Specular microscopy revealed a "hammered-silver" appearance of the posterior corneal surface.
Corectopia and ectropion uvea with minimal stromal iris atrophy in a patient with Chandler syndrome. A translucent membrane (between arrows) was visible on the corresponding hypochromic area obscuring iris crypts. Corneal edema reduced the photographic quality slightly.
Extensive iris atrophy with polycoria and ectropion uvea in a patient with progressive iris atrophy.
Clusters of pigmented iris nodules occurred only in the areas (presumably in the translucent membrane) that appeared hypochromic and had obscured iris details in a patient with the Cogan-Reese syndrome. The superotemporal iris defect is a surgical iridectomy.
Chaiwat Teekhasaenee, Robert Ritch. Iridocorneal Endothelial Syndrome in Thai PatientsClinical Variations. Arch Ophthalmol. 2000;118(2):187–192. doi:10.1001/archopht.118.2.187
To evaluate the spectrum of iridocorneal endothelial syndrome, to our knowledge, never studied previously in Orientals.
From 1986 to 1998, we examined 60 consecutive patients (20 men, 40 women) with characteristic signs of iridocorneal endothelial syndrome and compared the clinical manifestations to those reported in white patients.
Cogan-Reese syndrome (CRS) was most common (38 patients), while 14 patients had Chandler syndrome (CS), and 8 had progressive iris atrophy. Three patients initially classified as having CS and 1 as having progressive iris atrophy progressed to CRS. Glaucoma occurred in 46 patients (76.7%), most commonly in patients with progressive iris atrophy or CRS. Ten patients had slow progression of disease during the follow-up period of up to 12 years. Three patients (2 with CRS, 1 with CS) had asymptomatic localized islands of "hammered-silver" appearance and 11 (8 with CRS, 2 with CS, and 1 with progressive iris atrophy) had subclinical abnormal endothelium in the contralateral eyes. A translucent membrane was commonly seen on the brown iris surface. Total endothelial involvement was present in 49 patients, while 6 (4 with CRS, 2 with CS) had focal endothelial abnormalities with sharp demarcation from adjacent normal endothelium.
Iridocorneal endothelial syndrome occurs in Orientals. Cogan-Reese syndrome is the most common form and is strongly associated with glaucoma. Although several clinical manifestations were similar between whites and Orientals (mean age of onset, sex predilection, iris changes, peripheral anterior synechiae formation, or corneal edema), CRS was most prevalent; a translucent membrane were more noticeable in Orientals.
THE IRIDOCORNEAL endothelial (ICE) syndrome is characterized by extension or proliferation of corneal endothelium and Descemet membrane over the trabecular meshwork and onto the iris. Contraction of this membrane leads to distortion of iris structure. Blockage of the trabecular meshwork by membrane overgrowth or formation of peripheral anterior synechiae (PAS) by membrane contraction leads to secondary glaucoma. The ICE syndrome encompasses 3 clinical variations—Chandler syndrome (CS),1 progressive iris atrophy (PIA),2 and Cogan-Reese syndrome (CRS)3—that are believed to form a spectrum of disease manifestation.4- 6
The ICE syndrome has been reported preponderantly in whites, appears in early to middle adulthood, and affects women more frequently than men.7- 9 Among the previously published series in which race was indicated, no patient was Oriental, including a large series from San Francisco, Calif, where there is a large East Asian population (Table 1).10 A few cases have been reported from China11 and Japan.12 We describe the clinical variations of ICE syndrome in 60 Thai patients and compare them with previously published series of whites.
All 60 consecutive patients (20 men, 40 women) with clinical signs of ICE syndrome seen in the Department of Ophthalmology, Ramathibodi Hospital, Bangkok, Thailand, between July 1, 1986, and August 31, 1998, underwent complete ocular examination, including specular microscopy. Patients who had a history of ocular trauma or uveitis were excluded from the study. The diagnosis of ICE syndrome was made by the presence of a typical "hammered-silver" appearance of the posterior corneal surface (Figure 1), or corneal edema that precluded visualization of the posterior cornea, and characteristic iris stromal abnormalities. The patients were classified into 3 clinical variations based on iris changes.9 Chandler syndrome was diagnosed if there was minimal or mild stromal atrophy (Figure 2). Patients with extensive iris stromal atrophy and distortion with stretch and melting holes were diagnosed as having PIA (Figure 3). Those with iris nodules with any degree of iris stromal atrophy were diagnosed as having CRS (Figure 4).
Bilateral corneal endothelial photography was performed in 49 patients with sufficient corneal clarity using a specular microscope (model CSP 580; Konan, Tokyo, Japan). In addition, anterior segment and anterior chamber angle photography were performed periodically.
Complete slitlamp biomicroscopy, applanation tonometry, gonioscopy, and dilated ophthalmoscopy were performed to determine corneal edema, iris changes, intraocular pressure (IOP), and the extent of PAS. In some patients, severe corneal edema obviated assessment of PAS and performance of specular microscopy. The extent of PAS present on gonioscopy was graded as absent, mild (<90°), moderate (90°-180°), or extensive (>180°). Automated perimetry was performed in patients with sufficient visual acuity and corneal clarity. Because most of the patients had already been treated with antiglaucoma medications when first seen, initial pretreatment IOPs were unavailable. Previous and follow-up filtering surgical procedures or penetrating keratoplasty were recorded. Initial symptoms, age of onset, and medical and family histories were also recorded.
Fifty-one patients were followed up for 6 months to 12 years (mean ± SD duration of follow-up, 3.9 ± 3.1 years), while 9 patients were seen only on a single visit. Informed consent was obtained when indicated for diagnostic procedures and intervention. We compared our findings with those of similar referral-based white populations.7,9
We diagnosed 60 consecutive patients (20 men, 40 women) as having ICE syndrome. All were Orientals. Mean (±SD) patient age at the onset of symptoms was 43.7 ± 12.3 years (age range, 24-70 years) (Table 2). The right eye was involved in 26 patients; the left eye was involved in 34 patients. Other medical conditions included diabetes mellitus (2 patients), hypertension (2), hemorrhagic thyroid nodule (1), stroke (1), hyperthyroidism (1), and breast malignancy (1). Family history was noncontributory in all cases.
Initial complaints consisted of blurred vision, haloes, ocular pain and/or redness, or abnormal pupils. Originally 34 patients were diagnosed as having CRS, 17 as having CS, and 9 as having PIA. Three of the patients with CS and 1 with PIA developed iris nodules during follow-up and progressed to CRS. The final distribution for analysis was 38 patients with CRS, 14 with CS, and 8 with PIA. Patients in the 3 groups were similar to each other in age distribution (P = .34, analysis of variance) (Table 2).
A characteristic hammered-silver appearance of the posterior corneal surface was observed in all patients except for 11 who had corneal edema obscuring visualization. Specular microscopy revealed characteristic rounding of the endothelial cells and pleomorphism with intracellular dark areas. Forty-three patients had generalized endothelial abnormalities, while 6 (4 with CRS, 2 with CS) had localized islands of endothelial abnormalities with an abrupt demarcated border separating the adjacent normal areas of endothelium.
Corneal edema was present at the initial visit in 22 patients and was most common in CS (8 patients [57.1%]) (Table 2). Two patients with CRS and 1 with PIA developed corneal edema during follow-up. Eight patients required penetrating keratoplasty.
A translucent membrane with a distinct border was commonly visible on the anterior iris surface obscuring the iris crypts. The iris surface underneath the membrane appeared indistinct compared with the darker adjacent area (Figure 2).
Corectopia was present in 59 patients (13 with CS, 38 with CRS, and 8 with PIA). Patients with CS had slight pupil deviation while those with CRS and PIA had more severe displacement. The pupils generally deviated toward the site of the membrane and adjacent PAS. Ectropion uvea was present in 42 patients (5 with CS, 30 with CRS, and 7 with PIA). Its location usually corresponded to the direction of corectopia.
Iris stromal atrophy was mild or minimal in patients with CS and extensive in patients with PIA. Polycoria was present in all patients with PIA and 5 patients with CRS. The iris holes were usually opposite the direction of the corectopia.
Iris nodules in eyes with CRS were typically round or flat, irregular, hyperpigmented lesions and never pedunculated. They occurred in clusters within the area encompassed by the translucent membrane on the iris surface. The nodules were not present elsewhere on the iris surface.
Peripheral anterior synechiae were observed in 56 patients at the initial visit. Two patients with CS did not have PAS and 2 with CRS had corneal edema obscuring the view. The synechiae were broad and extended anteriorly to the Schwalbe line and were visible with conventional slitlamp examination. Peripheral anterior synechiae in patients with focal endothelial abnormality occurred in areas adjacent to the abnormal endothelium. Peripheral anterior synechiae more than 180° in extent occurred more frequently in patients with CRS (22 patients) and PIA (5 patients) than in patients with CS (4 patients) (Table 3).
Elevated IOP with or without glaucomatous cupping and/or visual field damage occurred in 46 patients. One patient with CS and focal endothelial changes slowly developed progressive PAS from less than 90° to greater than 180° during the 11 years of follow-up. Iris nodules developed at year 4 and elevated IOP at year 11.
Among patients with elevated IOP, the condition of 14 was controlled medically and 32 required filtering surgery. Patients with CRS needed filtering surgery more often than those with CS or PIA.
Automated perimetry performed in 37 patients with sufficient visual acuity and corneal clarity revealed intact visual fields in 21 and typical glaucomatous damage in 16. Visual field defects occurred most frequently in patients with CRS (36.8%) and less frequently in patients with CS (14.3%).
Ten patients (3 with CS, 6 with CRS, and 1 with PIA) had slow progression of the disease during the follow-up period of up to 12 years. Minimal changes were noted in corneal edema, PAS, and glaucoma during the follow-up period. None had spontaneous resolution. Their mean age and follow up were 40 ± 8.6 years (mean age, 27-58 years) and 7.2 ± 2.6 years (mean follow-up, 3.4-11 years), respectively. Five patients had glaucoma while the others did not. Among the 5 patients with glaucoma, the conditions of 2 were medically controlled and 3 had undergone trabeculectomy. Nine of the 10 patients had total endothelial abnormalities and 1 had focal changes.
One patient with CRS developed extensive iris progression following uncomplicated glaucoma filtering surgery. One patient with PIA who did not have glaucoma developed an ipsilateral idiopathic macular hole.
One patient with CRS had optic neuritis and 1 with CS had ocular hypertension in the contralateral eyes without iris abnormalities or PAS. Two patients with CRS and 1 with CS had asymptomatic localized islands of hammered-silver appearance. Specular microscopy revealed irregular, enlarged, and distorted endothelial cells (typical of ICE cells) in these focal areas. In addition, 8 patients with CRS, 2 with CS, and 1 with PIA had an increase in endothelial pleomorphism by specular microscopy but no noticeable iris abnormalities or PAS.
A significant difference exists in the distribution of the disease between the eyes of Orientals and whites (P <.001, Fisher exact test) (Table 4). While CS is the most common variant in whites,7,9 CRS was most prevalent in Thai patients. Progressive iris atrophy has the least prevalence in both populations. A translucent membrane was distinctly noticeable in 80% (48 of 60) of the eyes of our patients with dark brown irides who had sufficient corneal clarity to view the iris surface in detail. To our knowledge, this sign has not been previously reported. No significant differences were noted for mean age of onset, sex predilection, iris changes, PAS formation, or corneal edema. In both races, CRS has a higher prevalence of glaucoma development and visual field defects.
An endothelial abnormality is believed to be the primary event of the pathogenesis of the ICE syndrome accounting for all aspects of the disease.4,13 The abnormal endothelial cells may either derive from neural crest tissue14 or represent an epithelial-like metaplastic transformation.15,16 The abnormal endothelium leads both to corneal edema and to the proliferation of the corneal endothelium and Descemet membrane across the anterior chamber angle and onto the iris surface. Contraction of this membrane results in PAS formation with associated glaucoma, corectopia, and ectropion uveae. Stretching of the iris in the opposite direction to the corectopia accounts for iris atrophy and hole formation. In addition, this membrane may be responsible for the development of iris nodules, possibly by pinching off portions of the iris stroma.17,18
In our patients, CRS occurred most frequently. In dark brown irides, the endothelial Descemet membrane was clinically discernible using slitlamp biomicroscopy. The iris surface structure and crypts were obscured by the membrane and the covered areas appeared hypochromic compared with the adjacent areas with an abrupt junction. To our knowledge, this finding has not been previously noted. As mentioned earlier, the iris nodules histologically are areas of iris stroma containing pigmented melanocytes extruding through the holes in the membrane. Darker irides contain more melanin pigment granules in the superficial stromal melanocytes than do lighter irides. More densely pigmented iris stroma may be more easily visible clinically.
Eyes with CS, the most common form of ICE syndrome in the white population, tend to have a lower IOP and a greater tendency to develop corneal edema than eyes with CRS or PIA. Our patients with CS also developed corneal edema more frequently than those with CRS or PIA.
Because the reported series were studied in glaucoma clinics, there could have been referral bias. Although PIA is more readily diagnosed than the CS or CRS, it has the lowest prevalence in both our study and the study of Wilson and Shields.9 The study of Shields et al7 was a retrospective study and classification criteria then had not been definitively established. They divided the syndrome into only 2 entities—CS (55) and PIA (27)—noting in their "Discussion" section that among the total 82 patients, 9 were noted to have iris nevus-CRS.
Although the ICE syndrome has been described as a unilateral condition, subclinical mild to moderate pleomorphism of the corneal endothelium in the contralateral eye was present in 14 of our patients. Three had characteristic islands of endothelial abnormalities with an abrupt junction from adjacent endothelium. Subclinical endothelial abnormalities in the contralateral eye14,19- 21 or patients with bilateral involvement14,22- 24 have been reported. It remains unanswered whether these endothelial changes represent preexisting abnormalities that will lead to development of the disease or whether ICE is a bilateral disease.
Two patients had ocular hypertension and papillitis in the contralateral eye in the absence of PAS or of endothelial or iris abnormalities. One of our patients with PIA who did not have glaucoma developed an ipsilateral idiopathic macular hole. Because the ocular changes were inconsistent, no association could be made and they may merely represent coincidental findings.
Partial or focal corneal involvement with an abrupt junction between the normal endothelial and ICE cells has been described.9,25 Wilson and Shields9 examined 12 patients with focal endothelial involvement and found no correlation between the location of the focal endothelial abnormalities and the PAS. Six patients (4 with CRS, 2 with CS) of our patients had focal endothelial changes with a demarcating junction. However, they developed PAS with corresponding corectopia and ectropion uvea only in the areas adjacent to the abnormal endothelium.
Reports of prevalence of glaucoma in eyes with ICE syndrome range from 46% to 82%.7,9,20,26 The prevalence of elevated IOP was similar in CS and PIA and higher in CRS.9 However, another study reported the greatest prevalence of IOP elevation in CS.26 Although glaucoma in CS was reported to be less severe and easier to manage by most investigators,5,9,27 another study did not confirm this finding.26
Glaucoma occurred in 46 (76.7%) of our 60 patients. Cogan-Reese syndrome and PIA appeared to have more extensive PAS formation and glaucoma than CS. Visual field defects occurred most frequently in CRS (36.8%) and a greater proportion of patients with CRS required filtering surgery.
A study reported the success of additional surgery in ICE syndrome to be comparable to those of initial surgery in patients with primary open-angle glaucoma.28 Early surgical intervention after IOP has been normalized as much as possible with medicine has been suggested.26 However, 1 of our patients developed an extensive change of the iris following an uncomplicated trabeculectomy. It is possible that surgical trauma may aggravate the disease.
Ten of our patients, 5 of whom had glaucoma, had a slow clinical course during follow-up with minimal changes in corneal edema, PAS, and glaucoma. Among the 5 with glaucoma, the conditions of 2 were controlled medically and 3 had undergone trabeculectomy. Nine had total endothelial abnormalities and 1 had focal changes. It seems that the disease becomes latent or goes into remission regardless of the initial severity. Bourne and Brubaker29 described a patient who had spontaneous resolution of corneal edema and endothelial abnormalities. However, none of our patients had resolution of the iris or specular microscopic changes. Herpes simplex viral DNA detection was reported30 in the ICE syndrome. As in other herpes simplex virus infection, it is possible that our 10 patients are in the inactive or latent stage of the natural course of herpetic diseases.
In summary, ICE syndrome in Oriental eyes, which, to our knowledge, have never been reported in the American literature, does exist. Although most clinical and specular microscopic findings were similar to those reported in whites, a translucent membrane was distinctly noticeable in Oriental eyes with darker (brown) irides, and CRS seemed to be the most common variant with a strong association with glaucoma.
Accepted for publication August 5, 1999.
This investigation was supported in part by The Ramathibodi Foundation, Bangkok, Thailand, and the Brooke and Margaret Tunstall Research Fund of the New York Glaucoma Research Institute, New York.
Presented in part at the Annual Meeting of the American Academy of Ophthalmology, San Francisco, Calif, October 26, 1997.
Reprints: Chaiwat Teekhasaenee, MD, Department of Ophthalmology, Ramathibodi Hospital, Rama VI Rd, Bangkok 10400, Thailand (e-mail: firstname.lastname@example.org).