uveal trabecular meshwork may be a dense appearance.²³

Axenfeld's Anomaly

Axenfeld's anomaly results when posterior embryotoxon is accompanied by abnormal iris strands crossing the anterior chamber angle to attach to a prominent Schwalbe's line.²⁴ If glaucoma is also present (secondary to angle abnormality), the condition is called Axenfeld's syndrome.²⁵

Rieger's Anomaly and Syndrome

Rieger's anomaly is present if hypoplasia of the anterior iris stroma is found with the changes typical of Axenfeld's anomaly (Color Plate 1A).^26,27 Rieger's anomaly is associated with glaucoma in approximately 60% of cases, which may result from incomplete development of the aqueous outflow system. Rieger's syndrome²⁸ is present when the eye anomaly is accompanied by skeletal abnormalities such as maxillary hypoplasia, microdontia, and other limb and spine malformations. Marfan's syndrome has also been found in conjunction with Rieger's syndrome.

Posterior Keratoconus

Posterior keratoconus^29–32 has no relationship to anterior keratoconus. It consists of a discrete indentation of the posterior cornea with a variable degree of overlying stromal haze and may represent the mildest variant of Peters' anomaly. Posterior keratoconus tends to be sporadic, unilateral, and relatively central, In some cases, pigment surrounds the edges of the posterior depression, suggesting previous contact to the iris. On histologic examination, Descemet's membrane may be thinned with a concomitant endothelial abnormality in the focally abnormal area.³²

Although the irregularity of the posterior cornea may affect vision to some extent, the anterior surface is normal unless there is sufficient posterior thinning to cause ectasia, Rarely, the entire posterior cornea has increased curvature.³³ Since vision is usually acceptable, keratoplasty is rarely indicated.

Congenital Central Corneal Opacity (Peters' Anomaly)

Peters' anomaly is a congenital, central corneal opacity with corresponding defects in the posterior stroma, Descemet's membrane, and endothelium (Fig. 3).^16,23,34,35 Most cases of Peters' anomaly are sporadic, although both recessive and irregular dominant inheritances have been described. Eighty percent of reported cases are bilateral.

Although Peters' anomaly is, in general, characterized by a central corneal leukoma, two clinical variants have been recognized (Color Plate 1B).³⁶

Peters' anomaly type I shows the typical nebular opacity in the pupillary axis, bordered by iris strands that cross the anterior chamber from the iris collarette. The lens usually remains clear and is normally positioned. Associated anomalies such as microcornea, sclerocornea, and infantile glaucoma may be present, but, for the most part, no other ocular or systemic abnormalities are present.

In Peters' anomaly type II, in contrast, the lens is abnormal either in position or transparency in addition to the central corneal opacity and iridocorneal synechiae. Centrally, the posterior cornea and lens may be adherent, and there may be an anterior polar cataract. This type is more frequently bilateral and almost every involved case shows severe ocular and systemic malformations.³⁷ In general, 50% to 70% of cases of Peters' anomaly have concomitant glaucoma. Other associated abnormalities of the anterior segment include microcornea, microphthalmos, cornea plana, sclerocornea, colobomas, aniridia, and dysgenesis of the angle and iris.

Histopathologic changes are present in all layers of the cornea in Peters' anomaly.^{19,20,38–41} Often the anterior changes, which include disorganization of epithelium, fibrovascular pannus, and loss of Bowman's layer due to long-standing edema, are secondary to the posterior abnormalities. Fluid lakes are also present in the affected stroma.

In the peripheral and unaffected areas, the corneal endothelium forms a continuous monolayer, and Descemet's membrane is of normal, uniform thickness (approximately 5μm). In the area of defect, however, endothelium and Descemet's membrane can terminate abruptly or be severely attenuated. The affected Descemet's membrane is composed of multiple laminations of basement membrane-like material, with interspersed collagen fibrils and fine filaments. Since such abnormal material is elaborated by the corneal endothelium, a fibroblastic metaplasia of the endotheliogenic mesenchyme is likely, as is thought to occur in a number of corneal conditions in which the endothelium is similarly disturbed to secrete a posterior collagen layer.^42,43

The lens abnormalities in Peters' anomaly are characterized histologically by a stalklike connection between the lens and the posterior corneal defect, suggesting primary incomplete separation of the lens vesicle. Alternatively, there may be contact of a morphologically intact lens to the posterior cornea, suggesting subsequent anterior displacement of a normally developed lens.

There are several reasonable explanations for a central corneal leukoma of the Peters' variety. One is incomplete central migration of corneogenic mesenchyme (i.e., neural crest cells), accounting for posterior endothelial and stromal defects.²³ This is corroborated by the finding of abnormally large stromal collagen fibrils of 36 to 60 nm in some patients with Peters' anomaly. A similar abnormality of mesenchymal development is found also in sclerocornea and congenital hereditary endothelial dystrophy.²² Another explanation of posterior corneal leukoma of a Peters' type is an in utero subluxation of the lens, either prior to or after its full development, in either case interrupting the normal migration or function of the developing endothelium.

Historically, the internal ulcer of von Hippel has also been grouped with Peters' anomaly, but the former is probably an intrauterine inflammatory condition rather than a true developmental defect.²²

The management of these cases is complex and difficult, and the outcome of keratoplasty is usually related to the control of concomitant glaucoma.

Sclerocornea

In sclerocornea (Fig. 4), the limbus is ill-defined since opaque scleral tissue with fine vascular conjunctival arcades extends into the peripheral cornea. A broad range of corneal involvement is possible, with the most extreme being complete sclerification of the cornea. Ninety percent of cases are bilateral, although generally asymmetric. Most cases are sporadic; there is no known heredity. Sclerocornea is nonprogressive and must be differentiated from interstitial inflammatory conditions and arcus juvenilis (congenital peripheral lipid deposition, also known as anterior embryotoxon). Sclerocornea is associated with cornea plana in approximately 80% of cases.⁴⁴ Other associated ocular abnormalities include microphthalmos, iridocorneal synechiae, persistent pupillary membrane, dysgenesis of angle and iris, congenital glaucoma, colobomas, and posterior embryotoxon of the fellow eye.⁴⁵ Somatic abnormalities sometimes occur along with associated chromosomal abnormalities; they include mental retardation, deafness, and craniofacial, digital and skin abnormalities.⁴⁴

Ultrastructural studies^22,46,47 have shown the involved stroma to assume the morphologic features of scleral tissue, with irregularly arranged collagen fibrils of variable and immensely enlarged diameter for corneal tissue (up to 150 nm, comparable to normal scleral collagen). The precise lamellar organization of normal corneal stroma is not present; thus optical clarity is not achieved. Various abnormalities of endothelium and Descemet's membrane exist, from attenuation to focal absence. Descemet's membrane is generally thin, with multilaminar deposition of basement membrane-like collagen.

Pathophysiologically, sclerocornea may result from developmental arrest of limbal differentiation during neural crest migration, as occurs with the other mesenchymal dysgeneses.²²

Anterior Staphyloma

Anterior staphyloma is a congenital opacity of one or both corneas which become protuberant, often lined with iris tissue, and associated with an extremely disorganized anterior segment (Color Plate 1C). As in Peters' anomaly, the lens may be adherent to the posterior cornea. Anterior staphyloma may result from intrauterine inflammation or maldevelopment.⁴⁸ In the latter situation, there is no histologic evidence of inflammation, and there is failure of migration of mesenchymal tissues that ordinarily would form the posterior corneal structures, iris, and angle. This maldevelopment, probably coupled with increased intraocular pressure caused by the angle abnormality, leads to corneal opacity and thinning, plus prominent buphthalmic enlargement of the entire anterior segment. Hereditary cases have been reported.

ANTERIOR DYSTROPHIES

The anterior corneal dystrophies (Fig. 5) are confined to the epithelium, basement membrane, and, in some cases, Bowman's layer.

Epithelial Basement Membrane Dystrophy (Map-Dot-Fingerprint)

Disorders involving the epithelium and its basement membrane may have a variable clinical appearance, but likely involve a common pathophysiology and clinical course. Since the predominant abnormality involves the basement membrane complexes that mediate the tight attachment between epithelium and Bowman's layer, the clinical manifestations of these conditions predictably involve recurrent erosions and persistent defects of the corneal epithelium.

The appellation of map-dot-fingerprint dystrophy is appropriately descriptive of the biomicroscopically visible features of intraepithelial microcysts (dots), subepithelial ridges (fingerprints), and geographic opacities (maps) (Fig. 6; Color Plate 1D).^49–66 Family studies have revealed a probable dominant inheritance for map-dot-finger-print dystrophy, with variable penetrance.⁶⁷ Other clinical studies are more consistent with degeneration that is rather highly prevalent in the general population.⁵⁶

The symptoms of recurrent erosion can become prominent in early adulthood through middle age and range from mild irritation to painful, early-morning erosive episodes. Irregular corneal astigmatism with complaints of distortion or “ghost images” may also occasionally develop secondary to plaquelike accumulations of subepithelial cellular debris, basement membrane, and collagen.

The degree of clinical symptoms, however, often do not parallel the extent of abnormal slit lamp findings. Because of the presumed primary abnormality in the epithelial basement membrane, even minor trauma may cause a major epithelial breakdown, with impaired subsequent healing. In a patient who has had a trivially traumatic or seemingly spontaneous erosive episode, meticulous examination of the symptomatic eye, as well as the fellow eye, should be performed in an attempt to disclose an underlying dystrophy. Careful inspection of the fluorescein-stained tear film for localized irregularity or instability, and retroillumination at high magnification through a dilated pupil are helpful in uncovering these often subtle abnormalities in a patient who complains of spontaneous irritation.

Many ultrastructural studies of map-dot-finger-print dystrophy have disclosed a discontinuous multilaminar, thickened basement membrane under the abnormal epithelium.^49,64,65 Sometimes this abnormal basement membrane contains an admixture of collagenous and cellular debris suggestive of prior breakdown episodes. More widespread coalescence of this subepithelial material gives the clinical maplike picture. Other configurations of aberrant basement membrane and fibrillar collagens can be found extending in ridges into the epithelial layers, thereby explaining the fingerprint pattern. Epithelial microcysts are actually pseudo-cystic collections of cellular and amorphous debris within the epithelial layer. Their shape changes with time since they are formed from entrapped cellular material deeper within the epithelium. As they travel to the surface, they may coalesce with other cysts and finally break through the surface, giving rise to an irritative episode.

The primary defect in map-dot-fingerprint dystrophy is presumably the synthesis of abnormal basement membrane and adhesion complexes by the dystrophic epithelium. Unable to form proper hemidesmosomes or anchoring fibrils, the epithelium undergoes recurrent subclinical or overt episodes of dysadhesion. This periodic “lift-off” allows debris to accumulate subepithelially, providing an even less adequate substrate on which the already abnormal basement membrane must form. Moreover, intraepithelial extensions of abnormal basement membrane and collagenous material may block the normal surface migration of maturing epithelial cells, allowing the formation of encysted collections of debris. Thus, the cycle is to a degree self-perpetuating, with primary faulty epithelial adhesion secondarily causing abnormal epithelial maturation which, in turn, exacerbates the accumulation of abnormal basement membrane and collagenous debris and leads to further worsening of epithelial adhesion. Gentle débridement of severely aberrant epithelium and, in some instances, superficial keratectomy to remove subepithelial debris is an aid to conservative therapy with lubricants, hypertonic saline ointment, patching, or bandage soft contact lens.

Similar fingerprint, map, and intraepithelial microcyst changes may develop after traumatic, infectious, or ulcerative conditions, and particularly in cases of chronic epithelial edema where repeated lift-off of the epithelial sheet allows the interposition of material that can again thwart the development of proper basement membrane adhesion complexes.

Hereditary Epithelial Dystrophy (Meesmann; Stocker-Holt)

The corneal dystrophy of Meesmann^68–75 and of Stocker-Holt⁷⁶ is a dominantly inherited abnormality of the corneal epithelium, first described clinically by Pameijer in 1935.⁷⁷ A possibly recessive form has also been reported.

The condition is evident in the first few months of life as an asymptomatic, bilateral epithelial disorder. It is usually first discovered in an older relative, who complains of foreign body sensation and mildly decreased visual acuity.

Clinically, intraepithelial cysts (Figs. 5 AND 7) are seen with biomicroscopy as a myriad of small, clear to gray-white punctate opacities in the interpalpebral zone of the cornea. The cysts are uniform in size and shape, and few may stain with fluorescein.⁵⁰ Occasionally, the opacities are also noted at the level of Bowman's layer, although histopathologically Bowman's layer is not abnormal. It has been demonstrated that the cysts are actually accumulations of degenerated cellular material and basement membrane-like debris surrounded by adjacent cells. Although cells in Meesmann's dystrophy contain periodic acid-Schiff (PAS)-positive material, they do not contain excessive glycogen as was previously believed; rather they contain a dense intracellular substance of unknown composition.⁷³

In 1955, Stocker and Holt⁷⁶ similarly described a dominantly inherited condition in patients 7 months to 70 years of age, characterized by gray, punctate, scattered corneal opacities that on focal illumination appeared as minute droplets. Histopathologically, a PAS-positive thickening of a basement membrane was present overlying a normal-appearing Bowman's layer. This nodular thickening of the basement membrane gave, in some cases, an irregular epithelial surface.

Hereditary Anterior Membrane Dystrophy

Grayson and Wilbrandt⁷⁸ described a hereditary anterior corneal dystrophy presenting clinical symptoms suggestive of recurrent erosion in which the basal epithelial and basement membrane areas were affected. Slit lamp examination revealed discrete gray-white macular opacities in Bowman's layer extending into the epithelial layer with no abnormality of intervening clear cornea. Ultrastructural examination of the cornea from an elderly patient with histopathologic changes consistent with this disorder showed a thickened basement membrane and fibrocellular accumulations overlying an intact Bowman's layer.⁷⁹ Hence, this condition is probably most appropriately classified within the spectrum of epithelial basement membrane dystrophy.

Reis-Bucklers Dystrophy

In 1917 Reis⁸⁰ described a superficial corneal dystrophy that affected Bowman's layer, and in 1949 Bucklers⁸¹ noted an autosomal dominant mode of transmission in an additional family. The dystrophy is usually bilaterally symmetric and becomes evident in the first or second decade of life as painful recurrent erosive episodes. Patients develop decreased visual acuity due to anterior scarring and surface irregularity.

Slit lamp examination of the cornea shows an irregular epithelium with diffuse, irregular, patchy geographic opacities at the level of Bowman's layer (Figs. 5 AND 8). As time passes, central opacities develop as a reticulated pattern spreading into the midperiphery with a diffuse superficial stromal haze. Superficial keratectomy is helpful in managing the visual aspects of this disorder and should always be attempted before penetrating keratoplasty.⁸² Recurrence after keratoplasty has been described.^83,84

The pathogenesis of Reis-Bucklers dystrophy is unknown. The primary lesion may be due to fragmentation of the collagen fibrils of Bowman's layer, and the epithelial lesion may occur secondarily.⁸⁵ Alternatively, immunofluorescent localization of laminin and bullous pemphigoid antigen suggests a primarily epithelial disease.⁸⁶ Destruction of Bowman's layer and its replacement by fibrillar material are the defining changes in this disease and unequivocally distinguish it from other anterior dystrophies. Concomitant abnormalities in the epithelial basement membrane account for recurrent erosive episodes.^49,87–91

Vortex Dystrophy (Fleischer)

The terms vortex corneal dystrophy and corneal verticillata of Fleischer have been applied to patients who show pigmented, whorl-shaped lines in the corneal epithelium.^92,93 Since this same corneal abnormality is evident in Fabry's disease, it is now thought that these patients may have been asymptomatic female carriers of X-linked Fabry's disease.

In general, similar whorllike corneal lesions are evident in patients taking chloroquine, amiodarone,⁹⁴ phenothiazines, or indomethacin. Striate melanokeratosis and fingerprint dystrophic changes can also mimic the vortex pattern. In the absence of these etiologic factors, however, a thorough survey of family members should be made if such findings are noted.

Anterior Mosaic Crocodile Shagreen (Vogt)

Anterior mosaic crocodile shagreen appears as bilateral, polygonal, grayish white opacities in the deep layers of the epithelium and in Bowman's layer.^95,96 These opacities are usually axial and separated by clear cornea. Since visual acuity is usually not affected, treatment is not indicated. Limited histologic study has revealed interruptions of Bowman's layer and interposition of connective tissue between it and the epithelium. It is unclear whether mosaic crocodile shagreen is an actual corneal dystrophy or rather an age related process.

A juvenile form of anterior mosaic crocodile shagreen may occur in association with megalocornea, peripheral band keratopathy, and iris malformation. Similar changes may also arise in post-traumatic conditions.

The so-called anterior mosaic pattern is a different entity in which a delicate polygonal pattern is seen after topical instillation of fluorescein. The anatomic explanation for this pattern is not clear.

Idiopathic Band Keratopathy

Band-shaped keratopathy is a deposition of calcium in the interpalpebral basal epithelium and Bowman's layer.⁹⁷ Most often, calcium deposition is secondary to a chronic ocular disease such as uveitis or to a systemic disease such as hypercalcemia or chronic renal disease (Color Plate 1E). However, an inherited type of band keratopathy with both childhood and senile forms has been described without obvious associated cause. In clinical appearance, the inherited form is identical to that which occurs secondarily (see section on corneal degenerations).

STROMAL DYSTROPHIES

Granular Dystrophy (Groenouw Type I)

Granular dystrophy is manifested in the first decade of life and is transmitted as an autosomal dominant trait. The lesions are sharply demarcated, milky, opaque figures resembling snowflakes or bread crumbs and are confined to the axial portion of the cornea, usually beginning in the most superficial portion of the stroma (Figs. 5 AND 9; Color Plate 1F). During their evolution, they may extend more posteriorly. Between the dense opacities the intervening cornea is characteristically clear. Variants with confluent central opacities and epithelial involvement have been described.⁹⁸

Jones and Zimmerman⁹⁹ noted the opacities to consist of areas of hyaline degeneration in which stromal fibers appeared “granular.” Histologically, the deposits stain red with Masson trichrome stain and are less PAS-positive and less birefringent than the normal stroma. Numerous argyrophilic fibers are seen on Wilder's reticulin stain. Using histochemical techniques, Garner¹⁰⁰ concluded that the deposits consisted mainly of noncollagenous protein containing tryptophan, arginine, tyramine, and sulfur-containing amino acids, and he postulated that the abnormal proteins originated from the epithelium, keratocytes, and extracorneal sources. Rodrigues and co-workers¹⁰¹ found immunofluorescent evidence of microfibrillar protein, a poorly characterized glycoprotein, as well as a Luxol fast blue-staining phospholipid. Johnson and co-workers suggest an epithelial origin of the deposits based on light and electron microscopic studies of corneas with recurrent granular dystrophy.¹⁰² On transmission electron microscopy, the deposits appear as extracellular, rod-shaped, electron-dense paracrystalline structures with faintly visible periodicity. Keratocytes, endothelium, and Descemet's membrane appear unaffected.¹⁰³

Two atypical variants of granular dystrophy have been distinguished from the “classic” form. The first group, or “superficial” variants, includes a Reis-Bucklers-like type, and the formerly termed Waardenburg-Jonkers dystrophy.

Both superficial variants have an earlier onset and higher frequency of erosive episodes than typical granular dystrophy. On clinical examination, large rings and discs at the superficial stroma with a stellate figure extending to the deeper stroma characterize the former, while snowflakelike opacities forming a diffuse superficial stromal haze characterize the latter. Although the pathologic basis in these variants differ from that in Reis-Bucklers dystrophy, the histologic staining characteristics can be confused, and hence the definite diagnosis rests on the transmission electron microscopic studies.

A second variant of granular dystrophy has been described in a group of patients tracing their ancestry to Avellino, Italy.¹⁰⁶ These patients exhibit an appearance similar to typical granular dystrophy along with axial anterior stromal haze and the presence at midstroma of discrete linear opacities. On histologic and ultrastructural analysis, two groups of deposits are found. The first are found at Bowman's layer and superficial stroma, with classic granular dystrophy staining with regard to morphology and nature; the second exhibits latticelike amyloid deposits.

Granular dystrophy does not require keratoplasty as often as the other familial dystrophies, since visual acuity may be good if clear spaces in the cornea coincide with the visual axis. Recurrent erosions may occur when deposits involve the basement membrane zone, but this happens less frequently than in lattice dystrophy. When the opacity is dense enough to occlude the visual axis, the treatment is penetrating keratoplasty although in patients with predominantly anterior involvement, superficial keratectomy alone may be beneficial. As in the other familial dystrophies, recurrence in the graft (usually anterior and peripheral) may take place several years later, suggesting that the granular deposits are either the result of some acquired metabolic disturbance in the transplanted corneal tissue or the product of abnormal epithelium.^107–110

Lattice Dystrophy

Lattice dystrophy is an autosomal dominant condition characterized by pathognomonic, branching “pipestem” lattice figures within the stroma (Figs. 5 AND 10; Color Plate 1G). Symptoms usually begin in the first decade of life and include decreased vision as well as recurrent erosions because of subepithelial and stromal accumulations of amyloid material. In time, the condition progresses to involve marked opacification of the axial stroma, as well as in the superficial layers, leaving the limbus relatively free. At this stage, since the cornea also shows a superficial haze, it becomes difficult to visualize typical lattice lesions, and hence examination of younger affected family members is useful. Amyloid accumulation under the epithelium gives rise to poor epithelial-stromal adhesion with consequent recurrent erosion syndrome.⁴⁹ The dystrophy advances inexorably, and by age 40 or earlier these problems become markedly aggravated, causing considerable discomfort and visual incapacity.

Many published reports have documented the nature of the corneal deposits in lattice dystrophy. In 1961, Jones and Zimmerman⁹⁹ and others suggested that the disorder was due to amyloid degeneration of the stromal collagen fibers. In 1967, Klintworth¹¹¹ confirmed that the disorder was a familial form of amyloidosis limited to the cornea and showed that the fibrillar material stained with Congo red and exhibited the birefringence and dichroism typical of amyloid. On transmission electron microscopy, the fine, electron-dense fibrils of 8 to 10 nm diameter are similar to those of known amyloid fibrils. Using fluorescence microscopy, staining with thioflavin-T is helpful in further characterizing the amyloid material, as are immunofluorescent studies using antihuman amyloid anti-sera.¹¹² Evaluation of corneas with typical lattice dystrophy has demonstrated the presence of the amyloid P (AP) component, but staining for amyloid A (AA) protein has remained controversial.^113–117 The corneal endothelium and Descemet's membrane are not involved. Moreover, amyloid deposits have not been found in other excised tissues from patients with typical lattice dystrophy.¹¹¹

The specific etiology of the amyloid deposits is, as yet, unclear. They may be secondary to collagen degeneration, perhaps from lysosomal enzymes elaborated by abnormal keratocytes. An alternative theory holds that abnormal keratocytes actually produce the abnormal amyloid substance, although this process is not ultrastructurally evident.

Treatment of this disorder is symptomatic, depending on visual acuity and patient discomfort. Penetrating keratoplasty in this condition carries an excellent prognosis, although recurrence of the dystrophy in the graft may take place.^118–121

Systemic amyloidosis may be associated with lattice dystrophy (lattice dystrophy type II, Meretoja's syndrome, or type IV amyloidotic poly-neuropathy).^122,123 The onset of clinical corneal changes is usually later, with erosive episodes less common. Systemic manifestations include progressive cranial and peripheral neuropathy, and skin changes such as lichen amyloidosis and cutis laxa. Other variable features include polycythemia vera and ventricular hypertrophy. Biomicroscopically, the lattice lines are fewer, more radially oriented, and involve mainly the periphery of the cornea with relative central sparing. Amorphic deposits are fewer and more confined in distribution than in classic lattice dystrophy (type I). Open-angle glaucoma and pseudoexfoliation with or without glaucoma are frequently found.¹²⁴

Histologic examination of the cornea reveals characteristic amyloid deposits forming a layer beneath a normal-appearing Bowman's layer, and at the stroma. Deposits also may be found in arteries, basement membranes, skin, peripheral nerves, and sclera. However, the amyloid in this systemic disorder may differ from classic lattice dystrophy, showing loss of Congo red staining following treatment with permanganate.¹¹⁴ Although Meretoja's syndrome has not yet been chemically characterized, recent evidence suggests that the amyloid deposits do contain prealbumin (transthyretin).¹²⁵

Atypical variants of lattice dystrophy (type III) as well as rare cases of unilateral lattice dystrophy have also been reported.^126–128 The former, characterized by a probable autosomal recessive inheritance pattern, has its onset later in life without systemic involvement or episodic recurrent corneal erosions. Histologically, there is absence of subepithelial deposits with a normal epithelium and Bowman's layer. The stromal deposits are larger than in lattice dystrophy types I and II, which correlates with the thicker lattice lines clinically evident in this variant. Immunohistochemical analysis has revealed positive staining for AP protein but only weak staining for AA protein.¹²⁶

The cornea may also develop secondary amyloid deposits after various chronic ocular diseases, but such deposits are generally insignificant clinically (see section on corneal degenerations).

Macular Dystrophy (Groenouw Type II)

Among the classic corneal dystrophies, macular dystrophy, unlike granular and lattice dystrophies, is an autosomal recessive disorder and is far less common. It usually begins in the first decade of life and leads to progressive visual deterioration as the stroma becomes generally cloudy, with superimposed dense, gray-white spots (Figs. 5 AND 11; Color Plate 1H). Unlike granular dystrophy, these macular spots have indefinite edges and the intervening stroma is not clear. Young patients exhibit axial lesions in the superficial layers of the cornea, but with time, lesions approach the periphery and extend throughout the entire stromal thickness. Corneal thinning confirmed by central pachymetry has been documented.¹²⁹ Also unique is primary involvement of the endothelium as evidenced clinically by the presence of guttate changes of Descemet's membrane.

The lesions in macular corneal dystrophy stain intensely with alcian blue and colloidal iron, minimally with PAS, and not at all with Masson's trichrome. Birefringence is decreased. The lesions have been histochemically identified as an abnormal keratan sulfate-like glycosaminoglycan that accumulates extracellularly within the stroma and Descemet's membrane and intracellularly within keratocytes and endothelium.¹³⁰

As would be typical of an autosomal recessively inherited condition, macular dystrophy presumably results from deficiency of a hydrolytic enzymes (sulfotransferase) and may thus be considered a localized mucopolysaccharidosis.¹³¹ The effect of altered glycosaminoglycan metabolism is evident at the cellular level; on transmission electron microscopy, keratocytes and endothelial cells exhibit distention of rough-surfaced endoplasmic reticulum cisternae. With the acridine orange technique, compensatory generalized hyperactivity of the lysosomal enzyme system has been demonstrated.¹³² Eventually the accumulated undigested storage products engorge the cells, and the cells ultimately degenerate or rupture. The derivation of these intracytoplasmic storage vacuoles from endoplasmic reticulum suggests that the biochemical lesion in macular dystrophy occurs at a different metabolic location than in the systemic mucopolysaccharidoses, since in the latter, storage products accumulate within lysosomelike intracytoplasmic vacuoles associated with the Golgi complex.¹³³ Snip and associates¹³⁴ were able to determine that the storage phenomenon affecting endothelium and Descemet's membrane is likely also primary, since the intracellular and extracellular lesions appear ultrastructurally comparable to those evident in the keratocytes and stroma.

Two subtypes of macular dystrophy have been immunohistochemically identified. Type I is most prevalent and is characterized by the absence of antigenic keratan sulfate in the cornea as well as in the serum; it, in fact, may represent a more widespread systemic disorder of keratan sulfate metabolism.¹³⁵ In type 2, antigenic keratan sulfate is present in both cornea and serum.

The treatment for macular dystrophy is corneal transplantation. Recurrence in the graft has been reported.^119,136

Polymorphic Stromal Dystrophy

Polymorphic stromal dystrophy is another manifestation of amyloid deposition in the cornea, Thomsitt and Bron¹³⁷ described patients with a variety of posterior stromal opacities consistent with the type of dystrophic change reported in 1939 by Pillat.¹³⁸ They described axial polymorphic star-and snowflake-shaped and branching filamentous stromal opacities some of which indented the anterior surface of Descemet's membrane, thus causing an apparent irregularity of the posterior corneal surface. Punctate opacities were polymorphic, gray-white, and somewhat refractile when examined directly but were transparent in retroillumination. As intervening stroma appeared clear, visual acuity was not markedly affected. Histochemical staining and electron microscopy have shown the deposits to be composed of amyloid.^139,140 The late appearance of the linear opacities, the lack of progression, and the apparent nonfamilial pattern help to distinguish this condition from lattice dystrophy.

Gelatinous Droplike Dystrophy

Gelatinous droplike dystrophy is yet another clinical manifestation of primary, localized corneal amyloidosis that has been reported more frequently in the Japanese literature.^141,142 The disorder is bilateral, noninflammatory, and may exhibit an autosomal recessive inheritance pattern, It presents early in life as a milky-white, gelatinous, mulberrylike elevated lesion of the epithelium and anterior stroma. Histopathologic specimens have demonstrated mounds of amyloid interposed between the epithelium and Bowman's layer, as well as fusiform deposits similar to lattice dystrophy in the deeper stroma.¹⁴³ The type of corneal amyloid, containing protein AP but not AA, may be different from that found in lattice dystrophy, which contains both.¹⁴⁴ Treatment may include either superficial keratectomy or keratoplasty.

Central Crystalline Dystrophy (Schnyder)

This dominantly inherited dystrophy occurs in early life and is occasionally congenital (Figs. 5 AND 12).^145–147 The main feature of the disease is a bilateral, axial, ring-shaped corneal opacity consisting of polychromatic crystals (Color Plate 1 I) .

The yellow-white opacity is noted in Bowman's layer and the anterior stroma. The epithelium is normal, and the uninvolved stroma also appears normal, although in time a diffuse stromal haze can develop. In some cases, small white opacities scattered throughout the stroma have been noted.¹⁴⁸ Histologic examination using lipid stains on frozen sections reveals neutral fats and cholesterol.¹⁴⁹ The clinically apparent crystals correspond to cholesterol accumulations, both within keratocytes and extracellularly. Neutral fat is distributed within the stroma among the collagen fibrils. Both the limbal girdle of Vogt and corneal arcus are associated with this dystrophy. The disease may be considered a localized defect of lipid metabolism, although some patients may also exhibit hypercholesterolemia, xanthelasma, and genu valgum. Because the disorder stabilizes with time, only occasional patients with severe opacity require corneal grafting.

It is important to perform cholesterol and lipid studies on these patients since, although the severity of a systemic lipid abnormality does not necessarily correlate with the severity of the corneal disease, elevated serum lipid levels and concomitant cardiovascular disease are associated features in some patients.¹⁵⁰

Marginal Crystalline Dystrophy (Bietti)

Bietti¹⁵¹ described crystalline deposits in the paralimbal anterior corneal stroma, associated with a retinal pigmentary abnormality but without visual impairment. Welch has also reported a similar case demonstrating stromal lipid in corneal biopsy specimens.

Central Cloudy Dystrophy (Francois)

Francois described a group of mainly axial, predominantly posterior, cloudy stromal opacities with clear intervening stroma.^153,154 The disorder is dominantly inherited in some series. Vision is minimally affected and the patient is otherwise asymptomatic; hence, no therapy is required.

Posterior Amorphous Stromal Dystrophy

This autosomal dominant disorder was first described in 1977 in a family spanning three generations as symmetric gray-white, sheetlike posterior stromal opacities centrally and extending peripherally to the limbus.¹⁵⁵ Corneal thinning was also present in more advanced cases. Findings in a second reported pedigree included (1) both centro-peripheral and peripheral forms, (2) hyperopia with corneal flattening, (3) iris abnormalities including glassy sheets on the iris surface, corectopia, and pseudopolycoria, and (4) iris processes extending to Schwalbe's line.¹⁵⁶

The sheetlike opacities may be irregular and broken with clear intervening stroma. Descemet's membrane and endothelium may be indented by the opacities and focal endothelial abnormalities have been observed. Visual acuity is only mildly affected.

Johnson and co-workers¹⁵⁷ described the keratoplasty specimen from a 5-year-old child, which demonstrated fracturing of the posterior stromal collagen lamellae, a thin Descemet's membrane, and focal attenuation of endothelial cells.

Ultrastructural studies showed disorganization of the posterior stromal collagen. Since the iris is affected and the changes have been found in a child as young as 6 months of age, this disorder may be more appropriately classified as a mesenchymal dysgenesis rather than a dystrophy (see previous discussion of mesenchymal dysgeneses).

Congenital Hereditary Stromal Dystrophy

Congenital hereditary stromal dystrophy is characterized by flaky or feathery clouding of the stroma.¹⁵⁸ It is bilateral and dominantly inherited. Both the peripheral and central cornea is affected, the latter more severely.

Electron microscopy has revealed abnormally small stromal collagen fibrils with disordered lamellae, suggesting a disorder in collagen fibrogenesis. The corneal changes are congenital but seem to be nonprogressive.

Posterior Mosaic Crocodile Shagreen

Posterior crocodile shagreen is a bilateral condition marked by a series of small gray polygonal patches of various sizes, separated by dark regions, at the level of Descemet's membrane.¹⁵⁹ Vision is not compromised, and no treatment is required. Transmission electron microscopic studies have demonstrated the grayish opacities of posterior mosaic crocodile shagreen to correspond with sawtoothlike configurations of the corneal collagen lamellae (see previous discussion of anterior mosaic crocodile shagreen).¹⁶⁰

Fleck Dystrophy (Francois-Neetens)

This rare, autosomal dominant dystrophy is detectable very early in life and in some cases is congenital (Fig. 13).^161–166 Subtle grayish specks are present in all layers of both corneas, and some appear as rings with relatively less opacified centers. They cause no visual disability. Histopathologic examination has revealed abnormal keratocytes that on transmission electron microscopy show a fibrillogranular substance within intracytoplasmic vacuoles.¹⁶⁵ Histochemical staining shows glycosaminoglycans and lipids within these vacuoles.

PRE-DESCEMET'S DYSTROPHIES

This category of dystrophy has several very rare subgroups. They are generally compatible with good vision and comfort, and a clear pattern of heredity is not always obvious.

Cornea Farinata

Cornea farinata^167,168 is often a routine finding in older persons, and therefore may represent a degenerative process rather than a dystrophic one. Visual acuity is usually not decreased. Small gray punctate opacities can be seen in the pre-Descemet's area of the stroma on retroillumination. Sometimes larger and more polymorphous types of comma, circular, linear, filiform, and dotlike opacities are located in the pre-Descemet's area. The opacities may be distributed axially or annularly. Similar pre-Descemet's opacities may be found in association with ichthyosis.¹⁶⁹

Grayson-Wilbrandt Dystrophy

Grayson and Wilbrandt described asymptomatic opacities that were slightly larger and more diffusely scattered than those in cornea farinata and were distributed axially and paraxially (Fig. 14).^170,171 Familial associations were documented. Curran and associates¹⁷¹ described the ultrastructure of abnormal keratocytes anterior to Descemet's membrane in this disorder. These keratocytes contained membrane-bound intracytoplasmic vacuoles containing fibrillogranular material and electron-dense lamellar lipid bodies.

Deep Filiform Dystrophy

The deep filiform dystrophy of Maeder and Danis consists of multiple filiform, gray opacities in the pre-Descemet's area that affect the entire width of the cornea except for the perilimbal area.¹⁷² The original description occurred in a middle-aged woman with keratoconus. The histopathology has not yet been documented. This disorder may represent a degeneration rather than a dystrophy.

ENDOTHELIAL DYSTROPHIES

Congenital Hereditary Endothelial Dystrophy

Initially described by Maumenee¹⁷³ in 1960, this congenital disorder of the endothelium is characterized clinically by diffuse, bilaterally symmetric corneal edema (Figs. 5 AND 15; Color Plate 1J). The autosomal recessive variety is present at birth and is relatively stationary. Symptoms of discomfort are not prominent despite profound epithelial and stromal edema. Nystagmus is common.¹⁷⁴ A dominantly inherited form is less severe, developing in the first or second year of life, and, in contrast to the recessive variety, progressive photo(text continues on p. 27) phobia and tearing are the initial symptoms. Nystagmus is generally absent.¹⁷⁴ As in all instances of congenital corneal clouding, it is important to rule out congenital glaucoma.

The degree of edematous corneal clouding varies from a mild haze to a milky, ground-glass opacification. Epithelial microbullae may be obvious, and stromal thickness may be increased threefold or more. Uniform thickening of Descemet's membrane is sometimes evident on clinical examination, but no guttata are apparent. Interstitial inflammation and secondary vascularization are absent. There are no definitely associated ocular or systemic abnormalities.

Histologic study^175–181 reveals nonspecific anterior and stromal changes consistent with long-standing secondary edema: basal epithelial cell swelling, basement membrane thickening and disruptions, and irregularities of Bowman's layer with pannus formation. However, it may be significant that, in some cases, ultrastructural examination discloses greatly enlarged stromal collagen fibrils sometimes measuring as much as 60 nm in diameter. Descemet's membrane is uniform in a given specimen; it may display diffuse thinning of 3μm to massive thickening of 40 μm (normal thickness is 3 to 5 μm in neonates and 8 to 10 μm in adults). The anterior banded layer of Descemets membrane is always present and of relatively usual thickness; however, the posterior layer consists of multilaminar basement membrane-like material with fine filaments and of collagen fibrils with a 55- and 110-nm banded configuration. With the exception of the lack of guttata, these findings are similar to those in Fuchs' dystrophy and thus represent another example of posterior collagen layer formation by either primarily or secondarily abnormal endothelium.^{18,41,43,181,} It is postulated that in cases with thin Descemet's membrane, complete endothelial loss occurred in utero such that only the fetal anterior portion of Descemet's membrane was secreted.¹⁸⁰ In contrast, cases exhibiting thickened Descemet's membranes may be the product of dystrophic but persistent endothelium having secreted a hypertrophic posterior collagen layer.

The frequent finding of enlarged stromal collagen fibrils suggests some primary developmental abnormality of both keratocytes and endothelium, thus perhaps qualifying this disorder as another example of mesenchymal dysgenesis.²²

Cornea Guttata

Slit lamp examination of a patient with cornea guttata reveals a typical “beaten metal” appearance of Descemet's membrane. These wartlike, anvil-or mushroom-shaped excrescences are abnormal elaborations of basement membrane and fibrillar collagen by distressed or dystrophic endothelial cells (Figs. 5 AND 16). The endothelial cells over these excrescences become attenuated and eventually die prematurely.

Cornea guttata is usually seen as a primary condition in middle to older age groups. The lesions are often located in the axial areas of the cornea and may be sparsely distributed. Brownish pigmentation may be seen in a number of corneas at the level of the guttata, often associated with scattered pigment phagocytosis by the endothelium.

Guttata located in the periphery of the cornea may be seen even in young persons; they are called Hassall-Henle bodies and are of no clinical concern. If, however, the guttata become more numerous and central, this may portend functional compromise of the endothelial cells to the extent that their barrier and pump functions become insufficient. In this event, stromal edema occurs, followed by epithelial edema and bullous keratopathy, and the condition may then be justly termed Fuchs' dystrophy. However, mild to moderate corneal guttata can remain stationary for years without obligate dystrophic progression.

Secondary guttata are usually associated with degenerative corneal disease, trauma, or inflammation. The corneal endothelial cells may be adversely affected by iritis, deep stromal inflammation or infection, and anterior segment surgery. In severe inflammation, the endothelial mosaic may be affected by edema of the endothelial cells,¹⁸² this condition resembling corneal guttata. On removal of the causative agent, the pseudoguttata subside, whereas true corneal guttata are permanent.

The normal endothelial pattern can be well demonstrated with nitroblue tetrazolium stain. The cells form a uniform mosaic. If trypan blue stain is used, the decreasing endothelial viability is noted by staining of the nuclei, An abnormal entothelial cell population is suggested by abnormally sized and shaped cells, (pleomorphism and polymegethism), numerous guttata, and areas of Descemets membrane that are not covered by cells. Specular microscopy can also be used to study in vivo the size, shape, and number of endothelial cells.^183,184

Pachymetry of the corneal stroma is often helpful in monitoring the functional status of the endothelium. Corneal guttata per se do not require treatment. However, should endothelial decompensation and stromal edema progress to visually incapacitating and/or painful epithelial edema, then medical or surgical measures may be indicated.

Fuchs' Dystrophy (Late Hereditary Endothelial Dystrophy)

Fuchs' dystrophy (Figs. 5 AND 17)^185–189 is usually seen in the fifth or sixth decade of life, somewhat more commonly in women. It is bilateral and frequently of dominant inheritance.^185,186,190 The fundamental defect is progressive deterioration of the endothelium. The endothelial cells in the adult human lack significant miotic capability, and as they undergo attrition, the surviving cell population must enlarge and spread to maintain an intact monolayer in order to remain functionally competent as a barrier and pump in maintaining corneal deturgescence. Thus, as in patients with cornea guttata, serial pachymetry and specular microscopy are helpful in following the disease process. Both discrete (guttate) and diffuse thickening of Descemet's membrane usually develop with progressive endothelial degeneration and dysfunction (Color Plate 1,K).¹⁸⁷

Clinically evident edema starts axially and spreads peripherally. As stromal edema progresses to involve the epithelium, microbullous elevations of the epithelium bring decreased visual acuity, and in time, bullous keratopathy erupts (Color Plate 1L). When these epithelial blisters rupture, the patient experiences a foreign body sensation or pain that may be relieved by lubricants, occlusion, or bandage soft contact lens. Ultimately, penetrating keratoplasty is required for both comfort and visual rehabilitation. In rare instances when keratoplasty is not indicated, cautery of Bowman's layer may give symptomatic relief. The course of Fuchs' dystrophy may be accelerated after cataract extraction or other intraocular surgery, and precautions should be exercised to minimize intraoperative trauma.

On histologic examination, the sequelae of chronic epithelial and stromal edema are prominent. Anteriorly, abnormalities of the basement membrane adhesion complexes develop because of repeated lift-off of the edematous epithelium.¹⁸⁸ There are occasional breaks in Bowman's layer, and subepithelial debris and fibrovascular pannus collect in the zone of bullous edema. The most striking abnormality is diffuse thickening of Descemet's membrane (often to 20μm or more) with posteriorly projecting excrescences, corresponding to clinically apparent guttata. Histologic evidence of abnormal endothelial cell function is apparent many years before the clinical signs of corneal guttata and thickened Descemet's membrane appear.¹⁹¹

Ultrastructural examination shows the newly deposited abnormal portion of Descemet's membrane to consist of bundles and sheets of widely spaced banded collagen and multiple laminations of basement membrane material. The remaining endothelial cells appear in various stages of degeneration. These cells are enormously flattened, and attenuated in an effort to enlarge their surface area. They exhibit intracellular spaces and faulty intercellular junctions. The abnormal posterior collagenous layer of Fuchs' dystrophy can be considered analogous to the deposition of excess collagen and basement membrane material found in other circumstances of the “endothelial distress syndrome.”¹⁸

Posterior Polymorphous Dystrophy

This bilateral, dominantly transmitted corneal dystrophy may be stationary or only slowly progressive, such that affected patients generally retain normal visual acuity, and demonstrate no stromal edema or vascularization (Figs. 5 AND 18).^192–203 The condition is characterized by polymorphous opacities, some of them vesicular or annular with surrounding halos, at the level of Descemet's membrane (Color Plate 1M). Although careful biomicroscopy is usually adequate to establish the diagnosis,²⁰⁴ specular microscopy may be helpful in differentiating posterior polymorphous dystrophy from other corneal endothelial disorders.^205,206 When endothelial decompensation with stromal edema occurs, some cases are severe enough to decrease visual acuity and to require keratoplasty. As with other corneal dystrophies, posterior polymorphous dystrophy may recur in the graft.²⁰⁷

Posterior polymorphous corneal dystrophy has been associated with band keratopathy, peripheral anterior synechiae, and other anomalies of the anterior segment,^193,200 glaucoma,^195,208 and guttata.¹⁷⁹

Numerous histologic studies have demonstrated endothelial cells that morphologically and immunopathologically resemble epithelium.¹⁹⁷ These cells contain epithelial keratin and are connected by well developed desmosomes. Scanning electron microscopy of the posterior cell membrane reveals myriad microvilli, again suggestive of an epithelial-type cell. Ultrastructural studies have also revealed some endothelial cells that resemble fibroblasts.²⁰⁰ An aberrant developmental differentiation of the endotheliogenic mesenchyme (neural crest) has been suggested,²¹ possibly similar to the pathogenesis of the irido-corneal-endothelial syndromes.

Chandler's Syndrome (Irido-Corneal-Endothelial Syndrome)

Chandler's syndrome, essential iris atrophy, and iris nevus or Cogan-Reese syndrome have recently been regarded as variations of a single disease process and pathogenetic mechanism, the irido-corneal-endothelial or ICE syndrome.^209–213 These conditions are nonfamilial, unilateral, and generally arise in early adulthood, usually in women.

Typical of Chandler's syndrome is corneal edema secondary to endothelial abnormality, usually with an accompanying ipsilateral, unilateral glaucoma (Fig. 19). The degree of corneal edema is severe relative to the level of intraocular pressure. The various iris changes (stromal thinning, full-thickness holes, “nevi,” and broad, tenting peripheral anterior synechiae) vary, depending on the subcategory of ICE syndrome. Campbell has proposed that the primary abnormality resides in the corneal endothelium, which, besides malfunctioning and allowing corneal edema in Chandler's syndrome, tends to grow across angle structures and the iris surface, elaborating a Descemet's membrane-like tissue.²⁰⁹ Contraction of the membrane then leads not only to anterior synechiae but also to pupillary distortion and the iris abnormalities seen to a greater or lesser extent in all of the ICE syndromes.

Chandler's syndrome must be differentiated from Fuchs' dystrophy and posterior polymorphous dystrophy. The latter may also be considered within the spectrum of irido-corneal-endothelial syndromes, because a similar pathogenic defect in the corneal endothelium may be implicated, possibly reflecting abnormal proliferation or induction of embryonic neural crest cells.²¹ In contrast to the ICE syndromes, however, posterior polymorphous dystrophy is familial and bilateral, and without similar iris findings except peripheral anterior synechiae in some cases.²⁰⁰ In addition to posterior polymorphous dystrophy, the abnormal “beaten metal” appearance of Descemet's membrane in Chandler's syndrome resembles that of Fuchs' dystrophy. Specular microscopy may prove useful in better describing the in vivo characteristics of these conditions.^205,214

Histopathologic study of Chandler's syndrome has revealed abnormalities in the mesenchymally derived cells lining the cornea, trabecular meshwork, and anterior iris surface.²¹⁵ The corneas typically exhibit a posterior collagenous layer. The abnormal endothelium extends from the cornea over the trabecular meshwork and, in some specimens, onto the iris. Elaboration of excessive multilaminar basement membrane by flat and discontinuous corneal endothelial cells is further evidence of an “endothelial distress syndrome.”²¹⁶

NONINFLAMMATORY CORNEAL ECTASIAS

Keratoconus

The bilateral, noninflammatory condition is an axial ectasia of the cornea (Fig. 20; Color Plate 1N). Subtle irregular astigmatism is often the first clinical finding in keratoconus, and this is evidenced by a distortion of the corneal image as noted with the placido disc, retinoscope, keratometer, and keratoscope. Keratoconus becomes manifest at puberty and can progress either slowly, stabilizing over the course of about 10 years, or relatively rapidly, requiring keratoplasty. While familial in nature, no exclusive pattern of inheritance exists.

Thinning of the cornea with protrusion of the apex occurs, such that in downgaze the lower lid is distorted by the cone (Munson's sign). Two types of cones have been described: a well-demarcated nipple-shaped cone and a larger, oval or sagging cone.²¹⁷ The apex of the nipple cone is usually slightly inferonasal, whereas the oval-shaped cone is often slightly displaced to the inferotemporal quadrant and extends closer to the periphery. The cone often exhibits subepithelial scarring. Vertical stress lines (Vogt's striae) are seen deep in the affected stroma. Increased visibility of the corneal nerves and Fleischer's iron ring are additional diagnostic signs. The latter is caused by a deposition of hemosiderin pigment deep in the epithelium and Bowman's layer at the base of the cone.

An early histopathologic change is focal disruption of Bowman's layer,²¹⁸ which is replaced in affected areas with keratocytes and collagenous material. The epithelium itself is irregular in thickness and has an abnormal basement membrane in areas where Bowman's layer is destroyed.^219–221 Stromal changes, even in areas of extreme thinning, are nonspecific.

Acute hydrops may occur when Descemet's membrane is stretched beyond its elastic breaking point. Such a rupture leads to sudden, profound corneal edema. Endothelium bridges the gap in 6 to 8 weeks, with resultant stromal deturgescence and residual stromal scarring of varying severity. Ultrastructural examination in areas of healed hydrops has shown the torn edges of Descemet's membrane to have retracted as scrolls, and the disrupted endothelium to have migrated across the exposed surface of posterior stroma, depositing new Descemet's membrane material and renewing continuity of the endothelial monolayer.²²²

Keratoconus can occur in association with a variety of ocular and systemic diseases, including atopic dermatitis,²²³ vernal catarrh,²²⁴ Down's syndrome, retinitis pigmentosa,²²⁵ infantile tapetoretinal degeneration, Marfan's syndrome, aniridia, and blue sclera. The association with atopy and vernal keratoconjunctivitis has led to speculation that frequent, vigorous eye rubbing may aggravate, accelerate, or even cause keratoconus.²²⁶ Some investigators, moreover, have also inferred contact lens wear as causative.²²⁷

Initial treatment requires astigmatic spectacle correction or a rigid contact lens that compensates for the irregular corneal astigmatism. When lens fit or comfort becomes a problem, superficial keratectomy may be performed in selected cases to smooth the corneal surface. In cases without apical scarring involving the visual axis, epikeratoplasty may be useful.²²⁸ Thermokeratoplasty is generally only a temporary measure, because resteepening, scarring, or persistent epithelial defects usually ensue,²²⁹ although in some cases the result is acceptable.²³⁰ Penetrating keratoplasty remains highly successful for long-term visual rehabilitation of advanced cases.

Pellucid Marginal Degeneration

This disorder is evident as a bilateral, inferior corneal thinning that leads to marked irregular against-the-rule astigmatism. The normal cornea protrudes above an area of abrupt thinning inferiorly. There is some consensus that keratoconus, keratotorus, keratoglobus, and pellucid degeneration are related because these different conditions have been found to coexist in families. Histopathologic reports demonstrate abnormalities in the affected tissue similar to findings in keratoconus.

Because of extremely abnormal corneal topography, the treatment of pellucid degeneration is difficult. Contact lens wear should be attempted initially. If the patient is contact lens intolerant, a large penetrating keratoplasty may be performed.²³¹ Alternatively, tectonic lamellar grafting of the thinned periphery followed by a central penetrating keratoplasty may be attempted. Krachmer²³² suggests that thermokeratoplasty may be a reasonable alternative.

Keratoglobus

Keratoglobus (Fig. 21) is a rare bilateral condition resembling megalocornea, with the exception that the cornea is uniformly thinned, particularly peripherally. A familial association between keratoconus and keratoglobus has been made. Rupture of Descemet's membrane may occur, as in keratoconus, but this is not usually the case.^233,234 Especially in cases associated with Ehlers-Danlos syndrome type VI, patients must be cautious to avoid even minor ocular trauma because rupture of the globe can occur easily, and repair is difficult.

PERIPHERAL DEGENERATIONS

Corneal Arcus (Juvenilis and Senilis)

Corneal arcus appears as a whitish ring of the peripheral cornea with a clear zone between it and the limbus. Arcus juvenilis is sometimes called anterior embryotoxon. Both the juvenile and adult forms represent paralimbal stromal accumulations of cholesterol esters, triglycerides, and phospholipids.^235–237 In histologic section, the deposits appear wedge-shaped, being most prominent near Bowman's and Descemet's membranes. Abnormalities in blood lipids may be correlated in younger patients displaying corneal arcus and/or Schnyder's crystalline corneal dystrophy.

White Limbal Girdle of Vogt

The white limbal girdle of Vogt, type II, is a common finding in patients over 45 years of age. It is a white opacity in the medial and temporal limbal regions, and may be mistaken for corneal arcus. Fine white lines extend irregularly from the limbus. A clear interval may or may not be present between the girdle and the limbus. The limbal girdle is not associated with inflammation, is not vascularized, and does not progress. Sugar and Kobernick²³⁸ described the pathologic change in Vogt white limbal girdle type II as a subepithelial hyperelastosis with degeneration similar to that in pingueculae and pterygia.

The type I limbal girdle is likely to be more closely related to early calcific band keratopathy since it appears, as Vogt described it, as a white band with clear holes at several points and separated from the sclera by a clear interval.

Idiopathic Furrow Degeneration

A thinning of the cornea in older people in the area of an arcus senilis sometimes occurs. There is no tendency for this thinned area to perforate, and no vascularization develops. Visual acuity is generally not affected.

Furrow Degeneration Associated with Systemic Disease

Focal or extensive ring-type epithelial defects and sterile ulceration near the limbus can accompany certain systemic diseases, such as rheumatoid arthritis, Wegener's granulomatosis, polyarteritis nodosa, relapsing polychondritis, systemic lupus erythematosus, and other collagen vascular diseases (Fig. 22). The treatment of such immunogenic diseases is discussed elsewhere.

Postirradiation Thinning

Large areas of noninflammatory corneal excavation at the limbus may occur after high doses of beta irradiation.²³⁹

Terrien's Marginal Degeneration

Terrien's marginal degeneration is an uncommon but distinct variety of marginal thinning of the cornea (Fig. 23).²⁴⁰ It is usually bilateral, though often asymmetric, and seen mostly in younger males. The condition is slowly progressive over the course of years and generally starts superiorly as a marginal opacification. Stromal thinning and ectasia develop with an intact epithelium, and there is a lucid zone between the advancing edge and the limbus. A yellow border of lipid is characteristically present at the advancing edge (Color Plate 1 O). Vessels traverse the furrow and pass beyond it. Difficulties arise from the induced corneal astigmatism, and minor trauma may result in rupture if thinning is sufficient. Most cases of Terrien's marginal degeneration are noninflammatory, although patients with recurrent inflammation have been described.²⁴¹ Electron microscopic study demonstrates that collagen precursors, stromal ground substance, and possibly lipid are phagocytized by histiocytic cells with high lysosomal activity.²⁴⁰ The therapy of Terrien's degeneration is limited to tectonic grafting to prevent or to repair perforation of thinned areas.

Mooren's Ulcer

Mooren's ulcer (Fig. 24) is probably best considered a localized inflammatory ulceration rather than a degeneration of the corneal periphery. However, it must be differentiated from entities such as Terrien's marginal degeneration. Serious systemic connective tissue diseases with generalized vasculitis and collagen destruction must be excluded before the diagnosis of Mooren's ulcer can be made. It is, thus, a diagnosis of exclusion. Mooren's ulcer, in contrast to typical degenerations,is characterized by a fulminating, centrally progressive, and painful inflammation occurring more often in males (Color Plate 1P).^242–246 The leading edge of the ulcerative process often undermines the more central corneal stroma. Two types of Mooren's ulcer have been described. A benign type is seen in older patients and is usually unilateral and responsive to treatment more often than the more severe type that occurs in younger persons.²⁴⁵ The latter variety is relentlessly progressive and often bilateral. Young Nigerians have exhibited a severe form of Mooren's ulcer, with a rapid progression to perforation and marked involvement of the limbal sclera and episclera in a necrotizing process.²⁴³

Histologic studies reveal necrosis of collagen tissue, with vessels and chronic inflammatory cells in the overhanging limbal edges. Autoantibodies to human epithelium have been demonstrated.²⁴⁴ Histologic and ultrastructural studies reveal the presence of polymorphonuclear leukocytes within the zone of active ulceration, suggesting that acute inflammatory cells play a role in the collagenolytic process.²⁴⁶

The results of treatment have not been encouraging. Conjunctival resection adjacent to the ulcer may, in some cases, ameliorate the ulcerative process.²⁴⁷ In more aggressive cases, perforation may occur from collagenolytic processes or secondary infection, especially in the potentiating presence of topical corticosteroids. Tissue adhesive and lamellar grafting may be necessary in the event of perforation.²⁴⁸ Systemic immunosuppression may be of value in patients with progressive disease.^249–251

CENTRAL OR DIFFUSE DEGENERATIONS

Iron Lines

Iron deposition in the cornea occurs secondarily in a number of clinical settings^252,253: Hudson-Stähli line, Ferry's line,²⁵⁴ Stocker's line, Fleischer's ring, normal aging cornea, adjacent to a filtering bleb, adjacent to the head of a pterygium, and at the base of a keratoconus cone. Histologic examination reveals hemosiderin deposition in the basal corneal epithelial cells.²⁵⁴ The pathogenesis of corneal iron lines is unclear, although they may be related to chronic abnormalities of tear flow. Iron lines do not affect vision and are themselves asymptomatic.

Coat White Ring

This small corneal opacity is usually located in an area that previously harbored a foreign body.^255,256 The opacity, which contains iron, appears as a small, granular, oval ring when viewed with the slit lamp. It was originally thought to be lipid in nature, but likely contains iron from the foreign body.²⁵⁶ The condition causes no symptoms and requires no therapy.

Lipid Degeneration

This degeneration (Fig. 25) is characterized clinically by the accumulation of a yellow or cream-colored diffuse or crystalline material in the corneal stroma, which may be abnormally thick or thin. There is generally a history of prior corneal inflammatory episodes with resultant stromal vascularization. The lipid accumulations are therefore of a secondary nature, with extravasation of cholesterol and fatty acids from the vessels. Lipid keratopathy has been reported following hydrops²⁵⁷ and as a finding with no clear antecedent corneal damage or vascularization.^258,259

Amyloid Degeneration

Acquired corneal amyloidosis can be associated with intraocular disease or may be secondary to corneal trauma.^260–263 Such amyloid deposition may also occur as a result of long-standing diseases, such as retrolental fibroplasia, trachoma, glaucoma, uveitis, bullous keratopathy, keratoconus, and leprosy.²⁶⁴ These corneal amyloid lesions consist of salmon-pink to yellow-white, raised, fleshy masses that create a nodular surface (Fig. 26) and that may be amenable to treatment by superficial keratectomy. The cornea may be vascularized depending on other factors. The deposits seen in lattice and gelatinous dystrophies are also amyloid in nature, but those conditions are primary disorders.

The amyloid material in the cornea is identical to that present in other organs. It stains with Congo red, displays birefringence and two-color dichroism with the polarizing microscope, and is fluorescent with thioflavin-T stain and ultraviolet light. Amyloid contains protein, carbohydrate, and polysaccharide components, as well as alpha-chain immunoglobulins. Ultrastructural study reveals short 9- to 10-nm-diameter fibrils in a random pattern of aggregation within a granular background.

Spheroid Degeneration (Climatic Droplet Keratopathy, Keratinoid Degeneration)

Keratinoid degeneration,²⁶⁵ climatic droplet keratopathy,^266–279 proteinaceous degeneration,²⁷⁰ Labrador keratopathy,^271–273 and chronic actinic keratopathy²⁷⁴ are likely all similar nonhereditary degenerations related to geographic or climatic conditions.^277–279

Spheroid degeneration is characterized by yellow, oily-appearing subepithelial droplets within the interpalpebral fissure (Fig. 27). These droplets may replace Bowman's layer or may lie deeper. They generally begin at the periphery. Types of spheroid degeneration resulting from a local disease or chronic irritant may be unilateral and involve the central cornea as well as periphery. Spheroid degeneration has been described in association with lattice dystrophy.

Electron microscopy reveals that the lesions appear to develop from extracellular material deposited on collagen fibrils. Some suggest that this material is secreted by abnormal fibrocytes, forming collagenous spheroids.²⁷⁵ However, a report by Johnson and Overall²⁸⁰ suggests that an interaction between ultraviolet light and plasma proteins within the stroma results in the abnormal deposits. The deposits are PAS-negative but stain positively with rhodamine B, thus the designation keratinoid, even though keratin is not present. The condition is probably related to elastotic degeneration of collagen, as in conjunctival pingueculae.²⁷⁹

The conjunctiva may become involved with spheroid degeneration, often in association with pingueculae. Patients with spheroid degeneration are usually asymptomatic, but if aggravating local factors exist, the disorder may progress and lead to symptoms of irritation. In some cases, superficial keratectomy may be useful both for visual rehabilitation and comfort.

Band Keratopathy

Band keratopathy (Fig. 28) may arise from localized ocular inflammation or systemic disease. Hydroxyapatite deposits of calcium carbonate accumulate in the epithelial basement membrane, Bowman's layer, and the superficial stroma.^281,282 Calcific degenerations, phthisis bulbi, necrotic intraocular neoplasms, and conditions in which bone is formed in other parts of the eye are frequent associations.²⁸³

Band keratopathy is confined to the interpalpebral fissure area (see Color Plate 1E). A lucid interval separates the calcific band from the limbus. Small defects in the band are scattered throughout and probably represent areas where nerves penetrate Bowman's layer.

Histopathologically, the earliest changes consist of basophilic staining of the basement membrane of the epithelium; this is followed by involvement of Bowman's layer with calcium deposition and eventual fragmentation.

The factors that stimulate precipitation of calcium salts in the interpalpebral region of the anterior corneal layers are thought to involve gaseous exchanges at the corneal surface leading to decreased carbon dioxide and elevated pH.²⁸² Anatomic peculiarities in the basement membrane and Bowman's layer invite calcium deposition, as do decreased content of acid mucopolysaccharides in an edematous cornea.²⁸⁴ The calcific deposits due to local disease are usually extracellular. In systemic hypercalcemia the deposits are intracellular.

Band keratopathy may also result from deposition of urates in the cornea.²⁸⁵ These are customarily brown instead of the gray-white usually seen in calcific band keratopathy.

The instillation of mercury-containing eye drops, as in glaucoma and dry-eye states, has some circumstantial relationship to the development of band keratopathy in some patients.^286–288 The dry-eye state itself, through concentration of tear calcium, may also encourage its deposition near the corneal surface.

Some of the conditions that may result in band keratopathy are listed in Table 1.^289–294

TABLE 1. Conditions That May Result in Band Keratopathy

  Hypercalcemia^289–294

  Sarcoidosis (rare)
  Fanconi's disease
  Still's disease (nongranulomatous uveitis)
  Hypercalcemia (uremia, parathyroid adenoma)
  Hypophosphatasia
  Multiple myeloma
  Discoid lupus erythematosus
  Hyperphosphatemia
  Vitamin D toxicity
  Metastatic disease (lung and bone disease with increased calcium)
  Ichthyosis

  Chronic nongranulomatous uveitis (juvenile rheumatoid arthritis)
  Prolonged glaucoma
  Long-standing corneal edema
  Degenerated globe (phthisis bulbi)
  Spheroid degeneration
  Norrie's disease

  Spheroid degeneration
  Bietti's nodular keratopathy

Band keratopathy may be treated by application of the calcium binding agent, ethylenediaminetetraacetic acid (EDTA). After instillation of topical anesthesia, EDTA 0.4% is applied to the deepithelialized cornea. Superficial keratectomy is then performed by carefully stripping the calcific scale with forceps and blunt dissection with dry cellulose sponges.²⁹⁵

Salzmann's Nodular Degeneration

This degeneration is noninflammatory and creates multiple, bluish-white, superficial corneal nodules, usually in the midperiphery (Fig. 29). The nodules may be related to previous inflammation, especially phlyctenular disease, vernal keratoconjunctivitis, trachoma, or lues and interstitial keratitis. It has also been reported in patients with epithelial basement membrane dystrophy, contact lens wear, keratoconus, and after corneal surgery.²⁹⁶ Although often asymptomatic, patients may develop recurrent epithelial erosion or decreased vision.

The nodules represent focal areas of subepithelial fibrocellular, avascular pannus, replacing Bowman's layer and superimposed on a normal stroma. Transmission electron microscopy has shown reduplication of the epithelial basement membrane in some cases.²⁹⁶

Treatment may include simple stripping of the focal nodules by superficial keratectomy. Lamellar or penetrating keratoplasty may rarely be required for visual rehabilitation.

Corneal Keloids

Corneal keloids may be found either in the central or peripheral cornea and resemble the nodules in Salzmann's degeneration. They occur as hypertrophic scars following corneal injury, inflammation, or surgical trauma. Keloidlike lesions have also been reported in early life without antecedent trauma. Immunohistochemical and electron microscopic studies have demonstrated the presence of myofibroblasts in these lesions, differentiating them from Salzmann's nodules.²⁹⁷

CONJUNCTIVAL DEGENERATIONS

Pterygium

Pterygia are triangular, fibrovascular connective tissue overgrowths of bulbar conjuctiva onto the cornea (Fig. 30). They are horizontally located in the interpalpebral fissure on either the nasal or temporal side of the cornea. A pigmented iron line (Stocker's line) may be seen in advance of a pterygium on the cornea. The location of the pterygium is determined by exposure to ultraviolet energy, the amount of which varies with the geographic latitude. True pterygia are found only in the interpalpebral fissure. The wearing of glasses can decrease their incidence since the ultraviolet transmission is thereby decreased.

A pterygium may progress slowly toward axial cornea or may become quiescent. Indications of activity are corneal epithelial irregularity, opacification of Bowman's layer, and prominence of active blood vessels and inflammation.

Histopathologic examination reveals the subepithelial tissue to exhibit elastotic degeneration of collagen, resulting from breakdown of the collagen and destruction of Bowmans membrane.²⁹⁸ The subepithelial material stains for elastin but is not sensitive to elastase.

Generally, pterygium excision is indicated if the visual axis is threatened or if the pterygium causes extreme irritation. If a pterygium recurs following excision, it will do so within several weeks, starting from the cut conjunctival border. The rate of recurrence is significant—as high as 40%—when a bare scleral excision is performed. This rate is usually reduced if surgery is followed by beta irradiation with strontium 90. Treatment with autologous conjunctival transplantation²⁹⁹ has recently been shown to decrease the incidence of recurrence to about 5%, as has adjunctive treatment with mitomycin drops.^300,301

Pseudopterygia occur following chemical injury, corneal ulceration, or other inflammatory problems in which the conjunctiva becomes scarred and drawn upon the cornea. A probe can be passed between this conjunctival bridge and the sclera, a feature which distinguishes pseudopterygia from true pterygia.

Pinguecula

Like pterygia, pingueculae likely represent an age-related degeneration associated with ultraviolet light and general environmental exposure. Pingueculae appear as raised, cream-colored, white, or chalky perturbations of the conjunctiva adjacent to the limbus and within the palpebral fissure. Occasionally, they may become inflamed but generally do not require treatment. As in the case of pterygia, pingueculae may represent elastotic degeneration of the substantia propria of the conjunctiva.²⁹⁸

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