Diseases of cornea and sclera. Diseases of the uveal tract

Diseases of the Cornea

Pathologic changes in the cornea are associated with a wide variety of systemic diseases. In some instances, these changes are characteristic of the underlying disease process. Some corneal findings may be secondary to problems of the eyelids, eyelashes, and other adnexal structures that are involved in a systemic disorder. Traditionally, discussions of corneal involvement in systemic diseases have comprehensively categorized the various corneal findings associated with particular diseases. From a practical clinical standpoint, however, patients who consult an ophthalmologist do not usually have a clear-cut systemic diagnosis of their eye complaints. On the contrary, a patient usually presents because of a particular eye symptom, or for a routine examination. At that time, corneal changes may be recognized. It is therefore important for the clinician to be aware of the significance of certain corneal changes and their possible relationship to systemic disease processes. At the time of the ophthalmologist’s examination, certain systemic diseases may be subclinical and patients and their internists may be unaware of them, so the familiarity of the ophthalmologist with suspicious corneal findings is of substantial value. In other cases, patients may be referred with a diagnosed or suspected systemic disease, making the association between corneal change and systemic disease more apparent.

The dygeneses, dystrophies, and degenerations of the cornea account for a broad spectrum of ocular abnormalities, ranging from clinical curiosities to sight-threatening anomalies. Knowledge of these entities has accrued through both clinical study and examination of histopathologic specimens.

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).

CORNEAL DYSGENESES

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. 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. 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.

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 12 mm, 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.

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. Although 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. Simple megalocornea must also be differentiated from keratoglobus (see discussion later in chapter on ectatic corneal dystrophies).

 

Fig. 1 Megalocornea. Left. Light microscopy of a 62-year-old man with corneal diameters of 13 mm shows in pupil-optic nerve section an enlarged anterior segment with no abnormalities (except beveled scar of cataract incision and surgical aphakia) (hematoxylin-eosin, × 3). Right. Central section of the cornea demonstrates all layers to be normal except for some thinning of the epithelium (hematoxylin-eosin, × 165)

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, Apert’s syndrome, and mucolipidosis type II have been found in association with this disorder.

Cornea Plana

In cornea plana, the corneal curvature is flatter thaormal, often reaching levels as low as 20 to 30 D, with a radius of curvature similar to the sclera. 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. This condition also features concurrent anterior segment abnormalities, 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 tissues (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.

Neural crest cells migrate into the developing anterior segment in three waves, contributing to the corneal endothelium 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.

Whatever the exact pathogenesis, since corneal and iris tissues are likely derived at least in part from the neural crest 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.

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). 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.

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. If glaucoma is also present (secondary to angle abnormality), the condition is called Axenfeld’s syndrome.

Fig. 2 Composite illustration of the anatomic findings in mesenchymal dysgenesis of the anterior ocular segment.

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 (Fig. 2A). 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.

Fig. 2A Rieger’s anomaly. The central cornea is unaffected and visual acuity remains normal. However, there is anterior displacement of Schwalbe’s line and broad iridocorneal synechiae with distortion and displacement of the pupil.

Posterior Keratoconus

Posterior keratoconus 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.

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. 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).  Most cases of Peters’ anomaly are sporadic, although both recessive and irregular dominant inheritances have been described. Eighty percent of reported cases are bilateral.

Fig. 3 Peters’ anomaly. Schematic drawing of ocular features.

Bottom left. Clinical photo of typical bilateral Peters’ anomaly with large, dense central leukomata, which was successfully treated by penetrating keratoplasty with optical iridectomy of the fellow eye.

Bottom center. Intraoperative photo demonstrates adhesion of the lens to the posterior cornea as a corneal button (grasped with forceps) is trephined.

Bottom right. Successful penetrating keratoplasty of a patient with bilateral Peters’ anomaly.

Although Peters’ anomaly is, in general, characterized by a central corneal leukoma, two clinical variants have been recognized.

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. 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. 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.

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. 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. 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.

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. 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. Somatic abnormalities sometimes occur along with associated chromosomal abnormalities; they include mental retardation, deafness, and craniofacial, digital and skin abnormalities.

Fig. 4 Sclerocornea. Schematic drawing of ocular features Fig. 4.

Bottom left. In a minimally affected patient with additional findings of ptosis, strabismus, and hearing loss, only the peripheral cornea is opacified.

Bottom center. In this advanced case with chromosomal translocation and multiple congenital abnormalities, the entire cornea is sclerified and the fine vascular arcades extend centrally from the conjunctiva and sclera.

Bottom right. Light micrograph of anterior cornea shows edematous disorganization of epithelium, fragmentation of Bowman’s membrane (B), and interstitial vascularization (V) (hematoxylin-eosin, x200).

CORNEAL DYSTROPHIES

ANTERIOR DYSTROPHIES

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

Fig. 5 Characteristic corneal changes in various types of corneal dystrophy.

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). Family studies have revealed a probable dominant inheritance for map-dot-finger-print dystrophy, with variable penetrance. Other clinical studies are more consistent with degeneration that is rather highly prevalent in the general population.

Fig. 6 Map-dot-fingerprint dystrophy. Top left. Clinical photograph of a 37-year-old man with non-traumatic erosions shows characteristics of map dystrophy with superficial geographic haze interrupted by clear areas. Top right. In the dot form of Cogan’s mycrocystic dystrophy, superficial, opaque cysts are evident within the epithelium. Upper middle. Three variants of fingerprint dystrophy show subepithelial ridges, particularly enhanced by retroillumination.

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. 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 and of Stocker-Holt is a dominantly inherited abnormality of the corneal epithelium, first described clinically by Pameijer in 1935. 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.

In 1955, Stocker and Holt 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 Wilbrandt 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. Hence, this condition is probably most appropriately classified within the spectrum of epithelial basement membrane dystrophy.

Reis-Bucklers Dystrophy

In 1917 Reis described a superficial corneal dystrophy that affected Bowman’s layer, and in 1949 Bucklers 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.

Fig. 6.1 Left: Coarse geographic opacities in Reis-Bücklers corneal dystrophy. Right: Reticular opacity in the superficial cornea

Slit lamp examination of the cornea shows an irregular epithelium with diffuse, irregular, patchy geographic opacities at the level of Bowman’s layer. 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. Recurrence after keratoplasty has been described.

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. Alternatively, immunofluorescent localization of laminin and bullous pemphigoid antigen suggests a primarily epithelial disease. 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.

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. 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 whorl-like corneal lesions are evident in patients taking chloroquine, amiodarone, 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)

Fig. 7 Anterior Mosaic Crocodile Shagreen

Anterior mosaic crocodile shagreen appears as bilateral, polygonal, grayish white opacities in the deep layers of the epithelium and in Bowman’s layer. 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.

Idiopathic Band Keratopathy

Band-shaped keratopathy is a deposition of calcium in the interpalpebral basal epithelium and Bowman’s layer. 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. 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

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 (Fig. 9-1). 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.

Jones and Zimmermaoted 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, Garner 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-workers 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. 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.

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.

Fig. 9-1 Granular corneal dystrophy type I. Numerous irregular shaped discrete crumb-like corneal opacities

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. 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.

Fig. 9-2 Granular corneal dystrophy type II, Avellino corneal dystrophy. Variable sized crumb-like opacities in the corneal stroma that have become fused in areas giving rise to elongated and stellate shapes

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.

Lattice Dystrophy

Lattice dystrophy is an autosomal dominant condition characterized by pathognomonic, branching “pipestem” lattice figures within the stroma (Fig. 10). 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. The dystrophy advances inexorably, and by age 40 or earlier these problems become markedly aggravated, causing considerable discomfort and visual incapacity.

Fig. 10 Latice corneal dystrophy. A network of thick linear corneal opacities

Many published reports have documented the nature of the corneal deposits in lattice dystrophy. In 1961, Jones and Zimmerman and others suggested that the disorder was due to amyloid degeneration of the stromal collagen fibers. In 1967, Klintworth 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. 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. 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.

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.

Systemic amyloidosis may be associated with lattice dystrophy (lattice dystrophy type II, Meretoja’s syndrome, or type IV amyloidotic poly-neuropathy). 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.

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. Although Meretoja’s syndrome has not yet been chemically characterized, recent evidence suggests that the amyloid deposits do contain prealbumin (transthyretin).

Atypical variants of lattice dystrophy (type III) as well as rare cases of unilateral lattice dystrophy have also been reported. 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.

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 (Fig. 11). 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. Also unique is primary involvement of the endothelium as evidenced clinically by the presence of guttate changes of Descemet’s membrane.

Fig. 11 Macular corneal dystrophy (Groenouw Type II)

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. 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.

Polymorphic Stromal Dystrophy

Polymorphic stromal dystrophy is another manifestation of amyloid deposition in the cornea, Thomsitt and Bron described patients with a variety of posterior stromal opacities consistent with the type of dystrophic change reported in 1939 by Pillat. 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. 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. 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. The type of corneal amyloid, containing protein AP but not AA, may be different from that found in lattice dystrophy, which contains both. Treatment may include either superficial keratectomy or keratoplasty.

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. Corneal thinning was also present in more advanced cases. Findings in a second reported pedigree included  both  centro-peripheral and peripheral forms,  hyperopia with corneal flattening,  iris abnormalities including glassy sheets on the iris surface, corectopia, and pseudopolycoria, and  iris processes extending to Schwalbe’s line. Congenital Hereditary Stromal Dystrophy

Congenital hereditary stromal dystrophy is characterized by flaky or feathery clouding of the stroma. 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.

Fleck Dystrophy (Francois-Neetens)

This rare, autosomal dominant dystrophy is detectable very early in life and in some cases is congenital (Fig. 13). 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. Histochemical staining shows glycosaminoglycans and lipids within these vacuoles.

NONINFLAMMATORY CORNEAL ECTASIAS

Corneal ectasias are non-inflammatory diseases that are characterized by thinning and protrusion of the corneal stroma resulting in shape changes. This family of diseases consists of keratoconus, keratoglobus, and pellucid marginal degeneration. Normally, the stromal collagen lamellae run circumferentially in the corneal periphery, producing a round shape. However, progressive thinning of the stroma leads to flattening of the corneal curvature along that meridian. This induces the peripheral ring of collagen lamellae to assume a more oval shape and transmits a compressive force to the lamellae that are 90 degrees away, resulting in corneal steepening in that meridian. This mechanism is known as biomechanical coupling. Furthermore, intraocular pressure at the site of weakness causes protrusion of the cornea.

Keratoconus

Keratoconus is a bilateral but typically asymmetric ectasia that has onset in the late teens and usually progresses slowly over many years. Patients have a history of progressive myopia, oblique astigmatism, and reduction of spectacle-corrected visual acuity. Prior to the introduction of methods to assess corneal topography, the diagnosis was based on history and the presence of clinical signs. In mild disease, however, these clinical signs are subtle or altogether absent. The advent of refractive surgery has made the detection of subclinical keratoconus of increasing importance in order to prevent the surgical treatment of these eyes. Keratoconus has an incidence of 1 in 2000 in the general population but is being detected in 5% of myopes who present for refractive surgery evaluation.

Fig. 12 Keratoconus. Photograph in lateral projection demonstrates extreme anterior protrusion of the markedly ectatic cornea

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. 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.

Keratoconus can be categorized according to the severity of power (mild, moderate, severe); location of cone (superior, central, inferior); and shape of cone (oval, globus, nipple) (Fig. 13-A, B). Corneal thinning most commonly occurs in the inferocentral cornea, and protrusion also occurs in this region. The point of maximal protrusion is referred to as the apex of the cone. The steepest corneal slope lies just peripheral to the apex (usually inferior in central cones). The region of smallest radius of curvature (therefore the greatest corneal power) lies between the cone’s apex and its steepest slope. The mechanism of biomechanical coupling causes the flattest meridian to be approximately horizontal and the steepest meridian to lie close to the vertical meridian. Placido disk-based videokeratographs mirror this distortion by producing mires that are typically oval. The distance between rings is smallest at the steepest corneal slope and farthest apart superiorly where the cornea is flattest. Tangential curvature maps of projection-based systems provide additional information. On these maps the steepest slope is easily located as being inferior to the apex, producing an asymmetric bow tie. This corresponds to the exaggerated prolate shape of the keratoconic eye. Projection-based systems can be used to locate the apex of the cone on elevation maps as the highest point. The apex is surrounded by concentric zones of decreasing elevation.

Fig. 13-A Oval keratoconus pattern

Fig. 13-B Cross-sectional map through the 180-degree meridian demonstrates maximal protrusion in the paracentral cornea with thinning in the same area

Several authors have recommended topographical indices for detecting early keratoconus and suspected keratoconus. The diagnosis, however, still requires the presence of Vogt’s striae, a Fleischer ring, or corneal thinning. The surface asymmetry index (SAI) measures the irregularity of the cornea in the central 4.5-mm zone. It measures the difference in corneal power between points on the same ring 180 degrees apart. The inferior-superior (I-S) value measures the average power at five superior points 3 mm from the center at 30-degree intervals and compares this to five inferior points 3 mm from the center at 30-degree intervals. K is the central K-reading; when used alone, a value greater than 47.2 is suggestive of keratoconus. The KCI%, KPI% and KISA% are values derived by a combination of other indices. For example, the keratoconus predictability index (KPI) combines the SAI with seven other indices in an algorithm to predict the presence of keratoconus with 68% sensitivity and 99% specificity. Auffarth and co-workers. used the Orbscan to evaluate a series of keratoconus patients and noticed that the apex and thinnest point were located separately but with no consistent distance or pattern.20 The thinnest point was less than 0.500 mm. Furthermore, there is a high degree of nonsuperimposable mirror-image symmetry in the location of the cones between the right and left eyes of the same patient. The nonsuperimposability is due to the variation in radii between the apex and the thinnest point.

An early histopathologic change is focal disruption of Bowman’s layer, 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. 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.

Keratoconus can occur in association with a variety of ocular and systemic diseases, including atopic dermatitis, vernal catarrh, Down’s syndrome, retinitis pigmentosa, 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. Some investigators, moreover, have also inferred contact lens wear as causative.

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. Thermokeratoplasty is generally only a temporary measure, because resteepening, scarring, or persistent epithelial defects usually ensue, although in some cases the result is acceptable. 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.

There may be asymmetry in the severity of disease between the two eyes. Furthermore, there are reports of PMD in one eye and keratoconus in the fellow eye. Typically in PMD, a 2-mm wide band of thinned stroma occurs 1 to 2 mm from the inferior limbus and spans the central four clock hours. Unlike in keratoconus, the areas of thinning and protrusion are not the same; corneal protrusion occurs in the cornea that lies above the area of thinning. Cases of superior PMD, nasal PMD, and circumferential extension of inferior PMD have been recognized. Classically, in inferior PMD topography maps the lowest corneal power to a narrow corridor of central cornea that is close to the vertical meridian, producing an against-the-rule astigmatism. The power increases markedly toward the inferior periphery within this narrow corridor of central cornea. The mires show elongation along the vertical axis with compression inferiorly. The area of highest power extends along the inferior cornea and then turns toward the central cornea along the inferior oblique meridians. The term applied to this ring of high cylinder power is the loop cylinder. Progression to the superior corneal periphery does not show an increase in power (Fig. 14). Conversely, in superior PMD the area of highest corneal power is in the superior periphery with extension toward the central cornea from the superior nasal and superior temporal oblique semimeridians producing a superior loop cylinder. If the thinning progresses toward the horizontal, there is a shift in the meridians of highest and lowest corneal powers. Extension of thinning nasally will cause the lowest power to shift from the vertical toward the temporal and the highest power to shift toward a more nasal meridian.

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. Alternatively, tectonic lamellar grafting of the thinned periphery followed by a central penetrating keratoplasty may be attempted. Krachmer suggests that thermokeratoplasty may be a reasonable alternative.

Fig. 14 Pellucid marginal degeneration (PMD).

A.   Slit topography showing inferior corneal thinning (arrow) 1 to 2 mm from the limbus, extending from the 5- to 8-o’clock positions in both eyes.

B.   Videokeratoscopic image shows a typical pear-shaped image with compression of the inferior rings.

Fig. 14-C Pellucid marginal degeneration (PMD). Corneal topographic maps (absolute scale) showing against-the-rule astigmatism of 10.6 diopters (D) in the right eye. The left eye shows enantiomorphic symmetry (mirror image) to the right eye with 11.9 D of against-the-rule astigmatism. In early PMD the power of the cornea is least at a vertical axis very close to 90 degrees. The area of greater power is presented in a bow-tie configuration of two semimeridians inferior and oblique to the horizontal axis.

Keratoglobus

Keratoglobus (Fig. 15) 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. 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.

Keratoglobus is characterized by a diffuse globoid protrusion of cornea. The stroma is thinned diffusely, including the limbus. The condition is very rare and there were few reports in the literature. Keratoglobus may present bilaterally but has also been reported with the presence of other ectasias in the fellow eye. Karabatasas documented the topographic picture of keratoglobus in an individual who had classic PMD in the fellow eye. The keratoglobic eye had resolving hydrops in the inferotemporal quadrant and a band of circumferential peripheral thinning similar to that seen in PMD, suggesting that the condition may have arisen out of advanced PMD. The topography demonstrated a very asymmetric bow-tie pattern with a shift of 35 degrees from the vertical in the axis of lowest corneal power (Fig. 15-A, B).

Fig. 15 Photograph of acquired keratoglobus shows bulging globoid contour of cornea

Fig. 15-B The left eye shows irregular astigmatism with quite irregular power distribution. The axis of lowest corneal power is shifted about 35 degrees from the vertical axis, with a very asymmetric bow-tie configuration and with the inferior low-power semimeridian positioned above an area of high power at the inferior peripheral cornea. This area of peripheral inferior corneal steepening extends to the steep oblique semimeridians

 

Diseases of the Sclera

If the eye is considered as a much-modified ball and socket joint and the episclera as the synovial membrane, many of the conditions that afflict the sclera and episclera can be readily understood. The sclera consists of collagen, which resembles tendon, and much elastic tissue; therefore, the sclera suffers from the chronic, granulomatous, and destructive conditions that affect the joints and collagenous tissue elsewhere. Because the sclera is avascular, it is dependent on the vascular coats on either side, particularly the episclera, to provide a response to inflammation, so that scleral inflammation is almost always accompanied by an overlying episcleritis. Although the sclera is subject to degenerations and infections, these are insignificant when compared with the inflammatory changes of episcleritis and scleritis. Neoplasms of the sclera are unknown.

CLINICAL EXAMINATION

Because of the collagenous nature of the sclera, diseases that affect it tend to be indolent, painful, and destructive, presenting as local manifestations of a generalized condition. Conditions involving the episclera tend to be acute, transient, and of little importance unless they indicate the presence of intercurrent disease. Therefore, it is of considerable importance to decide which tissue is involved from the onset of the disease so that the correct treatment may be given and the correct prognosis determined.

HISTORY

Careful taking of the patient’s history sometimes reveals the cause. In general, the more rapid the onset, the more readily treatable the condition, and, consequently, the better the prognosis. Most scleral disease is bilateral and recurrent, and the history of suggestive attacks in the other eye should be sought. Alteration in visual acuity always indicates corneal or deep-seated disease.

Many eye diseases are relatively painless. However, pain is a prominent characteristic of scleral disease; it is often the pain, rather than the redness of the eye, that causes the patient to seek advice. The pain of deep-seated scleral disease is severe and boring in character. It often radiates to the forehead and brow and characteristically awakens the patient during the night. The pain in superficial conditions is localized to the eye.

On direct questioning, approximately one fourth of patients with episcleral and scleral disease will complain of lacrimation or photophobia. This is not a major symptom and is, surprisingly, not correlated with the presence of keratitis or any particular type of scleral condition.

Scleral disease can be a manifestation of disease of any system of the body; therefore, a routine inquiry should be made concerning the cardiovascular system for evidence of arteritis or hypertension; the respiratory system for evidence of tuberculosis or sarcoidosis; and the genitourinary system for evidence of renal tuberculosis or venereal disease. A very strong relationship exists between skeletal and scleral disease, and an attempt should be made to determine whether there is any suggestion of connective tissue disease (e.g., a history of general malaise, pains in multiple or single joints, pains in the back or in the neck, and the presence of morning stiffness). Skin disorders that accompany or precede the onset of scleral inflammation include herpes zoster, rosacea, psoriasis, and erythema nodosum or arteritis. No central nervous system disease appears to be associated with scleral disease. Many patients with episcleritis give a history of recent viral disease, hypersensitivity reactions, or contact with external irritants, particularly industrial solvents. A family history of atopy is occasionally found in patients with episcleritis.

Because most therapy for inflammatory scleral disease is administered systemically and is immunosuppressive in type, a history of gastric ulceration is of major importance because it may affect the type and extent of the therapy that can be given.

EYE EXAMINATION

Failure of vision is insidious, and the visual acuity must be measured at frequent intervals during the course of the disease. The external examination of the eye in daylight must never be omitted. This examination is essential to distinguish the deep discoloration, the increased transparency, and the area of maximum edema in deep scleral disease. No other method gives so much information; tungsten or fluorescent light is not as effective as daylight. Areas of deep inflammation and the extent of the progression of scleral disease have been seen quite often in daylight but have been invisible when examined with the slit lamp.

The object of slit lamp examination is to determine the depth and nature of scleral and episcleral conditions and the presence of corneal changes. The changes seen are drawn in the records. With the use of diffuse light with a neutral density filter, the vascular networks of both eyes are examined in detail to determine the layer in which the vessels show maximum congestion, the infiltration of episcleral tissues, and the edema of sclera, episclera, or subconjunctival space. Slit lamp examination is also used to ascertain the nature and depth of any corneal changes; the presence of scleral edema (for which it may be necessary to blanch the superficial tissues with epinephrine 1:1000 or phenylephrine 10%); the nature of any episcleral infiltration or mass; and the presence of cells in the anterior chamber or vitreous and posterior synechiae. The red-free (green) filter is extremely valuable in confirming the areas of maximum congestion and whether any areas are totally avascular. Because this is an important physical sign and is easily missed, examination in red-free light should be routinely performed. The green light brings the vessels into very sharp contrast with the background and enables the position of maximum inflammation to be determined with certainty. It also enables the paths and configurations of the vessels to be followed and will show lymphocytic infiltration of the episcleral tissue as yellow spots; this often indicates that the condition is more extensive than previously supposed (Fig. 8).

Glaucoma often occurs secondary to scleral disease. Applanation readings should be undertaken at the first visit and subsequently during treatment, especially if corticosteroids are used.

Direct and indirect ophthalmoscopy are performed. This is particularly important in all cases of posterior scleritis or if cells are observed in the anterior or posterior chamber. Some patients with scleritis have granulomatous changes in the posterior segment that give rise to an exudative retinal detachment. Posterior scleritis and orbital disease such as pseudotumor, both of which involve the sclera and surrounding structures, will produce not only proptosis but also limitation of ocular movements. It is worth noting that these lesions can sometimes be completely symptom free even when the patient has developed a complete ophthalmoplegia (see Figs. 53 and 54).

Fig. 53 Proptosis of the right eye in a patient with both anterior and posterior scleritis. (Left)

Fig. 54 Retraction of the left lower lid occurs as a patient with posterior scleritis attempts elevation of the eye. (Right)

OTHER INVESTIGATIONS

Because so many patients with scleral disease have systemic disease, a thorough physical examination is essential. In the Scleritis Clinic at Moorfields Eye Hospital, this examination has been undertaken by a rheumatologist; this is a most satisfactory arrangement because the particular features that need thorough investigation are the joints, the skin, and the cardiovascular and respiratory systems.

The following routine investigations are performed:

·        Hemoglobin

·        White blood cell count and differential count

·        Erythrocyte sedimentation rate

·        If connective tissue disease is suspected, full immunologic investigations are undertaken, including levels of immunoglobulins and immunofluorescent studies for autoantibodies (including rheumatoid factor and antinuclear and anti-DNA antibodies); circulating immune complexes are searched for. If Wegener’s granulomatosis or periarteritis nodosa are suspected, the anti-nuclear cytoplasmic antibody (ANCA) tests should be performed. The C-reactive protein is the best indicator of an active generalized inflammatory response.

·        Serum uric acid

·        Full serologic tests for syphilis

Radiologic investigations should include a chest roentgenogram and a roentgenogram of the sacroiliac joints. Physical examination may not reveal sacroiliitis of the rheumatoid type. Because this may be the only other systemic manifestation in scleral disease, this investigation should not be omitted. Roentgenograms of other joints are taken if a particular disease process such as gout, rheumatoid arthritis, or sarcoidosis is suspected.

Prick and patch testing of the skin has been universally unrewarding even when a known sensitizer has been found. Local challenge has been attempted, but the results are inconclusive.

Electroretinography and electro-oculography are of assistance only in the presence of cataract or severe necrotizing or posterior scleritis. There is sometimes a dramatic fall in the electric response at the onset of disease and an equally dramatic rise when the disease is suppressed, provided destructive changes have not occurred.

B-scan ultrasonography should never be omitted from the examination of patients with scleritis. Now that high-quality ultrasonography has become available, the extent and severity of the inflammation can be determined with great accuracy. Many patients who were formerly thought to have only anterior segment disease have been found to have extensive and sight-threatening posterior scleritis as well. It also has become known that many patients with posterior scleritis with few symptoms and signs have much more extensive disease than had previously been considered possible (Fig. 9). Anterior segment B-scan ultrasonography sometimes reveals extensive involvement of the deep scleral tissue around the ciliary body, indicating the need for urgent and intensive use of immunosuppressive therapy.

B-scan ultrasonography has proved to be a much more valuable investigation than even high-resolution computed tomography (CT) scanning. However, if orbital extension of disease is thought to have occurred, then CT or magnetic resonance imaging (MRI) should be performed.

EPISCLERITIS

Episcleritis is almost always a benign inflammatory condition occurring in young adults, with a marked tendency to recur. The condition, which is frequently bilateral, may be divided on clinical grounds into simple episcleritis and nodular episcleritis.

ETIOLOGY

Thirty percent of patients with episcleritis had some associated general conditions,6–8 but the rest defied all attempts to discover an etiology. Although some patients had a strong family history of atopy, results of patch and prick testing were uniformly negative. Of those in whom an etiology was found, only 5% showed any association with collagen disease, 7% had an association with herpes zoster, and 3% each had an association with gout or syphilis; the rest had associated conditions such as erythema nodosum, Schönlein-Henoch purpura, erythema multiforme, contact with industrial solvents, or penicillin sensitivity, indicating an immune basis for the condition.

PATHOLOGY

Microscopic and electron microscopic studies of biopsy specimens from patients with simple and nodular episcleritis have been totally noncontributory in the attempt to discover the etiology of this condition. The inflamed area is packed with lymphocytes and a few other inflammatory cells, but there are no mast cells, plasma cells, or eosinophils.

CLINICAL MANIFESTATIONS

The onset is usually acute; the eye may become red and painful in as short a time as half an hour. The patient’s main complaint is redness of the eye, which is often sectorial and may be accompanied by a feeling of hotness, pricking, and mild discomfort. There is no discharge, although the eye waters occasionally.

Pain may be absent, but the discomfort may be so severe that patients cannot pursue their normal occupation. The pain is localized to the eye, rarely radiating to the forehead and never producing the severe boring pain that is so commonly described in scleritis. In a severe attack the lids may become swollen, but this is a rare occurrence. If photophobia is present, an accompanying corneal condition should be suspected.

Simple and nodular episcleritis differ in their clinical courses, but in both the edema and infiltration are entirely within the episcleral tissues. The sclera is not involved. The maximum congestion is in the superficial episcleral network, with some slight congestion of the conjunctival vessels and deep episcleral vessels. The intraocular structures are not involved in either variety, nor is the visual acuity affected. Anterior segment fluorescein angiography reveals a normal vascular pattern but a very rapid flow rate, with the whole transit of the dye being completed within 2 or 3 seconds (Figs. 11 and 12).

 

Fig. 11 Anterior segment fluorescein angiogram of a 45-year-old woman with simple episcleritis. At first transit of dye, all the vessels are dilated and filling simultaneously. However, the vascular pattern is not disturbed (Left)

Fig. 12 Angiogram of the same 45-year-old woman in Figure 11 one second later. Within 1 second, all the vessels are filled and there is even, venular filling except in the deep episcleral plexus. This is the rapid filling pattern seen in all forms of episcleritis and in diffuse anterior scleritis (Right)

The redness of simple episcleritis may be intense, varying from a fiery-red or a brick-red discoloration to a mild red flush, but it does not have the bluish tinge that is seen in scleritis. The distribution is usually sectorial but can involve the whole anterior segment of the globe. The episcleral vessels are engorged but retain their normal radial position and architecture (Fig. 13). In simple episcleritis, there is a diffuse edema of the episcleral tissues. These tissues are sometimes infiltrated with gray deposits that appear yellow in red-free light. Surprisingly, the eye is rarely tender to the touch.

Fig. 14 Diffuse inflammation. Superficial vessels are maximally engorged and retain their radial pattern and architecture

In contrast to simple episcleritis, the infiltration and edema of nodular episcleritis are localized to one part of the globe, forming a nodule and some surrounding congestion (Color Plate 1B). The nodule can be moved over the underlying sclera, which is not edematous. The scleral plexus of vessels can be distinguished deep to the nodule, lying flat on the sclera and slightly congested but otherwise normal in color and configuration (Fig. 15). Episcleral nodules may be single or multiple but do not undergo necrosis. After multiple attacks of nodular episcleritis in the same location, the superficial lamellae of the sclera show some alteration and become slightly more transparent in this one area.

TREATMENT

Even without therapy, simple episcleritis improves considerably within the first week and resolves within 3 weeks (Fig. 17). Provided the eye is not too uncomfortable, most patients can be persuaded to leave the eye untreated, because the condition will resolve spontaneously. However, if it is believed that some treatment is desirable, topical corticosteroids or locally applied nonsteroidal anti-inflammatory drugs (NSAIDs) may make the eye more comfortable and speed resolution slightly. Use of corticosteroid drops must be continued for several days after the inflammation has subsided to prevent the exacerbation of the condition that occurs if they are stopped suddenly. Prednisolone, betamethasone, or dexamethasone drops may be administered hourly until redness disappears, and then three times daily for 4 to 5 days. Under no circumstances should topical steroids be administered continually for more than a few weeks at a time because of the very real danger of inducing steroid glaucoma and cataract. If the condition fails to respond immediately, other treatment regimens should be sought. Ocular NSAIDs can be administered four times daily until redness disappears. Glaucoma and cataract have not been observed after prolonged use, but many patients become intolerant to the use of the ointment or complain of stinging and irritation.

Whereas simple episcleritis resolves rapidly without therapy, the resolution of nodular episcleritis is much slower. Local therapy is consequently of much more value; the same regimen of treatment is followed.

In the few patients in whom episcleritis becomes indolent, or in whom recurrences are so numerous that the patient becomes incapacitated, it is reasonable to consider systemic therapy with NSAIDs such as flurbiprofen (Froben), 100 mg three times daily, which usually gives immediate and prolonged relief of symptoms and signs. It is important to note that not all of the NSAIDs work in this condition. Treatment may be terminated abruptly when the condition comes under control.

The complications of episcleritis are minor and are not responsible for any decrease in visual acuity.

COURSE AND PROGNOSIS

Whether treated or not, simple episcleritis will resolve in 10 to 21 days. It will usually reappear at irregular intervals and then eventually disappear. No etiologic or precipitating factor has been found.

Iodular episcleritis, the nodule initially increases rapidly in size, sometimes reaching the size of a split pea. Thereafter it gradually regresses over a variable period and eventually disappears, although this may take up to 2 months without treatment.

Recurrences occur also iodular episcleritis, but the two varieties are not mutually exclusive (a simple episcleritis may recur as a nodular episcleritis and vice versa). However, episcleritis never develops into scleritis in the same attack, although it invariably accompanies scleritis. Of 180 patients initially diagnosed as having episcleritis, only 4 developed scleral involvement.

Episcleritis is an entirely benign condition, although it may be a great nuisance to the patient. It may recur over a period of many years, but it rarely leaves any residual ocular changes except for some areas of scleral transparency or localized stromal keratitis in those patients who have had severe attacks of nodular disease occurring always at the same site. Of 180 patients analyzed, only 2% had a decrease in visual acuity of two lines or more within a year of the onset, and in every case this was from increasing involutional cataract.

SCLERITIS

Scleritis, unlike episcleritis, is a severe destructive disease, sometimes leading to the loss of an eye from deteriorating vision, severe pain, or even (occasionally) perforation of the globe. Such changes, when they occur, are rapid, so early diagnosis and effective treatment are essential. Scleral disease can be diagnosed when the patient is first seen if one remembers that whereas episcleritis rarely, if ever, involves the scleral tissue, in scleritis the episclera is always involved. Therefore, attention must be diverted to the sclera to detect the early changes of scleral edema or necrosis.

The onset of scleritis is usually gradual, building up over several days. By the time patients seek advice, the clinical types can be distinguished as anterior or posterior, or occasionally both. Anterior scleritis may be further subdivided into diffuse, nodular, or necrotizing. The last condition may present with signs of inflammation or with few or no signs of inflammation (scleromalacia perforans). Long-term follow-up of patients with scleral disease showed that only 8% of patients changed from one type of disease to another during the course of this disease, so although differentiation into these types does not usually indicate an etiology, it does have a direct bearing on the prognosis and the type of treatment to be used.

Scleritis is most common in the fourth to sixth decades of life and occurs more frequently in women than men (8:5). Necrotizing scleritis occurs later than the other varieties, the mean age being 61 years. Scleritis is bilateral in 52% of patients. In half of these, the condition starts in both eyes simultaneously, with the rest becoming bilateral in 5 or more years.

ASSOCIATED SYSTEMIC DISORDERS

In a review of 1200 patients with scleritis who have attended the Scleritis Clinic at Moorfields Eye Hospital in London, an associated systemic disorder was found in all patients with scleromalacia perforans, in half of those with nodular and necrotizing disease, in a third of those with diffuse anterior scleritis, and in only 10% of those with posterior scleritis. Severe polyarticular rheumatoid arthritis and a case of porphyria accounted for the patients with scleromalacia perforans.

Forty percent of the patients with necrotizing scleritis had other connective tissue disorders, but, surprisingly, only 21% of the patients with diffuse anterior or nodular scleritis had rheumatoid arthritis or other connective tissue disorders. This percentage is much lower than that reported by other authors, but this may be because patients with the less severe scleral disease are referred to us only if the etiology is in doubt, thus biasing the results. Twelve percent of the patients with diffuse anterior and nodular scleritis had ankylosing spondylitis, and in a further 15% the scleritis followed an attack of herpes zoster ophthalmicus. A variety of other conditions, including syphilis, tuberculosis, gout, Reiter’s disease, IgA nephropathy, and erythema nodosum, were thought to be definite etiologic factors because with appropriate treatment the eye changes disappeared. Fowler investigated a random selection of the patients with scleritis at Moorfields Eye Hospital and found only 7%, all of whom were young males, who did not have any other detectable physical abnormality.14 Forty percent of these patients had hypertension, which in some cases required treatment. It was thought that the hypertension could have been a manifestation of a generalized arteritis, but this was convincingly demonstrated in only 19% of these patients.

PATHOLOGY

The pathology of scleritis has received much attention in the past. Although certain inferences can be drawn from pathologic specimens of eyes removed because of pain, perforation, or mistaken diagnosis, these eyes have been severely damaged from advanced disease. Unfortunately, biopsies of scleral lesions have proved to be unsatisfactory, at best yielding material of limited diagnostic value and at worst leaving an area of exposed choroid that will not heal. Consequently, they should not be performed.

Scleritis usually affects the anterior segment of the eye, possibly because this is the area with the best blood supply, but with sluggish flow through the vessels. The sclera is thickened and roughened in the affected area, which appears to be sharply demarcated from the rest of the sclera. However, tissue obtained at surgery during the course of grafting of areas adjacent to necrotic tissue shows marked pathologic changes. The area of affected sclera may be swollen, excavated, or frankly ulcerated with undermined edges covered with a thin layer of fibrous tissue. However, spontaneous perforation is extremely unusual and, where seen in pathologic specimens, has usually occurred at the time of removal of the eye. A posterior scleritis often occurs as an extension of anterior disease; but, as in Figure 20, most of the inflammation (in some cases all of the inflammation) is in the posterior segment and the exudative detachments and subretinal granulomas can be mistaken for malignant melanoma.

CLINICAL MANIFESTATIONS

Lacrimation and photophobia are more common in scleritis than in episcleritis. However, they are not always clearly related to the severity of the scleritis or to the keratitis and uveitis that may accompany it.

The pain of scleritis is its most dominant feature and is the symptom that causes the patient to seek medical advice. The exception to this is scleromalacia perforans occurring in long-standing rheumatoid arthritis, which may be entirely pain free. Pain, when it occurs, may be localized to the eye, but in 66% of patients it is much more diffuse, radiating to the temple, the jaw, and the sinuses. It is boring iature, severe enough to prevent sleep, accompanied by malaise, and only temporarily relieved by analgesics. The pain is particularly severe in those patients suffering from progressive necrotizing scleritis with overlying inflammation; eyes have been removed for this reason alone. The pain can be a diagnostic problem, particularly in the early stages of posterior scleritis before the vision becomes affected. Patients with posterior scleritis are often referred to neurologists and others because of the severity of the headache or ophthalmoplegia. The pain is probably caused by distention of sensory nerve endings as a result of edema. In the necrotizing disease, the severity of the pain is increased by the destruction of the nerve endings that takes place.

The inflammation of the eye is a prominent feature. The inflammation has a bluish-red hue in contrast to the brighter red of episcleritis and may be sectorial or diffuse. The severity of inflammation seems to depend on the amount of episcleral tissue present. Therefore, it is more prominent in younger people and is least prominent in those with rheumatoid arthritis in whom the episcleral tissue almost disappears.

Each of the various types of scleritis can be distinguished by its typical clinical appearance. Because the pathologic change is in the sclera, there is always edema and/or necrosis of that tissue. This gives rise to an overlying episcleral edema and to congestion that may be very severe and may need blanching with epinephrine 1:1000 or phenylephrine 10% to detect the underlying edema.

The sclera that is edematous is pushed forward, and the deep episcleral network is more congested than the superficial networks. It is usually easy to ascertain by simple observation that the patient has scleritis and not episcleritis. However, it is not as easy to ascertain whether the patient has early necrotizing scleritis. It is in these patients that fluorescein angiography has considerable value, because the first changes are detectable in the ocular vasculature. Prompt and adequate treatment can prevent these changes from becoming irreversible.

Diffuse Anterior Scleritis

Diffuse anterior scleritis is the most common and least severe type of scleritis. The inflammation is widespread, and it may involve either a small segment or the whole of the anterior segment, sometimes with such severe overlying inflammation as to justify the name “brawny” scleritis (Fig. 29). On slit lamp examination, the vascular pattern of both deep and superficial layers may be distorted, so that the normal radial pattern of the vessels is lost; large anastomotic channels develop, leading to beading and tortuosity of the remaining vessels.

 

Nodular Anterior Scleritis

Although patients with nodular anterior scleritis resemble those with nodular episcleritis on cursory examination, detailed examination reveals marked differences. The nodule or nodules (they may be multiple) consist of scleral tissue that is immovable episclera is tightly adherent to the nodule, which is tender to the touch. Although the sclera sometimes becomes transparent below the nodule, it does not become necrotic, nor does the condition extend beyond the site of the nodule, as occurs iecrotizing scleral disease (Fig. 36).

Necrotizing Anterior Scleritis with Inflammation

Patients with necrotizing anterior scleritis with inflammatioot only suffer extremes of discomfort but are in serious danger of losing an eye. Therefore, it is of great importance that the condition be detected early and treated adequately. (It is of equal importance that those varieties of scleral inflammation that are not destructive to the eye should not be treated with drugs that are themselves dangerous.) Accurate diagnosis is the key.

Necrotizing scleritis accompanied by inflammation is always painful, waking the patient at night, increasing in intensity day by day, and leading to severe distress. The sclera is swollen, and the overlying inflammation is localized to the center of a lesion or to either end of an extending lesion (Fig. 37). After inflammation, the sclera becomes transparent so that the underlying choroidal pigment becomes visible when viewed in daylight. These areas may be invisible with the slit lamp. The area of inflammation extends outward around the globe from the original site of inflammation, often joining with other areas of scleritis that have subsequently appeared. If the inflammation is not suppressed, the process will progress around the globe until the whole anterior segment is involved.

Uveitis, lens changes, glaucoma and other serious complications such as central vein occlusion do not seem to occur until the disease process affects the whole circumference of the eye. Sometimes scleral thinning, as well as increased transparency, occurs, but unless the intraocular pressure rises above 40 mm Hg, staphylomas are extremely rare. As the disease is brought under control, the necrotic areas are absorbed or sequestered, leaving an ectasia with the underlying uvea exposed or covered with a thin film of conjunctiva or episclera. If the defect is small, new collagen will cover it. If the defect is large or if it is thought to have been the source of a persisting antigenic stimulus, the necrotic tissue may need to be excised and then covered by scleral grafts. However, this procedure is usually performed for aesthetic reasons rather than because the vision is endangered. The underlying disease process is not affected by the presence of a scleral graft, which has to be covered by conjunctiva and, preferably, episclera if it is to survive. Surgery must never be undertaken until the disease process has been suppressed. Temporary gluing may be used in perforated eyes until this has been achieved.

Fig. 37 Necrotizing anterior scleritis. Early stage in which there is diffuse, intense, scleral congestion in one segment of the globe, and anomalies of the vascular pattern.

Necrotizing Anterior ScleritisdWithout Adjacent Inflammationd (Scleromalacia Perforans)

Necrotizing anterior scleritis without adjacent inflammation appears to be a well-defined condition with little relation in clinical features to necrotizing scleral disease, even though the pathology is similar and the final result is the same. Scleromalacia perforans is characterized by the almost total lack of any symptoms. It occurs almost exclusively in patients with long-standing polyarticular rheumatoid arthritis, the majority of whom are female (Figs. 49).

The anterior sclera loses its covering of episclera and develops an area of yellow-white necrotic slough over many months; this eventually separates or is absorbed, leaving the underlying choroid covered by either conjunctiva or nothing at all. As with necrotizing disease, the choroid does not bulge into this ectatic area; but unlike necrotizing disease, spontaneous healing of even small perforations is very limited once the necrotic tissue has been removed.

Fig. 49 A white necrotic plaque developing in an area of sclera

Fluorescein angiography is not helpful, except to indicate areas of vascular closure in an otherwise extremely thin, atrophic episcleral tissue. The formation of a sequestrum appears to be caused by arteriolar closure as opposed to the venular disease seen in the other forms of necrotizing scleritis.

Posterior Scleritis

Because the posterior sclera is invisible, the diagnosis of posterior scleritis is made only if the anterior sclera is also involved or some other sign or symptom leads one to suspect it. Posterior scleritis is much more common than previously suspected, as recent clinical and pathologic studies have shown. There are two distinct forms of posterior scleritis. The first is usually associated with an anterior scleritis. This granulomatous disorder, like its anterior counterpart, can be diffuse, nodular, or necrotizing in character and is associated with the connective tissue diseases. The second form occurs in young patients of all races who are 9 to 40 years of age. It is always diffuse in character but is not associated with any systemic disorder. Both forms may cause uveitis if the inflammation affects the ciliary body, and in both forms the patient may develop exudative retinal detachments, choroidal folds, and swelling of the disc (Fig. 52). The granulomatous type may also involve the structures outside the globe, causing proptosis, limitation of ocular muscle movement, and, uniquely, retraction of the lower lid on attempted elevation of the eye. Diagnosis is with B-scan ultrasonography.

Fig. 52 Fundus appearance after resolution of exudative detachment in patient with severe posterior scleritis. Macula was affected and vision much impaired.

TREATMENT

Scleritis is almost always accompanied by very severe pain that prevents sleep. A response to treatment is heralded by a dramatic relief of pain even though the condition might appear to be getting worse. Treatment may be modified with confidence once the pain has disappeared.

Local Corticosteroids

Local steroid therapy increases the patient’s comfort, but it is not effective in suppressing scleral inflammation. It is occasionally justified to use local steroid therapy alone when the inflammation is mild, the pain is slight, and corneal involvement is present, or very occasionally between attacks in the more severe forms of the disease to prevent remission. However, local steroids should be used only sparingly, if at all, in scleral disease because of the high chance of developing steroid-induced glaucoma or cataract.

Systemic Therapy

NONSTEROIDAL ANTI-INFLAMMATORY AGENTS

Nonsteroidal anti-inflammatory agents are effective in suppressing the inflammatory response in the majority of patients with diffuse and nodular scleritis, especially if they exhibit a high flow pattern on fluorescein angiography. Dosage levels need to be high initially and, as a consequence, care must be taken to monitor the patients to ensure that no toxic side effects occur. Treatment must be continued until the inflammation subsides, after which it can be stopped abruptly.

In assessing the effect of treatment, pain, tenderness, episcleral and scleral injection, and corneal and intraocular involvement should be used as parameters of activity of the disease. In a series of double-blind controlled trials, the effects of different anti-inflammatory and immunosuppressive agents have been compared. The suggested routines of treatment are based on the results of these trials. Unfortunately, not all of the nonsteroidal anti-inflammatory agents are effective in controlling scleral inflammation. The current practice is to use flurbiprofen (Froben), 100 mg three times daily, for at least 1 week in all patients who present with scleritis of whatever type, provided there is no evidence of vascular closure or scleral destruction on slit lamp examination. The response, if it is going to occur, is immediate, with the pain disappearing within 48 hours. Within a week, the results of investigations are known, including those of the angiographic films if they have been done. If there is a poor response to flurbiprofen and the angiogram shows a high flow pattern, the drug is changed to another nonsteroidal anti-inflammatory agent, because there is an individual susceptibility among the patients. Only if there is no response in the progression of the disease or if there is evidence of vascular closure are systemic steroids or other immunosuppressive drugs used.

SYSTEMIC STEROID THERAPY

If the scleritis is severe or necrotizing or if areas of vascular closure are detected with slit lamp examination or fluorescein angiography, then the use of systemic steroids is mandatory. Prednisone and prednisolone are most commonly used.

The principle of treatment with systemic steroids is that a sufficient amount must be given to suppress the condition; once this has occurred, the dosage may be rapidly reduced to a maintenance level, which may have to be continued until a natural remission occurs, or the steroid may be replaced by a nonsteroidal anti-inflammatory agent. Provided sufficient amounts are given and the patient can tolerate them, systemic steroids will control scleritis. The problem is deciding what dosage is appropriate. The following scheme has been found to be effective. If the angiogram shows early vascular shutdown and treatment with flurbiprofen has not been effective, oral prednisolone, 60 or 80 mg, is given for 2 days and is reduced over 1 week to 20 mg. The dose of prednisolone is then reduced by 2.5 mg every other day until the pain recurs or signs of inflammation begin to recur. This maintenance dose is continued for about 1 month, and then the dose is reduced by 1-mg steps. This final phase may be aided by the addition of a nonsteroidal anti-inflammatory drug. Pain relief is by far the most sensitive indicator of control of the disease.

If this course of treatment is not effective, intravenous pulse therapy of high doses of methylprednisolone, with or without the use of immunosuppressive therapy, should be considered.

SUBCONJUNCTIVAL AND ORBITAL FLOOR STEROIDS.

Treatment with subconjunctival steroids is contraindicated in scleritis. Perforation can occur at the site of subconjunctival injections. Depot steroids should not be used because the particulate matter may induce or perpetuate the inflammatory reaction in the sclera. Orbital floor steroids are occasionally helpful in patients with necrotizing disease who are unable to take systemic steroids. The effects unfortunately tend to be transient, and the injections ofteeed to be repeated at 7- to 10-day intervals. In this situation, intravenous pulse therapy should be considered as an alternative.

COMPLICATIONS

Complications occur late in the disease and vary with the severity of inflammation. They occur most frequently in posterior scleritis and in severe necrotizing disease, particularly when the condition has become circumferential and when the inflammation is so severe as to produce secondary intraocular inflammation.

Visual Acuity

The object of early diagnosis and treatment is to prevent a decrease in visual acuity. The treatment must not produce iatrogenic changes that cause decreased acuity.

Over a 3-year period, approximately 27% of the patients who develop this disease will experience a decrease in visual acuity of two or more lines, which can be the result of cataracts and keratitis developing in patients with severe diffuse anterior scleritis. However, over a 25-year period, only 3% have lost useful vision.

Increased Scleral Transparency and Thinning

Alteration in the collagen and ground substance results in increased scleral transparency. Scleral thinning occurred, particularly iecrotizing disease or scleromalacia perforans. Of these patients, 22% showed increased scleral transparency after the first attack; however, only 6% developed a scleral defect. If scleral defects are small, they will refill with new collagen after treatment; but if they are very large, they may have to be covered with a graft.

Uveitis

Although roughly 35% of patients with scleral disease show some evidence of cellular activity in either the anterior or the posterior segment, a severe uveitis with a marked flare and heavy cellular response is very unusual. If it does occur, it is a serious sign, and intensive treatment must be instituted at once with systemic steroids. In posterior scleritis, if the granuloma is behind the equator, there may be little or no intravitreal cellular reaction, even though there is a visible granuloma and a retinal detachment. Scleritis occurring between the pars plana and the equator affects the ciliary body, so some inflammatory response occurs. Unless patients with this form of inflammation are treated rapidly, the intraocular pressure sometimes rises disastrously. Most patients with posterior scleritis have high intraocular pressures at some stage in the disease.

As the scleral disease is brought under control, the uveitis resolves, leaving anterior and posterior synechiae unless care is taken to prevent them. The inflammation of the pars plana sometimes leads to massive pigment migration at the retinal periphery, leaving a reaction rather like a diathermy or cryotherapy reaction in retinal detachment surgery.

Glaucoma

The intraocular pressure may become raised at any stage of the disease because of an acute congestion of the outflow channels, raised episcleral venous pressure, angle closure, or a steroid-induced rise. Therefore, it is important that the intraocular pressure be monitored; 13.5% of all patients with nodular or necrotizing scleritis had a pressure rise, albeit transient, during the course of the disease. Permanent field changes occurred in 5%. Patients with posterior scleritis are particularly prone to develop rises of intraocular pressure.

The treatment of the glaucoma is the treatment of the scleritis. Once the scleritis is controlled, the pressure will fall to normal. While the eye is inflamed, particularly if there is a limbitis, acetazolamide should be used to control the intraocular pressure. Should the pressure remain high after the attack, topical timolol can often help to control the intraocular pressure. If control fails, trabeculectomy can be performed successfully in an area of normal sclera and conjunctiva.

Cataract

Involutional changes that are already present will be increased by the presence of a severe inflammation. However, there is no doubt that the transparency of the lens can be affected directly in patients who have had previously normal lenses and who have developed severe necrotizing scleral disease.

If a cataract advances to the extent that it requires removal, the extraction can be performed with use of a corneal section in spite of the presence of scleritis. Healing is a little delayed in some cases, but no operative or postoperative complications have occurred.

Cataract extraction and, for that matter, any other surgical procedure can precipitate scleral inflammation in a patient who is predisposed, usually because of circulating immune complex disease. These patients usually have necrotizing scleritis and require vigorous therapy.

Retinal Detachment

Exudative retinal detachment occurs in patients who have posterior scleritis, and it may, indeed, be the only sign in a very painful eye. The detachment is poorly mobile. A pale gray granuloma can be seen extending from the choroid beneath the retina and is accompanied by a poorly mobile serous detachment that may become total. The scleral granuloma sometimes leaves a permanent, inward indentation of the retina and a subretinal mass, although this does not always occur. An increasing hypermetropia has also beeoted; it is of rapid onset (over a period of 1 week) and is caused by the diffuse scleral edema in the early stages of the disease before the detachment of the retina occurs.

The exudative detachment usually resolves completely with treatment of the scleritis. However, if the inflammatory changes have affected the macular area, vision will be severely and permanently affected. After resolution, the retina shows a diffuse, heavy pigmentation of the affected area with a “high-water mark” at the edge. Patchy changes outside this area do not seem to occur. Surgery is not indicated.

Optic Nerve Swelling

Granulomatous processes inside the muscle cone or affecting the optic nerve sheaths may be accompanied by edema of the optic nerve. Although it is not possible to make a diagnosis of posterior scleritis on the basis of this sign alone, should there be severe pain, proptosis, limitation of movement, and a retinal detachment, a presumptive diagnosis is permissible; however, it can be confirmed only if the anterior sclera becomes involved later in the disease. B-scan ultrasonography is very helpful in defining granulomas involving the sclera and the optic nerve. Swelling of the disc in patients who have presented with anterior scleritis is unusual, but it has occurred in patients in whom it was known that the process had advanced to involve the posterior segment.

 

Diseases of the UVea

UVEITIS

Uveitis is a general term used to describe inflammation of the middle vascular tunic of the eye, the uvea. The uvea comprises the iris, ciliary body, and the choroid. The name is derived from the Latin word uva, meaning grape, because early anatomists compared the vascular coat of the eye to the inside of a purple grape skin. In practice, the term uveitis is often applied to any intraocular inflammation, even if the inflammation is not predominantly in the uvea. For example, infectious retinitis such as that caused by cytomegalovirus is usually considered under the rubric of uveitis.

SYMPTOMS

PAIN

The pain of iritis is primarily related to ciliary spasm. The ciliary body is innervated by the trigeminal nerve, and pain caused by its inflammation may therefore radiate to the periorbital region and to the eye. Because branches of the trigeminal nerve supply the cornea and iris, inflammation of these areas can cause a retrograde reflex with vascular dilation and swelling in the ciliary body, the so-called axon reflex. Cycloplegia is therefore useful in cases of iritis and in some cases of keratitis because paralysis of the ciliary muscle alleviates the pain of ciliary spasm.

PHOTOPHOBIA

Photophobia (pain caused by light exposure) is often accompanied by tearing and blepharospasm. It must be distinguished from the photodysphoria or photoaversion in patients with achromatopsia, cone dystrophy, or retinitis pigmentosa and from glare caused by lenticular opacities. Photophobia is a prominent symptom in patients with inflammation of the iris or ciliary body and in patients with keratitis and scleritis because of the axon reflex. Again, cycloplegia may lessen photophobia and pain.

BLURRED VISION

Blurred vision may be caused by cloudy media, although vision is often surprisingly good in the presence of dense inflammatory reaction in the anterior chamber and vitreous. Floaters are a more frequent manifestation of cells and debris in the vitreous cavity. Macular edema, which frequently occurs with both anterior and posterior uveitis, can produce blurred vision, micropsia, and metamorphopsia.

SIGNS

CILIARY INJECTION

Ciliary injection, or “ciliary flush,” is manifest by a ring of dilated episcleral vessels radiating from the limbus. It should be distinguished from the deeper and more peripheral injection of scleritis and from the sectoral or diffuse injection of episcleritis. Overlying conjunctival injection may mask ciliary flush but topically applied neosynephrine blanches the overlying conjunctiva, allowing visualization of deeper episcleral vessels.

PUPILLARY MIOSIS OR IRREGULARITY

The pupil is typically small in patients with iritis because iris inflammation results in a release of prostaglandins, which constrict the pupil. One exception is patients with herpetic uveitis, who may present with a dilated pupil. The pupil in patients with anterior uveitis often becomes irregular and fixed because of the development of posterior synechiae.

BAND KERATOPATHY

Long-standing chronic iridocyclitis, may result in calcific band keratopathy, the deposition of calcium hydroxyapatite in the cornea at the level of Bowman’s membrane.

Fig. 1 Band keratopathy in the interpalpebral area in a patient with juvenile rheumatoid arthritis. Note the small holes in the opacity, which represent the location where corneal nerves penetrate Bowmans layer. Also note lucid interval between the band and the limbus.

Long-standing chronic iridocyclitis, especially in children, may result in calcific band keratopathy, the deposition of calcium hydroxyapatite in the cornea at the level of Bowman’s membrane. Band keratopathy usually begins as grayish-white opacities at the periphery of the interpalpebral region. The opacification may spread centrally and in time may form a complete band within the interpalpebral zone. A lucid interval is noted between the band and the limbus because Bowman’s layer does not extend to the absolute limbus. Small clear areas are noted in the opacity, representing the location where corneal nerves penetrate Bowman’s layer. These holes impart a “Swiss cheese” appearance to band keratopathy (Fig. 1). Band keratopathy should be distinguished from Vogt’s limbal girdle and spheroidal degeneration. Occasionally, band keratopathy is atypical and starts centrally. Rarely, it forms a reticular pattern resembling lattice dystrophy called superficial reticular degeneration of Koby.

KERATIC PRECIPITATES

Clusters of inflammatory cells deposited on the endothelial surface of the cornea are known as keratic precipitates. The cells, which have been deposited from the aqueous humor, are often found inferiorly on the cornea in a linear vertical formation (Turk’s line) or in the form of a base-down triangle (Arlt’s triangle; Fig. 2).

Fig. 2 Chronic iridocyclitis. Note large greasy keratic precipitates in Arlt’s triangle. Also note extensive posterior synechiae and bussacca nodules.

The inferior corneal distribution results from convection currents in the anterior chamber that rise along the warm iris and fall along the cool cornea. Exceptions to the rule of inferior distribution of keratic precipitates include inflammation secondary to herpes simplex and zoster, cytomegalovirus, and Fuchs’ heterochromic iridocyclitis, which result in fine stellate keratic precipitates, often throughout the whole cornea. Sarcoidosis and VKH may also result in keratic precipitates distributed above the midline but these keratic precipitates tend to be larger and greasier in appearance than those associated with Fuchs’ or herpetic iridocyclitis.

CILIARY BODY ABNORMALITIES

The pars plana of the ciliary body may be seen by indirect ophthalmoscopy with scleral depression. This is particularly important in cases of suspected pars planitis, where one may see “snowbanking” of inflammatory cells and neovascular membranes. The pars plicata of the ciliary body is more difficult to see, and the ultrasound biomicroscope may be used to provide information about its position and morphology. It may also be used to provide information about angle structures, ciliary body, and peripheral retina, particularly in patients without clear media.

Cyclitic membranes that form between the ciliary processes may lead to ciliary body detachment, hypotony, and phthisis bulbi. This process most frequently occurs in long-standing cases of iridocyclitis. Extension of the cyclitic membranes posteriorly may lead to tractional retinal detachment. These membranes may be difficult to detect. Sometimes they are seen in the retrolental space at the slit lamp but in other cases they are not seen clinically. Their presence may often be inferred because of profound hypotony that is unresponsive to anti-inflammatory therapy, and ultrasound biomicroscopy may be confirmatory.

FUNDUS ABNORMALITIES

Every patient with uveitis requires a complete fundus examination. Posterior foci inflammation or infection may be missed if one examines the anterior chamber only. For example, patients with cytomegalovirus retinitis or toxoplasmic retinochoroiditis may present with anterior chamber inflammation. If a complete dilated fundus examination is not performed, the patient may be misdiagnosed as having noninfectious iritis or iridocyclitis. Indirect ophthalmoscopy is necessary to see the peripheral retina. The macula should also be examined with slit-lamp biomicroscopy in all patients with uveitis because cystoid macular edema is a frequent cause of decreased vision in patients with anterior, intermediate, and posterior inflammation. It should be suspected in cases where visual acuity is decreased, even when the macula does not appear grossly edematous. Fluorescein angiography is a helpful adjunct to clinical examination, especially in cases with a compromised view of the fovea. Other causes of decreased visual acuity in patients with uveitis include epiretinal membranes and subretinal neovascularization. It is important not to overlook these findings because laser or surgical therapy may improve prognosis.

Examination of the posterior segment of the eye must also include an examination of the optic nerve head. Disc edema or hyperemia is frequent in uveitis patients, often preceding the development of macular edema. Neovascularization of the disc is another abnormality that may develop in patients with severe uveitis. The optic nerve head may also be a site of granuloma formation (Fig. 12).

Fig. 12 Large optic nerve head granuloma in a patient with sarcoidosis. Note the areas of periphlebitis.

Fig. 13 Fundus photograph of the right eye of a patient with cytomegalovirus retinitis and extensive “frosted branch angiitis.” The active cytomegalovirus retinitis is temporal to the fovea and along the superotemporal arcade.

The retinal vessels should be examined for evidence of vasculitis, noting whether the vasculitis affects primarily the veins (phlebitis) or the arteries (arteritis). Patients with sarcoid uveitis commonly have extensive periphlebitis, whereas patients with Behcet’ss disease may have more of an arteritic picture. Patients with herpetic retinitis may have extensive arteritis and phlebitis, which produce the appearance of “frosted branch angiitis” (Fig. 13).

Examination of the fundus also includes an evaluation of the choroid because choroidal lesions are seen in many infectious and noninfectious uveitides. They may range in size from small Dalen-Fuchs–like nodules to large patches of choroidal infiltration, as seen in large-cell lymphoma. Choroidal granulomas may resolve, leaving “punched-out” atrophic lesions, such as the peripheral spots seen in the ocular histoplasmosis syndrome.

A good history and clinical examination are invaluable in patients with uveitis. They are necessary for the development of a differential diagnosis and cannot be replaced by a barrage of nondirected laboratory tests. Once a good history has been elicited — including ocular and extraocular symptoms — and a detailed clinical examination performed, a rational differential diagnosis can be formulated and a directed work-up obtained.