Chapter 230 – Glaucomas Associated with Abnormalities of Cornea and Iris, Tumors, and Retinal Disease
STEVEN T. SIMMONS
• A heterogeneous group of disorders of the anterior and posterior segments resulting in secondary glaucoma.
• Iris abnormalities.
• Previous intraocular surgery.
• Rhegmatogenous retinal detachment.
• Elevated intraocular pressure.
• Ocular and metastatic tumors.
IRIDOCORNEAL ENDOTHELIAL SYNDROME
Iridocorneal endothelial (ICE) syndrome describes a group of disorders characterized by abnormal corneal endothelium that is responsible for variable degrees of iris atrophy, secondary angle-closure glaucoma in association with characteristic peripheral anterior synechiae (PAS), and corneal edema. Three clinical variations have been described:
• Iris nevus (Cogan-Reese) syndrome.
• Chandler’s syndrome.
• Essential (progressive) iris atrophy.
Since the initials ICE fit both the term iridocorneal endothelial syndrome and the first letter of each of the three component entities, Yanoff suggested the term ICE syndrome in 1979 for this spectrum of clinical and histopathological abnormalities. That term is now the one most commonly used.
EPIDEMIOLOGY AND PATHOGENESIS
Clinically, the condition is unilateral, with subclinical irregularities of the corneal endothelium commonly noted in the fellow eye. The syndrome affects those 20–50 years of age and occurs more often in women. No consistent association has been established with any other ocular or systemic disorder, and familial cases are very rare. In a study of 37 cases of ICE syndrome, approximately half (21 cases) were Chandler’s syndrome; the other two clinical variations each accounted for about one fourth of all cases. Glaucoma occurs in approximately half of all patients who have ICE syndrome. It is more severe in patients who have the progressive iris atrophy and Cogan-Reese variations, as opposed to those who have Chandler’s syndrome. The degree of angle closure does not always correlate with the elevation in intraocular
Figure 230-1 Hole formation in progressive iris atrophy.
pressure (IOP), since some angles may be closed functionally by the endothelial membrane without the occurrence of synechial closure.
Patients present with complaints of pain, decreased vision, and an abnormal iris appearance. The reduced vision and pain are secondary to corneal edema or secondary angle closure, which may occur later in the disease. Patients frequently note a mild blur of vision in the morning hours as a result of mild corneal edema that occurs during sleep. Microcystic corneal edema may be present without elevated IOP, especially in Chandler’s syndrome. In the advanced stages of the syndrome, symptoms of blurred vision and pain may persist throughout the day. Patients also may present with the complaint of an irregular shape or position of the pupil (corectopia), or they may describe a dark spot in the eye, which may represent hole formation (pseudopolycoria) or stromal atrophy of the iris. The various degrees of iris atrophy characterize the specific clinical entities.
Progressive (Essential) Iris Atrophy
This variation is characterized by severe iris atrophy that results in heterochromia, marked corectopia, ectropion uveae, and pseudopolycoria (hole formation). Hole formation is the hallmark finding of progressive iris atrophy ( Fig. 230-1 ).
This variation shows minimal or no iris stromal atrophy, but mild corectopia may occur. The corneal edema and angle findings predominate and are typical ( Fig. 230-2 ).
Figure 230-2 Corneal edema and iris findings are typical of Chandler’s syndrome.
Figure 230-3 Iridocorneal endothelial syndrome. Histological section of an eye that had essential (progressive) iris atrophy shows a peripheral synechia (P), various degrees of degeneration and loss of the central iris stroma, and total loss of the central iris pigment epithelium (IP). (C, Cornea; CB, ciliary body; IR, iris root; L, lens.) (With permission from Yanoff M, Fine BS. Ocular pathology. London: Mosby; 1996.)
The iris atrophy tends to be variable and less severe. Tan, pedunculated nodules may appear on the anterior iris surface. The entire spectrum of corneal and other iris defects may occur in this variant.
In each of the three clinical variations of ICE syndrome, corneal endothelial abnormalities are seen. A fine, hammered-silver appearance of the posterior cornea, similar to the guttae seen in Fuchs’ corneal endothelial dystrophy, is noted ; this results from the abnormal endothelial cells posterior to a normal Descemet’s membrane. Researchers, using electron microscopy, have shown this endothelial layer to vary in thickness from a single layer to multiple layers.  In addition, within the same eye, the endothelial cell layer may be of different thicknesses in different areas. Evidence of filopodial cytoplasmic processes and cytoplasmic actin filaments implies that the endothelial cells are able to migrate. The morphology of the endothelium suggests a widespread state of high metabolic activity.   Corneal edema is secondary to these marked endothelial abnormalities. The anterior chamber angle may show high PAS that extend beyond Schwalbe’s line. Such PAS are caused by the contraction of this endothelial cell layer and surrounding collagenous, fibrillar tissues, which are continuous and extend from the peripheral cornea over the trabecular meshwork and iris. An angle-closure glaucoma results as these PAS contract and close the angle. The pupil is drawn toward the sector that has the most prominent PAS. As stated earlier, secondary glaucoma with an open angle also may occur when the endothelial membrane covers the trabecular meshwork without evidence of synechiae formation.
The iris abnormalities differentiate the specific clinical variations. The endothelial cell layer that extends over portions of the anterior iris surface from the anterior chamber angle contracts, which distorts and pulls the iris toward itself. Hole formation occurs opposite the location of the abnormal endothelial cell layer secondary to the contracture ( Fig. 230-3 ). Hole formation may be associated with ischemia of the iris, as suggested by fluorescein angiography. In Cogan-Reese syndrome, the pigmented, pedunculated nodules seen are composed of underlying iris stroma pinched off by abnormal cellular membrane.
A viral cause has been postulated for the mechanism of ICE syndrome. Epstein-Barr and herpes simplex viruses have been found serologically in ICE patients.   This theory was postulated after lymphocytes were seen on the corneal endothelium of an ICE patient, which indicated the presence of chronic inflammation.
The diagnosis of ICE syndrome must be considered in younger patients who have unilateral angle-closure glaucoma; it is confirmed by specular or confocal microscopy. Corneal edema and secondary glaucoma are the major concerns to be addressed. Corneal edema can often be controlled using hypertonic saline solutions, and when the IOP is elevated, its reduction may help lessen corneal edema. Elevated IOP that occurs with secondary glaucoma can often be controlled medically using aqueous suppressants. Miotics are often ineffective, and hypotensive lipid–prostaglandin analogs can have variable results. If the IOP remains uncontrolled, filtration surgery may be indicated, although late failures have been reported secondary to fistular endothelialization.   These fistulae may be reopened successfully when the endothelial cell membrane is cut using the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser. In a study of 66 patients who had ICE syndrome, the success rates of initial trabeculectomy operations at 1 and 3 years were 64% and 36%, respectively, and those of second and third operations at 1-year intervals were both 58%. Seton procedures are indicated for cases refractory to the previously mentioned treatments and, more recently, have been used as primary procedures.
Axenfeld-Rieger (A-R) syndrome represents a rare spectrum of developmental disorders involving abnormalities of both ocular and extraocular structures derived from the neural crest. The term anterior cleavage syndrome was used in the past, but it incorrectly reflects the development in this syndrome. All clinical variations of this syndrome are now referred to as Axenfeld-Rieger syndrome.
EPIDEMIOLOGY AND PATHOGENESIS
A-R syndrome involves the anterior segment bilaterally and is associated with secondary glaucoma because of arrested angle development in about 50% of cases. It is a rare, autosomal dominant inherited disorder. Shields  postulated that developmental arrest that occurs late in gestation results in primordial endothelium being retained over parts of the iris and anterior chamber angle. Contraction of this primordial monolayer causes iris stromal thinning, corectopia, and hole formation. With contraction, the anterior uvea is hindered from posterior migration,
which results in a high insertion of the iris into the anterior chamber angle. The responsible gene (RIEG/P1x2) has been isolated to the long arm of chromosome 4 (4q25).  The affected anterior segment structures are primarily of neural crest derivation. The most common extraocular defects involve the teeth and facial bones.
The typical abnormality of the cornea is an anteriorly displaced Schwalbe’s line (posterior embryotoxon), which appears as a white ring on the posterior cornea near the limbus. It tends to be more common temporally and rarely involves all 360°. An anteriorly displaced Schwalbe’s line occurs in 8–15%   of the general population and may not always be present with A-R syndrome. The anterior chamber angle, observed using gonioscopy, exhibits posterior embryotoxon and iridocorneal adhesions that are broad to threadlike in nature. These iridocorneal adhesions may extend anteriorly to Schwalbe’s line and obscure the scleral spur and trabecular meshwork. Iris defects, ranging from stromal thinning to actual hole formation, corectopia, and ectropion uveae, may occur.
Developmental defects associated with A-R syndrome most commonly involve the teeth and facial bones. Microdontia (peglike incisors), hypodontia (decreased number of evenly spaced teeth), and anodontia (focal absence of teeth) are noted most commonly.  The facial abnormalities include maxillary hypoplasia and a protruding lower lid. Telecanthus, hypertelorism, and primary empty-sella syndrome have been documented with A-R syndrome. 
The peripheral cornea characteristically exhibits an anteriorly displaced Schwalbe’s line. This posterior embryotoxon shows a cellular monolayer with basement membrane that covers dense collagen.  The iridocorneal strands tend to be iris stroma mixed with the above-mentioned cellular monolayer. This cellular membrane also may extend over the iris surface, which distorts the iris, creates iris stromal thinning, and results in actual hole formation and corectopia as it contracts.
Medical therapy is recommended before the initiation of surgical intervention. Medications that decrease aqueous output (ß-blockers, a-agonists, and carbonic anhydrase inhibitors) have proved to be more beneficial than those affecting outflow (pilocarpine, hypotensive lipids). Glaucoma most often occurs in children and young adults. Surgical intervention may be goniotomy or trabeculectomy.  The procedure of choice in A-R syndrome is trabeculectomy with the adjunctive use of antimetabolites.  If the initial surgical treatment fails, seton procedures may have to be utilized. 
Secondary glaucoma is a common complication of penetrating keratoplasty and occurs with increased frequency in aphakic and pseudophakic patients and in those who have repeat grafts. The different mechanisms of secondary glaucoma formation are listed in Box 230-1 . Preexisting conditions, wound distortion of the trabecular meshwork, and chronic angle closure are the most common causes of long-standing glaucoma in these patients.
Mechanisms of Secondary Glaucoma Formation
Wound distortion of trabecular meshwork
Chronic angle closure
EPIDEMIOLOGY AND PATHOGENESIS
Penetrating keratoplasty has become a commonly performed procedure and is one of the most successful of all transplants, with a 1-year survival rate of 80–90%. Postkeratoplasty glaucoma occurs more frequently in patients affected by preexisting glaucoma. Aphakic and pseudophakic bullous keratopathies are the most common indications for penetrating keratoplasty, at rates of 20–70% and 18–53%, respectively. One study indicated no early or late glaucoma in patients who had penetrating keratoplasty for keratoconus, and a less than 2% incidence in patients who had Fuchs’ corneal endothelial dystrophy treated with penetrating keratoplasty. The most common mechanisms for glaucoma after penetrating keratoplasty are distortion of the trabecular meshwork secondary to graft wound closure and angle closure. Incidences of clinical glaucoma after keratoplasty for pseudophakic and aphakic bullous keratopathies are 18–53%     and 20–70%,     respectively.
It has been noted by investigators that graft clarity is reduced significantly when postkeratoplasty glaucoma is present.  In essence, postkeratoplasty glaucoma affects not only visual function but also graft integrity. In early postkeratoplasty glaucoma, epithelial edema is found along with stromal thinning and compression. Such findings are noted before endothelial damage occurs. Progressive angle closure from peripheral synechiae formation is a warning sign for potential glaucoma in postkeratoplasty patients. Some studies demonstrated that PAS are present in all eyes that showed elevated IOP after keratoplasty. One major study in which routine gonioscopy was conducted, however, found that progressive synechial closure was a plausible explanation for only 14% of eyes that had elevated IOP.
The role of corticosteroids and their influence on postoperative glaucoma must be addressed. The use of potent corticosteroids at frequent intervals was reported to reduce the rates of early IOP elevation. In contrast, certain cases of IOP elevation may be related to corticosteroid responders. Secondary to corticosteroid use, reported IOP rates are increased 5–60%.      This shows the two-edged sword of corticosteroids: (1) the need to use them to minimize postkeratoplasty inflammation, and (2) their possible influence on postkeratoplasty glaucoma.
Treatment modalities for postkeratoplasty glaucoma include medical control, trabeculectomy, seton procedures, and cyclodestructive procedures. The initial treatment of choice is medical therapy. However, in the presence of significant synechial closure, drugs that influence outflow facility (i.e., miotics) may have limited action. Similarly, the role of hypotensive lipid–prostaglandin analogs in this type of glaucoma and their influence on graft survival and graft clarity remain uncertain. Dorzolamide has been shown to decrease corneal endothelial function and to increase
corneal thickness, and reported cases of graft failure have been attributed to its use.
Setons (i.e., Ahmed, Krupin, Molteno, Baerveldt, Schocket) have been useful in controlling IOP among patients who have had difficult previous surgeries.  In one study, however, 29% of patients progressed to failure after Molteno implantation, and 20% after insertion of Schocket’s tube. The reason for these failure rates is unknown, but some investigators speculate that the cause may be chronic inflammation or a breakdown in the blood-ocular barrier. The valved implants cause less inflammation and may be better tolerated. Placement of the seton through the pars plana may also improve graft survival.
Filtration surgery shows success rates of 27–80%.      Aphakic eyes have a lower success rate than do pseudophakic or phakic eyes. Graft failure at 3 years after trabeculectomy is in the range of 11–20%.  Cyclodestructive procedures can lower IOP effectively after penetrating keratoplasty. Laser cyclophotoablation is used in preference to cyclocryotherapy because of its reduced side effects and improved visual result. The reported success rate for laser cyclophotoablation is 50–100%. Graft failure has been reported with laser cyclophotoablation.  
EPITHELIAL DOWNGROWTH AND FIBROUS INGROWTH (PROLIFERATION)
Epithelial and fibrous proliferations are rare postoperative surgical complications that may result in devastating secondary glaucomas and are caused by an invasion of the anterior chamber by epithelium or connective tissue through a defect in the wound site. Fortunately, with improved surgical techniques and improved wound closure, the incidence of these entities has been reduced greatly.
EPIDEMIOLOGY AND PATHOGENESIS
The incidence of epithelial downgrowth and fibrous ingrowth has declined greatly over the years. The prevalence of epithelial downgrowth was in the range of 0.12–0.6% in series of eyes after intracapsular cataract surgery in the 1940s and 1950s.   It once occurred more commonly after cataract surgery, but it now occurs more commonly with penetrating keratoplasty,   ocular trauma, glaucoma filtration surgery,   and other corneal surgical procedures. Fibrous ingrowth is more prevalent than epithelial downgrowth, progresses more slowly, and is often self-limited. Epithelial downgrowth and fibrous ingrowth can occur simultaneously. It has been shown that prolonged inflammation is a major risk factor for epithelial and fibrous proliferation. Other risk factors are wound dehiscence, delayed closure of the wound postoperatively, and stripping of Descemet’s layer. 
Normal healing of the corneal scleral wound entails ingrowth of connective tissue to the inner margin of the wound and formation of a fibrous plug. The inner wound margin usually is covered by endothelium by about the second week postoperatively. This ingrowth is halted through contact inhibition by migrated endothelium.   If the endothelium does not bridge this defect, epithelial and fibrous proliferation can occur; thus, an abnormality in the corneal endothelium is also a risk factor. It has been suggested that posterior limbal incisions may be associated with fibrous ingrowth, and anterior limbal incisions may be associated with epithelial downgrowth.  With the recent advent of small incision surgery, this disparity is almost nil. Other proposed risk factors for fibrous and epithelial proliferation are fornix-based conjunctival flaps, intraocular use of surgical instruments on the conjunctiva, and use of intracameral anticoagulant therapy.
Figure 230-4 Transluscent, nonvascular, anterior chamber epithelial cyst.
Figure 230-5 Grayish, sheetlike epithelial ingrowth with rolled edges.
Epithelial proliferation may be present in three forms: “pearl” tumors of the iris, epithelial cysts, and epithelial ingrowth. Epithelial cysts and epithelial ingrowth often cause secondary glaucoma. Epithelial cysts appear as translucent, nonvascular anterior chamber cysts that originate from surgical or traumatic wounds ( Fig. 230-4 ). Epithelial ingrowth presents as a grayish, sheetlike growth with rolled edges on the posterior surface of the cornea ( Fig. 230-5 ), trabecular meshwork, iris, and ciliary body; it is often associated with wound incarceration, wound gape, ocular inflammation, band keratopathy,  and corneal edema. Unlike epithelial proliferation, fibrous ingrowth is slow to progress and may be self-limited. A common cause of corneal graft failure, fibrous ingrowth appears as a thick, gray-white, vascular, retrocorneal membrane with an irregular, scalloped border reminiscent of woven cloth. The ingrowth often involves the angle, which results in the formation of PAS and the destruction of the trabecular meshwork. The resultant secondary angle-closure glaucoma is a frequent complication and is often difficult to control medically. A major advancement in the diagnosis of epithelialization is use of the argon laser to make burns on the surface of the iris—areas of epithelialization turn white when burned by the laser. Specular and confocal microscopy provides another means of diagnosis by direct visualization of epithelial cells in the ingrowth.
Epithelial downgrowth consists of a multilayered membrane composed of nonkeratinized, stratified, squamous epithelium that has surface microvilli; wide intercellular borders, with occasional hemidesmosomes attached to a subepithelial connective tissue layer; and epithelial cells of uneven sizes and shapes.  This epithelial sheet lacks blood vessels and shows multiple tonofilaments at its leading edge ( Fig. 230-6 ).  The underlying structures in contact with the epithelial sheet undergo disorganization and destruction.
Management of epithelial cysts includes observation until complications are observed. Numerous approaches have been used
Figure 230-6 Epithelial iris cyst and downgrowth. A, Scanning electron microscopy shows a sheet of epithelium that covers the trabecular meshwork, anterior face of the ciliary body, anterior iris, and pupillary margin. B, Epithelium lines the posterior cornea, anterior chamber angle, and peripheral iris and extends onto the vitreous posteriorly in a surgically aphakic eye. (With permission from Yanoff M, Fine BS. Ocular pathology. London: Mosby; 1996.)
to excise epithelial cysts, but currently a wide excision of the intact cyst is preferred. If the cyst is adherent to any intraocular structures, it may be collapsed by aspiration before excision. Photocoagulation of epithelial cysts, a less invasive procedure than surgical removal, has been performed successfully. Photocoagulation is less effective when the cyst is nonpigmented or adherent to underlying structures.
Management options for epithelial proliferation include:
• Freezing the involved corneal surface to close the wound gape or fistula.
• Swabbing the involved corneal surface with absolute alcohol.
• Resecting the posterior membrane.
Management of glaucoma is a difficult challenge and has a high failure rate using traditional filtration surgery techniques. Glaucoma drainage implants have been shown to be the most effective procedure with both fibrous and epithelial ingrowth.  Cycloablation is used only when other treatment modalities fail.
GHOST CELL HEMOLYTIC GLAUCOMA
Ghost cell glaucoma is a transient, secondary open-angle glaucoma caused by denatured, hemolyzed erythrocytes (ghost cells) that block the trabecular meshwork. These denatured erythrocytes develop within 2–4 weeks of a vitreous hemorrhage. Any event that causes hemorrhage in the vitreous cavity or, rarely, in the anterior chamber may result in ghost cell glaucoma.
EPIDEMIOLOGY AND PATHOGENESIS
Ghost cells are red blood cells that have lost their intracellular hemoglobin and appear as khaki-colored cells that are less pliant than normal red blood cells. This loss of pliability results in obstruction of the trabecular meshwork and subsequent secondary glaucoma. The cells gain access to the anterior chamber through a disrupted hyaloid face or a rent in the posterior capsule that may arise from previous surgery (pars plana vitrectomy, cataract extraction, or capsulotomy), trauma, or spontaneous disruption.
Clinically, patients present with increased IOP and a history of a recent vitreous hemorrhage resulting from trauma, surgery, or preexisting disease. The IOP may be elevated markedly and cause corneal edema. The anterior chamber is filled with circulating, small, tan-colored cells that can become layered in the inferior
Figure 230-7 Ghost cell glaucoma. Layered ghost cells in the inferior anterior chamber angle.
anterior chamber angle ( Fig. 230-7 ). The cellular reaction appears out of proportion to the aqueous flare, and the conjunctiva tends not to be inflamed unless the IOP is elevated markedly. Gonioscopically, the angle appears normal except for the ghost cells that lay over the trabecular meshwork inferiorly.
Ghost cells lose hemoglobin through permeable cell membranes. They are nonpliable, have lost their natural biconcavity, and are unable to exit through the trabecular meshwork efficiently. The ghost cell’s cytoplasm is lined with denatured hemoglobin, called Heinz bodies, which may be diagnostic in anterior chamber aspirates and are demonstrated using phase-contrast microscopy.
The initial treatment is medical, followed by surgery in eyes that are nonresponsive. Irrigation of the anterior chamber and pars plana vitrectomy are the surgeries of choice to eliminate the source of degenerative red blood cells. If this is unsuccessful, filtration surgery may be required.
ALKALI CHEMICAL TRAUMA
In the acute setting of a patient who has an alkali burn, glaucoma may be overlooked as a complication. It occurs in the acute and late settings, with a possible intermediate period of hypotony secondary to ciliary body damage. Secondary glaucoma occurs more often in association with alkali burns than with acidic burns.
EPIDEMIOLOGY AND PATHOGENESIS
As a result of saponification of fatty acids in tissue, severe damage to intraocular structures may occur with exposure to alkali, because alkaline chemicals are able to penetrate ocular tissues rapidly. In contrast, acidic chemicals have a tendency to coagulate tissue proteins, and the layer of precipitated protein helps buffer and limit the acid’s penetration through the cornea. Different mechanisms for each phase of IOP elevation have been postulated. The initial pressure elevation may be secondary to tissue shrinkage of the outer coats of the eye or to prostaglandin release that increases uveal blood flow. The intermediate and late phases show changes in the eye as part of the body’s response. In these phases, trabecular damage, PAS, and secondary pupillary block are possible mechanisms for the development of glaucoma.
Damage to the cornea may be widespread and progressive. Epithelial disintegration may be followed by stromal ulcerations and perforation. Measurement of IOP in eyes that have extensive
corneal damage may be difficult using Goldmann applanation tonometry. A Tonopen or pneumotonometer may be more accurate. Gonioscopy may be difficult in these patients because of corneal opacification, in which case ultrasound examination may be necessary to visualize the extent of optic nerve cupping and retinal damage. Later in the disease process, symblepharon formation of the palpebral conjunctiva may obliterate the fornices.
After exposure to an alkaline chemical, the corneal keratocytes rapidly coagulate to leave devitalized corneal stroma. The bulk of the corneal mucopolysaccharide ground substance also is destroyed, which is followed by collagen fiber swelling. The IOP elevation may result from anterior segment shrinkage or prostaglandin-mediated inflammation. Other possible mechanisms for secondary glaucoma include direct chemical injury or PAS formation. Intraocular lens damage may result in cataract formation, and the associated lens swelling may result in a secondary phacomorphic glaucoma.
Immediate ocular irrigation is needed to remove the chemical from the corneal surface and fornices. Neutralization of an acid with a base or vice versa is contraindicated. When neutralization of a chemical is attempted, a thermal reaction occurs, which produces heat and causes further damage. The management of increased IOP in the early phase is pharmacological; miotics and hypotensive lipid–prostaglandin analogs should be used cautiously, because they may increase intraocular inflammation, a common complication of chemical trauma. Anti-inflammatory medications and cycloplegics are important during the first week; topical corticosteroids are administered with caution because of their potential effect on corneal stromal melting. Conventional medical and surgical therapies are used for the later phases of IOP elevation associated with chemical trauma.
Aniridia is a rare, bilateral, hereditary absence of the iris. The condition rarely occurs in its pure form and usually presents with a rudimentary stump of iris.
EPIDEMIOLOGY AND PATHOGENESIS
Aniridia is seen in approximately 1.8/100,000 live births.  Three phenotypes are recognized, of which autosomal dominant aniridia is the most common; it is present in approximately 85% of all cases and is not associated with any other systemic manifestations. The second type is congenital sporadic aniridia, found in association with Wilms’ tumor (nephroblastoma), genitourinary anomalies, and mental retardation (Miller’s syndrome). It has been labeled WAGR syndrome (for Wilms’ tumor, aniridia, genitourinary anomalies, retardation), is linked with partial deletions of the short arm of chromosome 11 (11p13), and accounts for approximately 13% of all aniridias. Autosomal recessive aniridia is the third genetic type; it is seen in approximately 2% of all cases and is associated with cerebellar ataxia and mental retardation (Gillespie’s syndrome).
Different theories have been developed to explain the pathogenesis of aniridia. Some researchers consider it a subtype of coloboma. In addition, some aniridias are associated with hypoplastic discs and the absence of iris musculature, on the basis of which investigators have proposed mesodermal and neuroectodermal theories, respectively. Glaucoma develops in about 50% of patients who have aniridia. Glaucoma is rare in newborns; it is usually seen after the second decade of life, as anatomical changes occur in the angle secondary to contracture of peripheral iris strands. These iris strands bridge the space between the iris stump and trabecular meshwork, and the progressive contracture of the iris strands creates an angle-closure glaucoma. In addition, goniodysgenesis is noted in some cases.
The clinical manifestations of aniridia include photophobia related to the extent of iris involvement. Pendular nystagmus, decreased vision, amblyopia, and strabismus are seen secondary to foveal and optic nerve head hypoplasia. Bilateral ptosis also may occur in aniridia. With gonioscopy, the iris appears as a rudimentary stump with fibers that bridge the angle. This rudimentary iris leaflet appears to be pulled forward by iris strands, which results in posterior synechiae formation and subsequent angle-closure glaucoma. In addition to the anterior segment changes, findings in the posterior segment may include foveal and optic nerve head hypoplasia and choroidal coloboma. Lenticular changes include cataract, ectopia lentis, microphakia, and persistent pupillary membranes. Microcornea and corneal opacifications also have been observed in aniridic patients. The corneal opacification is often associated with a fine, vascular network and pannus formation. 
Wilms’ tumor (nephroblastoma) is found in association with aniridia in Miller’s syndrome; 25–33% of patients who have sporadic aniridia develop Wilms’ tumor. In addition to Wilms’ tumor, severe mental retardation, genitourinary anomalies, craniofacial dysmorphism, and hemihypertrophy can occur. In Gillespie’s syndrome, mental retardation and cerebellar ataxia are seen.
Arrestment of the neuroectodermal tissue is the most striking histopathological feature of this condition. With histological examination, a small stump of iris that lacks iris musculature may be observed. The iris remnant appears continuous with the trabecular meshwork. Glaucoma in Miller’s syndrome may develop secondary to angle anomalies, which include dysgenesis of the trabecular meshwork and Schlemm’s canal.
Glaucoma and its surgical complications are the main causes of blindness in patients with aniridia. By 20 years of age, most aniridic patients eventually fail pharmacological therapy and require surgery for adequate IOP control.   A prophylactic modified goniotomy has been advocated to prevent this secondary glaucoma in certain young patients with aniridia. 
TUMORS AND GLAUCOMA
A variety of tumors may cause unilateral glaucoma; the most common ones associated with glaucoma include primary melanomas, metastases, and retinoblastomas. The mechanism of glaucoma development varies with the location, type, and size of the tumor. Choroidal melanomas and other choroidal and retinal tumors tend to cause secondary angle-closure glaucoma, as a result of a forward shift in the lens-iris diaphragm and subsequent closure of the anterior chamber angle. Inflammation caused by necrotic tumors may result in posterior synechiae, which can exacerbate this angle closure through a pupillary block mechanism. Choroidal melanomas, medulloepitheliomas, and retinoblastomas also may cause anterior segment neovascularization that results in angle closure and may liberate tumor cells that obstruct aqueous outflow.
EPIDEMIOLOGY AND PATHOGENESIS
In 1987, Shields et al. studied 2704 eyes that had intraocular tumors, of which 5% were found to have IOP elevation secondary to the tumor. The most common tumor in adults to result in glaucoma was malignant uveal melanoma. Iris melanomas may cause an increase in IOP by local infiltration of the anterior chamber angle. Other reported mechanisms for glaucoma formation in association with iris melanomas are pigment, tumor, or inflammatory cell dispersion that results in obstruction of the trabecular meshwork. Shields et al. found glaucoma in 7 of 102 eyes that had iris melanoma. Iris melanocytomas are rare and have a predisposition to release pigment into the anterior chamber, which causes a secondary open-angle glaucoma. Ciliary body melanomas may present with increased IOP secondary to a variety of mechanisms. Forward displacement of the lens-iris diaphragm, direct invasion of the aqueous outflow system by melanin-laden macrophages, and pigmentary dispersion have been reported to cause glaucoma in these cases.
Shields et al. reported that 16 of 96 eyes that had ciliary body melanomas also had associated glaucoma. Medulloepithelioma (diktyoma) is a tumor of the nonpigmented ciliary epithelium and usually presents in childhood as a cystic or solid tumor. In one study, about 50% of eyes that had medulloepitheliomas presented with glaucoma. The study showed neovascularization of the anterior chamber with angle closure to be the most common cause of glaucoma.  Other secondary causes of glaucoma with medulloepitheliomas were mechanical displacement of the angle, direct invasion of the angle, and one case of recurrent hyphema.
Retinoblastoma is the most common malignant intraocular tumor of childhood. Approximately 1 in 14,000–20,000 newborns have retinoblastoma, and 30–35% of cases occur bilaterally, with no sex or race predisposition. Glaucoma secondary to retinoblastoma shows an incidence in the range of 2–22%.   Neovascular glaucoma accounts for 73% of the glaucomas associated with retinoblastoma secondary to tumor-induced retinal ischemia. It also has been postulated that angiogenic factors may be produced by the tumor itself. The second most common cause of glaucoma in these eyes is anterior displacement of the lens-iris diaphragm.
Uveal metastasis occurs most frequently to the posterior choroid. The most common sites of origin are breasts in women and lungs in men. In contrast to iris and ciliary body metastasis, metastatic tumors to the choroid show only about a 2% incidence of glaucoma. The main presentation of glaucoma results from a forward shift of the lens-iris diaphragm secondary to nonrhegmatogenous retinal detachment. Glaucoma is associated with 64% of iris metastases and 67% of ciliary body metastases. Elevated IOP results in patients with these tumors, usually from localized blockage of the trabecular meshwork by released tumor cells.
The clinical presentation of glaucoma that arises from intraocular tumors is dependent on the mechanism of inducement. Glaucoma secondary to tumors may present as a secondary angle-closure glaucoma by a posterior-push mechanism (i.e., a posterior segment tumor causes an anterior rotation of the ciliary body or a forward shift of the lens-iris diaphragm) or an anterior-pull mechanism (i.e., PAS and neovascularization of the angle). Other mechanisms include those of secondary open-angle glaucoma (i.e., pigmentary glaucoma; tumor cell, red blood cell, and cellular debris obstruction of the angle; inflammatory glaucoma; and direct invasion of the angle by tumor).
Iris melanoma usually appears as a well-circumscribed, variably pigmented, fixed or slow-growing tumor that may eventually invade the trabecular meshwork. The tumor is composed of spindle-shaped cells with occasional epithelioid cells. Ciliary body melanoma appears as a circumscribed mass that replaces the ciliary body. The cell types are both spindle and epithelioid, with a larger number of the latter found in ciliary body melanoma than in iris melanoma. Choroidal melanoma appears as a variably pigmented mass that may result in a secondary nonrhegmatogenous retinal detachment. Such melanomas also may be composed of epithelioid or spindle cells. The lesion may create a “mushroom” configuration if it breaks through Bruch’s membrane. Melanocytoma appears as a brown or black mass that may be well circumscribed and usually occurs at the optic disc but may arise anywhere in the uvea. Necrotic areas are present within the mass, which may result in fragmentation and liberation of tumor cells into the angle.
Iris and ciliary body metastases usually have poor differentiation, which makes determination of the primary site difficult. Choroidal metastases are ill-defined, relatively elevated or diffuse lesions, often associated with serous or choroidal retinal detachment. The lesions may present with a brown discoloration secondary to overlying pigment or with a gray to yellow–cream color. Retinoblastoma appears as a chalky white mass within the globe and is composed of neuroblastic cells; areas of calcification and necrosis are common findings. The differentiated tumors are characterized by highly organized Flexner-Wintersteiner rosettes. Medulloepithelioma is an embryonic tumor that usually occurs in the ciliary body. The tumor appears as a yellow–pink solid or cystic mass and may contain rosettes. Medulloepithelioma has two types of presentation: the nonteratoid type is composed of nonpigmented epithelium, and the teratoid type shows two different germ layers (i.e., cartilage and skeletal muscle).
Management of malignant ocular tumors often leads to enucleation. Traditional filtration techniques run the risk that tumor cells may be seeded to extraocular areas, even after treatment with radiation. In those patients who have secondary glaucoma as a result of benign tumors, medical management and traditional filtration surgeries may be appropriate. Proper diagnosis of tumors usually is made clinically. Fluorescein angiography and ultrasonography (A-scan, B-scan, UBM) help in the detection and diagnosis of intraocular tumors. In some patients, a fine-needle biopsy, aqueous aspiration, or biopsy is needed for diagnosis.
The first description of chronic open-angle glaucoma secondary to rhegmatogenous retinal detachment was presented in 1973 by Schwartz. He described a small number of patients who had unilateral, open-angle glaucoma and a history of retinal detachment. All 11 patients had uncontrolled glaucoma in association with untreated retinal detachments that ranged from 1 week to 1 year in duration. After successful reattachment of the retina, prompt resolution of the glaucoma occurred in all 11 patients; interestingly, all 11 had a concomitant appearance of iridocyclitis.
In 1977, Phelps and Burton surveyed 817 patients who underwent retinal detachment repair. They found 18 patients (2.2%) who fit the criteria for Schwartz’s syndrome. Several theories have been put forward to explain the increase in IOP accompanying retinal detachment. Schwartz postulated that the associated iridocyclitis causes a trabeculitis that decreases aqueous outflow. Matsuo et al. detected photoreceptor outer segments in the anterior chambers of seven patients who had retinal detachments, a discovery that established a connection between the subretinal space and the anterior chamber in this group of patients. The same authors also suggested that this connection may allow the transmission of a more viscous subretinal fluid that decreases outflow facility.
In 1989, Lambrou et al. injected rod outer segments into the anterior chambers of cats in vivo, which resulted in an average rise in IOP of 10?mmHg (1.33?kPa). Electron microscopy revealed occlusion of the intratrabecular spaces by the rod outer segments, with little evidence of inflammatory activity. An interesting observation was that injected rod outer segments mimicked cells in the anterior chamber, which may represent what Schwartz described as iridocyclitis in his original article.
Davidorf described four cases of retinal detachment with elevated IOP and heavy pigmentation of the trabecular meshwork. He explained the rise in IOP as a result of mechanical blockage of the trabecular meshwork; IOP decreased after successful reattachment of the retina. In spite of the different theories for the basis of Schwartz’s syndrome, treatment is repair of the retinal detachment. The increased IOP and iridocyclitis tend to be unresponsive to medical treatment.
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