By Sarwat Salim, MD, FACS, and M. Bruce Shields, MD
Edited by Ingrid U. Scott, MD, MPH, and Sharon Fekrat, MD
This article is from October 2011 and may contain outdated material.
Iridocorneal endothelial (ICE) syndrome comprises a spectrum of three clinical variations: Chandler syndrome, progressive iris atrophy and Cogan-Reese syndrome. Although initially described separately and with distinct clinical manifestations, these variants are linked by a fundamental defect of the corneal endothelium as shown by histopathologic and ultrastructural studies. This acquired disorder is usually unilateral and affects predominantly women in early to middle adulthood, although bilateral cases and occurrence in a child1 have been reported.
Visual loss associated with ICE syndrome usually is secondary to either corneal decompensation or refractory glaucoma, which frequently requires surgical intervention that has variable success rates.
Clinical Features
Distinguishing clinical features of ICE syndrome are as follows.
Symptoms. A common presenting complaint is an acquired abnormality of the shape or position of one pupil. Some patients with ICE syndrome report reduced vision, which is typically worse in the morning because of corneal edema that develops when the eyelids are closed during sleep and improves during the day as the cornea dehydrates with exposure to air.
Signs. Clinical examination of a patient with ICE syndrome usually reveals abnormalities of the cornea, anterior chamber angle and iris. The typical corneal abnormality in 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. On specular microscopy, corneal endothelial cells are reduced in number and reveal variable degrees of pleomorphism in size and shape, with loss of hexagonal margins. These abnormal cells also show dark-light reversal, with cell boundaries appearing bright and cell surfaces dark (Fig. 1). These cells are sometimes called “ICE cells,” and the tissue they form, “ICE tissue.”
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 may extend anterior to Schwalbe’s line (Fig. 2). These iridotrabecular adhesions are broad based and typically progress gradually around the circumference of the angle, eventually leading to angle closure and IOP elevation.
Differences in iris abnormalities are the primary means of distinguishing among the clinical variations of ICE syndrome:
- Chandler syndrome usually presents with corneal edema and minimal iris alterations. Although it is the most common ICE variant, it often is not recognized initially by clinicians. Intermediate variations may also occur, in which the degree of corectopia and stromal iris atrophy is more extensive than in typical Chandler syndrome, but the characteristic full-thickness hole formation of progressive iris atrophy is lacking.
- Progressive iris atrophy is characterized by marked atrophy of the iris, associated with variable degrees of corectopia and ectropion uveae. The hallmark of progressive iris atrophy is hole formation in the iris, which occurs in two forms: stretch holes and melting holes. Stretch holes result from thinning of the iris in the quadrant away from the direction of pupillary distortion (Figs. 3 and 4). Melting holes develop without associated corectopia or iris thinning. Fluorescein angiographic studies suggest that these holes are associated with iris ischemia.
- Cogan-Reese syndrome is characterized by any degree of iris atrophy, but the predominant feature is the presence of multiple, pigmented, pedunculated iris nodules (Fig. 5). These nodules are composed of tissue resembling iris stroma and often are surrounded by endothelial tissue. In some cases, other features of ICE syndrome may be present for many years before the nodules appear.
In their classic presentation, the three variations can be readily differentiated. However, given the progressive course of this disease, it is sometimes difficult to distinguish clearly among them, as clinical manifestations may change at various stages of the disease.
Mechanism
The underlying mechanism linking all three variants is an abnormality of the corneal endothelium. As previously mentioned, the endothelial cells are diminished in number, become pleomorphic and show dark-light reversal. The endothelial cells acquire characteristics of epithelial cells, such as the presence of desmosomes, intracytoplasmic filaments and microvilli. These abnormal cells then migrate to adjacent structures, including the iris and trabecular meshwork.
These altered endothelial cells also have been shown to secrete an abnormal basement membrane, similar to Descemet’s membrane. Contraction of this basement membrane leads to iris changes, iridotrabecular synechiae and secondary angle-closure glaucoma.2
Etiology
Although the mechanism is well established for the changes in the anterior chamber angle and iris, the precise etiology of ICE syndrome remains unclear. A history of iridocyclitis in some afflicted eyes and the presence of inflammatory cells in corneal specimens have led some researchers to postulate a viral etiology. For instance, serologic studies in patients with ICE syndrome suggest, but have not proved, an etiologic role for the Epstein-Barr virus.
More compelling evidence suggests that herpes simplex virus (HSV) may play a vital role in the pathogenesis of ICE syndrome. Evidence from primer pair and polymerase chain reaction (PCR) methods has revealed the presence of HSV DNA within the endothelium in corneal specimens of ICE syndrome patients. This finding was absent in normal corneas and in corneas from patients with three other chronic corneal diseases (aphakic bullous keratopathy, interstitial keratitis and keratoconus).3
In addition, corneal specimens yielded negative results for HSV after the endothelial layer was removed in eyes with ICE syndrome.
Differential Diagnosis
Several other disorders of the cornea and iris, many of which are associated with glaucoma, may be confused with ICE syndrome.4
Corneal disorders. The two main differential diagnoses for corneal endothelial disorders are posterior polymorphous dystrophy (PPMD) and Fuchs endothelial dystrophy. Patients with PPMD may exhibit an irregular pupil, iris changes and alterations in the anterior chamber angle that resemble ICE syndrome, but careful analysis of the specular microscopy findings noted above helps differentiate the two entities. Moreover, PPMD is a bilateral disorder with autosomal dominant inheritance. The corneal endothelial changes of Fuchs endothelial dystrophy more closely resemble those of ICE syndrome, but patients with Fuchs do not have the anterior chamber angle or iris features seen in ICE syndrome.
Iris disorders. Iris disorders that could be confused with ICE syndrome include Axenfeld-Rieger syndrome, aniridia and iridoschisis. Of these, Axenfeld-Rieger syndrome has striking clinical and histopathologic similarities to ICE syndrome but differs in being bilateral and congenital. The clinical findings in Axenfeld-Rieger syndrome usually are stationary, although some progression may be seen over time. In addition, the iris and angle alterations in Axenfeld-Rieger syndrome are due to retention and contraction of a primordial endothelial layer, whereas changes in ICE syndrome are secondary to migration and subsequent contraction of abnormal corneal endothelial cells. Nodular lesions of the iris that could be confused with Cogan-Reese syndrome include iris melanoma and Lisch nodules, seen in neurofibromatosis, as well as inflammatory nodules of granulomatous uveitic conditions such as sarcoidosis.
Glaucoma
Glaucoma occurs in approximately half of patients with ICE syndrome. Most studies indicate that glaucoma is more severe and difficult to control in those patients who have the progressive iris atrophy or Cogan-Reese variations than in those with Chandler syndrome. Some investigators have correlated the occurrence of glaucoma with specular microscopic appearance and have found a greater prevalence of glaucoma when abnormal endothelial cells involve the entire posterior surface of the cornea.5
The mechanism of glaucoma in ICE syndrome is believed to be related to the cellular membrane. Although the anterior chamber angle appears grossly normal early in ICE syndrome due to the presence of this transparent membrane, progression of the disease over time may result in contraction of the abnormal basement membrane and formation of peripheral anterior synechiae. These often extend to Schwalbe’s line, obstructing aqueous outflow and culminating in secondary angle-closure glaucoma.
Treatment
Management of glaucoma is often challenging in eyes with ICE syndrome.
Medical approaches. Medical therapy for glaucoma usually is initiated with aqueous suppressants, but it often fails. Miotics usually are ineffective, and the role of hypotensive lipids has not been fully explored in these eyes.
Surgical approaches. Laser trabeculoplasty is ineffective due to the structural alterations in the angle recess. Incisional surgery eventually is required in a high percentage of patients. The most commonly performed surgical procedure is trabeculectomy, which has success rates of 60 to 70 percent and 29 percent, respectively, at one and five years postoperatively.4,5 The success rates of glaucoma filtration surgery may be slightly better with the use of antifibrotic agents.5,6 In general, a higher failure rate after trabeculectomy is attributed to a younger patient population with excessive scarring. (As ICE affects people in early to middle adulthood, these patients tend to be younger than typical glaucoma patients.) Endothelialization with accumulation of an abnormal basement membrane in the ostium of a filtering bleb also causes late failures.
In one small series, aqueous drainage implants had favorable outcomes, but additional surgeries were required for revisions and tube repositioning.7 The study’s authors propose modifications in surgical technique to avoid the risk of occlusion or anterior migration of the tube from continued contraction of the abnormal endothelial membrane. Suggested modifications included longer distal tubes, curved course of the tube en route to the anterior chamber, and placement of the tube in the pars plana in pseudophakic eyes.
As with other forms of glaucoma, when IOP cannot be controlled with the more conventional therapies, cyclodestructive procedures, especially transscleral cyclophotocoagulation, may be beneficial.
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1 Salim, S. et al. J Pediatr Ophthalmol Strabismus 2006;43(5):308–310.
2 Campbell, D. G. et al. Am J Ophthalmol 1978;86(3):317–324.
3 Alvarado, J. A. et al. Arch Ophthalmol 1994; 112(12):1601–1609.
4 Salim, S. and M. B. Shields. “Pretrabecular Mechanisms of Intraocular Pressure Elevation,” in Mechanisms of the Glaucomas, ed. J. Tombran-Tink et al. (Totowa, N.J.: Humana Press, 2008), 83–97.
5 Laganowski, H. C. et al. Arch Ophthalmol 1992;110(3):346–350.
6 Doe, E. A. et al. Ophthalmology 2001;108(10):1789–1795.
7 Kim, D. K. et al. Ophthalmology 1999;106(5):1030–1034.
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Dr. Salim is associate professor of ophthalmology and director of the glaucoma service at the University of Tennessee, Memphis; Dr. Shields is professor and chairman emeritus of ophthalmology at Yale University.