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Iridocorneal Endothelial Syndrome

Sarwat Salim, MD, FACS and M. Bruce Shields, MD

Iridocorneal endothelial (ICE) syndrome represents a spectrum of disease, comprising 3 clinical variations: Chandler’s syndrome, progressive iris atrophy, and Cogan-Reese syndrome. These 3 variants, initially described separately and with distinct clinical manifestations, have been shown by histopathological and ultrastructural studies to be linked by a fundamental defect of the corneal endothelium. The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Clinically, anterior segment changes are most notable, affecting the cornea, anterior chamber angle, and iris. The progressive nature of this disease is associated with a high incidence of visual loss, either from corneal decompensation or refractory glaucoma, frequently requiring surgical intervention with variable success rates.

HISTORY AND TERMINOLOGY

There were several isolated case reports in the late 19th century of patients with extreme iris atrophy and associated glaucoma, but it was the paper by Harms in 1903¹ that led to our current understanding of the condition that has been called essential iris atrophy or progressive essential iris atrophy. In 1956, Chandler² reported cases that were similar but differed by having less severe iris atrophy and more frequent corneal edema, which often occurred with intraocular pressures (IOPs) that were normal or only slightly elevated. In all of his cases, Chandler noted an abnormality of the corneal endothelium that he described as having a fine, hammered silver appearance. The condition became known as Chandler’s syndrome.

Given the similar clinical features and associated secondary angle-closure glaucoma in patients with either essential iris atrophy or Chandler’s syndrome, Chandler and Grant³ concluded, in the first edition of their textbook, that the 2 conditions are likely variations of a spectrum of disease.

In 1969, Cogan and Reese⁴ described 2 patients with pigmented nodules of the iris. Malignant melanoma was suspected, and the eyes were enucleated, but the nodules were found to be benign, composed of tissue resembling that of the iris stroma.

Subsequent studies revealed that these nodules may occur on the surface of the iris in association with the other changes seen with essential iris atrophy and Chandler’s syndrome, and this condition be came known as Cogan-Reese syndrome.

Continued study of these 3 conditions revealed the common denominator of a characteristic abnormality of the corneal endothelium, which may lead to corneal edema, progressive closure of the anterior chamber angle with associated glaucoma, and the spectrum of iris abnormalities. Scheie and Yanoff⁵ described a fourth condition with flat nevi on the surface of the iris that they called the iris nevus syndrome, and lumped it with Cogan-Reese syndrome as a single entity. However, the iris lesions in the 2 conditions are distinctly different, and the iris nevus syndrome has not been shown to have the corneal endothelial abnormality, as with the other 3 conditions.

Eagle and associates⁶ suggested the term ICE syndrome, and this has now become the most commonly used term for the spectrum of disease, which includes essential iris atrophy, Chandler’s syndrome, and Cogan-Reese syndrome. Because atrophy of the iris is neither an essential nor fundamental aspect of these disorders, the term progressive iris atrophy may be preferable for the first of these 3 clinical variations. In any case, Chandler and Grant were correct in believing that these conditions do represent a broad spectrum of ocular disease.

ICE syndrome is typically a unilateral disorder that usually manifests in early to middle adulthood with a predilection for women, although bilateral involvement and its occurrence in a child have been reported.7–10 In some cases, subclinical abnormalities of the corneal endothelium may be seen in the asymptomatic fellow eye.^11–13 Kupfer and colleagues¹³ also demonstrated decreased aqueous outflow facility without IOP elevation in the contralateral eye of 4 out of 6 patients with ICE syndrome. Familial cases are rare, and there is no consistent association with systemic diseases, although an isolated case was recently described with progressive iris atrophy and sensorineural deafness.¹⁴ The report¹⁴ suggested reevaluation of the neural crest hypothesis (discussed in “Differential Diagnosis”) as an etiological association for these findings with abnormal proliferation and degeneration of undifferentiated neural crest-derived cells in the cornea, iris, and superior cervical ganglion, with the latter causing microcirculation dysregulation of the internal ear.

In a study of 37 consecutive cases of ICE syndrome, approximately half were Chandler’s syndrome, while the other 2 clinical variations each accounted for about one-fourth of all cases.¹⁵ Chandler’s syndrome was characterized by more severe corneal edema, even though the glaucoma tended to be less severe than in the other 2 variations. However, another study¹⁶ reported a higher incidence of elevated IOP in Chandler’s syndrome and reported similar response to treatment among different variants.

ICE syndrome has been described in different ethnic groups, although the prevalence of the 3 clinical variations may vary among ethnicities. For example, Cogan-Reese syndrome has been reported to be the most common form of ICE syndrome in a Thai population, with other characteristics of the spectrum being similar to the White population, including age of onset and gender predilection.¹⁷ This article also described a clinically discernible translucent membrane by slit-lamp examination on the dark irides.

A common presenting manifestation is the recognition of an abnormal shape or position of the pupil, which the patient may describe as a localized or diffused dark spot on the iris. Other patients may present with a chief complaint of reduced vision that is typically worse in the morning, due to the corneal edema that develops while the lids are closed during sleep, and which improves during the day as the cornea dehydrates with exposure to air. Corneal permeability and hydration control have been investigated in ICE syndrome in a few in vivo studies.^18,19 Reduced corneal swelling secondary to decreased endothelial permeability and slower deswelling responses have been demonstrated in eyes with ICE syndrome. Some patients may also present with pain, which is usually due to the corneal edema. Patients with more advanced disease may have persistent reduction in vision due to severe corneal edema or glaucomatous optic atrophy. Kocaoglan and colleagues²⁰ reported cystoid macular edema in a patient with Chandler’s syndrome and proposed increased levels of prostaglandin-like inflammatory mediators inducing cystoid macular edema, possibly secondary to a viral infection. The role of viral etiology in the pathogenesis of ICE syndrome will be discussed in detail in “Theories of Mechanism.”

Clinical examination of a patient with ICE syndrome typically reveals abnormalities of the cornea, ante rior chamber angle, and iris.

The corneal abnormality, which is a common feature throughout ICE syndrome, is seen by slit-lamp examination as a fine, hammered silver appearance of the posterior cornea, similar to that of Fuchs’ dystrophy, but less coarse (Figure 33-1). The cornea may be otherwise clear with no associated symptoms, or there may be corneal edema with variable degrees of reduced vision and pain, as noted previously. In some cases, islands of the endothelial abnormality may be seen in the fellow eye, which is other wise unaffected by the disease process.

Specular microscopy of the corneal endothelial cells reveals a characteristic, diffuse abnormality with variable degrees of pleomorphism in size and shape and loss of hexagonal margins. These abnormal cells also show dark-light reversal, with cell boundaries appearing bright and cell surfaces dark²¹ (Figure 33-2). These cells have been called ICE cells, and the tissue they form has been termed ICE tissue.²² In some cases, the cells cover the entire posterior cornea (total ICE), while in other eyes they are scattered throughout the cornea (disseminated ICE) or occur in areas that are sharply demarcated from endothelial cells that are normal, abnormally large (subtotal ICE minus), or abnormally small (subtotal ICE plus). In some cases, the focal area of abnormal cells may spread over time to eventually cover the entire cornea, although one case has been reported in which the abnormal cells disappeared almost entirely over a 10-year observation period.23

The typical anterior chamber angle abnormality, which is also common to all variations of ICE syndrome, is seen by gonioscopy as peripheral anterior synechiae that extend to or beyond Schwalbe’s line. These iridotrabecular adhesions are broad based and typically progress around the circumference of the angle, eventually leading to IOP elevation. Glaucoma occurs in approximately half of all patients with ICE syndrome. Most studies indicate that glaucoma is more severe and difficult to control in patients with progressive iris atrophy and Cogan-Reese variations, as opposed to those with Chandler’s syndrome.^15,17,24 However, Laganowski and colleagues¹⁶ reported both a higher prevalence of glaucoma in eyes with Chandler’s syndrome and similar response to treatment among different variants. The latter authors also correlated the occurrence of glaucoma with the specular microscopic appearance and found a greater prevalence of glaucoma when abnormal endothelial cells involved the entire posterior surface of the cornea (total ICE). In general, glaucoma is believed to be related to the angle closure in most cases of ICE syndrome, but it does not correlate precisely with the degree of synechial closure. It may be observed in eyes with entirely open angles due to the presence of a transparent Descemet’s-like basement membrane over the trabecular meshwork that is secreted by ICE cells, obstructing aqueous outflow.²⁵

The iris abnormalities constitute the primary basis for distinguishing the clinical variations within ICE syndrome. Progressive iris atrophy is characterized by marked atrophy of the iris, associated with variable degrees of corectopia and ectropion uvea (Figure 33-3). The latter 2 features are usually directed toward the quadrant with the most prominent area of peripheral anterior synechiae. The hallmark of progressive iris atrophy is hole formation of the iris, which occurs in 2 forms: stretch holes and melting holes.²⁶ With stretch holes, the iris is markedly thinned in the quadrant away from the direction of pupillary distortion, and the holes develop within the stretched area. Melting holes develop without associated corectopia or iris thinning, and fluorescein angiographic studies suggest that these holes are associated with iris ischemia.²⁶

In Chandler’s syndrome, there is typically minimal corectopia and mild atrophy of the iris stroma (Figure 33-4). In some cases, there may be no detectable change in the iris.

Intermediate variations may also occur in which the degree of corectopia and stromal iris atrophy is more extensive than that of typical Chandler’s syndrome, but the characteristic hole formation of progressive iris atrophy is lacking.

Eyes with Cogan-Reese syndrome may have any degree of iris atrophy, but are distinguished by the presence of pigmented, pedunculated nodules on the surface of the iris (Figure 33-5). The iris stroma surrounding the nodules is typically flat, with loss of the normal iris architecture. In some cases, other features of ICE syndrome may be present for many years before the nodules appear.

HISTOPATHOLOGIC FEATURES

Numerous ultrastructural and immunohistochemical studies have enhanced our understanding of the abnormal endothelial cells in ICE syndrome.^27–35 These cells display marked alterations in size, shape, and density. Abnormal intercellular junctions are noted, consistent with loss of contact inhibition and migratory features that these cells exhibit. Both metabolically active and necrotic cells have been demonstrated. Examination of the endothelial apical surfaces revealed presence of filopodial cytoplasmic projections and cytoplasmic actin filaments, indicative of cellular mitosis and migration.²⁸ Kramer and colleagues²⁹ demonstrated increased expression of cytokeratins in corneal endothelium, although another immunohistochemical study revealed no evidence of epithelial characteristics.³⁰ Hirst and colleagues,³³ in addition to demonstrating epithelial-like characteristics of ICE cells, also reported cross-reactivity with vimentin, suggesting that these cells retain some endothelial features as well. The abnormal ICE cells have been shown to secrete a basement membrane with multilayered collagenous tissue posterior to Descemet’s membrane^27,28 (Figure 33-6). Description of this cellular membrane differs among studies and may be related to the extent or stage of the disease at the time of examination. Compared to the 2 layers of normal Descemet’s membrane, additional layers are seen in eyes with ICE syndrome. In addition to a striated prenatal layer and a normal early postnatal layer, there is a thicker, nonstriated third layer that is formed postnatally and is composed of a variety of collagenous and noncollagenous material.^27,31 This pattern of membrane deposition supports an acquired etiology of this spectrum of disease. Occasional lymphocytes have been seen on or within the abnormal cellular layer.^28,30

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