Iridocorneal endothelial (ICE) syndrome is a rare, acquired, and typically unilateral ocular condition characterized by abnormal proliferation and migration of corneal endothelial cells. These cells undergo a pathological transformation, adopting epithelial-like properties, forming tight junctions, and migrating through the trabecular meshwork onto the anterior iris surface.1
This aberrant membrane contracts, distorting anterior segment structures and leading to corneal edema, peripheral anterior synechiae (PAS), iris abnormalities, and secondary angle-closure glaucoma.2 ICE syndrome is most commonly seen in women between 30 and 50 years of age, with a strong predilection for light-skinned females. It almost always occurs unilaterally and progresses slowly.
ICE syndrome is often misdiagnosed as uveitis, Fuchs’ endothelial dystrophy, or primary angle-closure glaucoma.3 Early recognition is essential, as delayed diagnosis increases the risk of irreversible glaucomatous damage and corneal decompensation.4
Pathophysiology of iridocorneal endothelial syndrome
The hallmark of ICE syndrome is the presence of endothelial “ICE cells,” which appear large, pleomorphic, and dark under specular microscopy, and are easily mistaken for guttata.
These cells cross Schwalbe’s line and produce a contractile membrane that invades the trabecular meshwork and iris, leading to PAS and obstruction of aqueous outflow.1,5 Structural studies show abnormal layering and thickening of Descemet’s membrane, consistent with endothelial-to-epithelial transition.6,7
The underlying mechanism of ICE syndrome is not entirely understood. Historical evidence suggests a viral etiology, specifically herpes simplex (HSV), some studies show otherwise.8,9 Recent molecular studies confirm that ICE syndrome is driven by endothelial-to-mesenchymal transition (EMT).
Dysregulation of genes such as COL4A1, MMP9, and SPARC, along with aberrant ZEB1 methylation, suggests a shift toward a myofibroblast-like phenotype, explaining the clinical findings of iris contraction and membrane formation.10 Upregulation of ACTA2 further supports this link. These specific genetic insights have important implications for targeted molecular therapies.
Clinical presentation of ICE syndrome
Although many are initially asymptomatic, eventually patients may present with:2,3,11
- Pain which may be sporadic
- Blurry or distorted vision
- Halos or monocular diplopia
Common clinical findings of ICE syndrome include:2,3,12
- Beaten bronze or hammered silver appearance of the corneal endothelium
- Microcystic corneal edema
- Iris changes (e.g., corectopia, polycoria, ectropion uveae, iris atrophy, iris nodules) which vary by subtype
- Anterior segment angle abnormalities (e.g., PAS)
- Elevated intraocular pressure (IOP), which can slowly progress over years
Subtypes of ICE syndrome
ICE syndrome has three clinical subtypes, and while corneal edema and PAS are consistently seen in all three, the iris changes can be used to distinguish one subtype from another as follows:
- Chandler syndrome: The most common variant, with corneal changes predominating. Patients often report monocular blurred vision from corneal edema. Mild iris thinning and correctopia may be present.5,13
- Progressive (essential) iris atrophy: Marked by severe iris thinning, stretching, corectopia, and polycoria. Secondary glaucoma from traction of the membrane and pronounced PAS can be difficult to control.4
- Cogan-Reese (iris nevus) syndrome: Characterized by multiple pigmented iris nodules or a diffuse pigmented lesion on the iris surface, with less iris atrophy than in essential iris atrophy. Glaucoma risk is high.14
Figures 1-3: Slit lamp images of Chandler syndrome, progressive (essential) iris atrophy, and Cogan-Reese syndrome.
Figure 1: Chandler Syndrome©Courtesy of Marta Sacchetti et al. Image used under CC BY 4.0.
Figure 2: Essential Iris Atrophy©Courtesy of Gustavo Espinoza. Image used under CC BY-NC-ND 4.0.
Figure 3: Cogan-Reese Syndrome©Courtesy of Annadurai Parivadhini et al. Image used under CC BY 3.0.
Download the cheat sheet here!
ICE Syndrome Subtype and Differential Diagnosis Cheat Sheet
Use this cheat sheet to review clinical features of ICE syndrome, including key characteristics of each subtype, and as a guide for differential diagnoses.
Diagnostic advances in ICE syndrome
Historically, slit lamp examination and gonioscopy were the main diagnostic tools.
Today, multimodal imaging enhances early detection and confirmation of disease:
- Specular and confocal microscopy: Identifies ICE cells and endothelial changes with high precision.7
- Anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM): Provide detailed visualization of angle compromise and membrane extension.
These tools are invaluable for early diagnosis, staging, and surgical planning. Suspected cases of ICE syndrome can be referred to an OD or OMD with one or more of these technologies as indicated.
Management strategies for ICE syndrome
The general approach to the management of ICE syndrome is to be proactive. Both chronic corneal edema and elevated IOP can result in permanent vision loss. Recognizing these early enough to intervene, often with surgical management, is key.
When secondary glaucoma develops
Secondary angle-closure glaucoma develops in up to 80% of patients, and is most commonly seen in the essential iris atrophy and Cogan-Reese subtypes.2,15 The progressive formation of PAS and trabecular dysfunction makes glaucoma management challenging.
Medical therapy targeting aqueous suppression (e.g., beta-blockers, alpha agonists, and carbonic anhydrase inhibitors) can provide temporary control, though long-term outcomes are poor. Given the plausible but unclear viral etiology, practitioners should use caution or avoid treatment with prostaglandin analogs due to their potential to reactivate HSV infection.1,16
Considering the high failure rate with medical management, paired with the progressive physical blockage of aqueous outflow, secondary glaucoma in ICE syndrome provides an elevated sense of urgency compared to traditional primary open-angle glaucomas. Co-management with a glaucoma surgeon is often indicated.
Ultimately, 50% of patients with ICE syndrome require surgical intervention for glaucoma, with limited surgical options.17 For example, selective laser trabeculoplasty and peripheral iridotomy are typically ineffective.
Trabeculectomy with mitomycin C has limited long-term success due to membrane regrowth, causing glaucoma drainage devices to be increasingly favored.18 In refractory cases, cyclodestructive procedures may be considered.4
Corneal edema and degeneration
Management of early corneal edema with topical hypertonic saline solutions may provide some relief, though decompensating corneas will eventually require transplantation.
Endothelial keratoplasty (DSAEK or DMEK) provides better outcomes than penetrating keratoplasty, especially in Chandler syndrome. However, success depends on IOP control and careful patient selection.7
Follow-up and co-management for ICE syndrome patients
Given the progressive and complex nature of ICE syndrome, along with its long-term degenerative impact on both corneal integrity and optic nerve function, patients require vigilant and ongoing monitoring.
Corneal edema and IOP that are not responsive to topical management warrant early referral. Surgical intervention for corneal transplantation and glaucoma drainage procedures is best coordinated by a surgeon who can perform both procedures, if possible.
Future directions for managing ICE syndrome
The discovery of EMT and epigenetic alterations in ICE syndrome provides potential targets for therapy. Downregulating ZEB1 with CRISPR-Cas9 or RNA interference, or modulating MMP9 and SPARC, could halt membrane formation.10
Reversing aberrant methylation with agents such as 5-azacytidine is another promising approach.10 The integration of these therapies with advanced imaging could usher in personalized, earlier-stage interventions.
Conclusion
ICE syndrome is a rare but vision-threatening condition that challenges clinicians with its subtle presentation, high risk of glaucoma, and corneal complications.
Advances in imaging, histopathology, and molecular biology have deepened understanding of the disease and hold promise for targeted future therapies.
For optometrists and ophthalmologists, vigilance is key: in a young, otherwise healthy patient presenting with unilateral corneal edema and glaucoma, ICE syndrome should always remain on the differential.
