Iridocorneal Endothelial Syndrome

Etiology

The pathogenesis of ICE is not fully understood; several working hypotheses exist. Corneal endothelial cells are postmitotic and typically do not proliferate in vivo; the quantity of these cells decreases with age.[7][8] ICE can develop when corneal endothelial cells regain proliferative capacity.[3] Corneal endothelial cells play an important role in regulating corneal hydration and transparency, and endothelial dysfunction leads to corneal edema and visual defects.[9] 

The neural crest theory is one proposed pathogenic mechanism for ICE development. This theory stratifies different ocular endothelial disorders by neural crest origin. ICE was thought to be related to abnormal neural crest cell (NCC) proliferation, compared to NCC formation in cyclopia, NCC migration in Peters anomaly, or NCC differentiation in Fuchs dystrophy.[10]

In Peters anomaly, an abnormality in the development of the first wave of neural crest cells leads to a failure of separation between lens vesicles and surface ectoderm, causing corneal opacification.[11][12][13] Type 1 Peters anomaly is characterized by iridocorneal adhesions, the development of corneal opacity, and a striking similarity to ICE.[14][15][16] However, compared with ICE, Peters anomaly presents at a younger age and occurs bilaterally in 80% of cases.[17] Fuchs dystrophy is also a bilateral endothelial disorder, but unlike Peters anomaly and ICE, it does not present with iridocorneal adhesions.[1] Similar to ICE, Fuchs dystrophy may present with corneal edema.[18] 

Cambell, Shields, and Smith proposed their membrane theory in 1978 to better explain the corneal endothelial structural changes and abnormalities associated with ICE.[19] The membrane theory characterizes ICE as primary proliferative endothelial degeneration and emphasizes that this disease is primarily corneal in origin with secondary impacts on the iris. According to the membrane theory, the initial pathologic insult involves corneal endothelial degeneration that progresses to abnormal endothelial membrane overgrowth around the iridocorneal angle. Obstruction of the trabecular meshwork and contraction of the membrane leads to structural changes in the iris, secondary glaucoma, and ectropion uveae.[20] Further histological studies of ICE cell characteristics have supported the membrane theory.[19][21]

Although these hypotheses discuss the progression of ICE, the causal factor of ICE remains undetermined. Various studies have described an association between ICE and inflammation or uveitis.[1] Another proposed pathogenic mechanism points to a viral trigger. In 1994, Alvarado et al investigated ICE's potential viral etiology using polymerase chain reaction and identified Herpes simplex viral (HSV) DNA in >60% of tested ICE specimens.[22] In this study, corneal control specimens consisted of normal corneas and corneas with keratoconus, interstitial keratitis, or aphakic bullous keratopathy. None of the control corneas tested positive for HSV DNA. Interestingly, when the corneal endothelial layer was removed from ICE specimens, HSV DNA was no longer detected. This finding provided direct evidence to support the idea that viral DNA was confined to the endothelial cell layer.[1][22] Other studies report an association between Epstein-Barr virus (EBV) and ICE.[23]

Epidemiology

ICE is an acquired syndrome that typically presents unilaterally and predominantly affects females between the age of 20 and 50.[5] However, there are case reports of bilateral presentation, and ICE has been diagnosed in male patients.[24] Despite reports of concurrent ICE and sensorineural hearing loss, no definitive association has been established. 

Observational studies indicate varying incidences of ICE subtypes among racial and ethnic groups. For instance, CS is the most common variant of ICE diagnosed in White patients.[1] In contrast, CRS is the least frequently reported subtype in India at 14.29%, and EIA has the highest incidence at 66.67%.[25] This study also documented the incidence of ICE in Indian male patients at 62%, compared with studies from North America and Europe, which reported the incidence in males as 17%.[26]

Pathophysiology

The pathophysiology of ICE results from the increased proliferation and migration of corneal endothelial cells to the iridocorneal angle and iris, leading to secondary angle-closure glaucoma (see Image. Iridocorneal Endothelial Syndrome: Secondary Angle-Closure Glaucoma), corneal edema, and iridic atrophy.[1]

Histopathology

The cornea comprises multiple highly organized layers that maintain corneal transparency and barrier function. The nonproliferative layer of corneal endothelial cells is a barrier and a pump, helping to maintain the clarity and transparency of the cornea.[27] The corneal epithelial cells in patients with ICE are typically taller, and the multilayer organization is abnormal. These abnormal endothelial cells retain the microvilli or their normal counterparts.[1] 

Corneal decompensation occurs when persistent corneal insults lead to increasing corneal opacity.[28] The development of secondary glaucoma is due to the formation of peripheral anterior synechiae (PAS) or the growth of abnormal endothelial cells over the trabecular meshwork.[1] These histological changes lead to elevated intraocular pressure (IOP), the characteristic finding of glaucoma.[1]

History and Physical

The typical presenting clinical symptoms of patients with ICE include changes in the shape of their pupil due to atrophy of the iris and visual changes such as decreased vision upon waking or blurred halo of lights due to corneal edema and subsequent corneal decompensation.[1] Patients may also develop ocular pain or headache if they have a severe increase in IOP due to secondary glaucoma.[29]

The external appearance of the affected eye is abnormal in patients with ICE but will vary with the stage of the disease and clinical variant.[1] The atrophic iridic changes characteristic of EIA may not be seen without careful slit-lamp examination.[1] Due to extensive endothelial dystrophy, patients with CS or CRS may develop significantly increased IOP, severe glaucoma, and corneal edema, which grossly appears as corneal opacification.[1]

Ophthalmic examination of the corneal endothelium may reveal “hammered silver” or “beaten bronze” irregularities during slit-lamp examination, a reversal light pattern during specular microscopy, or changes in the iridocorneal angle on gonioscopy. (see Image. Iridocorneal Endothelial Syndrome: Corneal Endothelium Irregularities). Cupping of the optic nerve may be seen in patients with secondary glaucoma).[30]

A thorough physical examination includes a slit-lamp examination, a careful exam of the angle with gonioscopy, and tonometry or applanation. Techniques such as specular microscopy and in vivo corneal confocal microscopy (IVCM) can reveal pathognomonic findings.[1][2]

Evaluation

Early diagnosis of ICE is essential to prevent the complications of corneal edema and secondary glaucoma.[2] If significant corneal edema prevents clear visualization of the anterior chamber structures, IVCM can be employed.

IVCM is a noninvasive imaging technique that allows visualization of corneal layers at the cellular level. The abnormal corneal epithelial cells of patients with ICE appear as epithelial-like endothelial cells varying in size and shape, with bright cell borders and hyperreflective nuclei.[26] Specular microscopy is another imaging tool to evaluate the corneal epithelium; epithelial cells in patients with ICE are characterized by an abnormally large and round shape and display a pattern of "light-dark reversal." These abnormally dark cells have a light central spot with light borders, which is the opposite of normal endothelial cell light patterns. In addition to IVCM and specular microscopy, gonioscopy is required to visualize the iridocorneal angle. In ICE, there are often progressive broad-based synechiae located on the iris and around the trabecular meshwork. 

If gonioscopy is challenging due to corneal edema, ultrasound biomicroscopy can be used to visualize the anterior chamber angle and detect abnormalities.[31] Gonioscopy, in combination with ultrasound biomicroscopy, can be used to assess the size and extent of PAS fully.[2]

Patients with ICE and subsequent secondary glaucoma should be evaluated with Humphrey visual field testing, central corneal thickness measurements, intraocular pressure evaluation with Goldmann applanation tonometry, evaluation of the iridocorneal angle and trabecular meshwork with gonioscopy, optic nerve evaluation on physical examination, as well as optical coherence tomography of the optic nerve head and retinal nerve fiber layer.[32][33]

Treatment / Management

The treatment of ICE is typically centered around managing corneal decompensation and preventing irreversible glaucomatous vision loss. Surgical procedures may address iridic changes to improve cosmesis or vision-impacting defects.[1] (B3)

Endothelial keratoplasty techniques such as Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK) are preferred over penetrating keratoplasty (PK) for the treatment of ICE-related corneal edema.[1] DMEK improves outcomes and shortens recovery time when compared to DSAEK.[34] A recent study evaluating the effectiveness of DMEK in patients with ICE showed an 85.7% cumulative graft success rate after 1 year.[34] However, DSAEK is the preferred procedure for patients with significant iris changes or copious synechiae. If patients have failed multiple keratoplasty procedures, keratoprosthesis may be considered.[35] (B3)

ICE damages the functionality of the trabecular meshwork in the iridocorneal angle, blocking aqueous outflow and causing secondary glaucoma. Therefore, topical eyedrops that decrease aqueous humor production are preferred over those that increase trabecular aqueous outflow.[1] The primary treatment regimen for secondary glaucoma includes topical beta blockers, carbonic anhydrase inhibitors, and alpha agonists. Topical prostaglandins have been associated with intraocular reactivation of HSV and should be avoided in patients with ICE.[1][36] (B3)

ICE-induced secondary glaucoma may be very challenging to control. If IOP is not adequately controlled with topical ophthalmic medications, surgical interventions such as goniotomy, trabeculectomy with antifibrotic agents such as mitomycin-C or 5-fluorouracil, glaucoma drainage implants, or cyclodestructive procedures must be considered.

Goniotomy is an excellent surgical option to relieve the obstruction to aqueous outflow caused by the ICE membrane over the angle.[37] However, a new membrane can subsequently form over the goniotomy site resulting in recurrent obstruction. Trabeculectomy with antimetabolites can be performed to manage IOP but usually fails over time due to the proliferation of the endothelial membrane in the trabecular meshwork, ostium, and fistula, and the deposition of abnormal basement membrane within the bleb.[38] (B2)

Trabeculectomy outcomes in patients with ICE are typically worse than in other disease processes, such as primary open-angle glaucoma, pigmentary glaucoma, and juvenile open-angle glaucoma.[39][40] Success rates for patients with ICE are higher when trabeculectomy is performed early in the disease process.[41] In general, the success rate of trabeculectomy is approximately 60% at 1 year and 40% at 2 years.[42] (B2)

Trabeculectomy with antimetabolites and glaucoma drainage implants offer postoperative IOP reduction for patients with ICE syndrome. Still, the long-term failure rate for trabeculectomy may be higher than for glaucoma drainage devices.[43] Glaucoma drainage devices may fail if the continued proliferation of the endothelial membrane blocks the drainage tube. Inserting the tube behind the iris at the ciliary sulcus, especially in pseudophakic eyes, may avoid this phenomenon.[1] Nd:YAG laser may be employed to reopen blocked drainage tubes due to endothelial proliferation.(B3)

Cyclodestructive procedures may be employed when surgical interventions fail to control the IOP, resulting in a painful blind eye. The options for cyclodestructive procedures include diode laser cyclophotocoagulation, cyclocryotherapy, and endocyclophotocoagulation. 

Femtosecond-assisted keratopigmentation (KTP) has shown promising results in eliminating the diplopia and photophobia common in patients with ICE.[44] Alternatively, multiple endocapsular iris prosthesis devices can be implanted inside the capsular bag in front of the intraocular lens to address iris atrophy and photophobia and improve cosmesis.[1][45](B3)

Differential Diagnosis

ICE should be considered a potential diagnosis in any young female with unilateral corneal edema, visual disturbances, iris abnormalities, or glaucoma.[2] The variants of ICE may present similarly to other disease processes, and it is essential to obtain a comprehensive medical history and perform a thorough physical examination to identify the correct underlying disease.

The differential diagnosis for CS includes posterior polymorphous corneal dystrophy (PPCD) and Fuchs endothelial dystrophy. PPCD is a corneal disorder that is typically bilateral and inherited in an autosomal dominant fashion. Similar to the ICE variants, patients with PPCD have areas of PAS that increase their risk for secondary glaucoma. However, the Descemet membrane of patients with PPCD is thickened and may reveal vesicular, band-like, or diffuse opacities; the Descemet membrane in CS is normal. Fuchs endothelial dystrophy is a bilateral disorder and does not present with iridocorneal abnormalities, and IVCM reveals hyporeflective nuclei compared to the hyperreflective nuclei seen in ICE. Fuchs endothelial dystrophy often presents with endothelial guttae, or the deposition of an extracellular collagen-like matrix, in addition to corneal edema.[1][18]

The differential diagnosis for EIA includes Axenfeld-Rieger syndrome (ARS), aniridia, and iridoschisis.[46][47][13] ARS is a congenital disorder usually inherited in an autosomal dominant fashion but can occur sporadically. Patients with ARS display changes at birth and may have associated anomalies such as abnormal teeth. ARS is typically a bilateral disease, whereas ICE is usually unilateral. ICE and ARS display a similar pattern of an endothelial cell monolayer extending over the cornea, iridocorneal angle, and iris. However, since ARS is a congenital disorder, it is hypothesized that the iridocorneal membrane is due to the retention of primordial endothelium. A distinct differentiating factor between ARS and ICE is the posterior embryotoxon with iris strands of ARS. 

Aniridia is another congenital disorder that is typically bilateral and often associated with other conditions, such as optic nerve hypoplasia. The age of onset can be an important factor in helping differentiate aniridia from late-stage EIA. Most cases of aniridia present within the first 6 weeks of life; other associated sensory deficits, such as hearing loss and decreased sense of smell, are common.[48] Iridoschisis is the progressive separation of the layers of the iris, is frequently bilateral, and most often occurs in older patients.[1]

The differential diagnosis of CRS is broad and includes Tapioca melanoma and diffuse malignant melanoma of the iris. Tapioca melanoma presents with nodules on the iris similar to those in CRS. However, these nodules are typically hypopigmented compared to the hyperpigmented nodules in CRS. In addition, typical features of CRS, including PAS and iris atrophy, are not present in Tapioca melanoma. Diffuse malignant melanoma of the iris typically does not present with distortion of the pupillary margin and PAS, which are more suggestive of CRS.[1]

Prognosis

The prognosis of ICE is dependent on how advanced the disease is at the time of diagnosis and the presence of secondary complications. Corneal surgeries may not be able to excise the abnormal endothelium entirely and, therefore, may not prevent the progression of PAS and the development of secondary glaucoma.[2] 

A small case series of 8 eyes in 7 patients studied the outcome of DMEK in patients with both ICE and PPCD. This 2018 case series reported a statistically significant increase in best-corrected visual acuity in all eyes at 6 and 24 months following the procedures.[49] A more extensive study in 2020 analyzed 86 patients undergoing their first corneal transplants for ICE syndrome and the 5-year graft survival rates in patients who underwent penetrating keratoplasty (PKP) or endothelial keratoplasty (EK). There was no significant difference between corneal graft survival rates for PKP or EK procedures, with 64.3% and 66.8% survival rates, respectively.[50]

Complications

The complications of ICE include iris abnormalities, corneal edema and decompensation, and secondary glaucoma.[2] Glaucoma occurs in approximately 50% of patients with ICE and is more common in the EIA variant.[29][37] Corneal edema and decompensation, however, are higher in the CS subtype. Depending on the severity of endothelial disease in any subtype of ICE, patients may be approached differently during intraocular surgeries such as cataract extraction; patients may undergo combined DSAEK and cataract extraction to address their corneal endothelial disease.[51]