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Part vii

Diseases of the Cornea

Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations

Chapter 73
Iridocorneal Endothelial Syndrome
Emmett F. Carpel

anterior synechiae (PAS) were noted.6 The condition was


Key Concepts called essential or progressive iris atrophy to denote the
absence of an identifiable cause and its progressive nature.2,4,5
Iridocorneal Syndrome (ICE) is a disorder of the corneal Glaucoma was a frequent finding in this disorder, and was
endothelium manifested by abnormal endothelial cell poorly controlled with medical treatment, although success-
formation and a proliferating membrane that may ful filtering operations were described.3 Later, the description
overlie the endothelium, chamber angle, and iris. of an abnormal corneal endothelium and the formation of
The etiology of ICE syndrome is unknown, although iris nodules were added to the manifestations of essential
viral associations have been reported. (progressive) iris atrophy.711
ICE syndrome may present with any of three clinically Chandler10,12 reported a group of patients with abnormal
noticeable forms: iris nodules (iris nevus and Cogan corneal endothelium, described as a hammered silver
Reese syndromes), corneal endothelial abnormality or appearance, and corneal edema that occurred at a normal
edema (Chandler syndrome), or essential (progressive) or slightly increased intraocular pressure. Iris nodules and
iris atrophy. PAS were also described, with glaucoma as an associated
ICE syndrome should be considered a unilateral finding. This unilateral, nonfamilial disorder came to be
disorder. known as Chandler syndrome.
ICE syndrome is not hereditary. Cogan and Reese13 later described patients with many
ICE syndrome is progressive but variably so, from features in common with those described here. Most often,
minimal over decades, to quickly. patients presented with blurred vision or reported noticing
Slit lamp biomicroscopy and gonioscopy are mainstays spots on the iris. Iris nodules and PAS were clinically the
for detection, but specular microscopy and confocal most noticeable part of this disorder. Glaucoma was invari-
microscopy are invaluable for diagnosis and follow-up. ably present. This condition was also nonfamilial and uni-
Glaucoma is a significant problem, control of which lateral and came to be termed the CoganReese syndrome.
usually determines the ultimate fate of vision, but Scheie and Yanoff14 reported a series of patients with uni-
surgical success with a filter or drainage device is lateral glaucoma and iris changes that included heterochro-
possible. mia, ectropion uveae, PAS, and fine iris nodules. Corneal
Corneal edema may be successfully treated by edema occurred at normal or slightly elevated intraocular
endothelial or penetrating keratoplasty. pressure. Iris nevus cells diffusely infiltrated the anterior iris,
which showed a blunted or effaced surface because of abnor-
mal Descemet membrane extending across the chamber
angle onto the anterior iris surface. This nonfamilial condi-
tion became known as the iris nevus syndrome.
History and Background Common threads running through all these conditions
included a unilateral, progressive, nonfamilial ocular disor-
In the early part of the twentieth century, several case reports der of young adulthood with abnormal corneal endothelium
described a curious disorder in which the iris underwent and peripheral anterior synechiae. Glaucoma, iris atrophy,
progressive atrophy.16 Patients presented with complaints of and nodules were associated findings. Through the accumu-
blurred vision or changes in the shape of the pupil, although lated clinical and histopathologic reports, Campbell etal.11
occasionally the iris changes were first noted during a routine concluded that an abnormality of the corneal endothelium
examination. In this unilateral condition in young adults, with production of abnormal basement membrane was the
the iris underwent a change from mild eccentricity of the common etiologic basis and unified these disorders. Because
pupil and stromal atrophy to marked corectopia and com- corneal endothelial and iris abnormalities were found in all
plete iris hole formation. The pupil remained intact, but was entities, it was termed the iridocorneal endothelial syn-
displaced toward the periphery where extensive peripheral drome (ICE syndrome).8,1517 This unifying hypothesis has

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CHAPTER 73
Iridocorneal Endothelial Syndrome

Chapter Outline
History and Background
Clinical Features
Etiology
Clinical Course
Differential Diagnosis
Management
Summary

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CHAPTER 73
Iridocorneal Endothelial Syndrome

Table 73.1 Iridocorneal endothelial syndrome: clinical variations

Progressive (essential) Chandler syndrome Cogan-Reese Iris nevus syndrome


iris atrophy syndrome

Main clinical feature Marked iris atrophy; holes Corneal edema at normal Pedunculated, pigmented Diffuse nevus or
and corectopia or slightly elevated iris nodules heterochromia of iris
intraocular pressure

Corneal endothelium abnormal Yes, may be subclinical Yes Yes (not originally Yes
(slit lamp or specular microscopy) reported)

Corneal edema Variable late Present early Present Present

Peripheral anterior synechiae Present Present Present Present


beyond Schwalbes line

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 Abnormal endothelium Abnormal endothelium Abnormal endothelium
basement membrane and basement membrane and basement membrane and basement membrane
proliferation proliferation proliferation proliferation

Heterochromia Absent Absent Absent Present

been reviewed extensively and supported.1821 Coinciden- The signs of the disorder are usually unmistakable, but
tally, the acronym ICE also signifies commonly used names vary from a spectrum of bare eccentricity of the pupil to
of these conditions iris nevus syndrome, Chandler syn- severe corectopia. Iris atrophy and partial-thickness holes
drome, and essential (progressive) iris atrophy. in the iris stroma appear on the side opposite the pupillary
The diagnosis of the ICE syndrome is considered when eccentricity, and, with continued stretch, full-thickness iris
two of the three main clinical features are present unilater- holes develop (Fig. 73.1). Atrophic iris holes also develop
ally: typical iris changes, abnormal corneal endothelium, in areas not affected by stretching and are attributed to
and PAS.9,2225 Because the common etiology and features of ischemia.9,11,32 The underlying pathophysiologic event is
these disorders are accepted, as long as a patient is correctly an abnormal corneal endothelium, which produces abnor-
diagnosed with ICE syndrome, labeling of the particular mal basement membrane that extends beyond Schwalbes
subtype is not necessary. It is still useful for descriptive pur- line, covering the anterior chamber angle and anterior iris
poses, however, to categorize the entities separately, since surface (Fig. 73.2).11,33,34 The abnormal basement membrane
the presentation and clinical course may vary markedly is referred to by various names in the literature: cuticular
among them (Table 73.1). membrane, glass membrane, cellular membrane, hyaline
membrane, and ectopic Descemet membrane.7,14,3538 Multi-
Clinical Features layered collagenous tissue posterior to the Descemet mem-
brane associated with abnormal endothelium has been
Essential iris atrophy demonstrated by electron microscopy (Fig. 73.3). Contrac-
tion of this membrane draws the iris toward that side, result-
Essential (progressive) iris atrophy, although described in ing in corectopia and stretching atrophy in the opposite
childhood26,27 and in teenage years,28,29 first presents typi- iris quadrant.11 Progressive peripheral anterior synechiae
cally in young adults, unilaterally, and in women more than develop, which are usually seen anterior to Schwalbes line,
men. The presenting symptoms are blurred vision or a resulting in progressive angle closure.25 Even in the absence
noticeable change in the iris substance or pupil. It is also of PAS, the angle may be functionally closed because of the
occasionally first observed during a routine eye examina- presence of a clinically invisible membrane overlying the
tion.9,20,30 Rarely, pain is reported, but usually only in trabecular meshwork.20,39,40 Thus, there may be no correla-
advanced cases with high intraocular pressure and corneal tion between the degree of PAS and the level of intraocular
edema.9,31 pressure.

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PART vii Diseases of the Cornea

Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations

1 2

Fig. 73.3 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 endo-


thelial derived membrane lead to a variable clinical presenta-
tion. 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.8,33,41 The nodules begin as fine, yellow, raised areas
and progress from light to dark brown pedunculated forms.9
The normal architecture of the adjacent iris is lost, giving a
B flat, effaced surface.
Glaucoma, iris atrophy, or nodules may be seen relatively
Fig. 73.1 (A, B) ICE syndrome. Essential (progressive) iris atrophy. early or late, depending on the degree of endothelial prolif-
Typical advanced iris changes of corectopia, thinning of iris, and stretch eration and membrane formation in the anterior chamber
holes. (Courtesy of Jonathan E. Pederson, MD.) angle. Corneal edema occurs, usually associated with ele-
vated intraocular pressure, but it may occur early with wide-
spread endothelial dysfunction. On slit lamp examination,
the fine, hammered silver appearance of the endothelium
described in Chandler syndrome10 is not always seen.24 A
total endothelial abnormality may exist, detected only by
specular microscopy or confocal microscopy.25,42,43
1
Specular microscopy is an invaluable tool for early or
2 confirmatory diagnosis.4446 Although endothelial cell pleo-
3 morphism and a decrease in the percentage of hexagonal
cells of the contralateral eye have been described,47,48 typical
morphologic specular microscopic changes (ICE cells)49 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.47,4954 Oval dark and light
Fig. 73.2 Toluidine blue stain of corneal, anterior angle, and iris tissue bodies within cell boundaries and smaller round structures
in Chandler syndrome; light microscopy. Degenerating endothelial cells with either a bright or dark appearance near cell centers are
and pathologic basement membrane material on the posterior cornea thought to be endothelial cell nuclei and blebs of the apical
(1), causing peripheral anterior synechiae (2), and on the iris surface (3). cell membrane.55 Epithelialization of the endothelial cells is

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CHAPTER 73
Iridocorneal Endothelial Syndrome

nerves. There may be small cells or larger epithelioid-like


cells detected.65 The highly disorganized cells mimic super-
ficial 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 pro-
gression of cellular changes when edema precludes specular
microscopy.
Aside from the unilateral presentation in the ICE syn-
drome, confocal microscopy also may not always be able to
distinguish between ICE syndrome and PPD. Epithelializa-
tion of the endothelium characteristic of PPD has been
reported in ICE syndrome,6972 but endothelial cells retain
their typical characteristics and lineage.34,49,55,7375

Fig. 73.4 Top, Specular microscopic appearance of patient with ICE Chandler syndrome
syndrome, showing total abnormality of endothelium. ICE cells are
seen with dark/light reversal. The patient was asymptomatic, and the The first symptoms of Chandler syndrome are usually blurred
pachymetry was normal. Bottom, Contralateral normal eye of same vision or seeing colored halos around lights.10,30 These symp-
patient. toms occur unilaterally in young adults as a result of corneal
edema and are at first most evident in the morning. Corneal
edema was first described as occurring at a normal or slightly
elevated intraocular pressure and, because of the abnormal
thought to be the histological correlate of the ICE cell seen endothelium, is the dominating clinical characteristic of
on specular microscopy.49 this subtype of ICE syndrome.10,12 The abnormal corneal
It must be emphasized, however, that the typical ICE cell endothelium, best seen with specular reflection, has a fine
is not necessary for the diagnosis in the presence of suspi- hammered silver appearance (Fig. 73.5), which is finer in
cious clinical findings (i.e. a solitary PAS or unilateral glau- appearance than the guttata of Fuchs endothelial dystro-
coma in an otherwise normal eye30,46), as many unilateral phy.10,52 Iris changes may occur but are usually minimal and
abnormal patterns on specular microscopy also may be confined to the stroma with no hole formation, although
seen.56,57 Partial endothelial involvement and regression of nodules are seen.
the abnormal endothelium has been reported.52,53,58 Total Considerable endothelial abnormality may exist before
cellular disorganization with no identifiable cells may be extensive PAS are seen,47 but gonioscopy will usually reveal
seen, even with a clinically clear and thin cornea (Fig. 73.4). a membrane or PAS in the angle. Glaucoma eventually
Patchy areas of diffuse endothelial disorganization or typical occurs, but the syndrome and signs of Chandler syndrome
ICE cells abruptly adjacent to normal endothelium may may be rather advanced before damage from glaucoma
occur.18,52 Areas with increased cell density of smaller than develops. Chandler suggested that if intraocular pressure
normal endothelial cells18,51 may represent the result of com- could be normalized, corneal edema might be avoided.10
paction or replication.18,52 There appears to be no relation Because of the progressive nature of this disorder, one expects
between duration of the disease and degree of endothelial corneal decompensation to occur eventually, even with
abnormality,47 nor is there a correlation of the ICE cells and good intraocular pressure control.
endothelial density with corneal edema.59 Single vesicular Specular microscopy may show all or any of the findings
lesions, round doughnut-like elevations, and bands or ridges previously described with essential iris atrophy, but often a
typical of posterior polymorphous dystrophy (PPD) are not total diffuse abnormality is seen.19,50 In extreme cases of
seen.52,54,5961 Specular microscopy is very useful in general in corneal edema, specular microscopy may not be possible.
distinguishing between ICE syndrome and PPD,54 but may Confocal microscopy may be of value in these cases;6568,76
not always differentiate between progressive PPD and ICE however, clinical characteristics and gonioscopy are often
syndrome which may share a final common pathological adequate to make the diagnosis.
progression.62
Other diagnostic tools of great value in the diagnosis of CoganReese syndrome
ICE syndrome are ultrasound biomicroscopy (UBM) and in
vivo confocal microscopy. They are especially helpful when CoganReese syndrome13 is the least common of the major
corneal edema prevents gonioscopic view of the angles or variants of ICE syndrome in Caucasians.45 One series in the
specular microscopy. UBM has revealed peripheral anterior Chinese literature found it the most common,77 as did a
synechiae, iris atrophy, arborized shape of the iridocorneal report on Thai patients.78 As originally described, the disor-
angle, and closed angles.63 der presented in two patients with unilateral glaucoma and
Confocal microscopy has been of great use as an early pedunculated iris nodules. A hyaline membrane (ectopic
diagnostic tool, and invaluable in cases with corneal Descemet membrane)13 extending from the posterior surface
edema.6468 Consistent findings are loss of regularity in size of the cornea, around the anterior chamber angle, onto the
and shape, irregular or indistinct endothelial cell borders anterior iris surface, and resulting in peripheral anterior syn-
with bright hyper-reflective nuclei, and prominent corneal echiae was described. Mild iris atrophy, ectropion uvea, and

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PART vii Diseases of the Cornea

Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations

Fig. 73.6 Slit lamp photograph of patient with ICE syndrome (Cogan-
Reese). Inferotemporal iris has dark nodules, surrounded by effaced iris
architecture. The dark nodules are normal stroma (inset).

malignant melanoma on the one hand and essential iris


atrophy on the other. The nodules were hypopigmented
and clustered; PAS and iris atrophy for the most part did
not occur. Heterochromia and blunting of the normal iris
architecture were the distinguishing iris features rather
than the atrophy and hole formation seen in essential iris
atrophy.
Although the CoganReese syndrome and iris nevus syn-
Fig. 73.5 Slit lamp view of patient with early ICE syndrome (Chandler drome are thought to be part of the ICE syndrome, there is
syndrome). Note fine hammered appearance of endothelium (inset) and some confusion about whether these are two distinct sub-
reversal of cell borders (white instead of normal black). types,81 and they are often lumped together and the terms
are often used interchangeably.37,40,52,77,81 This confusion was
fostered, in part, by the title of the Scheie and Yanoff report
Iris nevus (CoganReese) syndrome.14 A primary clinical
numerous lightly pigmented pedunculated nodules were sign in the CoganReese report, iris nodules, is now known
also seen. Histopathologic examinations of the nodules to be buds of normal stroma surrounded by an effaced iris
revealed a core of normal iris stroma and cells consistent covered with endothelium-derived abnormal basement
with nevus cells covered by an ectopic Descemet membrane membrane (Figs 73.6 and 73.7).35,36,40,41,82 The clinically strik-
and endothelium. Klien79 and Wood7 had described similar ing feature of the iris nevus syndrome was heterochromia or
cases. Endothelial changes were not described, nor were a diffuse iris nevus, although fine nodules and a matted iris
holes in the iris or marked distortion of the pupil, and all architecture were present.15,37 Referring to the CoganReese
reported cases occurred in women. Optical coherence tomog- entity as the iris nodule syndrome may lessen the confusion.
raphy (OCT) was used in one case to demonstrate iris find- Unilateral endothelial proliferation with excess basement
ings. The Fourier-domain OCT showed a folded iris surface, membrane, PAS, iris surface effacement, and glaucoma in
increased iris thickness, and increased distance between young adults places these within the ICE spectrum, whether
anterior and posterior iris layers due to traction by the or not they are a single subtype or two.9
abnormal endothelial cell layer on the iris surface.80
Etiology
Iris nevus syndrome
Ischemic,4,83 toxic,5 and inflammatory5,84 etiologies have
14
Scheie and Yanoff reported 14 patients with a unilateral been reviewed5,20 and dismissed. The etiology at this time is
diffuse nevus of the iris and several other signs including still unknown. A viral origin has been proposed and sup-
loss of surface architecture of the iris resulting in a matted ported with laboratory data.85 Using the polymerase chain
appearance, ectropion uvea, heterochromia, PAS, corneal reaction (PCR), herpes simplex virus (HSV) DNA was reported
edema, and unilateral glaucoma. Fine iris nodules and mild to be present within the endothelium of a large percentage
iris atrophy were also described. This report emphasized of ICE syndrome patients.86,87 This finding is specific for HSV
the difficulty in distinguishing these patterns from diffuse DNA but is not invariably present, and the observation has

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CHAPTER 73
Iridocorneal Endothelial Syndrome

Clinical Course
The iridocorneal endothelial syndrome is a progressive dis-
order,5,9,10,18,19,53,74 but the subtypes may progress slowly (over
decades)18 or relatively quickly.10,73 Glaucoma may be an
early (before PAS)11,33,90 or late5 finding, depending on the
degree of trabecular meshwork covered by the endothelial-
derived membrane or the number of peripheral anterior
synechiae. Scanning electron microscopy of a single surgical
specimen revealed a monolayer of corneal endothelium-like
cells with a thick basement membrane-like material. Neovas-
cularization was observed in the corneal-scleral trabeculum,
posing yet another mechanism of elevation of intraocular
pressure in ICE patients.103 It is important to establish the
diagnosis early so that the patients may have realistic expec-
tations and to monitor the progress of the disease, especially
if glaucoma is not present and gross corneal changes have
not occurred. Careful slit lamp examination and gonioscopy
at regular intervals and selective use of specular microscopy
and confocal microscopy are valuable to assess progression
Fig. 73.7 Same patient as in Figure 73.6. View of inferonasal iris. (Figs 73.9 and 73.10).42,104

not been corroborated. Varicella-zoster (VZV) anterior uveitis Differential Diagnosis


with Chandler syndrome using PCR has been reported.88
Antibodies to EpsteinBarr virus (EBV) were noted in a high A variety of different clinical entities must be distinguished
percentage of patients with ICE syndrome, but no direct role from components of the ICE syndrome: (1) Fuchs endothe-
for EBV as a cause of the ICE syndrome was established.89 lial dystrophy;10,47 (2) zipper cell endotheliopathy;105 (3) iris
Given the prevalence of DNA viral infections in the popula- abnormalities including ischemic atrophy, aniridia, iridos-
tion, the scarcity of ICE syndrome, and even fewer cases of chisis,20 and PAS from prior trauma or uveitis;106 (4) angle
ICE syndrome with a viral association, this association may abnormalities from neovascular glaucoma106 and trauma;107
be coincidental. (5) iris melanocytoma;108 (6) metastatic lesions to iris;109 and
What is certain is that some event, as yet unknown, (7) iris nodules from malignant melanoma and neurofibro-
causes the endothelium and basement membrane to extend matosis.8,13,14,20,110 However, careful evaluation of the constel-
beyond the peripheral cornea, leading to the clinical char- lation of symptoms and signs associated with ICE syndrome
acteristics described (Fig. 73.8).11,14,15,34,37,50,90 This endothelial limits consideration to only two conditions: posterior poly-
cell-derived overgrowth has led to some confusion as these morphous dystrophy (PPD) and Axenfeld-Rieger syndrome
endothelial cells have exhibited epithelial characteristics (Table 73.2).
by electron microscopic (EM) and immunohistochemistry Posterior polymorphous dystrophy is an endothelial dys-
studies.49,75 Epithelialization of the endothelium was previ- trophy that may have protean manifestations including
ously thought to be characteristic of PPD. A study of an early diffuse corneal edema, corectopia, glass membrane forma-
case of ICE syndrome reported the appearance of a dual cell tion, iridocorneal adhesions, and glaucoma.73,111114,115 Gen-
population, suggesting a transformation from normal hex- erally, the corneal changes are discrete, focal, bilateral, and
agonal endothelial cells to ICE cells.91 Dual populations of asymptomatic. Round or oval vesicular changes, irregularly
epithelial-like cells and normal endothelial cells were shaped gray opacities, and parallel lines or ridges befitting
reported in cases of subtotal ICE syndrome.58 Epithelial the term polymorphous are observed in Descemet mem-
characteristics of endothelial cells may be a final common brane.111 The bilateral changes may be rather asymmetric
cytologic transformation in these two, as well as other, dis- with only a single vesicle or group of vesicles as evidence of
orders of the corneal endothelium.92 Theories put forth to involvement.112 Specular microscopy reveals dark rings,
explain this phenomenon include a primordial nest of rounded hills or ovals, parallel ridges, and lesions corre-
neural crest-derived pluripotential cells that under the right sponding to the clinical features.54,60 Epithelialization of the
stimulus proliferate and, more likely, metaplasia of the endothelium is thought to be the characteristic endothelial
neuroectoderm-derived endothelial cells.75,77,9294 The stimu- change,82,113,116118 although fibroblastic metaplasia has been
lus for metaplastic transformation is unknown, but a viral reported.119 Epithelial characteristics of endothelial cells
cause is considered a good possibility. This also would be include myriad microvilli, keratofibrils, desmosomal attach-
consistent with the two-hit hypothesis proposed.48 ments, and scant mitochondria in contrast to rich micro-
Although there are isolated case reports of familial or organelles, apical tight junctions, and flat apical surfaces
bilateral involvement,20,32,83,9599,100 strong evidence indi- characteristic of endothelium.73,119 These endothelial cells
cates that ICE syndrome is nonfamilial23,52,54 and is stain positive for cytokeratins using immunohistochemical
unilateral.23,34,52,56,101,102 techniques.114

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PART vii Diseases of the Cornea

Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations

A B

1
2 2

1 3
4

C D

1 1

2
3
2

3 4

E F G

Fig. 73.8 Development and variation of ICE syndrome (after the membrane theory of Campbell). (A) Earliest stage of iris and anterior chamber angle
involvement. Solitary peripheral anterior synechiae (PAS), but no pupil and iris abnormality. (B) Growth and extension of abnormal membrane from
posterior corneal surface over the anterior chamber angle onto the surface of the iris. Multiple PAS (1), contraction of membrane on iris surface (2),
and early stretch-induced iris stromal atrophy in the quadrant opposite the membrane (3). The pupil is mildly eccentric. (C) Diffuse anterior chamber
angle and iris involvement with abnormal membrane growth. Matting of iris surface caused by growth and contraction of membrane (1), broader PAS,
and wider iris and pupil involvement as membrane grows and contracts (2), and increase in iris stromal atrophy from increased membrane contraction
and PAS 180 degrees opposite (3). Pigment epithelium of iris is visible through atrophic holes in iris stroma. (D) Progressive (essential) iris atrophy at
an advanced stage. Clinically visible membrane covers trabecular meshwork and anterior chamber angle, functionally closing angle between PAS (1).
Increase in effacement of iris (2). Ectropion uveae (3). Nonstretch melting hole (4), possibly caused by ischemia. Iris nodule (5), which is a bud of
normal iris protruding through membrane-covered, flattened iris. (E) ICE variation: progressive (essential) iris atrophy with 360 degrees of anterior
chamber angle involvement. Multiple iris holes but no corectopia because of relatively symmetric 360-degree membrane contraction and PAS. (F) ICE
variation: iris nevus syndrome (Cogan-Reese syndrome). Diffuse iris lesioniris nevus (1) and multiple iris nodules (2), which are really buds of normal
iris surrounded by effaced iris architecture. Iris atrophy (3) is usually mild, but is variable. (G) ICE variation: Chandler syndrome. Microcystic corneal
edema (1) and hammered silver appearance of corneal endothelium (2). Mild stromal iris atrophy (3) and an iris nodule (4).

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CHAPTER 73
Iridocorneal Endothelial Syndrome

PPD is inherited, usually in an autosomal dominant


mode,111113,116 and examination of asymptomatic affected
family members reveals characteristic lesions at the Des-
cemet membrane. Iris atrophy has been described rarely, and
nodules are very rarely encountered.115 Glaucoma tends to
be associated with significant corneal changes, but may not
parallel the presence of PAS.112 The corneal endothelium in
PPD produces an abnormal Descemet membrane-like mate-
rial that may extend from the posterior cornea onto the iris,
resulting in PAS and corectopia.111,112 The Descemet mem-
brane appears thickened.116 Although there is overlap with

Fig. 73.9 Early ICE syndrome. Subtle eccentricity of pupil in superior Fig. 73.10 Goniophotograph of same patient as in Figure 73.9. View of
quadrant. superior angle showing early PAS, corresponding to pupil eccentricity.

Table 73.2 General characteristics of ICE, posterior polymorphous dystrophy, and Axenfeld-Rieger syndrome

ICE PPD A-RS

Age of onset Young adult Congenital Congenital

Laterality Unilateral* Bilateral* Bilateral*

Sex predilection F>M F=M F = M*

Posterior embryotoxin No* No Yes

Cornea abnormal (slit lamp) Yes (fine, guttae-like changes, Yes (vesicles, plaques at No
hammered silver) Descemet membrane)

Specular microscopy Diffuse changes, ICE cell Focal change* Normal

Basic defect Abnormal proliferation of endothelium Epithelialization of endothelium Retention of primordial endothelial layer

Glaucoma 80100% 25% 50%

Glaucoma mechanism Membrane or PAS occluding angle Unknown, membrane or PAS Incomplete or maldevelopment of trabecular
occluding angle meshwork and Schlemms canal

Iris atrophy Mild to severe Minimal Mild to severe

Iris nodules Yes No No*

Progression Yes may be relentless Minimal No*

Inheritance No Autosomal dominant* Autosomal dominant

PPD, posterior polymorphous dystrophy; A-RS, Axenfeld-Rieger syndrome; F, female; M, male.


*Denotes rare exceptions.

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PART vii Diseases of the Cornea

Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations

regard to pathologic endothelial changes, ICE and PPD may of the bleb or tube, and retrocorneal membrane forma-
be differentiated histopatholgically. PPD has a multilayered tion.15,21,34,35,37,77,126,127 Antifibrotic agents,128 mini aqueous
Descemet membrane, may lack the anterior banded layer, shunts,129 and glaucoma drainage implants (GDIs) have been
and fibrous tissue may be present in the posterior portion. evaluated and used with variable success.126,129131 One would
In ICE syndrome there is a lack of multilayered Descemet generally first use trabeculectomy with mitomycin C, and
membrane, normal anterior banded and posterior nonbanded then proceed with GDIs if failure occurred. No matter which
layers of Descemet membrane, with fibrous tissue between technique is employed, the success rate often diminishes
the Descemet membrane and endothelium.120 A common markedly with time and multiple procedures may be
pathogenesis for PPD and the iridocorneal endothelial syn- required.126,130132
drome has been postulated.33,121 Early in the clinical course, corneal edema may respond
The difference between ICE syndrome and Axenfeld- to lowering intraocular pressure.10,20,24,39 Hypertonic saline
Rieger syndrome has been reviewed extensively.25,122 solutions and soft contact lenses may be helpful. As the
Axenfeld-Rieger syndrome is a congenital condition that endothelial dysfunction progresses, however, corneal edema
may have dramatic iris atrophy, iris hole formation, and may be present even with excellent control of intraocular
corectopia. Glaucoma is a frequent component of this dis- pressure. Persistent corneal edema may occur at any time
order. Gonioscopy reveals a prominent Schwalbes line in because of progressive endothelial degeneration, elevated
all cases, with strands of tissue stretching from the iris intraocular pressure, trauma of prior intraocular surgery, or
periphery to Schwalbes line. In addition to enlargement, some combination of these. When corneal clarity can no
Schwalbes line is often anteriorly displaced, but much longer be maintained with good intraocular pressure control,
variation exists.25 The corneal endothelium is normal, but and if advanced glaucomatous changes are not present, pen-
specular microscopy may reveal some pleomorphism and etrating keratoplasty and Descemet stripping endothelial
intracellular dark spots.25 It has been postulated that the keratoplasty (DSEK), are therapeutic options.20,24,128136 Des-
ocular signs are due to a developmental arrest in gestation cemet membrane endothelial keratoplasty (DMEK) is not as
of tissues derived from neural crest cells.25 The bilateral yet considered to be a good choice.137 Many successes with
involvement may be asymmetric,20 and iris nodules are not keratoplasty are reported with Chandlers variation of ICE
usually seen. Axenfeld-Rieger syndrome has autosomal dom- syndrome,22,23,31,137139 but penetrating keratoplasty in the
inant inheritance and frequently has associated develop- progressive iris atrophy variant of ICE syndrome may have
mental anomalies.20,122 Molecular genetic techniques have a poorer prognosis because of continued inflammation.140
linked chromosomal loci and phenotypic expression.123125 Heavy use of anti-inflammatory medications may improve
the outcome in these cases, but multiple grafts may be
Management needed. Control of glaucoma is the key factor in the ultimate
visual success of keratoplasty in any of the subtypes of the
Treatment is geared to the dominant clinical type. Because ICE syndrome.
there is no prevention or cure, early endothelial or iris Cataracts may develop de novo or subsequent to glau-
changes are observed only. Until a specific viral origin is coma or corneal surgery. As part of surgical rehabilitation in
firmly established, antiviral therapy cannot be recom- patients with iris deficiencies when the iris is not amenable
mended.87 Medical treatment is generally ineffective,14,46,104 to suturing techniques, iris diaphragm intraocular lenses or
but when glaucoma develops it may be managed initially iris prostheses have been used.141143 In ICE patients, cataract
with aqueous suppressants. Pilocarpine and other miotics extraction with implantation of an intraocular lens and a
have no place in the management of the glaucoma because multipiece endocapsular iris prosthesis through a small inci-
the problem is one of access to the trabecular meshwork, not sion can achieve visual rehabilitation while sparing conjunc-
an intrinsic defect in the meshwork itself. Intraocular pres- tiva should future glaucoma surgeries be needed (Fig.
sure control with aqueous suppressants is usually short-lived 73.12).143 The prosthetic iris helps to minimize postsurgical
because further angle closure develops (Fig. 73.11). Ulti- glare and photophobia. To ameliorate photophobia and
mately, glaucoma filtering surgery is required.46 Some reports assist in cosmesis, corneal tattooing with femtosecond laser
have suggested a bleak prognosis,9,35,77 but there are many channel creation has been described.144
reports of success. In addition to the usual causes of bleb
failure, other sources of failure in the ICE syndrome are Summary
aggressive subconjunctival fibrosis and endothelialization
The ICE syndrome is a unilateral, acquired corneal endothe-
lial disorder, usually first seen in young adulthood. This
abnormal proliferating endothelium produces a basement
membrane that extends across the chamber angle onto the
anterior iris surface and causes the characteristic clinical
picture. Glaucoma may occur early or very late during the
development of the clinically characteristic signs, and ICE
syndrome should be strongly considered in any case of uni-
lateral glaucoma without other obvious causes.30,46
Fig. 73.11 Goniophotograph of inferior angle; patient with ICE Corneal edema at normal or slightly elevated intraocular
syndrome. Note broad PAS extending beyond trabecular meshwork pressure and any unilateral change in the iris surface or
and Schwalbes line. No normal angle structures are seen. irregularity of the pupil, in the absence of a history of trauma

852
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CHAPTER 73
Iridocorneal Endothelial Syndrome

A B C

Fig. 73.12 (A) Preoperative photograph showing extensive iris abnormalities in ICE syndrome. The lens is cataractous. (B) Insertion of iris device into
the capsular bag through a small incision. (C) Postoperative appearance showing the iris elements aligned and locked. (From Khng C, Snyder ME. Iris
reconstruction with a multipiece endocapsular prosthesis in iridocorneal endothelial syndrome. J Cataract Refract Surg 2005;31(11):20514. Copyright
Elsevier 2005.)

or inflammation, should raise suspicion for the ICE syn- 16. Yanoff M. Discussion of presentation by Dr. M Bruce Shields et al. Trans
Am Acad Ophthalmol 1979;86:154950.
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formed. A single PAS,34 or irregular appearance in the angle, spectrum. Surv Ophthalmol 1979;24:12.
also should suggest the diagnosis of ICE syndrome. Specular 18. Neubauer L, Lund O, Leibowitz HM. Specular microscopic appearance
microscopy and confocal microscopy are invaluable tools for of the corneal endothelium in iridocorneal endothelial syndrome. Arch
Ophthalmol 1983;101:91618.
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PART vii Diseases of the Cornea

Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations

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