Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

flavonoid derivative of rutin, which improves microvascular circulation by inhibiting platelet and erythrocyte aggregation (17).

IRIDOCORNEAL ENDOTHELIAL SYNDROME

Another tissue element that may line the inner surface of the trabecular meshwork and lead to aqueous outflow obstruction is a monolayer of endothelial cells with an underlying descemet-like membrane. This is seen most commonly in a spectrum of disease called the iridocorneal endothelial (ICE) syndrome.

Clinical Features

The condition usually appears in early to middle adulthood, with no family history but with a predilection for women. It is typically uniocular, involving the cornea, anterior chamber angle, and iris.

A corneal endothelial abnormality is the common feature throughout the ICE syndrome and is the primary disorder from which the other ocular changes are derived. It is seen by slit-lamp examination as a fine hammered-silver appearance of the posterior cornea, similar to that of Fuchs’ dystrophy. Specular microscopy reveals a characteristic, diffuse abnormality of the corneal endothelial cells, with various degrees of pleomorphism in size and shape, dark areas within the cells, and loss of clear hexagonal margins. In some cases, the endothelial abnormality leads to corneal edema, which may blur vision in the morning hours until the cornea dehydrates from exposure to ambient air. In more advanced cases, it may cause persistent visual impairment and pain. The fellow eye, while typically asymptomatic, may have islands of the hammered-silver appearance by slit-lamp examination and subtle specular microscopic changes, but corneal edema and the other features of ICE syndrome are extremely rare.

Some patients with the ICE syndrome may have glaucoma in the effected eye despite an open, grossly normal appearing anterior chamber angle. In the typical patient, however, there are broad areas of iridocorneal adhesion, in which the peripheral iris may extend anterior to Schwalbe’s line. A high percentage of these patients will have uniocular glaucoma.

Various degrees of iris abnormality, including corectopia, ectropion uvea, thinning of the iris stroma, full-thickness iris holes and iris nodules, have led to clinical subdivisions within the ICE syndrome. In Chandler’s syndrome, the iris changes are minimal or absent, but corneal edema is more frequent than in the other clinical forms (18).

Progressive iris atrophy (previously called essential iris atrophy) is characterized by extensive iris distortion, with marked corectopia and full-thickness holes (19) (see Fig. 5). In the Cogan–Reese syndrome, there may be any degree of iris distortion, with the distinguishing feature being small, pigmented iris nodules on the iris stroma (20).

Etiology and Mechanism

The absence of a family history and the presence of a fully developed Descemet’s membrane suggest that the ICE syndrome is an acquired disorder. Some patients have a past history of inflammation in the involved eye, and chronic inflammatory cells have been observed in corneal specimens, leading to a viral theory of etiology (21).

Fig. 5. Slit-lamp view of eye with progressive (essential) iris atrophy clinical variation of iridocorneal endothelial syndrome, demonstrating inferior displacement of pupil (corectopia) with large iris holes superiorly.

Using primer pairs and polymerase chain reaction in 25 corneas from patients with the ICE syndrome, 16 were positive for herpes simplex virus DNA but negative for herpes zoster or Epstein–Barr viruses (22). These findings support a viral etiology for the ICE syndrome although further study is needed.

While the etiology of the ICE syndrome is still under study, the mechanism of the anterior chamber angle and iris changes have been fairly well established. The abnormal corneal endothelium, in addition to causing the corneal edema, leads to migration of the endothelial monolayer and associated Descemet-like membrane over the trabecular meshwork and iris stroma (23). Observations of filopodial processes (see Fig. 6), cytoplasmic actin filaments, and apparent loss of contact inhibition are consistent with the concept of migrating cells. The presence of the abnormal tissue over the internal surface of the trabecular meshwork obstructs aqueous outflow and may cause an open-angle form of glaucoma. By the time most patients are seen, however, the endothelial cells have contracted, causing the broad areas of iridocorneal adhesion, with further compromise of outflow and elevation of the IOP.

The abnormal endothelial layer on the iris stroma also contracts, leading to the corectopia and ectropion uvea, as seen in Chandler’s syndrome. The distortion of the iris is associated with the thinning of iris stroma and full-thickness holes of progressive iris atrophy although it is likely that additional factors, including iris ischemia, are also involved with these changes. The iris nodules in the Cogan–Reese syndrome are composed of tissue resembling iris stroma and are typically surrounded by the endothelial tissue (see Fig. 7). It is believed that the advancing endothelial layer pinches off portions of iris stroma as it advances, creating the nodules in this subset of the ICE syndrome.

Differential Diagnosis

There are three categories of disorders that might be confused with various features of the ICE syndrome: those with corneal endothelial disorders, distortion of the iris, and iris nodules.

Posterior polymorphous dystrophy (PPD) is a bilateral, familial disorder of the corneal endothelium, typically of autosomal dominant inheritance, in which the

The Axenfeld–Rieger syndrome has striking clinical and histologic similarities to the ICE syndrome, including an endothelial layer over the angle and iris, but is an inherited, bilateral developmental condition. Other disorders associated with abnormalities of the iris that might be confused with the ICE syndrome include aniridia and iridoschisis.

Conditions with iris nodules, which might be confused with those of the Cogan– Reese subset, include iris melanomas (eyes have been enucleated due to this misdiagnosis), iris melanosis, the Lisch nodules of neurofibromatosis, and inflammatory nodules, such as those seen in sarcoidosis. A condition called iris nevus syndrome was once mistakenly thought to be synonymous with the Cogan–Reese syndrome.

Management

The management of patients with the ICE syndrome may focus on the corneal edema, the glaucoma, or both. Mild forms of corneal edema may be controlled with hypertonic saline solutions and soft contact lenses. In some cases, reduction of the IOP, even in the absence of glaucoma, may help to relieve the edema. In more advanced cases, however, penetrating keratoplasty is required.

At the present time, the glaucoma is controlled in much the same way as with other chronic forms of glaucoma. Medications that reduce aqueous production are often sufficient although a significant percentage eventually require surgical intervention. These patients do well with filtration surgery although the endothelial layer may eventually grow over the internal fistula, suggesting that a drainage implant might be preferable.

Future treatments for the ICE syndrome may focus more on the specific etiology and mechanism. For example, if the viral theory proves to be correct, antiviral agents might be useful although this has yet to be demonstrated. Another approach might be to arrest the growth of the abnormal endothelial cells. An immunotoxin has been reported, which inhibits the proliferation of human corneal endothelium in tissue culture (24). To date, however, no effective disease-specific treatment has been reported for the ICE syndrome.

EPITHELIAL AND FIBROUS MEMBRANES

There are also conditions in which an epithelial or fibrous membrane covers the trabecular meshwork, leading to outflow obstruction. These are much less common and will be dealt with briefly.

Posterior Polymorphous Dystrophy

Similar to the ICE syndrome, PPD is a primary disorder of the corneal endothelium. Unlike ICE, however, PPD is bilateral and familial, usually with autosomal dominant inheritance. The clinical appearance by slit-lamp examination is of blisters or vesicles at the posterior surface of the cornea, which may be linear or in groups and surrounded by an aureole of gray haze. The cornea may remain clear and produce no symptoms, whereas corneal edema may develop in some patients, but usually not until adulthood. A small subset of PPD is associated with peripheral iridocorneal adhesions, iris atrophy, and corectopia (25). Glaucoma occurs in approximately 15% of patients with PPD with or without iridocorneal adhesions.

Ultrastructual studies of the posterior cornea reveal an incomplete Descemet’s membrane covered by multiple layers of collagen and lined by cells that have been variably described as abnormal endothelium, epithelium, or fibroblasts. The incomplete nature of Descemet’s membrane in PPD, compared with the fully developed membrane in ICE, suggests that the former condition began during gestation, whereas the latter was acquired after birth. In the small subset of PPD patients with the iris and angle anomalies, a membrane composed of endothelial-like or epithelial-like cells and a Descemet’s-like membrane may be seen extending over either an openor closed-anterior chamber angle and onto the iris.

The mechanism of the glaucoma in these patients may be related to the abnormal membrane, which arises from dystrophic corneal endothelium, grows down across the anterior chamber angle and onto the iris, initially covering the open angle and then contracting to close the angle. In other cases, the angle may be open, with a high insertion of anterior uvea to the trabecular meshwork, which causes collapse of the trabecular beams, as is seen in several developmental glaucomas with anomalies of the anterior chamber angle.

Many patients remain asymptomatic and are followed without treatment while some require penetrating keratoplasty for corneal edema. When associated glaucoma is present, medical therapy with aqueous suppressants may be sufficient although some will eventually require filtering surgery.

Epithelial Ingrowth

Epithelial ingrowth, also known as epithelial downgrowth, is an uncommon and devastating complication of penetrating trauma or multiple ocular surgeries. The epithelial cells gain access to the intraocular structures through an open wound, inducing alterations in the architecture of trabecular meshwork and impairing aqueous outflow, culminating in intractable glaucoma.

Clinical Features

Epithelial ingrowth is usually characterized by the presence of a whitish retrocorneal membrane. Although anterior segment structures are frequently involved, including posterior corneal endothelium, iris, and TM, any intraocular structure can be affected. Extension of the membrane onto the iris surface renders a flat appearance to an otherwise normal iris collarettes appearance. Clinical signs can vary from mild diminution of visual acuity to severe inflammation and pain secondary to uncontrolled glaucoma. In some cases, it is challenging to delineate the extent of the membrane due to its transparent nature. A simple method to outline the iris involvement is application of argon laser photocoagulation, which causes blanching when applied to the epithelial membrane and charring when delivered to the normal iris.

Etiology and Mechanism

Once the epithelial cells have invaded the anterior chamber, they undergo proliferation to form either epithelial cysts or opaque sheets (26). The sheetlike form is more difficult to diagnose due to its diffuse nature. It also tends to run an aggressive course with frequent recurrence after treatment. Histological studies have shown that the

source of this epithelium is either cornea or conjunctiva, and it is composed of nonkeratinized, stratified squamous cells (27). Glaucoma can result from either obstruction of aqueous outflow from lining of the TM by these epithelial cells through an open-angle mechanism or contraction of this epithelial membrane resulting in peripheral anterior synechiae and angle closure glaucoma. Other uncommon mechanisms include pupillary block from occlusion of the pupil from the epithelial cells and blockage of the TM from “desquamating epithelium” and resultant inflammatory cells.

Differential Diagnosis

An important differential is fibrous ingrowth, which is discussed below. This can also result from gaping of an unsutured wound from either surgery or penetrating injury. Clinically, this can be difficult to distinguish from epithelial ingrowth, except for the presence of vascularity.

Management

Therapeutic modalities include irradiation, cryotherapy, laser photocoagulation, and surgical excision (26). The cyst form is more amenable to surgical removal because of its circumscribed margins. The sheet-like form often requires radical excision of involved tissues with need for corneal and scleral grafts. Overall, the success rate for surgery is low for these advanced cases, emphasizing the need for early recognition and prompt intervention.

Fibrous Ingrowth

As noted above, this condition is similar to epithelial ingrowth, with the exception that fibroblasts from subepithelial connective tissue enter the eye through a penetrating wound, caused by surgery or trauma, and grow over cornea, angle, and iris. It may be difficult distinguish from epithelial ingrowth although the retrocorneal membrane is often vascularized, and the clinical course is typically less progressive and less destructive. The mechanism of the associated glaucoma is either the membrane over the trabecular meshwork or direct damage to the outflow system from the surgery or trauma.

Angle Recession Glaucoma

Angle recession glaucoma is one of the manifestations of blunt ocular trauma and involves rupture of the face of the ciliary muscle, resulting in tear between the longitudinal and circular fibers of the ciliary muscle. The resultant glaucoma is most often due to initial trauma to the trabecular meshwork, with subsequent degenerative changes and scarring, leading to obstruction of aqueous outflow (28). Less often, a hyalinized membrane may cover the inner surface of the TM (29). This membrane may be continuous with Descemet’s membrane and may extend peripherally into the recessed angle and onto the anterior surface of the iris. The membrane obstructs aqueous outflow, causing an open-angle form of glaucoma, and may later undergo contraction, resulting in angle-closure glaucoma.

INFLAMMATORY MEMBRANES

Fuchs’ Heterochromic Iridocyclitis

Clinical Features

Fuchs’ heterochromic iridocyclitis is an important and often underdiagnosed form of iridocyclitis. Patients with this entity usually lack typical symptoms of uveitis, including redness, pain, and photophobia. This is a unilateral condition, presenting in the third or fourth decade of life. It is essentially a clinical diagnosis without any laboratory tests. Clinical features include mild anterior uveitis, stellate keratic precipitates on the corneal endothelium, iris heterochromia, cataract, and glaucoma. Anterior segment inflammation tends to run a protracted course although it may be intermittent initially. Iris heterochromia is a classically defined feature, and a review of literature indicates that some level of iris depigmentation is more common than frank iris heterochromia (30). Heterochromia is more difficult to detect in dark complexion individuals. In blacks, the presence of iris nodules has been reported as a common manifestation of iris involvement (31). The presence of these nodules can lead to diagnostic confusion with the granulomatous uveitides. However, the lack of synechiae in Fuchs’ uveitis helps to differentiate it from these other inflammatory etiologies. Posterior segment findings have been reported as well, including chorioretinal lesions, suggesting a possible link with toxoplasmosis (32).

Etiology and Mechanism

Glaucoma is a serious and late complication of Fuchs’ heterochromic iridocyclitis. It usually persists after the inflammation has been controlled. The prevalence of glaucoma has been reported to be as high as 59% (33). In some cases, the angle is normal in appearance, and the etiology is thought to be similar to that of chronic open-angle glaucoma. Others are associated with active trabeculitis with various inflammatory cell types, which may play a role in outflow obstruction (34). Fine rubeotic vessels may be seen gonioscopically, and the reported histology includes sclerosis of the trabecular meshwork with an inflammatory membrane over the angle (34,35). An electron microscopic study has demonstrated atrophy of the inner and outer wall of the Schlemm’s canal and loss of the endothelium lining of the trabecular meshwork (36). Other rare mechanisms of elevated IOP include lens-induced glaucoma, phacolytic glaucoma, steroid-induced glaucoma, and hyphema.

Differential Diagnosis

The main differential diagnosis is Posner Schlossman syndrome, which also presents as unilateral uveitis but with recurrent attacks of mild anterior chamber inflammation and IOP spikes. The pressure elevations are usually higher and respond better to corticosteroid therapy as compared with those in Fuchs’ heterochromic iridocyclitis. These patients often have systemic disorders, mostly of gastrointestinal origin. Other forms of intermediate uveitis should be considered and can usually be distinguished from Fuchs’ iridocyclitis by features such as inflammatory snowballs in the pars plana and macular edema in pars planitis.

Management

Glaucoma typically does not respond to corticosteroid therapy. Failure of medical therapy was reported to be 73% in one of the largest series of patients (37). Surgical intervention with filtration surgery and adjunctive antimetabolites appears to be effective in these patients. The course of glaucoma is not altered by cataract extraction.

Interstitial Keratitis

Interstitial keratitis of congenital syphilis typically appears in later childhood with marked ciliary flush, lacrimation, photophobia, and pain. A concomitant iridocyclitis is often present, and mechanisms of associated glaucoma include trabeculitis in the acute phase and peripheral anterior synechiae in the chronic phase. In addition, some patients may have a membrane over the anterior chamber angle.

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