Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

separate entity. Management

The primary concern about the management of ocular defects in a patient with the Axenfeld-Rieger syndrome is detection and control of the associated glaucoma. IOP elevation most often develops between childhood and early adulthood, but it may appear in infancy or, in rare cases, not until late adulthood (79, 154). Patients with the Axenfeld-Rieger syndrome must be followed to detect glaucoma throughout their lives.

With the exception of infantile cases, medical therapy should usually be initiated before surgical intervention is recommended. Drugs that reduce aqueous production, such as ß-adrenergic blockers, carbonic anhydrase inhibitors, and a2-adrenergic agonists, are most likely to be beneficial. Initial

surgical options include goniotomy, trabeculotomy, and trabeculectomy. Goniotomy and trabeculotomy have been used in infantile cases with limited success. Trabeculectomy is the surgical procedure of choice for most patients with glaucoma associated with the Axenfeld-Rieger syndrome; the success rate in older children has been about 75%, but with the same risks of late bleb leak and infection as seen in other children after trabeculectomy, especially if mitomycin C has been used (Freedman SF, unpublished data) (see Chapter 40). In infants and in cases refractory to medication and trabeculectomy, glaucoma drainage-device surgery and cycloablation remain options for treatment. In a retrospective clinical series of 126 patients with Axenfeld-Rieger syndrome attributable to mutations in PITX2 and FOXC1, Strungaru and colleagues noted that glaucoma in only 18% of the patients with PITX2 or FOXC1 genetic defects responded to medical or surgical treatment (used solely or in combination) (186).

Peters Anomaly

In 1897, von Hippel (196) reported a case of buphthalmos with bilateral central corneal opacities and adhesions from these defects to the iris. Peters, beginning in 1906 (197), described similar patients with what has become generally known as Peters anomaly.

General Features

Peters anomaly is present at birth and is usually bilateral. Most cases are sporadic, although there are reported cases of autosomal recessive inheritance and, less commonly, autosomal dominant transmission (198, 199). Peters anomaly occurs in the absence of additional abnormalities, although associations with a wide range of systemic and other ocular anomalies have been reported, including defects of the ear and auditory system, orofacial system, heart, genitourinary system, spine, and musculoskeletal system (200, 201 and 202). Because of the varied genetic and nongenetic patterns and the spectrum of ocular and systemic abnormalities, Peters anomaly is probably a morphologic finding rather than a distinct entity (200). Peters anomaly can be caused by mutation in the PAX6, PITX2, CYP1B1, or FOXC1 gene (OMIM 607108, 601542, 601771, and 601090, respectively) (16) (Table 8.2).

Figure 14.13 External appearance of the right eye of a 10-dayold infant with unilateral Peters anomaly. The IOP is normal, but a dense central corneal opacity covers the pupil. Anterior segment ultrasonography demonstrated a formed anterior chamber centrally, without apparent corneal-lens contact.

Clinicopathologic Features

The hallmark of Peters anomaly is a central corneal abnormality —a defect in the Descemet membrane and corneal endothelium with thinning and opacification of the corresponding area of corneal stroma (203, 204, 205 and 206) (Fig. 14.13). Iris adhesions may extend to the borders of this corneal defect. Bowman layer may also be absent centrally (205, 206). Immunohistochemical studies of the cornea suggest that extracellular matrix elements, such as fibronectin, may be important in the pathogenesis of Peters anomaly (207). The disorder has been subdivided into three groups (Fig. 14.14), each of which may have more than one pathogenetic mechanism (204).

In Peters anomaly not associated with keratolenticular contact or cataract, the defect in the Descemet membrane may represent primary failure of corneal endothelial development (205). However, rare cases may result from intrauterine inflammation (208), which was originally postulated by von Hippel (196) and gave rise to the term von Hippel internal corneal ulcer.

In eyes with Peters anomaly associated with keratolenticular contact or cataract, histopathologic studies suggest that the lens developed normally and was then secondarily pushed forward against the cornea by one of several mechanisms, causing the loss of Descemet membrane (204, 205, 209). Some cases may result from incomplete separation of the lens vesicle from surface ectoderm.

Peters anomaly may rarely be associated with Axenfeld-Rieger syndrome (see above). P.234

defects of Axenfeld-Rieger syndrome (c). Associated Glaucoma

Approximately one half of the patients with Peters anomaly will develop glaucoma, which is frequently present at birth. The mechanism of the glaucoma is uncertain, because the anterior chamber angle is usually grossly normal by clinical examination. Histopathologic studies have revealed peripheral anterior synechiae in some cases (204), whereas ultrastructural studies of two young patients with Peters anomaly and open angles revealed changes in the trabecular meshwork that are characteristic of aging (209, 210). In cases of Peters anomaly associated with the anterior chamber angle abnormalities of the Axenfeld-Rieger syndrome, the mechanism of glaucoma is presumably the same as in the latter condition (discussed earlier in this chapter). Some cases of Peters anomaly demonstrate a shallow or flat anterior chamber, which may also play a role in the manifestation of glaucoma.

Differential Diagnosis

Other Causes of Central Corneal Opacities in Infants

The corneal clouding of Peters anomaly must be distinguished from that of PCG, birth trauma, the MPS, and congenital hereditary endothelial dystrophy.

Posterior Keratoconus

This rare disorder is characterized by a thinning of the central corneal stroma, with excessive curvature of the posterior corneal surface and variable overlying stromal haze (153, 211). An ultrastructural study revealed a multilaminar Descemet membrane with abnormal anterior banding and localized posterior excrescences (212). Glaucoma is rarely associated with posterior keratoconus (153).

Congenital Corneal Leukomas and Staphylomas

These cases represent the more severe forms of central dysgenesis of the anterior segment and are frequently associated with glaucoma (156).

Management

All infants and children with cloudy corneas must be examined carefully for the possibility of associated glaucoma. The glaucoma associated with Peters anomaly usually requires surgical intervention, although some mild cases may be managed medically (Freedman SF, unpublished data). Although trabeculotomy or trabeculectomy may be reasonable in milder cases with adequate anterior chamber depth, glaucoma drainage-device surgery or cyclodestructive surgery is often needed in refractory or more severely affected cases.

Penetrating keratoplasty is also frequently necessary, although the results are typically poor, which probably is caused partly by the associated glaucoma and its surgical treatment. A study of 47 children reported on 144 penetrating keratoplasty procedures; 29% of eyes had visual acuity better than 20/400, while 38% had light perception or no light perception. This series included only 14 eyes with glaucoma (213). Although Zaidman and colleagues reported more favorable visual outcomes after corneal transplantation in patients with mild Peters anomaly (i.e., no lens involvement), the eyes with glaucoma in that series had poorer outcomes (214).

Diode endocyclophotocoagulation has been applied in patients after corneal transplantation with uncontrolled glaucoma; limited success and high rates of corneal graft failure have occurred (215, 216; Freedman SF, unpublished data). The uniformly poor prognosis for long-term corneal graft survival in patients with Peters anomaly (especially in the presence of glaucoma) suggests that partially clear corneas be considered for initial conservative management or that alternatives to corneal transplantation, such as sector iridectomy, be used in hopes of attaining some useful visual function (217, 218) (Fig. 14.15). Although endoscopic diode laser has limited success when used as the sole treatment for refractory glaucoma associated with Peters anomaly, glaucoma drainage-device

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surgery may be a reasonable surgical option in selected cases, often combined with careful vitrectomy in aphakic eyes (219).

Figure 14.15 Left eye of a 3-year-old child with bilateral Peters anomaly and severe congenital glaucoma. The other eye has a failed penetrating keratoplasty. This eye has undergone implantation of an Ahmed glaucoma drainage device and optical iridectomy; IOP is controlled without the use of medications, and the child has ambulatory vision.

Aniridia General Features

Aniridia is a bilateral developmental disorder characterized by the congenital absence of a normal iris. The name aniridia is a misnomer because the iris is only partially absent, with a rudimentary stump of variable width. Aniridia is associated with multiple ocular defects, some of which are present at birth, whereas others may become manifest later in childhood or early adulthood. Some forms of aniridia may have associated systemic abnormalities.

Four phenotypes of aniridia have been identified on the basis of associated ocular and systemic abnormalities (220): associated with foveal hypoplasia, nystagmus, corneal pannus, glaucoma, and reduced vision; predominant iris changes and normal visual acuity; associated with Wilms tumor (i.e., the aniridia-Wilms tumor syndrome) or other genitourinary anomalies; and associated with mental retardation.

Aniridia is inherited in an autosomal dominant fashion with almost complete penetrance but variable expression in about two thirds of cases. The remaining one third of cases are sporadic. Aniridia has been shown to be associated with mutations in the PAX6 gene, located on chromosome 11p13 (locus symbol AN2), telomeric to the Wilms tumor predisposition gene (WT1) (OMIM 106210) (16) (Table 8.2). Approximately 68% of patients with a deletion of chromosome 11 and aniridia will develop Wilms tumor before the age of 3 years (221). Patients with the 11p13 deletion, aniridia, and Wilms tumor also

have a wide range of other ocular and nonocular developmental disorders (221).

Aniridia is caused by a reduction in the activity of PAX6, a paired-box transcription factor, located on the short arm of chromosome 11 (11p13) (222). This can occur by heterozygous null mutations in PAX6, by cytogenetic deletions of chromosome 11p13 that encompass PAX6, or even by chromosomal rearrangements that disrupt 11p13 remote from PAX6. Lauderdale and colleagues (223) provide further support for haploinsufficiency as the basis of aniridia rather than a dominant-negative mechanism. A high frequency of chromosomal rearrangements was associated with sporadic and familial aniridia in a cohort of 77 patients with aniridia (224). The PAX6 gene on chromosome 11p13 is located telomeric to the Wilms tumor predisposition gene, WT1 (225). Phenotypic aniridia (along with Peters anomaly) has been reported in association with PITX2 mutations, occurring in families where most members have Axenfeld-Rieger syndrome (185).

Figure 14.16 Aniridia in a 6-month-old patient. Note the peripheral iris rim and the clear view of the lens equator.

Clinicopathologic Features Iris

In some cases, the iris is so rudimentary that it can only be seen by gonioscopy (Fig. 14.16), whereas other eyes may have enough peripheral iris to be visible by external and slitlamp examination. In some cases, the iris involvement is so minimal that other features of the disorder must be used to make the diagnosis (226). Iris and retinal fluorescein angiography have also been shown to help in identifying these patients by showing abnormal iris vascular remodeling that resulted in incomplete iris collarettes and decreased retinal foveal avascular zones (227).

Cornea

In a high percentage of cases, corneal pannus and opacity begin in the peripheral cornea in early life and advance toward the center of the cornea with increasing age. A study of ocular surface abnormalities in nine patients with nearly total aniridia and superficial corneal opacification and vascularization of the peripheral or entire cornea revealed a complete absence of the palisades of Vogt and an increase in

goblet cell density, suggesting that the conjunctival epithelium had invaded the cornea (228). Microcornea and iridocorneal and keratolenticular adhesions have also been reported (229, 230, 231 and 232). Aniridic eyes have a high central corneal thickness, compared with healthy eyes, which has been attributed to thicker stroma (233), although

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certainly corneal edema must be considered in advanced cases with corneal decompensation. Lens

Localized congenital opacities of the lens are common but usually insignificant. However, progressive cataracts may lead to significant visual impairment by approximately the third decade of life. The lens may also be subluxated or congenitally absent, or it may be reabsorbed (229, 230, 234).

Foveal Hypoplasia

Poor visual acuity and nystagmus are typical findings in patients with aniridia. The absence of a pupillary effect was once thought to cause the visual impairment, although some patients with aniridia have reasonably good vision and no nystagmus despite significant hypoplasia of the iris (220). Foveal hypoplasia is a frequent finding in aniridia and presumably accounts for the poor visual acuity and nystagmus. Spectral-domain OCT can be used to confirm the presence of foveal hypoplasia in eyes with aniridia, and this correlates well with visual acuity independent of the iris rim width (Freedman SF, unpublished data).

Other Ocular and Systemic Defects

Aniridia has been associated with a wide range of other ocular and nonocular developmental anomalies. These anomalies include choroidal colobomas, persistent pupillary membranes, sclerocornea and the Hallermann-Streiff syndrome, small optic nerve heads, strabismus, ptosis, Marfan syndrome with cervical ribs and dental anomalies, tracheomalacia and delayed closure of the anterior fontanelle, and retinoblastoma (231, 234, 235, 236, 237 and 238).

Associated Glaucoma

Glaucoma occurs in 50% to 75% of patients with aniridia, but it usually does not appear before late childhood or adolescence (239), although congenital onset has been reported and carries a poor prognosis (Freedman SF, unpublished data). The development of the glaucoma appears to correlate with the gonioscopic appearance of the anterior chamber angle. In infancy, the angle is usually open and unobstructed, although some eyes may have strands of tissue with occasional fine blood vessels extending from the iris root to the trabecular meshwork or higher (239). Some patients have congenital anomalies in the filtration angle, which may lead to glaucoma early in life (240).

During the first 5 to 15 years of life, many eyes with aniridia undergo progressive change in the anterior chamber angle as the rudimentary stump of iris comes to lie over the trabecular meshwork. The progressive obstruction of the anterior chamber angle may be caused by contracture of the tissue strands between the peripheral iris and angle wall (239).

Management Glaucoma

Conventional medical therapy, especially with agents to reduce aqueous production, may control the IOP initially, but this approach eventually proves to be inadequate in most cases. Goniotomy is of no value in advanced cases, but published experience suggests that early goniotomy to separate the strands between the iris and the trabecular meshwork in high-risk cases of aniridia may prevent the development of glaucoma (239, 241). Others have reported that trabeculotomy can effectively reduce IOP after glaucoma has developed in eyes with aniridia; in one series, IOP was controlled in 10 of 12 eyes after one or two trabeculotomy procedures (mean follow-up, 9.5 years) (242).

Trabeculectomy is often used as the first surgical procedure in cases of aniridic glaucoma refractory to medical treatment, but the postoperative period is made difficult by the propensity to develop a flat anterior chamber (Freedman SF, unpublished data). Trabeculectomy in infants and very young children carries with it the same difficulties and poor success rates found in those with other refractory glaucoma (see Chapter 40). In one small series of 10 eyes in patients younger than 40 who had aniridia, the

investigators reported a 14.6-month “ mean good IOP control period” after trabeculectomy, with no serious complications (243).

Glaucoma drainage devices may offer a reasonable alternative to trabeculectomy, especially in infants and patients with aphakia. In a retrospective series of eight eyes, investigators reported favorable success with glaucoma drainage-device surgery for aniridic glaucoma, citing success of 88% at 1 year, according to Kaplan-Meier analysis (244). Care must be taken to place the tube of the glaucoma drainage device far from the corneal endothelium, because corneal decompensation often ensues in cases of tube-corneal proximity (Fig. 14.17). Cyclocryotherapy and transscleral cyclophotocoagulation are reasonable options in cases refractory to trabeculectomy or glaucoma drainage-device surgery, but aniridic eyes may be more prone than others to phthisis after cyclocryotherapy (245).

Cataracts and Corneal Opacities

Cataract surgery is often difficult in the aniridic eye because of reduced corneal clarity, limited iris support, and poor zonular integrity. The remaining anterior capsule often opacifies, which can create a “pseudoiris”(Fig. 14.18). Other attempts to compens ate for the missing iris (which would not be expected to improve visual acuity but may reduce photophobia) include

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insertion of an intraocular lens with a peripheral black diaphragm or a frosted surface (246, 247).

Figure 14.17 Right eye of a 10-year-old girl with aniridia, glaucoma, and acute progression of a developmental cataract. Note the corneal edema overlying the Baerveldt glaucoma drainage device in the superotemporal anterior chamber.

Figure 14.18 Same eye as in Figure 14.17, now pseudophakic. Note the proximity of the glaucoma drainage-device tube to the cornea, with resultant overlying edema. Note also the pseudoiris where the peripheral capsule has opacified.

Penetrating keratoplasty is also difficult in these patients, likely because of the high incidence of corneal vascularization as well as peripheral corneal pannus. In a series of 8 patients who underwent keratoplasty in 11 eyes, graft rejection occurred in 7 eyes, and the glaucoma became more difficult to control in 5 of 9 eyes (248). Another series reported a high incidence of graft failure and limited visual improvement after corneal transplantations in one large family with aniridia (249).

OTHER SYNDROMES WITH ASSOCIATED GLAUCOMA

In addition to the disorders already considered in this chapter, glaucoma may be a feature of many other congenital syndromes. This discussion is limited to syndromes that represent multisystem, developmental anomalies and represents only a partial list of this extensive group of developmental disorders. (Further information on the loci and genes for systemic diseases associated with glaucoma can be found in Table 8.1.)

Chromosomal Anomalies Trisomy 21: Down Syndrome

This condition is characterized by mental retardation and atypical facies. Ocular findings include epicanthus, blepharitis, nystagmus, strabismus, light-colored and spotted irides, keratoconus, cataracts, and congenital glaucoma (250). The glaucoma, although not commonly reported in series on the ocular features of Down syndrome (251), usually appears in infancy, with the typical findings of PCG (252). Trisomy 13-15: Trisomy D Syndrome

The principal systemic features of trisomy D syndrome include mental retardation, deafness, heart disease, and motor seizures. The condition is usually not compatible with life, although milder forms

have been reported (253). Ocular findings include microphthalmia, coloboma with cartilage, congenital cataracts, retinal dysplasia, persistent fetal vasculature, and dysembryogenesis of the anterior chamber angle (254). Glaucoma may be a result of several of these developmental defects.

Trisomy 18: Edwards Syndrome

The ocular histopathologic findings in one infant with trisomy 18 included an anterior position of the iris obstructing the anterior chamber angle (255).

XO: Turner Syndrome

Patients with Turner syndrome are typically short stature, postadolescent females with sexual infantilism and multiple systemic anomalies. Ocular findings include ptosis, epicanthus, cataract, strabismus, blue sclera, corneal nebulae, and color blindness (256). Developmental glaucoma is rarely associated (257). Cystinosis

Cystinosis is a rare autosomal recessive metabolic disorder characterized by widespread accumulation of cystine crystals in ocular and nonocular tissues. The disorder is caused by mutation in the gene encoding cystinosin (CTNS, gene map locus 17p13, OMIM 219800) (16). Pupillary block glaucoma in one patient was thought to be caused by the cystine accumulation in the iris stroma (258).

Fetal Alcohol Syndrome

Fetal alcohol syndrome presumably results from a teratogenic effect of alcohol during a critical period of gestation, possibly influenced by a genetic background. The anterior ocular segment may be involved, with developmental abnormalities resembling those of the Axenfeld-Rieger syndrome and Peters anomaly (201, 259). Mouse studies suggest that the ocular abnormalities result from an acute insult to the optic primordia during a specific period that corresponds to the third week after fertilization in the human (260).

Hepatocerebrorenal Syndrome: Zellweger Syndrome

Zellweger syndrome, or the hepatocerebrorenal syndrome, is a multisystem congenital disorder characterized by central nervous system abnormalities, hepatic interstitial fibrosis, and renal cysts. Ocular findings include nystagmus, corneal clouding, cataracts, retinal vascular and pigmentary abnormalities, optic nerve head lesions, and congenital glaucoma (261). Iridocorneal adhesions may be the mechanism of the glaucoma (262). This disease is a peroxisomal biogenesis disorder, inherited in an autosomal recessive manner and resulting from mutations in any of at least 12 genes associated with exfoliation syndrome that encode peroxins. Affected individuals rarely live beyond the first year of life (263, 264).

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Hallermann-Streiff Syndrome

Micrognathia and dwarfism in persons with Hallermann-Streiff syndrome may be associated with ocular findings, including cataracts and microphthalmos. Glaucoma may also occur because of absorption of lens material or associated aniridia or after cataract surgery (236, 265). This condition has been reported only in isolated cases, with no pattern of inheritance demonstrated.

Kniest Dysplasia

Kniest dysplasia resembles classic metatropic dwarfism, but it has an autosomal dominant inheritance pattern and is caused by mutations in the COL2A1 gene (gene map locus 12q13.11-q13.2, OMIM 156550) (16). Congenital glaucoma has been described in a patient with presumed Kniest syndrome (266).

Lowe Syndrome

Lowe syndrome (i.e., oculocerebrorenal syndrome) is an autosomal recessive, X-linked disorder characterized by mental retardation, renal rickets, aminoaciduria, hypotonia, acidemia, and irritability. The two principal ocular abnormalities are cataracts, which are usually bilateral and occur in nearly all cases, and glaucoma, which is seen in approximately two thirds of patients. Other ocular findings include microphthalmia, strabismus, nystagmus, miosis, and iris atrophy. Female carriers may be identified by cortical lens opacities and genetic studies (267). Lowe syndrome (OMIM 309000) can be caused by mutation in the OCRL1 gene, locus Xq26.1 (OMIM 300535), mutations that also cause Dent