Decreased Endothelial Permeability in the Iridocorneal Endothelial Syndrome

Decreased Endothelial Permeabili1y in the lridocorneal Endothelial Syndrome WILLIAM M. BOURNE, MD, RICHARD F. BRUBAKER, MD

Abstract: Five patients with the iridocorneal endothelial (ICE) syndrome were examined by fluorophotometry. All patients had typical abnormal corneal endothelium, peripheral anterior synechiae, and distortion of the iris (pupillary irregularity or anterior stromal traction tears) in one eye only. Fluorescein was deposited in the superior cornea of both eyes by iontophoresis, and the cornea and anterior chamber concentrations and total mass of fluorescein were measured hourly over the ensuing eight hours. In all five patients, the endothelial permeability to fluorescein was within normal limits in the normal eye. In four of the five abnormal eyes, endothelial permeability was markedly decreased. In these four patients, the permeability to fluorescein in the normal eye was approximately six times that in the abnormal eye. In the fifth patient, the endothelial permeability was normal in both eyes. The central corneal thicknesses were normal in both eyes of all five patients. These results indicate that in many eyes with the ICE syndrome, corneal endothelial permeability to solutes is markedly decreased. Decreased endothelial permeability to solutes has not been documented previously in any clinical corneal disorder and may be of importance in the pathophysiologic changes that accompany endothelial disease. [Key words: Chandler's syndrome, Cogan-Reese syndrome, endothelial permeability, essential iris atrophy, fluorophotometry, ICE syndrome, iris nevus syndrome.] Ophthalmology 89:591-595, 1982

The iridocorneal endothelial (ICE) syndrome is a nonfamilial, unilateral ocular disease characterized by abnormal corneal endothelial cells that are present on the surface of the iris as well as the cornea and cause progressive peripheral anterior synechiae. 1- 3 The ICE syndrome encompasses three ocular disorders that were described separately but appear to have the same etiology: essential iris atrophy, Chandler's syndrome ,4 and the Cogan-Reese iris nevus syndrome. s Corneal edema often develops in advanced ICE syndrome, alFrom the Department of Ophthalmology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.

though the cornea may remain clear for years with markedly abnormal endothelial cells. The permeability of the corneal endothelium to solutes is a measure of the barrier function of endothelial cells and can be determined by fluorophotometry. 6 An earlier study of abnormal endothelium due to early Fuchs' dystrophy (cornea guttata) documented increased endothelial permeability to fluorescein in that disorder. 7 In this study the endothelial permeability to fluorescein and anterior chamber fluorescein clearance in five patients with the ICE syndrome was measured.

Supported by NIH grants EY 02037 and EY 00634 and by the Mayo Foundation.

MATERIALS AND METHODS

Reprint requests to W. M. Bourne, MD, Mayo Foundation, 200 First Street Southwest, 901 Guggenheim Building, Rochester, MN 55901.

Five patients with the ICE syndrome had endothelial permeability and clearance rate measurements

0161-6420/82/0600/5911$00.75

© American Academy of Ophthalmology

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Fig 1. Central endothelium of affected eye of patient 1. The endothelial cells are enlarged and irregular with many dark (nonreflecting) areas.

with a clinical fluorophotometer 8 and endothelial photographs and pachymetry with a clinical specular microscope (Table 1). All five patients had abnormal corneal endothelium, peripheral anterior synechiae, and distortion of the iris (pupillary irregularity or anterior stromal traction tears) in one eye; the opposite eyes were normal. All five abnormal eyes had a typical endothelial appearance (Fig 1) of enlarged, irregular cells with dark (nonreflecting) areas within them (grade 3 as described by Hirst et al 9). Patients 1-4 had marked pupillary distortion. Large traction holes were present in the anterior iris stroma in patients 1 and 4 (Fig 2). Patient 5 had a round pupil, but a small traction tear in the anterior iris stroma was present near a prominent peripheral iridocorneal synechia. None of the patients had taken any ocular medications for at least a week prior to testing. Progression of the iridocorneal synechiae had been documented in patients 1-4; the fifth patient had been followed for only five months and no change had been noted. There was mild central band keratopathy in patient 4 and minimal corneal epithelial edema (bedewing) in patient 5. No other ocular abnormalities were noted. The visual acuity was 20/20 in four of the abnormal eyes and 20/25 in the fifth (patient 5). In a preliminary study of these patients, it was observed that an iontophoretically placed central depot of fluorescein 6,10 spread laterally but remained in the stroma for a prolonged time, interfering with the measurement of what appeared to be very low concentrations of fluorescein in the anterior chamber. For this reason, fluorescein was placed in the upper portion of the cornea in order to permit more accurate measurements of anterior chamber fluorescence from which endothelial permeability could be calculated. Both eyes of each subject, the normal eye and the abnormal eye, were studied in the same way. The fluorescence of the initial depot was measured in an 8-mm diameter field that did not include the sclera or the conjunctiva. The total fluorescence of the cornea and the anterior chamber were measured hourly in a 12-mm diameter field that was centered in the cornea and included a small strip of conjunctiva and sclera. The effect of scleral scatter on the measurement of fluorescence in the larger field was determined by comparing the measured fluorescent intensity in the smaller and the larger fields immediately after iontophoresis when all of the fluorescein was located in a circumscribed area approximately 5 mm in diameter. All subsequent measurements of fluores-

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cence in the larger area were corrected for this effect, although none of the total fluorescence measurements in the larger field were used to calculate endothelial permeability. The intensity of fluorescence was measured in the lower cornea and in the lower portion of the anterior chamber every hour. During these measurements, the subject was asked to look at a fixation target located 30° above the horizon. All measurements were corrected for background fluorescence. The volume of the anterior chamber was measured photogrammetrically. 11 The cornea to anterior chamber transfer coefficient (kea ) and the rate of clearance of fluorescein from the anterior chamber were calculated from the fluorescence measurements by the method ofleast squares on the assumption that the kinetics of topically applied fluorescein closely mimic the two-compartment model of Jones and Maurice. 10 The curve fitting procedure made use of all hourly anterior chamber concentrations and the initial fluorescence of the stromal depot as measured in an 8 mm field. The details of this method are described by Nagataki and Brubaker (Method 2).12 The endothelial permeability to fluorescein was calculated from kea using the following relationship6,13: Permeability = kea x CT/rae , where CT is the central corneal thickness and rae is the equilibrium distribution ratio between fluorescein in the anterior chamber and cornea, as determined by Ota et aP3 and by Sawa et al. 14

Fig 2. Photograph of the affected eye of patient 1. Note the progressive peripheral anterior synechiae at 1:00 and 9:00, causing pupillary irregularity and traction tears in the adjacent anterior iris stroma.

BOURNE AND BRUBAKER • ICE SYNDROME: ENDOTHELIAL PERMEABILITY

RESULTS The results of the measurements on all five patients with the ICE syndrome are shown in Table 1. The endothelial permeability was within normal limits in the normal eye of each patient (mean ± SD = 2.41 x 10- 4 ± 0.93 x 10-4 cm/min). In four of the five eyes with the ICE syndrome, endothelial permeability was markedly decreased (mean ± SD = 0.35 x 10-4 ± 0.16 x 10- 4 cm/min), lower than any of 113 normal patients tested by a similar technique. IS In patient 5 the endothelial permeability to fluorescein was within normal limits in both eyes. The intraocular pressure and the central corneal thickness, were within the normal ranges for these values in all ten eyes. The clearance ?f fluorescein from the anterior chamber was normal m most of the eyes, except perhaps for the involved eyes of patients one and two who exhibited rather large rates of clearance. These higher rates may have been due to losses of fluorescein into the posterior chamber. If so, the kinetics of such a loss would be likely to be first order, would conform to two-compartment model used, and would not have interfered with the calculation of the cornea to anterior chamber transfer coefficient. However, such a loss would interfere with the calculation of the rate of aqueous humor flow through the anterior chamber. As compared to the fellow eye, the rate of loss of fluorescein from the affected cornea was abnormally slow in cases 1-4 but normal in case 5. In these cases, the mass of fluorescein appearing in the stroma after a seven-second iontophoretic application was 263 ± 72 ng (mean ± SD) in the affected eyes and 227 ± 21 ng in the unaffected eyes. Eight hours later, 61% ± 11 % of the initial dose remained in the corneas of the affected eyes, but 28% ± 9% remained in the corneas of the unaffected eyes. In spite of the slow disappearance of fluorescein from these four affected corneas,the lateral diffusion of fluorescein in the stroma appeared normal as compared to the fellow eye.

DISCUSSION The calculation of endothelial permeability from topically applied fluorescein according to the meth-

od used in this study depends on accurate measurements of the time profile of anterior chamber concentrations of fluorescein. High concentrations of fluorescein in the cornea interfere with measurements of weak fluorescence in the anterior chamber because of internal reflections and scattering in the cornea.6.10.16 Our preliminary study demonstrated that the slow passage of fluorescein from the cornea to the anterior chamber reduced the signal-to-noise ratio for a centrally placed depot below acceptable levels and prompted us to place the fluorescein in the superior portion of the cornea as was done .by Jones and Maurice in their studies. lo With eccentnc placement of the depot, a clear measurement of the fluoresce!lce of the anterior chamber is possible, but a more rapId loss of fluorescein from the limbus, not considered in the two-compartment model, is likely. Jones and Maurice, however, have observed that central and eccentric placement produce almost identical results,lo an observation that we have confirmed in a group of five normal subjects in whom kca was measured in one eye with central placement (mean ± SD = 3.0 x 10-3 ± 0.6 x 10-3 min- I) and simultaneously in the fellow eye with eccentric placement (mean ± SD = 3.3 x 10- 3 ± 0.5 x 10-3 min- I).17 Furthermore, computer simultation of fluorescein movement in the cornea and anterior chamber suggests that eccentric placement of a 5-mm depot should predictably have little effect on the resultY Regardless of one's opinion about the role of direct limbal loss of fluorescein in this study, both eyes of all subjects were studied by the same t~ch­ nique, and limballoss per se could not have explamed the results. Failure of the depot to leave the stroma and enter the anterior chamber in the affected eyes of cases 1-4 could be explained by abnormal binding of fluorescein in the stroma. Fluorescein is known to concentrate in the normal stroma in vivo and in vitro. IO ,13,14,18,19 The fluorescent intensity in the stroma is 1.2-1.7 times the fluorescent intensity in the anterior chamber when these two compartments are in steady state. This characteristic distribution can be explained by the binding of fluorescein to albumin in the stroma. 17 ,20,21 In this study, we have not measured the distribution ratio but have calculated endothelial permeability from the value of the ratio found in normals. If abnormal bind-

Table 1. Iridocorneal Endothelial Syndrome: Patient Data Normal Eye

ICE Syndrome

Patient No.

Age (yrs)

1 2 3 4 5

34 36 40 57 60

Sex

Intraocular Pressure (mm Hg)

Corneal Thickness (mm)

Endothelial' Permeability (x 10' cm/min)

Clearance of Fluorescein from Anterior Chamber /LUmin

F F F F M

16 20 15 13 13

.55 .58 .57 .54 .56

.17 .27 .53 .42 4.03

6.09 5.33 1.68 2.10 2.48

, Calculated from the relation, permeability

~

(k" x corneal thickness)/r", where roo

~

Intraocular Pressure (mm Hg)

Corneal Thickness (mm)

Endothelial' Permeability (x lO' cm/min)

Clearance of Fluorescein from Anterior Chamber /LUmin

14 21 15 13 15

.54 .56 .57 .54 .52

1.86 2.28 1.43 3.88 2.60

2.37 4.49 1.60 3.58 1.69

0.64 (13).

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ing of fluorescein were to account for the results of the involved eyes of subjects 1-4, binding in the stroma would have had to be many times normal. Such a situation seems unlikely because abnormal binding of this degree would have greatly retarded lateral diffusion of the dye. On the contrary, lateral diffusion of the dye was readily observed in both eyes and the rate of spread appeared to be the same or even more rapid in the affected eyes. The number of subjects in this study is small. One subject was found to have a normal endothelial permeability in the affected eye. Could the permeabilities of the other four have been lower than their fellow eyes simply because of random measurement errors or because of normally occurring right to left differences between two fellow eyes? In our experience, the calculated endothelial permeability of the two corneas of a normal person are seldom identical when measured by the technique described by Coakes and Brubaker. 6 In a group of 30 normal patients, the mean ratio of measured permeabilities between the eye with the higher value and the eye with the lower value was 1.5 ± 0.4. The same ratio in subjects 1-4 ranged from 2.7 to 10.9. It seems likely therefore that these four corneas are abnormal and that the simplest explanation, which is consistent with all of the observations, is that the permeability of the endothelium to fluorescein in these four eyes is abnormally low. Decreased corneal endothelial permeability to fluorescein has not been reported previously in any clinical corneal disorder. This finding was unexpected, since ultrastructural studies of corneal endothelium in the ICE syndrome show attenuated or absent endothelial cells with poor junctional complexes , 1,2.22-26 suggesting increased, rather than decreased, permeability. The corneas in these studies, however, had all been subjected to chronic topical drug therapy or previous intraocular surgery, and may not be typical of the early ICE syndrome. A thickened, abnormal Descemet's membrane was present beneath the endothelial cells in these electron microscopic studies. Could the abnormal Descemet's membrane constitute a barrier to fluorescein movement, thus decreasing the endothelial permeability? This is unlikely, since similar changes in Descemet's membrane are seen in early Fuchs' dystrophy, 27 where the endothelial permeability is increased rather than decreased. 7 Patient 5 did not have decreased endothelial permeability in his affected eye. There are some possible explanations for this discrepancy. First, his cornea may have been in a more advanced stage of the ICE syndrome than those of the other four patients. By specular microscopy, however, his endothelial cells were not more abnormal than those of the other four patients. Second, the wide spectrum of the ICE syndrome may include corneas that do not develop decreased endothelial permeability. Third, patient 5 may not actually have the ICE syndrome, but rather a different endothelial abnormality such as posterior

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polymorphous dystrophy, which in this case would be manifest in only one eye. Decreased permeability to fluorescein may mean decreased permeability to metabolites such as glucose. Since the corneal epithelium depends upon the aqueous humor for its supply of glucose,28.29 epithelial nutrition and metabolism may be impaired in the ICE syndrome. This could explain epithelial edema in the presence of normal intraocular pressure and normal central corneal thickness. Normally, epithelial edema does not occur in the absence of elevated intraocular pressure until the corneal thickness has increased approximately 30%.30.31

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