Iridocorneal Endothelial Syndrome

Key Concepts

Iridocorneal endothelial syndrome (ICE) is a disorder of the corneal endothelium manifested by abnormal endothelial cell formation and a proliferating membrane that may overlie the endothelium, chamber angle, and iris.
The etiology of ICE syndrome is unknown, although viral associations have been reported.
ICE syndrome may present with any of three clinically noticeable forms: iris nodules (iris nevus and Cogan-Reese syndromes), corneal endothelial abnormality or edema (Chandler syndrome), or essential (progressive) iris atrophy.
ICE syndrome should be considered a unilateral disorder.
ICE syndrome is not hereditary.
ICE syndrome is noninflammatory.
ICE syndrome is progressive but variably so, from minimal over decades, to quickly.
Slit lamp biomicroscopy and gonioscopy are mainstays for detection, but specular microscopy and confocal microscopy are invaluable for diagnosis and follow-up.
Glaucoma is a significant problem, control of which usually determines the ultimate fate of vision, but surgical success with a filter or drainage device is possible.
Corneal edema may be successfully treated by endothelial or penetrating keratoplasty (PK).

History and Background

In the early part of the 20th century, several case reports described a curious disorder in which the iris underwent progressive atrophy. Patients presented with complaints of blurred vision or changes in the shape of the pupil, although, occasionally, the iris changes were first noted during a routine examination. In this unilateral condition in young adults, the iris underwent a change from mild eccentricity of the pupil and stromal atrophy to marked corectopia and complete iris hole formation. The pupil remained intact but was displaced toward the periphery where extensive peripheral anterior synechiae (PAS) were noted. The condition was called essential or progressive iris atrophy to denote the absence of an identifiable cause and its progressive nature. ^, ^, Glaucoma was a frequent finding in this disorder and was poorly controlled with medical treatment, although successful filtering operations were described. Later, the description of an abnormal corneal endothelium and the formation of iris nodules were added to the manifestations of essential (progressive) iris atrophy.

Chandler ^, reported a group of patients with abnormal corneal endothelium, described as a “hammered silver appearance,” and corneal edema that occurred at a normal or slightly increased intraocular pressure. Iris nodules and PAS were also described, with glaucoma as an associated finding. This unilateral, nonfamilial disorder came to be known as Chandler syndrome.

Cogan and Reese later described patients with many features in common with those described here. Most often, patients presented with blurred vision or reported noticing spots on the iris. Iris nodules and PAS were clinically the most noticeable part of this disorder. Glaucoma was invariably present. This condition was also nonfamilial and unilateral and came to be termed the Cogan-Reese syndrome.

Scheie and Yanoff reported a series of patients with unilateral glaucoma and iris changes that included heterochromia, ectropion uveae, PAS, and fine iris nodules. Corneal edema occurred at normal or slightly elevated intraocular pressure. Iris nevus cells diffusely infiltrated the anterior iris, which showed a blunted or effaced surface because of abnormal Descemet membrane extending across the chamber angle onto the anterior iris surface. This nonfamilial condition became known as the iris nevus syndrome.

Common threads running through all these conditions included a unilateral, progressive, noninflammatory, nonfamilial ocular disorder of young adulthood with abnormal corneal endothelium and PAS. Glaucoma, iris atrophy, and nodules were associated findings. Through the accumulated clinical and histopathologic reports, Campbell et al. concluded that an abnormality of the corneal endothelium with production of abnormal basement membrane was the common etiologic basis and unified these disorders. Because corneal endothelial and iris abnormalities were found in all entities, it was termed the iridocorneal endothelial syndrome (ICE syndrome). ^, This unifying hypothesis has been reviewed extensively and supported. Coincidentally, the acronym ICE also signifies commonly used names of these conditions—iris nevus syndrome, Chandler syndrome, and essential (progressive) iris atrophy.

The diagnosis of the ICE syndrome is considered when two of the three main clinical features are present unilaterally: typical iris changes, abnormal corneal endothelium, and PAS. ^, Because the common etiology and features of these disorders are accepted, as long as a patient is correctly diagnosed with ICE syndrome, labeling of the particular subtype is not necessary. It is still useful for descriptive purposes, however, to categorize the entities separately, since the presentation and clinical course may vary markedly among them ( Table 74.1 ).

TABLE 74.1

Iridocorneal Endothelial Syndrome: Clinical Variations

	Progressive (Essential) Iris Atrophy	Chandler Syndrome	Cogan-Reese Syndrome	Iris Nevus Syndrome
Main clinical feature	Marked iris atrophy; holes and corectopia	Corneal edema at normal or slightly elevated intraocular pressure	Pedunculated, pigmented iris nodules	Diffuse nevus or heterochromia of iris
Corneal endothelium abnormal (slit lamp or specular microscopy)	Yes, may be subclinical	Yes	Yes (not originally reported)	Yes
Corneal edema	Variable—late	Present—early	Present	Present
Peripheral anterior synechiae beyond Schwalbe line	Present	Present	Present	Present
Iris surface change	Present	Present	Present	Present
Iris atrophy	Marked	Minimal	Variable	Variable
Iris nodules	Present—late	Present—late	Present—early	Variable
Ectropion uveae	Present	Infrequent	Present	Present
Glaucoma	Present	Present	Present	Present
Pathogenesis	Abnormal endothelium and basement membrane proliferation	Abnormal endothelium and basement membrane proliferation	Abnormal endothelium and basement membrane proliferation	Abnormal endothelium and basement membrane proliferation
Heterochromia	Absent	Absent	Absent	Present

Clinical Features

Essential Iris Atrophy

Essential (progressive) iris atrophy, although described in childhood ^, and in teenage years, first presents typically in young adults, unilaterally, and in women more than men. The presenting symptoms are blurred vision or a noticeable change in the iris substance or pupil. It is also occasionally first observed during a routine eye examination. ^, ^, Rarely, pain is reported, but usually only in advanced cases with high intraocular pressure and corneal edema. ^,

The signs of the disorder are usually unmistakable, but vary from a spectrum of bare eccentricity of the pupil to severe corectopia. Iris atrophy and partial-thickness holes in the iris stroma appear on the side opposite the pupillary eccentricity, and, with continued stretch, full-thickness iris holes develop ( Fig. 74.1 ). Atrophic iris holes also develop in areas not affected by stretching and are attributed to ischemia. ^, ^, The underlying pathophysiologic event is an abnormal corneal endothelium, which produces abnormal basement membrane that extends beyond Schwalbe line, covering the anterior chamber angle and anterior iris surface ( Fig. 74.2 ). ^, ^, The abnormal basement membrane is referred to by various names in the literature: cuticular membrane, glass membrane, cellular membrane, hyaline membrane, and ectopic Descemet membrane. ^, ^, The multilayered collagenous tissue posterior to the Descemet membrane associated with abnormal endothelium has been demonstrated using electron microscopy ( Fig. 74.3 ). Contraction of this membrane draws the iris toward that side, resulting in corectopia and stretching atrophy in the opposite iris quadrant. Progressive PAS develop, which are usually seen anterior to Schwalbe line, resulting in progressive angle closure. Even in the absence of PAS, the angle may be functionally closed because of the presence of a clinically invisible membrane overlying the trabecular meshwork. ^, ^, Thus there may be no correlation between the degree of PAS and the level of intraocular pressure.

Fig. 74.1, ( A and B ) Iridocorneal endothelial syndrome. Essential (progressive) iris atrophy. Typical advanced iris changes of corectopia, thinning of iris, and stretch holes.

Fig. 74.2, Toluidine blue stain of corneal, anterior angle, and iris tissue in Chandler syndrome; light microscopy. Degenerating endothelial cells and pathologic basement membrane material on the posterior cornea (1) , causing peripheral anterior synechiae (2) , and on the iris surface (3) .

Fig. 74.3, Transmission electron micrograph of Chandler syndrome cornea. Degenerating endothelial cell (1) on pathologic basement membrane material (2) containing posterior banding (3) and extracollagenous material (4) .

The differences in growth and contracture of this endothelial derived membrane lead to a variable clinical presentation. If there is a 360-degree angle coverage and equal contraction, little corectopia and iris atrophy may be present, but loss of normal iris architecture is generally seen. Later in the clinical course, buds of normal iris stroma, seen as iris nodules, protrude through the membrane-lined iris surface. ^, ^, The nodules begin as fine, yellow, raised areas and progress from light to dark brown pedunculated forms. The normal architecture of the adjacent iris is lost, giving a flat, effaced surface.

Glaucoma, iris atrophy, or nodules may be seen relatively early or late, depending on the degree of endothelial proliferation and membrane formation in the anterior chamber angle. Corneal edema occurs, usually associated with elevated intraocular pressure, but it may occur early with widespread endothelial dysfunction. On slit lamp examination, the fine, hammered silver appearance of the endothelium described in Chandler syndrome is not always seen. A total endothelial abnormality may exist, detected only by specular microscopy or confocal microscopy. ^, ^,

Specular microscopy is an invaluable tool for early or confirmatory diagnosis. Although endothelial cell pleomorphism and a decrease in the percentage of hexagonal cells of the contralateral eye have been described, ^, typical morphologic specular microscopic changes (ICE cells) are unilateral. The following changes are usually seen in Chandler syndrome, but may be seen in any of the ICE syndrome patients. The endothelial mosaic may contain a typical ICE cell in which the hexagonal borders are lost, a light or dark area is seen within, and reversal of the usual normal light/dark pattern occurs. ^, Oval dark and light bodies within cell boundaries and smaller round structures with either a bright or dark appearance near cell centers are thought to be endothelial cell nuclei and blebs of the apical cell membrane. Epithelialization of the endothelial cells is thought to be the histologic correlate of the ICE cell seen on specular microscopy.

It must be emphasized, however, that the typical ICE cell is not necessary for the diagnosis in the presence of suspicious clinical findings (i.e., a solitary PAS or unilateral glaucoma in an otherwise normal eye ^, ), as many unilateral abnormal patterns on specular microscopy also may be seen. ^, Partial endothelial involvement and regression of the abnormal endothelium has been reported. ^, ^, Total cellular disorganization with no identifiable cells may be seen, even with a clinically clear and thin cornea ( Fig. 74.4 ). Patchy areas of diffuse endothelial disorganization or typical ICE cells abruptly adjacent to normal endothelium may occur. ^, Areas with increased cell density of smaller than normal endothelial cells ^, may represent the result of compaction or replication. ^, There appears to be no relation between duration of the disease and degree of endothelial abnormality, nor is there a correlation of the ICE cells and endothelial density with corneal edema. Single vesicular lesions, round doughnut-like elevations, and bands or ridges typical of posterior polymorphous dystrophy (PPMD) are not seen. ^, ^, Specular microscopy is generally very useful in distinguishing between ICE syndrome and PPMD, but may not always differentiate between progressive PPMD and ICE syndrome, which may share a final common pathologic progression.

Fig. 74.4, Top, Specular microscopic appearance of patient with iridocorneal endothelial (ICE) syndrome, showing total abnormality of endothelium. ICE cells are seen with dark/light reversal. The patient was asymptomatic, and the pachymetry was normal. Bottom , Contralateral normal eye of same patient.

Other diagnostic tools of great value in the diagnosis of ICE syndrome are ultrasound biomicroscopy (UBM) and in vivo confocal microscopy. They are especially helpful when corneal edema prevents gonioscopic view of the angles or specular microscopy. UBM has revealed PAS, iris atrophy, arborized shape of the iridocorneal angle, and closed angles.

Confocal microscopy has been of great use as an early diagnostic tool, and invaluable in cases with corneal edema. ^, Consistent findings are loss of regularity in size and shape, irregular or indistinct endothelial cell borders with bright hyperreflective nuclei, and prominent irregular corneal nerves. ^, There may be small cells or larger epithelioid-like cells detected. The highly disorganized cells mimic superficial epithelium. A transition between uniform cells with dark nuclei seen with confocal microscopy is consistent with patterns previously described with specular microscopy. In vivo confocal microscopy is especially useful to follow progression of cellular changes when edema precludes specular microscopy.

Aside from the unilateral presentation in the ICE syndrome, confocal microscopy also may not always be able to distinguish between ICE syndrome and PPMD. Epithelialization of the endothelium characteristic of PPMD has been reported in ICE syndrome, but endothelial cells retain their typical characteristics and lineage. ^, ^, ^,

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