Part vii
Diseases of the Cornea
Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations
Chapter 73
Iridocorneal Endothelial Syndrome
Emmett F. Carpel
Key Concepts
Iridocorneal Syndrome (ICE) is a disorder of the corneal
endothelium manifested by abnormal endothelial cell
formation and a proliferating membrane that may
overlie the endothelium, chamber angle, and iris.
The etiology of ICE syndrome is unknown, although
viral associations have been reported.
ICE syndrome may present with any of three clinically
noticeable forms: iris nodules (iris nevus and Cogan
Reese syndromes), corneal endothelial abnormality or
edema (Chandler syndrome), or essential (progressive)
iris atrophy.
ICE syndrome should be considered a unilateral
disorder.
ICE syndrome is not hereditary.
ICE syndrome is progressive but variably so, from
minimal over decades, to quickly.
Slit lamp biomicroscopy and gonioscopy are mainstays
for detection, but specular microscopy and confocal
microscopy are invaluable for diagnosis and follow-up.
Glaucoma is a significant problem, control of which
usually determines the ultimate fate of vision, but
surgical success with a filter or drainage device is
possible.
Corneal edema may be successfully treated by
endothelial or penetrating keratoplasty.
History and Background
In the early part of the twentieth century, several case reports
described a curious disorder in which the iris underwent
progressive atrophy.16 Patients presented with complaints of
blurred vision or changes in the shape of the pupil, although
occasionally the iris changes were first noted during a routine
examination. In this unilateral condition in young adults,
the iris underwent a change from mild eccentricity of the
pupil and stromal atrophy to marked corectopia and com-
plete iris hole formation. The pupil remained intact, but was
displaced toward the periphery where extensive peripheral
844
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anterior synechiae (PAS) were noted.6 The condition was
called essential or progressive iris atrophy to denote the
absence of an identifiable cause and its progressive nature.2,4,5
Glaucoma was a frequent finding in this disorder, and was
poorly controlled with medical treatment, although success-
ful filtering operations were described.3 Later, the description
of an abnormal corneal endothelium and the formation of
iris nodules were added to the manifestations of essential
(progressive) iris atrophy.711
Chandler10,12 reported a group of patients with abnormal
corneal endothelium, described as a hammered silver
appearance, and corneal edema that occurred at a normal
or slightly increased intraocular pressure. Iris nodules and
PAS were also described, with glaucoma as an associated
finding. This unilateral, nonfamilial disorder came to be
known as Chandler syndrome.
Cogan and Reese13 later described patients with many
features in common with those described here. Most often,
patients presented with blurred vision or reported noticing
spots on the iris. Iris nodules and PAS were clinically the
most noticeable part of this disorder. Glaucoma was invari-
ably present. This condition was also nonfamilial and uni-
lateral and came to be termed the CoganReese syndrome.
Scheie and Yanoff14 reported a series of patients with uni-
lateral glaucoma and iris changes that included heterochro-
mia, ectropion uveae, PAS, and fine iris nodules. Corneal
edema occurred at normal or slightly elevated intraocular
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.
Common threads running through all these conditions
included a unilateral, progressive, nonfamilial ocular disor-
der of young adulthood with abnormal corneal endothelium
and peripheral anterior synechiae. Glaucoma, iris atrophy,
and nodules were associated findings. Through the accumu-
lated clinical and histopathologic reports, Campbell etal.11
concluded that an abnormality of the corneal endothelium
with production of abnormal basement membrane was the
common etiologic basis and unified these disorders. Because
corneal endothelial and iris abnormalities were found in all
entities, it was termed the iridocorneal endothelial syn-
drome (ICE syndrome).8,1517 This unifying hypothesis has
 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-
tally, the acronym ICE also signifies commonly used names
of these conditions iris nevus syndrome, Chandler syn-
drome, and essential (progressive) iris atrophy.
The diagnosis of the ICE syndrome is considered when
two of the three main clinical features are present unilater-
ally: typical iris changes, abnormal corneal endothelium,
and PAS.9,2225 Because the common etiology and features of
these disorders are accepted, as long as a patient is correctly
diagnosed with ICE syndrome, labeling of the particular
subtype is not necessary. It is still useful for descriptive pur-
poses, however, to categorize the entities separately, since
the presentation and clinical course may vary markedly
among them (Table 73.1).
Clinical Features
Essential iris atrophy
Essential (progressive) iris atrophy, although described in
childhood26,27 and in teenage years,28,29 first presents typi-
cally in young adults, unilaterally, and in women more than
men. The presenting symptoms are blurred vision or a
noticeable change in the iris substance or pupil. It is also
occasionally first observed during a routine eye examina-
tion.9,20,30 Rarely, pain is reported, but usually only in
advanced cases with high intraocular pressure and corneal
edema.9,31
The signs of the disorder are usually unmistakable, but
vary from a spectrum of bare eccentricity of the pupil to
severe corectopia. Iris atrophy and partial-thickness holes
in the iris stroma appear on the side opposite the pupillary
eccentricity, and, with continued stretch, full-thickness iris
holes develop (Fig. 73.1). Atrophic iris holes also develop
in areas not affected by stretching and are attributed to
ischemia.9,11,32 The underlying pathophysiologic event is
an abnormal corneal endothelium, which produces abnor-
mal basement membrane that extends beyond Schwalbes
line, covering the anterior chamber angle and anterior iris
surface (Fig. 73.2).11,33,34 The abnormal basement membrane
is referred to by various names in the literature: cuticular
membrane, glass membrane, cellular membrane, hyaline
membrane, and ectopic Descemet membrane.7,14,3538 Multi-
layered collagenous tissue posterior to the Descemet mem-
brane associated with abnormal endothelium has been
demonstrated by electron microscopy (Fig. 73.3). Contrac-
tion of this membrane draws the iris toward that side, result-
ing in corectopia and stretching atrophy in the opposite
iris quadrant.11 Progressive peripheral anterior synechiae
develop, which are usually seen anterior to Schwalbes line,
resulting in progressive angle closure.25 Even in the absence
of PAS, the angle may be functionally closed because of the
presence of a clinically invisible membrane overlying the
trabecular meshwork.20,39,40 Thus, there may be no correla-
tion between the degree of PAS and the level of intraocular
pressure.

845
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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-

B flat, effaced surface.
Fig. 73.1 (A, B) ICE syndrome. Essential (progressive) iris atrophy.
Typical advanced iris changes of corectopia, thinning of iris, and stretch
holes. (Courtesy of Jonathan E. Pederson, MD.)
1
2 confirmatory diagnosis.4446 Although endothelial cell pleo-
3 morphism and a decrease in the percentage of hexagonal
Fig. 73.2 Toluidine blue stain of corneal, anterior angle, and iris tissue
in Chandler syndrome; light microscopy. Degenerating endothelial cells
and pathologic basement membrane material on the posterior cornea
(1), causing peripheral anterior synechiae (2), and on the iris surface (3).
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
Glaucoma, iris atrophy, or nodules may be seen relatively
early or late, depending on the degree of endothelial prolif-
eration and membrane formation in the anterior chamber
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
Specular microscopy is an invaluable tool for early or
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
bodies within cell boundaries and smaller round structures
with either a bright or dark appearance near cell centers are
thought to be endothelial cell nuclei and blebs of the apical
cell membrane.55 Epithelialization of the endothelial cells is

846
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Fig. 73.4 Top, Specular microscopic appearance of patient with ICE
syndrome, showing total abnormality of endothelium. ICE cells are
seen with dark/light reversal. The patient was asymptomatic, and the
pachymetry was normal. Bottom, Contralateral normal eye of same
patient.
thought to be the histological correlate of the ICE cell seen
on specular microscopy.49
It must be emphasized, however, that the typical ICE cell
is not necessary for the diagnosis in the presence of suspi-
cious clinical findings (i.e. a solitary PAS or unilateral glau-
coma in an otherwise normal eye30,46), as many unilateral
abnormal patterns on specular microscopy also may be
seen.56,57 Partial endothelial involvement and regression of
the abnormal endothelium has been reported.52,53,58 Total
cellular disorganization with no identifiable cells may be
seen, even with a clinically clear and thin cornea (Fig. 73.4).
Patchy areas of diffuse endothelial disorganization or typical
ICE cells abruptly adjacent to normal endothelium may
occur.18,52 Areas with increased cell density of smaller than
normal endothelial cells18,51 may represent the result of com-
paction or replication.18,52 There appears to be no relation
between duration of the disease and degree of endothelial
abnormality,47 nor is there a correlation of the ICE cells and
endothelial density with corneal edema.59 Single vesicular
lesions, round doughnut-like elevations, and bands or ridges
typical of posterior polymorphous dystrophy (PPD) are not
seen.52,54,5961 Specular microscopy is very useful in general in
distinguishing between ICE syndrome and PPD,54 but may
not always differentiate between progressive PPD and ICE
syndrome which may share a final common pathological
progression.62
Other diagnostic tools of great value in the diagnosis of
ICE syndrome are ultrasound biomicroscopy (UBM) and in
vivo confocal microscopy. They are especially helpful when
corneal edema prevents gonioscopic view of the angles or
specular microscopy. UBM has revealed peripheral anterior
synechiae, iris atrophy, arborized shape of the iridocorneal
angle, and closed angles.63
Confocal microscopy has been of great use as an early
diagnostic tool, and invaluable in cases with corneal
edema.6468 Consistent findings are loss of regularity in size
and shape, irregular or indistinct endothelial cell borders
with bright hyper-reflective nuclei, and prominent corneal
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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
Chandler syndrome
The first symptoms of Chandler syndrome are usually blurred
vision or seeing colored halos around lights.10,30 These symp-
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
endothelium, is the dominating clinical characteristic of
this subtype of ICE syndrome.10,12 The abnormal corneal
endothelium, best seen with specular reflection, has a fine
hammered silver appearance (Fig. 73.5), which is finer in
appearance than the guttata of Fuchs endothelial dystro-
phy.10,52 Iris changes may occur but are usually minimal and
confined to the stroma with no hole formation, although
nodules are seen.
Considerable endothelial abnormality may exist before
extensive PAS are seen,47 but gonioscopy will usually reveal
a membrane or PAS in the angle. Glaucoma eventually
occurs, but the syndrome and signs of Chandler syndrome
may be rather advanced before damage from glaucoma
develops. Chandler suggested that if intraocular pressure
could be normalized, corneal edema might be avoided.10
Because of the progressive nature of this disorder, one expects
corneal decompensation to occur eventually, even with
good intraocular pressure control.
Specular microscopy may show all or any of the findings
previously described with essential iris atrophy, but often a
total diffuse abnormality is seen.19,50 In extreme cases of
corneal edema, specular microscopy may not be possible.
Confocal microscopy may be of value in these cases;6568,76
however, clinical characteristics and gonioscopy are often
adequate to make the diagnosis.
CoganReese syndrome
CoganReese syndrome13 is the least common of the major
variants of ICE syndrome in Caucasians.45 One series in the
Chinese literature found it the most common,77 as did a
report on Thai patients.78 As originally described, the disor-
der presented in two patients with unilateral glaucoma and
pedunculated iris nodules. A hyaline membrane (ectopic
Descemet membrane)13 extending from the posterior surface
of the cornea, around the anterior chamber angle, onto the
anterior iris surface, and resulting in peripheral anterior syn-
echiae was described. Mild iris atrophy, ectropion uvea, and
847
 PART vii Diseases of the Cornea
Section 3 Corneal Dystrophies, Ectatic Disorders, and Degenerations
Fig. 73.5 Slit lamp view of patient with early ICE syndrome (Chandler
syndrome). Note fine hammered appearance of endothelium (inset) and
reversal of cell borders (white instead of normal black).
numerous lightly pigmented pedunculated nodules were
also seen. Histopathologic examinations of the nodules
revealed a core of normal iris stroma and cells consistent
with nevus cells covered by an ectopic Descemet membrane
and endothelium. Klien79 and Wood7 had described similar
cases. Endothelial changes were not described, nor were
holes in the iris or marked distortion of the pupil, and all
reported cases occurred in women. Optical coherence tomog-
raphy (OCT) was used in one case to demonstrate iris find-
ings. The Fourier-domain OCT showed a folded iris surface,
increased iris thickness, and increased distance between
anterior and posterior iris layers due to traction by the
abnormal endothelial cell layer on the iris surface.80
Iris nevus syndrome
14
Scheie and Yanoff reported 14 patients with a unilateral
diffuse nevus of the iris and several other signs including
loss of surface architecture of the iris resulting in a matted
appearance, ectropion uvea, heterochromia, PAS, corneal
edema, and unilateral glaucoma. Fine iris nodules and mild
iris atrophy were also described. This report emphasized
the difficulty in distinguishing these patterns from diffuse
848
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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-
drome are thought to be part of the ICE syndrome, there is
some confusion about whether these are two distinct sub-
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
sign in the CoganReese report, iris nodules, is now known
to be buds of normal stroma surrounded by an effaced iris
covered with endothelium-derived abnormal basement
membrane (Figs 73.6 and 73.7).35,36,40,41,82 The clinically strik-
ing feature of the iris nevus syndrome was heterochromia or
a diffuse iris nevus, although fine nodules and a matted iris
architecture were present.15,37 Referring to the CoganReese
entity as the iris nodule syndrome may lessen the confusion.
Unilateral endothelial proliferation with excess basement
membrane, PAS, iris surface effacement, and glaucoma in
young adults places these within the ICE spectrum, whether
or not they are a single subtype or two.9
Etiology
Ischemic,4,83 toxic,5 and inflammatory5,84 etiologies have
been reviewed5,20 and dismissed. The etiology at this time is
still unknown. A viral origin has been proposed and sup-
ported with laboratory data.85 Using the polymerase chain
reaction (PCR), herpes simplex virus (HSV) DNA was reported
to be present within the endothelium of a large percentage
of ICE syndrome patients.86,87 This finding is specific for HSV
DNA but is not invariably present, and the observation has

Fig. 73.7 Same patient as in Figure 73.6. View of inferonasal iris.
not been corroborated. Varicella-zoster (VZV) anterior uveitis
with Chandler syndrome using PCR has been reported.88
Antibodies to EpsteinBarr virus (EBV) were noted in a high
percentage of patients with ICE syndrome, but no direct role
for EBV as a cause of the ICE syndrome was established.89
Given the prevalence of DNA viral infections in the popula-
tion, the scarcity of ICE syndrome, and even fewer cases of
ICE syndrome with a viral association, this association may
be coincidental.
What is certain is that some event, as yet unknown,
causes the endothelium and basement membrane to extend
beyond the peripheral cornea, leading to the clinical char-
acteristics described (Fig. 73.8).11,14,15,34,37,50,90 This endothelial
cell-derived overgrowth has led to some confusion as these
endothelial cells have exhibited epithelial characteristics (Table 73.2).
by electron microscopic (EM) and immunohistochemistry
studies.49,75 Epithelialization of the endothelium was previ-
ously thought to be characteristic of PPD. A study of an early
case of ICE syndrome reported the appearance of a dual cell
population, suggesting a transformation from normal hex-
agonal endothelial cells to ICE cells.91 Dual populations of
epithelial-like cells and normal endothelial cells were
reported in cases of subtotal ICE syndrome.58 Epithelial
characteristics of endothelial cells may be a final common
cytologic transformation in these two, as well as other, dis-
orders of the corneal endothelium.92 Theories put forth to
explain this phenomenon include a primordial nest of
neural crest-derived pluripotential cells that under the right
stimulus proliferate and, more likely, metaplasia of the
neuroectoderm-derived endothelial cells.75,77,9294 The stimu-
lus for metaplastic transformation is unknown, but a viral
cause is considered a good possibility. This also would be
consistent with the two-hit hypothesis proposed.48
Although there are isolated case reports of familial or
bilateral involvement,20,32,83,9599,100 strong evidence indi-
cates that ICE syndrome is nonfamilial23,52,54 and is
unilateral.23,34,52,56,101,102
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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
(Figs 73.9 and 73.10).42,104
Differential Diagnosis
A variety of different clinical entities must be distinguished
from components of the ICE syndrome: (1) Fuchs endothe-
lial dystrophy;10,47 (2) zipper cell endotheliopathy;105 (3) iris
abnormalities including ischemic atrophy, aniridia, iridos-
chisis,20 and PAS from prior trauma or uveitis;106 (4) angle
abnormalities from neovascular glaucoma106 and trauma;107
(5) iris melanocytoma;108 (6) metastatic lesions to iris;109 and
(7) iris nodules from malignant melanoma and neurofibro-
matosis.8,13,14,20,110 However, careful evaluation of the constel-
lation of symptoms and signs associated with ICE syndrome
limits consideration to only two conditions: posterior poly-
morphous dystrophy (PPD) and Axenfeld-Rieger syndrome
Posterior polymorphous dystrophy is an endothelial dys-
trophy that may have protean manifestations including
diffuse corneal edema, corectopia, glass membrane forma-
tion, iridocorneal adhesions, and glaucoma.73,111114,115 Gen-
erally, the corneal changes are discrete, focal, bilateral, and
asymptomatic. Round or oval vesicular changes, irregularly
shaped gray opacities, and parallel lines or ridges befitting
the term polymorphous are observed in Descemet mem-
brane.111 The bilateral changes may be rather asymmetric
with only a single vesicle or group of vesicles as evidence of
involvement.112 Specular microscopy reveals dark rings,
rounded hills or ovals, parallel ridges, and lesions corre-
sponding to the clinical features.54,60 Epithelialization of the
endothelium is thought to be the characteristic endothelial
change,82,113,116118 although fibroblastic metaplasia has been
reported.119 Epithelial characteristics of endothelial cells
include myriad microvilli, keratofibrils, desmosomal attach-
ments, and scant mitochondria in contrast to rich micro-
organelles, apical tight junctions, and flat apical surfaces
characteristic of endothelium.73,119 These endothelial cells
stain positive for cytokeratins using immunohistochemical
techniques.114
849
 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).

850
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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.

851
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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
be differentiated histopatholgically. PPD has a multilayered
Descemet membrane, may lack the anterior banded layer,
and fibrous tissue may be present in the posterior portion.
In ICE syndrome there is a lack of multilayered Descemet
membrane, normal anterior banded and posterior nonbanded
layers of Descemet membrane, with fibrous tissue between
the Descemet membrane and endothelium.120 A common
pathogenesis for PPD and the iridocorneal endothelial syn-
drome has been postulated.33,121
The difference between ICE syndrome and Axenfeld-
Rieger syndrome has been reviewed extensively.25,122
Axenfeld-Rieger syndrome is a congenital condition that
may have dramatic iris atrophy, iris hole formation, and
corectopia. Glaucoma is a frequent component of this dis-
order. Gonioscopy reveals a prominent Schwalbes line in because of progressive endothelial degeneration, elevated
all cases, with strands of tissue stretching from the iris
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
specular microscopy may reveal some pleomorphism and
intracellular dark spots.25 It has been postulated that the
ocular signs are due to a developmental arrest in gestation
of tissues derived from neural crest cells.25 The bilateral
involvement may be asymmetric,20 and iris nodules are not
usually seen. Axenfeld-Rieger syndrome has autosomal dom-
inant inheritance and frequently has associated develop-
mental anomalies.20,122 Molecular genetic techniques have
linked chromosomal loci and phenotypic expression.123125
Management
Treatment is geared to the dominant clinical type. Because
there is no prevention or cure, early endothelial or iris
changes are observed only. Until a specific viral origin is
firmly established, antiviral therapy cannot be recom-
mended.87 Medical treatment is generally ineffective,14,46,104
but when glaucoma develops it may be managed initially
with aqueous suppressants. Pilocarpine and other miotics
have no place in the management of the glaucoma because
the problem is one of access to the trabecular meshwork, not
an intrinsic defect in the meshwork itself. Intraocular pres-
sure control with aqueous suppressants is usually short-lived
because further angle closure develops (Fig. 73.11). Ulti-
mately, glaucoma filtering surgery is required.46 Some reports
have suggested a bleak prognosis,9,35,77 but there are many
reports of success. In addition to the usual causes of bleb
failure, other sources of failure in the ICE syndrome are
aggressive subconjunctival fibrosis and endothelialization
Fig. 73.11 Goniophotograph of inferior angle; patient with ICE
syndrome. Note broad PAS extending beyond trabecular meshwork
and Schwalbes line. No normal angle structures are seen.
852
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of the bleb or tube, and retrocorneal membrane forma-
tion.15,21,34,35,37,77,126,127 Antifibrotic agents,128 mini aqueous
shunts,129 and glaucoma drainage implants (GDIs) have been
evaluated and used with variable success.126,129131 One would
generally first use trabeculectomy with mitomycin C, and
then proceed with GDIs if failure occurred. No matter which
technique is employed, the success rate often diminishes
markedly with time and multiple procedures may be
required.126,130132
Early in the clinical course, corneal edema may respond
to lowering intraocular pressure.10,20,24,39 Hypertonic saline
solutions and soft contact lenses may be helpful. As the
endothelial dysfunction progresses, however, corneal edema
may be present even with excellent control of intraocular
pressure. Persistent corneal edema may occur at any time
intraocular pressure, trauma of prior intraocular surgery, or
and if advanced glaucomatous changes are not present, pen-
etrating keratoplasty and Descemet stripping endothelial
keratoplasty (DSEK), are therapeutic options.20,24,128136 Des-
cemet membrane endothelial keratoplasty (DMEK) is not as
yet considered to be a good choice.137 Many successes with
keratoplasty are reported with Chandlers variation of ICE
syndrome,22,23,31,137139 but penetrating keratoplasty in the
progressive iris atrophy variant of ICE syndrome may have
a poorer prognosis because of continued inflammation.140
Heavy use of anti-inflammatory medications may improve
the outcome in these cases, but multiple grafts may be
needed. Control of glaucoma is the key factor in the ultimate
visual success of keratoplasty in any of the subtypes of the
ICE syndrome.
Cataracts may develop de novo or subsequent to glau-
coma or corneal surgery. As part of surgical rehabilitation in
patients with iris deficiencies when the iris is not amenable
to suturing techniques, iris diaphragm intraocular lenses or
iris prostheses have been used.141143 In ICE patients, cataract
extraction with implantation of an intraocular lens and a
multipiece endocapsular iris prosthesis through a small inci-
sion can achieve visual rehabilitation while sparing conjunc-
tiva should future glaucoma surgeries be needed (Fig.
73.12).143 The prosthetic iris helps to minimize postsurgical
glare and photophobia. To ameliorate photophobia and
assist in cosmesis, corneal tattooing with femtosecond laser
channel creation has been described.144
Summary
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
Corneal edema at normal or slightly elevated intraocular
pressure and any unilateral change in the iris surface or
irregularity of the pupil, in the absence of a history of trauma

A B
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-
drome. Gonioscopy, when possible, should always be per-
formed. A single PAS,34 or irregular appearance in the angle,
also should suggest the diagnosis of ICE syndrome. Specular
microscopy and confocal microscopy are invaluable tools for
early diagnosis of ICE syndrome, and any of the previously
described unilateral changes will confirm the diagnosis.
Bilateral involvement and ocular involvement in family
members almost always negate the diagnosis of ICE syn-
drome, and other causes should be sought. Later in the
clinical course, progressive unilateral endothelial changes,
iris holes, and nodules confirm the diagnosis of ICE syn-
drome. Treatment ranges from observation to medical man-
agement of the glaucoma, to surgical management of the
glaucoma, and keratoplasty.
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