Ophthalmology – Iridocorneal Endothelial (ICE) Syndrome

Basics

Description

Iridocorneal endothelial (ICE) syndrome is a rare, acquired disorder of the anterior segment characterized by abnormal proliferation of the corneal endothelium. It usually affects one eye and occurs most often in young to middle-aged women.

The abnormal endothelial cells spread from the posterior corneal surface across the anterior chamber angle and onto the iris. As this abnormal membrane contracts, it can produce progressive iris distortion, peripheral anterior synechiae, angle closure, corneal edema, and secondary glaucoma.

The three major clinical variants are progressive iris atrophy, Cogan–Reese syndrome, and Chandler syndrome. All three may produce corneal disease and glaucoma, although the dominant clinical features differ.

Epidemiology

ICE syndrome is uncommon, and its exact incidence and prevalence are not known.

It can affect individuals of any race but has a strong female predominance. Most patients are diagnosed in young or middle adulthood.

The disease is almost always unilateral.

Pediatric Considerations

ICE syndrome is extremely uncommon in children, although isolated pediatric cases have been reported.

Geriatric Considerations

Older patients may have substantial visual impairment from chronic corneal edema, glaucomatous optic nerve damage, or both.

Pregnancy Considerations

If glaucoma is present, medications may need to be adjusted during pregnancy or breastfeeding because some pressure-lowering agents may not be appropriate.

Risk Factors

No definite environmental or genetic risk factors have been established.

Unlike many corneal dystrophies, ICE syndrome is not considered an inherited disorder.

General Prevention

There is no known way to prevent ICE syndrome.

The main preventive strategy is early recognition and close follow-up to reduce the risk of irreversible vision loss from glaucoma or corneal decompensation.

Etiology

The exact cause is unknown.

A possible viral mechanism, particularly involving herpes simplex virus, has been proposed. HSV DNA has been detected in the corneal endothelium of some affected eyes, but a definitive causal relationship has not been established.

Pathophysiology

The central abnormality is a population of pathologic corneal endothelial cells that behave more like epithelial cells than normal endothelium.

These abnormal cells proliferate and form a membrane that extends:

Corneal endothelium → anterior chamber angle → iris

As the membrane contracts, several structural changes can develop.

Peripheral anterior synechiae form as the iris is pulled toward and adheres to the angle. Progressive angle closure can obstruct aqueous outflow and lead to secondary angle-closure glaucoma.

The same membrane can pull on the iris and produce:

• Corectopia
• Iris stromal atrophy
• Pseudopolycoria
• Iris nodules
• Distortion of normal iris architecture

At the corneal level, abnormal endothelial pump function causes stromal and epithelial edema and may eventually produce chronic corneal decompensation.

Clinical Variants

Progressive Iris Atrophy

This form is dominated by marked iris changes.

Typical findings include progressive iris stromal atrophy, severe corectopia, pseudopolycoria, and broad peripheral anterior synechiae.

Angle closure tends to be prominent, and secondary glaucoma is common.

This variant often produces the most dramatic iris distortion.

Cogan–Reese Syndrome

Cogan–Reese syndrome, also called iris nevus syndrome, is characterized by pigmented iris abnormalities.

Patients may have a diffuse iris nevus-like lesion or multiple nodules over the iris surface.

The appearance can mimic an iris melanoma, making careful examination important.

Glaucoma and corneal edema can also occur.

Chandler Syndrome

Chandler syndrome is characterized primarily by corneal disease.

The corneal endothelium may have a characteristic hammered-silver appearance, and corneal edema is often the major cause of symptoms.

Compared with the other variants, iris abnormalities may be less prominent and glaucoma may be somewhat less frequent.

Commonly Associated Conditions

The major associated ocular conditions are:

• Secondary angle-closure glaucoma
• Progressive peripheral anterior synechiae
• Corneal edema
• Corneal endothelial failure
• Iris atrophy
• Corectopia
• Pseudopolycoria

There is no established systemic syndrome consistently associated with ICE.

Diagnosis

History

Patients usually present with symptoms in one eye.

Common complaints include:

• Blurred vision
• Fluctuating vision
• Vision worse in the morning
• Ocular discomfort
• Pain
• Halos around lights
• Visible change in pupil shape
• Progressive visual loss from glaucoma

Morning blurring is often related to increased corneal edema after overnight eyelid closure.

Pain may result from epithelial edema, bullous changes, or elevated IOP.

Physical Examination

A complete anterior segment and glaucoma examination is essential.

Cornea

Slit-lamp examination may show:

• Corneal edema
• Abnormal endothelial appearance
• Reduced corneal clarity
• Bullous epithelial change in advanced disease

The endothelial surface may look irregular or hammered silver.

Iris

Possible findings include:

• Corectopia
• Iris stromal atrophy
• Pseudopolycoria
• Iris nodules
• Diffuse nevus-like pigmentation
• Irregular pupil shape

The pattern often helps determine the clinical subtype.

Anterior Chamber Angle

Gonioscopy is very important.

Findings may include:

• Broad peripheral anterior synechiae
• Progressive synechial angle closure
• Abnormal membrane extending across the angle

In some eyes, synechiae can extend unusually far anteriorly, including beyond Schwalbe’s line.

Intraocular Pressure

IOP may be normal early in the disease.

As the angle progressively closes, IOP may rise and secondary glaucoma may develop.

The glaucoma can become severe and difficult to control.

Diagnostic Tests and Interpretation

Visual Acuity

Visual acuity may be reduced because of:

• Corneal edema
• Cataract
• Glaucomatous damage

Fluctuating vision can occur as corneal edema varies.

Visual Field Testing

Visual fields are indicated when glaucoma is suspected or established.

Defects reflect the degree of glaucomatous optic neuropathy.

Optic Nerve Imaging

OCT of the retinal nerve fiber layer and optic nerve can help detect and follow glaucoma progression.

Serial optic disc photography may also be useful.

Specular Microscopy

Specular microscopy can demonstrate the characteristic abnormal endothelial cells.

Findings may include:

• Irregular cell size
• Abnormal cell shape
• Loss of the normal hexagonal endothelial pattern
• Characteristic ICE-cell appearance

This test can strongly support the diagnosis.

Pachymetry

Pachymetry is useful for measuring corneal thickness and following progression of corneal edema.

Differential Diagnosis

Fuchs Endothelial Corneal Dystrophy

Fuchs dystrophy can produce similar corneal edema and endothelial changes, but it is usually:

• Bilateral
• Associated with guttae
• Not associated with progressive iris distortion or broad PAS

Posterior Polymorphous Corneal Dystrophy

Posterior polymorphous dystrophy can also resemble ICE syndrome, but it is generally:

• Bilateral
• Familial
• Present earlier in life

Axenfeld–Rieger Syndrome

Axenfeld–Rieger syndrome may produce angle and iris abnormalities, but it is usually congenital and bilateral.

Systemic findings such as dental or craniofacial abnormalities may also be present.

Iris Melanoma

Cogan–Reese syndrome may resemble an iris melanoma.

Progressive mass growth, intrinsic tumor vessels, secondary cataract, and localized angle invasion may favor melanoma.

Treatment

Treatment is directed mainly at corneal edema and glaucoma.

There is no therapy that reliably eliminates the abnormal endothelial membrane itself.

Corneal Edema

Mild corneal edema can be treated with hypertonic sodium chloride 5% drops or ointment.

These therapies may reduce epithelial edema and improve vision temporarily.

They do not correct the underlying endothelial dysfunction.

If corneal decompensation becomes visually significant, endothelial keratoplasty may be required.

Glaucoma

Topical glaucoma medications are generally used initially.

Because the angle becomes progressively closed by PAS and abnormal endothelial membrane, medical treatment may eventually become insufficient.

Laser Trabeculoplasty

Laser trabeculoplasty is generally not effective because the problem is not primarily an open trabecular meshwork with increased resistance. Instead, there is progressive structural angle closure.

Laser Peripheral Iridotomy

Laser peripheral iridotomy usually does not halt progression.

ICE-related angle closure is not primarily caused by pupillary block, so the abnormal endothelial membrane continues to contract even after an iridotomy.

Surgical Treatment

Trabeculectomy

Trabeculectomy may be performed when medications fail.

An antimetabolite such as mitomycin C may improve surgical success.

However, trabeculectomy can fail because abnormal endothelial tissue may proliferate over the internal filtering ostium.

Glaucoma Drainage Devices

Tube shunts are often considered in refractory ICE-associated glaucoma.

They may be more successful than trabeculectomy in some patients because the drainage pathway is less vulnerable to direct closure by the endothelial membrane.

Even so, tube positioning must be carefully planned because the corneal endothelium is already compromised.

Corneal Transplantation

Persistent corneal edema and endothelial failure may require corneal transplantation.

Modern endothelial procedures such as:

• DSAEK
• DMEK

may be used when appropriate.

Because the underlying ICE process can remain active, recurrent endothelial failure or graft decompensation can occur.

Cataract Surgery

Cataract surgery may be more complicated because of:

• Poor pupillary dilation
• Iris distortion
• PAS
• Fragile iris tissue
• Corneal endothelial dysfunction

Extra care is required to protect the corneal endothelium.

Iris Reconstruction

Iris reconstruction may be considered when severe corectopia or iris defects cause:

• Glare
• Photophobia
• Cosmetic concerns

The iris can be friable and technically difficult to repair.

Artificial iris implantation may be considered in selected patients.

Ongoing Care

Follow-Up Recommendations

ICE syndrome is progressive, so long-term follow-up is required.

Patients with mild disease and no glaucoma may be monitored periodically, often annually.

Patients with glaucoma or significant corneal disease require more frequent follow-up.

Patient Monitoring

Follow-up should assess:

• Visual acuity
• IOP
• Gonioscopic angle changes
• Optic nerve appearance
• Visual fields
• OCT of the retinal nerve fiber layer
• Corneal edema
• Corneal thickness
• Progression of iris abnormalities

Referral to a glaucoma specialist or corneal specialist may be needed when complications become significant.

Patient Education

Patients should understand that ICE syndrome is a chronic, usually unilateral, progressive condition.

They should be informed that the two major threats to vision are:

• Glaucoma
• Corneal decompensation

They should seek prompt evaluation for worsening pain, halos, blurred vision, or sudden reduction in vision.

Prognosis

The visual prognosis depends mainly on the severity of glaucoma and the degree of corneal endothelial failure.

Patients with well-controlled IOP and manageable corneal edema may maintain useful vision for many years.

Advanced glaucoma can cause irreversible visual loss even if corneal clarity is restored later.

Corneal transplantation can improve vision, but repeated graft failure or rejection can limit the final outcome.

Complications

Important complications include:

• Secondary angle-closure glaucoma
• Progressive optic nerve damage
• Permanent visual field loss
• Chronic corneal edema
• Bullous keratopathy
• Corneal decompensation
• Cataract
• Surgical complications
• Graft failure after endothelial keratoplasty

The key clinical concept is that ICE syndrome is an acquired, usually unilateral disease in which abnormal corneal endothelial cells spread over the angle and iris, producing corneal edema, progressive iris distortion, peripheral anterior synechiae, and potentially severe secondary glaucoma.