are islands of normal iris pinched by the contracting endothelial membrane.The iris may have any degree of dissolution from mild to severe. A similar variability is noted in the degree of corneal edema and the severity of the angle-closure glaucoma. Especially in the early stages, characteristics of both progressive iris atrophy and iris nevus syndrome may be seen in the same iris.

The differential diagnosis of the ICE syndrome is very large because the clinical features of the syndrome are so variable. Included are corneal conditions such as posterior polymorphous dystrophy and Fuchs’ dystrophy, iris abnormalities such as iridoschisis and malignant melanoma, developmental disorders such as Rieger’s syndrome and aniridia, and miscellaneous conditions such as neurofibromatosis and anterior uveitis with nodules. The diagnosis is often missed early because the corneal and iris signs may be subtle.200 Most of the conditions in the differential diagnosis are bilateral, so a unilateral condition should raise the possibility of the ICE syndrome.

Treatment

The treatment of the ICE syndrome is as variable as the clinical picture. If corneal edema produces pain or reduced vision, the patient may be helped by hypertonic solutions or soft contact lenses. In many cases corneal edema is improved if IOP is reduced by medical or surgical therapy. Some patients with the ICE syndrome eventually require penetrating keratoplasty.201–203

Glaucoma is initially treated with the full range of medical therapy. Laser trabeculoplasty offers no help in this condition because most of the angle is covered by a membrane or sealed with synechiae. Short-term success has been reported with a goniotomy procedure.204 But as the entire angle is progressively covered by a membrane or sealed by synechiae, medical therapy or angle surgery eventually fail because of relentless angle closure. Filtering surgery or glaucoma drainage devices are often required to control glaucoma in patients with the ICE syndrome. However, clinicians should be aware that functioning filtering blebs often fail after 2–5 years, perhaps related to proliferation of a membrane over the internal opening of the sclerostomy, despite the use of adjunctive antimetabolite therapy.205 In such cases, some would attempt a repeat trabeculectomy with mitomycin application206 or tube operation. In most cases, corneal edema clears after successful filtering surgery; in other cases, edema persists, presumably because of corneal endothelial dysfunction.207 At one time it was proposed that

eyes with the ICE syndrome undergo a wide basal iridectomy to prevent total closure of the angle by PAS.208,209 This approach has

not proved to be useful.210 Ultimately, the discovery of the stimulus to epithelialization of the corneal endothelium will lead to inhibitors, and possibly prevent this difficult angle-closure disease.

Posterior polymorphous dystrophy

Posterior polymorphous dystrophy is a disease of the corneal endothelium that is sometimes associated with glaucoma.This condition affects both eyes and is usually inherited as an autosomal dominant trait, although autosomal recessive patterns have been reported. Association with an abnormality on the long arm of chromosome 20 has been reported for at least one large pedigree.211 Posterior polymorphous dystrophy occurs without known racial or sexual predilections,212 although several Thai families have been reported with this condition in association with Alport’s syndrome.213

Histopathology

Histopathologic study of eyes from individuals with posterior polymorphous dystrophy reveals a thin Descemet’s membrane covered

by multiple layers of collagen.214 This is lined by a layer of cells that various investigators have stated resembles endothelium,97,98,107,126 epithelium,20,208 or fibroblasts.98,126,211 In some cases a membrane

has been noted in the angle and on the anterior surface of the iris.211

Pathogenesis

The cause of posterior polymorphous dystrophy remains controversial. Analogous to the ICE syndrome, some investigators postulate that a dysplastic corneal endothelium produces a basement membrane-like material that extends into the angle and onto the iris. When the membrane contracts, it causes iris atrophy, corectopia, and iridocorneal adhesions.49 Most authorities believe posterior polymorphous dystrophy is a developmental disorder; a few authorities have postulated that a viral infection, perhaps herpes simplex, causes metaplasia of the corneal endothelium. Perhaps several different stimuli can produce similar epithelialization of endothelium.

Clinical presentation

Although the clinical picture of posterior polymorphous dystrophy is quite variable,214 the most typical physical finding is a cluster or linear arrangement of vesicles in the posterior cornea surrounded by a gray haze.215 The deep corneal stroma and Descemet’s membrane may also have band-like thickenings, white patches, peau d’orange appearance, or excrescences that project into the anterior chamber. Posterior polymorphous dystrophy may also have associated corneal edema, iris atrophy, mild corectopia, and iridocorneal adhesions.216 Most cases of this syndrome are non-progressive, and the individuals affected maintain good vision throughout their lives.These eyes are often asymptomatic. The diagnosis is made on routine examination or because other members of the family have been affected.

A minority of the individuals with posterior polymorphous dystrophy develop progressive corneal changes including corneal edema. Glaucoma occurs in 10–15% of patients with this disorder. In some cases glaucoma occurs in eyes with iris atrophy, corectopia, and iridocorneal adhesions.217 However, in other cases glaucoma occurs in eyes with open angles and an anterior insertion of the iris into the ciliary body, which resembles congenital glaucoma.218

The differential diagnosis of posterior polymorphous dystrophy includes Fuchs’ corneal dystrophy, congenital hereditary corneal dystrophy, Axenfeld’s syndrome or Rieger’s syndrome, and congenital glaucoma.These conditions should be distinguished readily by slit-lamp examination.The Haab’s striae of congenital glaucoma are thin areas surrounded by a thickened, retracted Descemet’s membrane. In contrast, the corneal involvement of posterior polymorphous dystrophy consists of thickened areas without breaks in Descemet’s membrane.

Treatment

Most cases of posterior polymorphous dystrophy require no treatment. If the cornea becomes edematous, the patient should be treated with hypertonic solutions, soft contact lenses, and penetrating keratoplasty as needed.The presence of iridocorneal adhesions is a risk factor for failure of keratoplasty. Eyes with glaucoma are treated with medication and then filtering surgery as necessary.

Epithelial downgrowth

Pathophysiology

Epithelial downgrowth (also called epithelial ingrowth) occurs when an epithelial membrane enters an eye through a wound and

(A)

(B)

Fig. 16–8  (A) Epithelialization of anterior chamber angle.

(B) High-power view.

(Courtesy of Ramesh C Tripathi, MD, PhD and Brenda J Tripathi, PhD, Chicago, Ill.)

then proliferates over the corneal endothelium, trabecular meshwork, anterior iris surface, and vitreous face (Fig. 16–8). The epithelial membrane in the angle contracts, producing PAS and severe angle-closure glaucoma without pupillary block.

Cataract surgery is the most common cause of epithelial down-

growth. In the past it was estimated that this complication occurred in about 1 in 1000 ICCE cataract operations.219,220 A relatively

recent review cites a 0.12% incidence decreasing to 0.08% in the decade of the 1980s.221 Furthermore, epithelial downgrowth was

found in 8–26% of eyes enucleated for complications of cataract sur- gery.222–224 In recent years epithelial downgrowth has been encoun-

tered less commonly because of the wide adoption of microsurgery and better techniques of cataract extraction. Epithelial downgrowth has also been reported after penetrating keratoplasty,225,226 glaucoma

surgery, penetrating trauma, and unsuccessful removal of epithelial cysts of the anterior segment.227,228

In most cases the epithelium invades the eye through a fistula or a wound gape;229 fistulas have been detected in 23–50%

of such eyes.230 It is also possible that epithelium can grow into a suture tract,231,232 or it can be introduced into an eye at the time of surgery or trauma.233,234 Epithelial downgrowth can occur after

uncomplicated surgery but is more likely to occur if surgery is associated with hemorrhage, inflammation, vitreous loss, or incarcerated tissue.235 Other factors seem to be endothelial damage and stromal vascularization. In the past it was observed that epithelial downgrowth occurred more frequently when cataract surgery was performed with a corneal section rather than with a limbal section. Furthermore, many authorities believed that epithelial downgrowth was less common when the cataract wound was covered with a limbus-based conjunctival flap rather than with a fornixbased conjunctival flap.These observations came from uncontrolled

studies, and their significance is not clear. Furthermore, modern

cataract extraction techniques have markedly reduced the incidence but have not eliminated the problem.236–238

Histopathology

Histopathologic study of biopsy specimens and enucleated globes

reveals the presence of stratified squamous epithelium on the corneal endothelium, iris, and angle structures.239–241 The epithelium,

which resembles conjunctival epithelium, is one to three cells thick except at the advancing corneal edge, where it may be five cells thick. However, the epithelium may also originate from cornea.242 The epithelial membrane passes posteriorly in some eyes to cover the ciliary processes, pars plana, and retina.243 If a fistula is present, it is also lined by stratified squamous epithelium.244

Clinical presentation

Epithelial downgrowth usually is seen as a low-grade persistent postoperative inflammation, including conjunctival injection, photophobia, discomfort, and aqueous humor cells.245 Careful examination may reveal large whitish cells floating in the anterior chamber.Affected eyes often have some evidence of current or past wound leak and are hypotonic if the fistula is still functional. The key to diagnosing this condition is finding a grayish white membrane with a scalloped, thickened leading edge on the posterosuperior corneal surface. The cornea overlying the membrane may be edematous, and the iris may be drawn up to the old wound or incision. The anterior surface of the iris often appears compacted, with loss of its normal architecture. In advanced cases the eye is painful with bullous keratopathy and intractable glaucoma.

The diagnosis of epithelial downgrowth is usually made on clinical grounds as indicated above. Specular microscopy may be

helpful in some cases, but this technique requires a clear cornea overlying the membrane.246,247 Involvement of the iris is dramati-

cally demonstrated when it is treated with large, low-energy argon laser burns (200–500  m, 100–400 mW, 0.1 second), which turn the epithelial membrane white. (Normal iris does not respond this way.) Because of the gravity of the situation, it is usually desirable to confirm the diagnosis histopathologically. Aqueous humor can be aspirated, passed through a Millipore filter, and then examined to identify epithelial cells. An alternative approach is to obtain a specimen by scraping a small portion of the posterior cornea with a blunt spatula. If these approaches are unfeasible or inadequate, biopsies should be taken of the posterior cornea and iris.

Most cases of epithelial downgrowth are associated with severe glaucoma. Usually the glaucoma is caused by a membrane that lines the angle and contracts to form PAS. Other factors contributing to the glaucoma include chronic inflammation, pupillary block, and obstruction of the trabecular meshwork by desquamating epithelial cells.248

Treatment

The treatment of epithelial downgrowth is often difficult and unrewarding. All of the techniques in current use attempt to close the fistula and then to excise or destroy the epithelium in the eye. It is common to determine the extent of iris involvement using the argon laser as described above. The corneal portion of the membrane can then be destroyed with cryotherapy or chemical cauterization. The affected iris can be excised, and cryotherapy can be applied to any remaining membrane on the ciliary body and retina.249 An alternative approach is to do an en-bloc excision of all involved tissues.250 Others have excised the involved iris and vitreous with a vitrectomy instrument and destroyed any remaining