Ординатура / Офтальмология / Английские материалы / The Pediatric Glaucomas_Mandal, Netland_2006

Sphingolipidoses are caused by a deficiency of lysosomal enzymes required for the metabolism of sphingolipids, including gangliosides, cerebrosides, and sphingomyelin. In these disorders, sphingolipids accumulate in lysozymes of cells, which can be identified by electron microscopy as multimembranous inclusion bodies (zebra bodies). Corneal clouding may occur in Fabry disease and metachromatic leukodystrophy. Fabry disease is an X-linked recessive sphingolipidosis caused by a lack of alpha-galactosidase, which results in accumulation of ceramide trihexoside. The most typical ocular feature is a fine, whorl-like superficial corneal opacity (cornea verticillata). It resembles the corneal opacities found after administration of chloroquine and amiodarone. Corneal opacities have been seen as early as 6 months of age and are presumably caused by the accumula-

tion of sphingolipids in the corneal epithelium. Visual acuity is generally unaffected. Metachromatic leukodystrophy is an

autosomal recessive disorder caused by a defect of acylsulfatase A, leading to accumulation of cerebroside sulfate. Corneal clouding may be observed and, unlike Fabry disease, macular grayness or a cherry-red spot and optic atrophy may be

observed.

In glucose-6-phosphatase deficiency (Von Gierke disease), the cornea may show a faint brown peripheral clouding. In general, metabolic disorders with corneal clouding or opacity are associated with normal intraocular pressure and no corneal enlargement, which clinically differentiates them from primary congenital glaucoma.

In addition to metabolic disorders, corneal dystrophies

may be associated with corneal clouding at an early age.

Congenital hereditary stromal dystrophy is an autosomal dominant disease that appears at birth as a bilateral, symmetrical, non-progressive clouding of the central superficial corneal stroma. The epithelium is unaffected, and the stromal opacity is flaky, feathery and diffuse, fading in intensity as it approaches the periphery. This dystrophy was described

by Witschel and associates in 1978.57

Posterior polymorphous dystrophy, described by Koeppe in 1916, has an autosomal dominant inheritance pattern with good penetrance and can be asymmetric. The opacities can occur anywhere in the posterior cornea and may either remain stationary or progress slowly. Polymorphous opacities, typically vesicular, are located at the level of Descemet’s membrane. In some cases, when viewed by retro-illumination, the posterior cornea has the appearance of beaten metal. In severe cases, there may be stroma and epithelial edema with or without elevated intraocular pressure58 and peripheral

anterior synechiae.59

Congenital hereditary endothelial dystrophy (CHED) was described by Laurence in 1863. It may have autosomal dominant and recessive inheritance patterns with a variable expressivity ranging from minimal posterior corneal changes to severe corneal edema. In contrast with congenital hereditary stromal dystrophy, the corneal thickness is usually increased. Congenital hereditary endothelial dystrophy can present at birth or in the first 1 to 2 years of life. Descemet’s membrane appears thickened and gray, and has a peau d’orange texture. The endothelial mosaic may be absent or

irregular. The patient may present with diffuse, bilaterally symmetric corneal edema associated, in some patients, with tearing and photophobia (Figure 6-14). To avoid unnecessary glaucoma surgery, it is crucial to differentiate this disease from congenital glaucoma. A mistaken diagnosis of congenital glaucoma is unlikely because there is no corneal enlargement, the intraocular pressure is normal, and corneal stromal thickness can be up to three times the normal in congenital hereditary endothelial dystrophy.1,5

Congenital hereditary endothelial dystrophy may be associated with glaucoma.60,61 Patients usually are identified when corneal edema persists after surgical treatment for glaucoma and normalization of intraocular pressure. After treatment with penetrating keratoplasty, histopathological studies of the corneal button showed changes of Descemet’s membrane and attenuation of the endothelium typical of congenital hereditary endothelial dystrophy.60,61 In patients with congenital glaucoma who have persistent and total corneal opacification that persists after normalization of intraocular pressure, the combination of congenital hereditary endothelial dystrophy and congenital glaucoma should be suspected.

Other causes of corneal opacification in early childhood are

not commonly confused with congenital glaucoma. Corneal dermoid is a hamartoma that is a rare cause of congenital

corneal opacification. They may contain mesodermal elements including fibrous tissue, fat, muscle, cartilage, and bone. The severity may vary greatly, from the least severe and most common limbal variety to those that involve the entire cornea and anterior chamber.8 In the milder variety, only the superficial cornea is involved. Peters anomaly is a posterior corneal defect, frequently associated with iris

A

B

Figure 6.14 Congenital hereditary endothelial dystrophy (CHED) may be associated with diffuse, bilaterally symmetric corneal edema, which must be distinguished from congenital glaucoma. CHED in an eye, viewed with diffuse illumination (A). Another eye with CHED, viewed by slit beam illumination (B).

strands connected to the edge of the defect, which causes central corneal opacification at birth.

Conditions with overlapping signs of optic nerve abnormalities

Congenital malformations of the optic disc must be distinguished from disc changes caused by glaucoma. These pseudoglaucomatous anomalies include congenital optic nerve pits, optic nerve colobomas, and optic nerve hypoplasia.62 The tilted disc syndrome may be associated with hypopigmentation and staphylomatous ectasia in the direction of the tilt. Axial myopia can be associated with a large optic nerve cup or even a tilted disc and accompanying scleral crescent. Optic nerve hypoplasia is associated with a small disc, but difficulties in interpretation of the appearance of the disc may be caused by the abnormal termination of the retinal pigment epithelium in the peripapillary area, known as the ‘double ring sign.’ A variant of optic nerve hypoplasia associated with large cups and periventricular leukomalacia may be observed in premature infants.63

Large physiologic cups must also be distinguished from pathological cupping caused by glaucoma. This is not a common problem in the infant where accompanying signs and symptoms are evident, but it can be a problem in the child over 3 years of age who is too young for precise visual field testing and in whom the changes secondary to globe elasticity are not evident. Careful examination is essential, and follow-up examination may be required before a definitive diagnosis can be made. Examination of the family members can be helpful as this may reveal similar optic cups in several members.64

Conditions associated with increased intraocular pressure

Inflammatory disease such as maternal rubella syndrome may cause an angle anomaly virtually indistinguishable from that seen in primary infantile glaucoma, with identical clinical stigmata, and a good response to goniotomy (Fig. 6.15). However, the other ocular manifestations of the rubella syndrome in the neonate, including deafness, cardiac anomalies (patent ductus arteriosus, atrial and ventricular septal defects), mental retardation, and cataracts should distinguish this syndrome from primary infantile glaucoma.5 When rubella viremia occurs in the third trimester, anterior chamber angle involvement and glaucoma may occur, without other signs of rubella infection. These cases may be mistakenly identified as primary infantile glaucoma.4 A transient or permanent corneal edema has been observed in infants with maternal rubella syndrome, even without elevated intraocular pressure.4

Primary congenital glaucoma is diagnosed by the finding of glaucoma in a child with isolated trabeculodysgenesis and no other ocular diseases that could result in an increased intraocular pressure. The differential diagnosis of primary congenital glaucoma should also include developmental

Figure 6-15 Maternal rubella syndrome. The clinical presentation in this child resembles the appearance of primary infantile glaucoma.

glaucomas with associated anomalies, as well as childhood glaucomas secondary to systemic or other ocular disorders, which will be discussed in the subsequent chapter.

Conclusion

The clinical features, the diagnostic examination, and the differential diagnosis of primary congenital glaucoma has been discussed. Early diagnosis is important to prevent glaucomatous damage. Any child with tearing, photophobia, blepharospasm, corneal cloudiness, or ocular enlargement should be examined with the possibility of congenital glaucoma in mind. Pressure measurements in all children old enough to cooperate will provide a low yield of glaucoma because of the rarity of this disease in childhood. Nevertheless, when the diagnosis can be made before advanced field loss occurs, it is extremely gratifying. Even in children who can not cooperate for pressure measurements, it is a simple matter to examine at the optic nerve head. A cup-to-disc ratio exceeding 0.3 indicates a need for further investigation. Prevention of visual loss is the goal in the treatment of glaucoma. Early diagnosis is essential to accomplish this goal.

References

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3.Kwitko ML. The pediatric glaucomas. Int Ophthalmol Clin 1981; 21:199–222.

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5.Kwitko ML. Glaucoma in infants and children. Appleton-Century-Crofts: New York; 1973.

6.Scheie HG. Symposium on congenital glaucoma: Diagnosis, clinical course and treatment other than goniotomy. Trans Am Acad Ophthalmol Otolaryngol 1955; 59: 309.

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13.Hass J. Principles and problems of therapy in congenital glaucoma. Invest Ophthalmol 1968; 7:140.

14.Barkan O. Goniotomy. Trans Am Acad Ophthalmol 1955; 59:322–332.

15.Scheie HG. Management of infantile glaucoma. Arch Ophthalmol 1959; 62:35.

16.Morin JD, Merin S, Sheppard RW. Primary congenital glaucoma. A survey. Can J Ophthalmol 1974; 9:17–28.

17.Quigley HA. The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 1977; 84:358–370.

18.Broughton WL, Parks MM. An analysis of treatment of congenital glaucoma by goniotomy. Am J Ophthalmol 1981; 91:566–572.

19.Robin AL, Quigley HA, Pollack IP, et al. An analysis of visual acuity, visual fields and disc cupping in childhood glaucoma. Am J Ophthalmol 1979; 88:847–858.

20.Richardson KT, Shaffer TN. Optic-nerve cupping in congenital glaucoma. Am J Ophthalmol 1966; 62:507–509.

21.Shaffer RN. New concepts in infantile glaucoma. Can J Ophthalmol 1967; 2:243.

22.Shaffer RN. New concepts in infantile glaucoma. Trans Ophthalmol Soc UK 1967; 87:581–590.

23.Shaffer RN, Hetherington J Jr. Glaucomatous disc in infants. A suggested hypothesis for disc cupping. Trans Am Acad Ophthalmol Otolaryngol 1969; 73:929–935.

24.Chandler PA, Grant WM. Glaucoma. Lea and Febiger: Philadelphia; 1980.

25.Iwata K, Sobuek, Imai A, Sakurai I. On the reversibility of glaucomatous disc cupping and the visual field. Jpn J Clin Ophthalmol 1977; 31:759.

26.Hetherington J, Shaffer RN, Hoskins HD. The disc in congenital glaucoma. In: Etienne R, Patterson GD, eds. XXII Congress Internationale Ophthalmologie. International glaucoma symposium, Albi, France, 1974, Varseille, France, Diffusion Generale de Librarie, 1975.

27.Anderson DR. Glaucomatous disc changes in infants. In: Symposium on Glaucoma. Trans New Orleans Acad Ophthalmol. CV Mosby: St Louis; 1975:104–155.

28.Kiskis AA, Markowitz SN, Morin JD. Corneal diameter and axial length in congenital glaucoma. Can J Ophthalmol 1985; 20:93–97.

29.Quigley HA. Childhood glaucoma: Results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–226.

30.Dominguez A, Banos S, Alvarez G, Contra GF, Quintela FB. Intraocular pressure measurements in infants under general anesthesia. Am J Ophthalmol 1974; 78:110–116.

31.Van Buskirk EM, Palmer EA. Office assessment of young children for glaucoma. Ann Ophthalmol 1979; 11:1749–1751.

32.Radtke ND, Cohen BF. Intraocular pressure measurement in the newborn. Am J Ophthalmol 1974; 78:501–504.

33.Raab EL. Congenital glaucoma. Pers Ophthalmol 1978; 2:35.

34.Ytteborg J. Investigations of the rigidity coefficient in children’s eyes. Acta Ophthalmol 1960; 38:658–674.

35.Kaufman HE, Wind CA, Waltman SR. Validity of Mackay-Marg electronic applanation tonometer in patients with scarred irregular corneas. Am J Ophthalmol 1970; 69:1003–1007.

36.McMillan F, Forster RK. Comparison of Mackay-Marg, Goldmann, and Perkins tonometers in abnormal corneas. Arch Ophthalmol 1975; 93:420–424.

37.West CE, Capella JA, Kaufman HE. Measurement of intraocular pressure with pneumatic applanation tonometer. Am J Ophthalmol 1972; 74:505–509.

38.Hoskins HD, Shaffer RN. Evaluation techniques for congenital glaucomas. J Pediatr Ophthalmol Strabismus 1971; 8:81.

39.Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157.

40.Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485.

41.Worst JGF. The pathogenesis of congenital glaucoma, an embryological and goniosurgical study. CC Thomas: Springfield; 1966.

42.Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classification of the developmental glaucomas. Arch Ophthalmol 1984; 102:1331–1336.

43.Khoo BK, Koh A, Cheong P, Ho NK. Combination cyclopentolate and phenylephrine for mydriasis in premature infants with heavily pigmented irides. J Pediatr Ophthalmol Strabismus 2000; 37:15–20.

44.Khodadaust AA, Ziai M, Biggs SL. Optic disc in normal newborns. Am J Ophthalmol 1968; 66:502–504.

45.Reibaldi A. Biometric ultrasound in the diagnosis and follow-up of congenital glaucoma. Ann Ophthalmol 1982; 14:707–708.

46.Sampaolesi R, Caruso R. Ocular echometry in the diagnosis of congenital glaucoma. Arch Ophthalmol 1982; 100:574–577.

47.Buschmann W, Bulth K. Ultrasonographic followup examination of congenital glaucoma. Graefe’s Arch Ophthalmol 1983; 61:618.

48.Tarkkanen A, Uusitalo R, Mianowicz J. Ultrasonographic biometry in congenital glaucoma. Acta Ophthalmol 1983; 61:618–623.

49.Kobayashi H, Kiryu J, Kobayashi K, Kondo T. Ultrasound biomicroscopic measurement of anterior chamber angle in premature infants. Br J Ophthalmol 1997; 81:460–464.

50.Kobayashi H, Ono H, Kiryu J, Kobayashi K, Kondo T. Ultrasound biomicroscopic measurement of development of anterior chamber angle. Br J Ophthalmol 1999; 83:559–562.

51.Azuara-Blanco A, Spaeth GL, Araujo SV, et al. Ultrasound biomicroscopy in infantile glaucoma. Ophthalmology 1997; 104:1116–1119.

52.Kolker AE, Hetherington J. Diagnosis and therapy of glaucoma, 4th edn. CV Mosby: St Louis; 1976:276–321.

53.Duke-Elder S. System of ophthalmology, Vol III, Pt 2, Congenital deformities. CV Mosby: St Louis; 1969:548–565.

54.Cibis A, Bunde R. Herpes Simplex virus-induced congenital cataracts. Arch Ophthalmol 1971; 85:220–223.

55.Hagler WS, Walters PV, Nahmias AJ. Ocular involvement in neonatal herpes simplex virus infection. Arch Ophthalmol 1969; 82:169–176.

56.Yamamoto GK, Schulman JD, Schneider JA, Wong VG. Long-term ocular changes in cystinosis: observations in renal transplant recipients. J Pediatr Ophthalmol 1979; 16:21–25.

57.Witschel H, Fine BS, Grutzner P, McTigue JW. Congenital hereditary stromal dystrophy of the cornea. Arch Ophthalmol 1978; 96:1043–1051.

58.Grayson M. The nature of hereditary deep polymorphous dystrophy of the cornea: its association with iris and anterior chamber dysgenesis. Trans Am Ophthalmol Soc 1974; 72:516–559.

59.Cibis GW, Krachmer JH, Phelps CD, Weingeist TA. Iridocorneal adhesions in posterior polymorphous dystrophy. Trans Sect Ophthalmol Acad Ophthalmol Otolaryngol 1976; 81:770–777.

60.Pedersen OO, Rushood A, Olsen EG. Anterior mesenchymal dysgenesis of the eye. Congenital hereditary endothelial dystrophy and congenital glaucoma. Acta Ophthalmol (Copenh) 1989; 67:470–476.

61.Mullaney PB, Risco JM, Teichmann K, Millar L. Congenital hereditary endothelial dystrophy associated with glaucoma. Ophthalmology 1995; 102:186–192.

62.Campbell DG, Netland PA. Stereo atlas of glaucoma. Mosby: St. Louis; 1998.

63.Jacobson L, Hellstrom A, Flodmark O. Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia in children with periventricular leukomalacia. Arch Ophthalmol 1997; 115:1263–1269.

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Introduction

Axenfeld–Rieger syndrome

Peters anomaly

Aniridia

Glaucoma in the phakomatoses

Metabolic diseases

Persistent hyperplastic primary vitreous Retinopathy of prematurity (retrolental fibroplasia) Chromosomal anomalies

Broad thumb syndrome (Rubenstein–Taybi syndrome) Conclusion

Introduction

There are several conditions characterized by developmental defects of the anterior chamber angle with additional ocular and systemic abnormalities, which may be associated with glaucoma. These disorders are typically bilateral, are usually diagnosed at birth or in early childhood, and most have a genetic basis. Furthermore, a large number of other syndromes with ocular and systemic abnormalities may be associated with developmental glaucoma. All these conditions have been grouped under the term secondary congenital glaucoma. The purpose of this chapter is to outline the characteristics of these conditions wherein glaucoma plays a significant role.

Axenfeld–Rieger syndrome

Axenfeld described, in 1920, a patient with a white line in the posterior aspect of the cornea, near the limbus, and tissue strands extending from the peripheral iris to this prominent line. Beginning in the mid-1930s, Rieger reported cases with similar anterior segment anomalies, but with additional changes in the iris, including corectopia, atrophy, and hole formation. It was also discovered that some of these patients had associated non-ocular developmental defects, especially of the teeth and facial bones. Axenfeld referred to his case as ‘posterior embryotoxon of the cornea,’ while Rieger used the term ‘mesodermal dysgenesis of the cornea and iris.’

In current nomenclature, these conditions are commonly designated by three eponyms. Axenfeld’s anomaly is limited to peripheral anterior segment defects. Rieger’s anomaly includes peripheral anterior segment abnormalities with additional changes in the iris. Rieger syndrome includes ocular

anomalies plus non-ocular developmental defects. Within each category, glaucoma occurs in approximately half the cases. The similarity of anterior chamber angle abnormalities in Axenfeld’s anomaly, Rieger’s anomaly, and Rieger syndrome has led most investigators to agree that these three arbitrary categories represent a spectrum of developmental disorders.1,2 The overlap of ocular anomalies is such that the traditional classification is difficult to apply in all patients. For example, the degree of iris stromal atrophy is so slight in some patients that it is hard to know whether the term Axenfeld’s anomaly or Rieger’s anomaly should be used. Indeed, Axenfeld described mild stromal atrophy of the iris in his patient, further compounding the difficulty of clearly separating this entity from Rieger’s anomaly. In addition, the association between ocular and non-ocular abnormalities is not always as clear as the traditional classification would imply. Although most patients with non-ocular developmental defects have changes in the central iris, as with Rieger’s anomaly, some have only the peripheral ocular abnormalities of Axenfeld’s anomaly3 or no ocular changes at all.4 There are also families in which the ocular and non-ocular anomalies vary considerably among family members.

These observations have led many investigators to place all of these conditions within a single diagnostic category. There seems to be no advantage in splitting this spectrum of disorders into sub-categories, since the entire group of patients, irrespective of ocular manifestations, shares the same general features. First, there is a bilateral, developmental disorder of the eyes. Second, there is frequently a family history of the disorder (with an autosomal dominant mode of inheritance). Third, there is no sex predilection. Fourth, there are frequent non-ocular developmental defects. Fifth, there is a high incidence of secondary glaucoma. A single diagnostic category has the advantage not only of eliminating the difficulty of selecting an arbitrary subclassification, but also of reminding the physician to search for additional ocular and non-ocular disorders in all cases.

Most of the names for this spectrum of anomalies were based on presumed common developmental mechanisms, which in turn were dependent upon a particular concept of the related embryology. The terms used include ‘anterior chamber cleavage syndrome,’1 ‘mesodermal dysgenesis of the cornea and iris (dysgenesis mesodermalis corneae et iridis),’5 and ‘primary dysgenesis mesodermalis of the iris.’6 However, the concepts of normal development on which the above terms were based no longer appear to be entirely correct. It was for this reason that the alternative title ‘Axenfeld–Rieger

syndrome’ was proposed. This term retains reference to the traditional subclassifications, but is not dependent upon a particular concept of development, knowledge of which is still incomplete.

Clinical features

The age at which Axenfeld–Rieger syndrome is diagnosed ranges from birth to adulthood, with most cases recognized during infancy or childhood. The diagnosis may result from discovery of an abnormal iris or other ocular anomaly, signs of congenital glaucoma, reduced vision in older patients, or non-ocular anomalies. Other cases are diagnosed during a routine examination, which may have been prompted by a family history of the disorder. There is no apparent racial or sex predilection.5 The family history is often positive for the spectrum of disorders, typically with an autosomal dominant mode of inheritance, although sporadic cases are also common.3

Ocular defects in Axenfeld–Rieger syndrome are typically bilateral. The structures most commonly involved are the peripheral cornea, anterior chamber angle, and iris. The characteristic abnormality of the peripheral cornea is a prominent, anteriorly displaced Schwalbe’s line. This appears on slit-lamp examination as a white line on the posterior cornea near the limbus. In some cases, the line is incomplete, usually limited to the temporal quadrant, while in other patients it may be seen for 360 degrees. Strands of peripheral iris stroma may occasionally be seen by slit-lamp biomicroscopy extending to the prominent Schwalbe’s line. While a prominent Schwalbe’s line is a typical feature of Axenfeld–Reiger syndrome, it is neither a consistent nor pathognomonic finding. In some cases, the prominent line can only be seen by gonioscopy. A rare case may have other ocular and non-ocular abnormalities of this spectrum of disorders, with grossly normal Schwalbe’s lines.4

More commonly, a patient may have a prominent Schwalbe’s line with no other evidence of the Axenfeld– Rieger syndrome (Fig. 7.1). This isolated defect has been referred to by the term, originally given by Axenfeld, as ‘posterior embryotoxon.’ The prevalence of this condition has been reported ranging from 8%5 to 15%.7,8 While a prominent

Schwalbe’s line, as an isolated finding, may represent a forme fruste of Axenfeld–Rieger syndrome, it is not included within this spectrum of anomalies, because it is neither associated with an increased incidence of secondary glaucoma nor with non-ocular anomalies. In addition to the isolated finding, a prominent Schwalbe’s line is occasionally seen in patients with primary congenital glaucoma9 or the iridocorneal endothelial syndrome.10

The cornea is otherwise normal in the typical case of Axenfeld–Rieger syndrome, with the exception of occasional patients with variation in the overall size or shape of the cornea. Microcornea may be seen, although megalocornea, in the absence of known intraocular pressure elevation, is more common. Congenital opacities of the central cornea have also been observed in a few of these cases. The corneal endothelium is typically normal, with the exception of occasional subtle changes consistent with age or longstanding intraocular pressure elevation. The corneal endothelial appearance by specular microscopy reveals distinct cell margins, although mild to moderate variation in the size and shape of the endothelial cells is commonly observed. These changes are more prominent in older patients and in those longstanding glaucoma or previous intraocular surgery.

Gonioscopic examination typically reveals a prominent Schwalbe’s line, although there is considerable variation among the patients in the extent to which Schwalbe’s line is enlarged and anteriorly displaced. In occasional cases, the line is suspended from the cornea in some areas by a thin membrane.3,11 Tissue strands bridge the anterior chamber angle from the peripheral iris to the prominent ridge (Fig. 7.2). These strands range in size from threadlike structures to broad bands extending nearly 15 degrees of circumference. In some eyes, only one or two tissue strands are seen, while others have several per quadrant.

In addition to the characteristic gonioscopic features of Axenfeld–Rieger syndrome, a more subtle abnormality has also been noted in the anterior chamber angle.3,5,7,8 Beyond the tissue strands, the anterior angle is open and the trabecular meshwork is visible, but the scleral spur is typically obscured by peripheral iris which inserts into the posterior portion of the meshwork. This alteration is distinctly different from the coarser strands of tissue that bridge the angle. In

Figure 7.3 Rieger’s anomaly. Iris abnormalities include iris hole formation with polycoria.

some eyes, this abnormality is continuous for 360 degrees, while in others it involves only one or more quadrants.

Aside from peripheral abnormalities, the iris is normal in some eyes with Axenfeld–Rieger syndrome. In other cases, defects of iris range from mild stromal thinning to marked atrophy with hole formation, corectopia and ectropion uvea (Fig. 7.3). When corectopia is present, the pupil is usually displaced toward a prominent peripheral tissue strand, which is often visible by slit-lamp biomicroscopy. The atrophy and hole formation typically occur in the quadrant away from the direction of the corectopia.

In a small number of patients with Axenfeld–Rieger syndrome, abnormalities of the central iris have been observed to progress.3,12,13 This is more often seen during the first years of life, but may occur at a later time. The progressive changes usually consist of displacement or distortion of the pupil and occasional thinning or hole formation of the iris. Abnormalities of the peripheral iris or anterior chamber angle do not appear to progress after birth, except for occasional thickening of iridocorneal tissue strands.3

Aside from abnormalities of the cornea, anterior chamber angle, and iris, no additional ocular anomalies occur with sufficient regularity to be included as typical features of the Axenfeld–Rieger syndrome. However, many additional ocular abnormalities have been reported in one or more cases or pedigrees. Strabismus has been reported, although it is difficult to know whether this is a primary muscle imbalance or is secondary to reduced visual acuity from the glaucoma. Other rarely associated ocular anomalies include limbal dermoids, cataracts of many types (including congenital), peripheral spoke-like transillumination defects of the iris, retinal detachment, macular degeneration, chorioretinal colobomas, choroidal hypoplasia, and hypoplasias of the optic nerve head.3,5,8

Slightly more than half of the patients with Axenfeld– Rieger syndrome develop glaucoma. This may become manifest during infancy, although it more commonly appears in childhood or young adulthood. Glaucoma seems to occur more often in patients with central iridic changes, although the extent of the defects does not correlate precisely with the presence or severity of the glaucoma. The abundance or paucity of peripheral tissue strands does not correlate with the presence or absence of glaucoma, whereas high insertion of peripheral iris into the trabecular meshwork is associated

with glaucoma.3 The glaucoma associated with Axenfeld– Rieger syndrome is typically difficult to control, often leading to significant optic nerve head damage and vision loss. Rare cases have been reported to regress spontaneously.

The systemic anomalies most commonly associated with the Axenfeld–Rieger syndrome are developmental defects of the teeth and facial bones. The dental abnormalities include a reduction in crown size (microdontia), a decreased but evenly spaced number of teeth (hypodontia), and a focal absence of teeth (oligodontia or anodontia).14 The teeth most commonly missing are anterior maxillary primary and permanent central incisors. Facial anomalies include maxillary hypoplasia with flattening of the mid-face, a receding upper lip and a prominent lower lip, especially in association with dental hypoplasia. Hypertelorism, telecanthus and a broad flat nose have also been described.5

Anomalies in the region of the pituitary gland are not common, but may be a significant finding associated with the Axenfeld–Rieger syndrome. A primary empty sella syndrome has been documented in several patients,3,15 and one case of congenital parasellar arachnoid cyst has been reported.3 Growth hormone deficiency and short stature have also been described in association with this entity.16,17 Other abnormalities reported in association with the Axenfeld–Rieger syndrome include redundant periumbilical skin, hypospadias,18 oculocutaneous albinism,19 heart defects, middle ear deafness, mental deficiency, and a variety of neurologic and dermatologic disorders.5

Histopathologic features

The central cornea is typically normal, while the peripheral cornea has the characteristic prominent, anteriorly displaced Schwalbe’s line. The Schwalbe’s line is composed of dense collagen and ground substance covered by a monolayer of spindle-shaped cells with basement membrane.3,7,11 The peripheral iris is attached in some areas to the corneoscleral junction by tissue strands which usually connect with the prominent Schwalbe’s line. Occasionally, however, the adhesions insert either anterior or posterior to Schwalbe’s line or on both sides of the ridge.3 The strands consist of either iris stroma, a membrane composed of a monolayer of spindleshaped cells and/or a basement membrane-like layer, or both.

A membrane, similar to that seen in association with the iridocorneal tissue strands, has also been observed on the iris, usually on the portion towards which the pupil is distorted.3,5,20 In the quadrants away from the direction of pupillary displacement, the stroma of the iris is often thin or absent, exposing pigment epithelium that may also contain holes.

The iris peripheral to the iridocorneal adhesions inserts into the posterior aspect of the trabecular meshwork. The meshwork may be composed of a scant number of attenuated lamellae, which extend from beneath peripheral iris to the prominent Schwalbe’s line and are often compressed, especially in the outer layers. Transmission electron microscopic examination suggests that the apparent compression may be due to incomplete development of the trabecular meshwork. Schlemm’s canal is either rudimentary or absent.

Differential diagnosis

The condition most frequently confused with Axenfeld– Rieger syndrome is another spectrum of disorders that has been referred to as the iridocorneal endothelial syndrome.21

Indeed, similarities of certain clinical and histopathologic features of the two disorders have led some investigators to suggest a common mechanism.22 However, comparison of the clinical features of the Axenfeld–Rieger and the iridocorneal endothelial syndromes suggest that these are two distinctly separate entities (Table 7.1).23

The ICE syndrome is composed of three major clinical variations. In Chandler’s syndrome, there are corneal endothelial changes while iris changes are mild to absent.24 In progressive (essential) iris atrophy, iris changes predominate, with marked corectopia, atrophy, and hole formation. In Cogan–Reese (or iris nevus) syndrome, nodular, pigmented lesions of the iris are the hallmark, and may be seen with the entire spectrum of corneal or other iris abnormalities.25,26

In each type of iridocorneal endothelial syndrome, the condition is typically unilateral, usually becomes manifest in young adulthood, and has a predilection for women. There is rarely a positive family history and no additional ocular or systemic abnormalities are associated with the disease.10,27 In all variations, there is an abnormality of the corneal endothelium which frequently leads to edema of the cornea.28 The specular microscopic appearance of the endothelial cells is virtually pathognomonic in the iridocorneal endothelial syndrome, with pleomorphism in shape and size, dark areas within the cells (causing a reversal of the normal shading pattern), and loss of hexagonal margins.29 Ultrastructural studies of corneas with advanced edema reveal markedly abnormal cells lining a thickened, multilayered Descemet’s membrane.28

A characteristic feature common to all forms of the iridocorneal endothelial syndrome is peripheral anterior synechiae, which often extend to or beyond Schwalbe’s line. Progressive closure of the anterior chamber angle leads to secondary glaucoma in a high percentage of patients. The appearance

of the angle and the associated glaucoma are features that may be confused with the Axenfeld–Rieger syndrome, although a prominent Schwalbe’s line is rarely seen in the ICE syndromes.10 Another similarity between the Axenfeld– Rieger and iridocorneal endothelial syndrome is the range of changes observed in the iris. Progressive iris atrophy is characterized by marked corectopia and atrophy of the iris with hole formation, which may also be observed in advanced cases of the Axenfeld–Rieger syndrome. Patients with Cogan– Reese syndrome may have any degree of iris changes, as well as fine nodules or diffuse nevi on the stromal surface.25,26,30 Such nodules are not a typical feature of the Axenfeld–Rieger syndrome, although the association has been described.31

Histopathological studies of the iridocorneal endothelial syndrome have demonstrated a membrane, composed of a single layer of endothelial cells and a basement membrane, extending from the cornea, across the anterior chamber angle, and onto the surface of the iris.32–35 The similarity between this membrane and those seen in Axenfeld–Rieger syndrome is the main feature leading some investigators to suspect a common mechanism for these two syndromes. There may be, however, a difference in the origin of the membranes in these syndromes. According to the theory proposed by Campbell and co-workers for the iridocorneal endothelial syndrome, the fundamental defect is an abnormality of the corneal endothelium which leads to proliferation of the endothelial layer across the anterior chamber angle and over the iris. Subsequent contraction of the membrane pulls the peripheral iris to the anterior chamber angle, forming peripheral anterior synechia and frequently causing secondary glaucoma.32,36,37

The theory of pathogenesis of Axenfeld–Rieger syndrome differs from the mechanism proposed for iridocorneal endothelial syndrome because the membrane is derived not from abnormal corneal endothelium but from retention of the primordial endothelial layer lining the anterior chamber angle during gestation. Several observations are believed to support this concept. In contrast with the iridocorneal endothelial syndrome, the specular microscopic appearance of

the corneal endothelium in Axenfeld–Rieger syndrome is within normal limits, allowing for age, chronic intraocular pressure elevation, and surgical intervention. In addition, continuity in the membrane between the iris and the peripheral cornea was rarely observed in histopathologic specimens from patients with the Axenfeld–Rieger syndrome. This is in contrast with the iridocorneal endothelial syndrome, in which the membrane is typically continuous, from the peripheral cornea across the anterior chamber angle and onto the iris.32

In the theories of mechanism for both Axenfeld–Rieger and iridocorneal endothelial syndrome, contraction of a membrane is believed to be the principal cause of the iris changes. The situation in the anterior chamber angle is not the same, however, since the tissue strands in the iridocorneal endothelial syndrome are believed to develop at some point after birth, as the membrane pulls peripheral iris into the angle, while those in the Axenfeld–Rieger syndrome are congenital but may become thicker and shorter by contraction of the associated membrane. Furthermore, the mechanism of the glaucoma differs in the two conditions, in that the membrane over the trabecular meshwork or the peripheral anterior synechia are believed to cause the secondary glaucoma in the iridocorneal endothelial syndrome, whereas maldevelopment of the trabecular meshwork and Schlemm’s canal, and the associated tissue strands, cause the secondary glaucoma in the Axenfeld–Rieger syndrome.

Posterior polymorphous dystrophy represents yet another broad spectrum of abnormalities involving the cornea, anterior chamber angle and iris, which may be confused with both the Axenfeld–Rieger and iridocorneal endothelial syndromes (Table 7.1).38 posterior polymorphous dystrophy resembles the Axenfeld–Rieger syndrome in that it is congenital, typically with autosomal dominant inheritance, has bilateral ocular involvement, and has no significant race or sex predilection.39 It resembles the iridocorneal endothelial syndrome, however, in that association of glaucoma is usually not recognized until adulthood and corneal edema may be present.40,41

The common feature throughout the spectrum of posterior polymorphous dystrophy is an abnormality of the corneal endothelium and Descemet’s membrane, giving the slitlamp appearance of blisters or vesicles on the posterior surface of the cornea, which are often linear or in groups and surrounded by an area of gray haze (Fig. 7.4).40,41 Most patients remain asymptomatic, although secondary stromal and epithelial edema occurs in some cases. An even smaller

number of patients may have broad iridocorneal adhesions, occasionally with corectopia, ectropion uvea, and rarefaction of the iris.41,42 Some of these cases will be associated with glaucoma, while other patients with posterior polymorphous dystrophy may have glaucoma in the absence of these anterior chamber angle and iris changes.

In those cases with glaucoma and iridocorneal adhesions, ultrastructural studies have revealed a layer of Descemet’s membrane and transformed endothelial cells with epithelial characteristics covering the trabecular beams and iris.35 It has been postulated that this layer extends down from the abnormal corneal endothelium and that subsequent contraction leads to the secondary synechiae formation and iris changes,40 similar to that which has been proposed for the iridocorneal endothelial syndrome.32 In the other form of glaucoma associated with posterior polymorphous dystrophy, a high insertion of the iris into the posterior trabecular meshwork has been observed by gonioscopy and microscopic examination, and ultrastructural examination revealed collapse of the trabecular beams.43 These changes resemble those seen in primary congenital glaucoma5 and Axenfeld– Rieger syndrome,3 suggesting a developmental anomaly of the anterior chamber angle in this variation of posterior polymorphous dystrophy.43 It may be that this abnormality of the angle represents a common pathway, which leads to glaucoma in several developmental disorders. Distinctions between the Axenfeld–Rieger and iridocorneal endothelial syndromes and the posterior polymorphous dystrophy are summarized in Table 7.1.

Peters anomaly is a developmental abnormality involving the central cornea, iris, and the lens. Similar changes have been reported in association with the peripheral iris and angle abnormalities of the Axenfeld–Rieger syndrome, and the two conditions were once included in a single category of developmental disorders.1,2 However, this association is rare and the mechanisms for the two groups of developmental disorders are distinctly different.

Patients may have congenital hypoplasia of the iris without the anterior chamber angle defect of Axenfeld–Rieger syndrome or any other ocular abnormality. Iris hypoplasia has also been reported in association in juvenile-onset glaucoma with autosomal dominant inheritance.

Congenital ectropion uvea is a rare, non-progressive anomaly characterized by the presence of pigment epithelium on the stroma of the iris.44–47 It may be an isolated finding, or may occur in association with ptosis (Fig. 7.5). Congenital

ectropion uvea may also occur in association with systemic anomalies, including neurofibromatosis, facial hemiatrophy, and the Prader–Willi syndrome.44 Glaucoma is present in a high percentage of cases, and ectropion uvea may be confused with that found in some cases in the Axenfeld–Rieger syndrome. The extent of ectropion uvea usually remains unchanged, but progressive changes have been identified.48

In iridoschisis, there is bilateral separation and dissolution of the stromal layers of the iris, which may be associated with glaucoma.49 Iridoschisis differs from Axenfeld–Rieger syndrome and other abnormalities of the iris by the age of onset in the 6th or 7th decade of life. The rudimentary iris and anterior chamber abnormalities with associated glaucoma in aniridia may, in some cases, lead to confusion with the Axenfeld–Rieger syndrome.

Ectopia lentis et pupillae is an autosomal recessive condition that is characterized by bilateral displacement of the lens and pupil,50 with the two structures typically displaced in opposite directions. The corectopia in this disorder may resemble that of the Axenfeld–Rieger syndrome, but the absence of anterior chamber angle defects is a differentiating feature. In oculodentodigital dysplasia, the dental abnormalities are similar to those seen in the Axenfeld–Rieger syndrome. In addition, these patients may occasionally have mild stromal hypoplasia of the iris, anterior chamber angle defects, microophthalmia, and glaucoma.51

Management of Axenfeld–Rieger

syndrome

The primary concern regarding the management of ocular defects in a patient with the Axenfeld–Rieger syndrome is detection and control of the associated glaucoma. Intraocular pressure elevation most often develops between childhood and early adulthood, but may appear in infancy, or in rare cases, not until the elderly years.3 Therefore, patients with the Axenfeld–Rieger syndrome must be followed for suspicion of glaucoma throughout their life. Patients should also be examined for associated ocular and systemic abnormalities.52

With the exception of infantile cases, medical therapy should usually be tried before surgical intervention is recommended. Pilocarpine and other miotics are often ineffective, and drugs which reduce aqueous production, such as betablockers and carbonic anhydrase inhibitors are most likely to be beneficial. Laser surgery has not been found effective in managing the glaucoma in the Axenfeld–Rieger syndrome. Options for conventional surgery include goniotomy, trabeculotomy, and trabeculectomy. The former two have been utilized in infantile cases with limited success. Goniotomy may be impeded due to iris strands. Trabeculectomy is the surgical procedure of choice for most patients with glaucoma secondary to the Axenfeld–Rieger syndrome. Difficulty with intraoperative airway management has been described in a child with Axenfeld–Rieger syndrome.53

Peters anomaly

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

General features

Most cases are sporadic, although there is evidence of autosomal recessive inheritance, and chromosomal defects have been described.54 The condition is present at birth and is usually bilateral. It typically occurs in the absence of additional abnormalities, although rare associations with various systemic and other ocular anomalies have been reported.

Clinicopathologic features

The hallmark of Peters anomaly is a central defect in Descemet’s membrane and corneal endothelium with thinning and opacification of the corresponding area of corneal stroma (Fig. 7.6).55–58 Adhesions may extend from the borders of this

Glaucoma associated with Peters

anomaly

Approximately half of the patients with Peters anomaly will develop glaucoma, which is frequently present at birth. The mechanism of the glaucoma is uncertain. The anterior chamber angle is usually grossly normal by clinical examination. One histopathological report of the eye of a young child with Peters anomaly described changes in the trabecular meshwork that are characteristic of aging.61 Patients with glaucoma may be at increased risk for other systemic abnormalities.62

B

Figure 7.6 Schematic representation of Peters anomaly (A). Abnormalities include a central defect in Descemet’s membrane and the corneal endothelium, adhesions extending from the borders of this defect to the iris and lens, and frequently cataract. Clinical appearance of an infant with Peters anomaly (B). A central corneal leukoma is present. The day before the photograph, the child underwent trabeculotomy combined with trabeculectomy for marked elevation of intraocular pressure despite medical therapy.

defect to the iris. Bowman’s membrane may also be absent centrally.57,58 The disorder has been subdivided into three groups, each of which may have more than one pathogenic mechanism: those not associated with keratolenticular contact or cataract, those associated with keratolenticular contact or cataract, and those associated with Axenfeld– Rieger syndrome.56 The association of Peters anomaly with Axenfeld–Rieger syndrome is rare.

Some cases of Peters anomaly are not associated with keratolenticular contact or cataract. In these cases, the defect in Descemet’s membrane may represent primary failure of corneal endothelium to develop. However, rare cases may be secondary to intrauterine inflammation,59 which was originally postulated by Von Hippel and gave rise to the term ‘Von Hippel’s’ internal corneal ulcer.

Other cases are associated with keratolenticular contact or cataract. Most histopathologic studies of this variation 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’s membrane.56,57,60 It is also possible that some cases may result from incomplete separation of the lens vesicle from the surface ectoderm.

Differential diagnosis

The corneal clouding of Peters anomaly must be distinguished from primary congenital glaucoma, birth trauma, the mucopolysaccharidoses, and congenital hereditary corneal dystrophy. In addition, posterior keratoconus may be confused with Peters anomaly. Posterior keratoconus is a rare disorder that is characterized by a thinning of the central corneal stroma, with excessive curvature of the posterior corneal surface and variable overlying stromal haze.2,63 An ultrasound study revealed a multilayered Descemet’s membrane with abnormal anterior banding and localized posterior excresences. Glaucoma is rarely associated with posterior keratoconus. Congenital corneal leukomas and staphylomas represent severe forms of central dysgenesis of the anterior ocular segment and are frequently associated with glaucoma.

Management

All infants and children with cloudy corneas must be examined carefully for the possibility of associated glaucoma, which usually requires surgical intervention. Initial trabeculectomy may offer the best chance of success. Penetrating keratoplasty is also frequently necessary. Visual outcomes are poor due to the presence of congenital anterior and posterior segment anomalies, structural defects of the central nervous system, cognitive dysfunction, and amblyopia, as well as postoperative complications such as graft failure, cataract, inoperable retinal detachment, and phthisis.64,65

Aniridia

Aniridia (Greek: absence of iris) is a bilateral, uncommon panocular disorder affecting not only the iris, but also the cornea, anterior chamber angle, lens, retina and optic nerve. The name ‘aniridia,’ however, is a misnomer, since a small portion of the iris tissue can be present. The term ‘iridemia’ better describes the condition than does ‘aniridia.’ Since Barrata’s first description of aniridia in 1818, the ophthalmic literature has contained many scattered reports on the subject.

Most cases are inherited by autosomal dominant transmission,66 although sporadic cases also occur. Other patients, especially those with mental retardation, have an autosomal