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

Introduction

Terminology

Classification

Neurocristopathies

Conclusion

Introduction

The glaucomas that occur at birth or as a result of improper ocular development have been called by many names indicating a variety of structural changes, etiologic factors, inheritance patterns, prognoses and preferred treatments. The terminology used in the literature to describe these rare diseases is confusing and inconsistent. In infancy, elevated intraocular pressure alters the anterior segment in a way that obscures the structural defects responsible for the glaucoma. Also, terms that have general meanings have been employed to describe specific syndromes. Familiarity with terminology and classification systems used to describe the developmental glaucomas is important for clinicians who encounter these patients.

until 3 years of life. Juvenile glaucoma occurs after the age of 3 to teenage years. These terms relate to the age at onset of signs and symptoms of glaucoma and do not imply etiologic factor or inheritance pattern of the glaucoma.

Developmental glaucoma

Developmental glaucoma refers to glaucoma associated with developmental anomalies of the eye present at birth. This is a broad term that encompasses most of the glaucomas in infants and children. Primary developmental glaucoma refers to glaucoma resulting from maldevelopment of the aqueous outflow system. Secondary developmental glaucoma indicates glaucoma resulting from damage to the aqueous outflow system due to maldevelopment of some other portion of the eye. Secondary developmental glaucoma may, for example, present as angle closure due to pupillary block in a small eye, an eye with micropherophakia, or an eye with a dislocated lens; or it may present as a forward shift of the lens-iris diaphragm as occurs in persistent hyperplastic primary vitreous or retinopathy of prematurity.

Terminology

Different terms have been used to describe glaucoma in infants and children. These are either general terms, terminology related to the age of onset, or terms related to the presumed cause of the glaucoma.

General terms

Buphthalmos (Greek: bous = ox + ophthalmos = eye) is derived from the Greek term for ‘ox-eye’, and refers to the marked enlargement that can occur as a result of any type of glaucoma present in infancy. Hydrophthalmia (Greek: hydor = water + ophthalmos = eye) refers to the high fluid content present with marked enlargement of an eye, which can occur in any type of glaucoma presenting in infancy. Buphthalmos and hydrophthalmia are both descriptive terms that do not imply etiology or appropriate therapy, and these terms should not be used diagnostically.

Terminology relating to age of onset

In congenital glaucoma, the glaucoma exists at birth, and usually before birth. Infantile glaucoma occurs from birth

Terminology relating to structural

maldevelopment

Goniodysgenesis indicates fetal maldevelopment of the iridocorneal angle.1 Trabeculodysgenesis is maldevelopment of the trabecular meshwork, iridodysgenesis is maldevelopment of the iris, and corneodysgenesis is maldevelopment of the cornea. These may present either singly or in some combination. Isolated trabeculodysgenesis is the hallmark of primary developmental glaucoma.

Primary congenital glaucoma

Primary congenital glaucoma was described by Shaffer and Weiss2 as follows:

The most common hereditary glaucoma of childhood, inherited as an autosomal recessive pattern, with a specific angle anomaly consisting of absence of angle recess with iris insertion directly into the trabecular surface. There are no other major abnormalities of development. Corneal enlargement, clouding and tears in Descemet’s membrane result from elevated intraocular pressure.

In many areas of the world this term is used synonymously with infantile glaucoma to designate this particular syndrome

defined by Shaffer and Weiss. In other areas, however, the term infantile retains its intended meaning, indicating glaucoma occurring at birth.3

Classification

Various classifications of the developmental glaucomas have been employed. Initial efforts at classification were directed toward eponyms and syndrome names, and many of these terms are now widely employed and recognized. The Shaffer– Weiss (1970) disease classification divides the developmental glaucomas into primary congenital glaucoma, glaucomas associated with congenital anomalies of the eye or the body, and acquired glaucomas (Table 2.1).2,4 This system uses commonly known syndrome or eponym names for the developmental glaucomas, which can be used for most glaucomas in the pediatric age group. Some patients with developmental glaucomas may be difficult to categorize due to unusual or overlapping features. One type of glaucoma not mentioned in the Shaffer–Weiss classification is glaucoma associated with aphakia.

DeLuise and Anderson (1983)5 classified the congenital and infantile glaucomas as primary or secondary infantile glaucomas. The secondary infantile glaucomas were associated with different variables (Table 2.2). This system circumvented the need to differentiate between potentially confusing syndromes that had been grouped on the basis of superficial characteristics.

Table 2.1 Shaffer–Weiss (1970) classification of congenital glaucoma

I.Primary congenital glaucoma (primary infantile glaucoma)

II. Glaucoma associated with congenital anomalies

A.Late developing primary infantile glaucoma (late developing primary congenital glaucoma)

C.Sturge–Weber syndrome

D.Neurofibromatosis

E.Marfan’s syndrome

F.Pierre Robin syndrome

G.Homocystinuria

H.Goniodysgenesis (iridocorneal neural crest cell dysgenesis: Axenfeld–Reiger syndrome, Peters anomaly)

I.Lowe’s syndrome

J.Microcornea

K.Microspherophakia

L.Rubella

M.Chromosomal abnormalities

N.Broad thumb syndrome

O.Persistent hyperplastic primary vitreous III. Secondary glaucomas in infants

A.Retinopathy of prematurity

B.Tumors

1.Retinoblastoma

2.Juvenile xanthogranuloma

C.Inflammation

D.Trauma

Table 2.2 DeLuise–Anderson (1983) classification of congenital and infantile glaucoma

1.Primary infantile glaucoma (congenital glaucoma, trabeculodysgenesis)

2.Secondary infantile glaucoma

A.Associated with mesodermal neural crest dysgenesis

1.Iridocorneotrabeculodysgenesis

a.Axenfeld’s anomaly

b.Rieger’s anomaly

c.Peters anomaly

d.Systemic hypoplastic mesodermal dysgenesis (Marfan’s syndrome)

e.Systemic hyperplastic mesodermal dysgenesis (Weill– marchesani syndrome)

2.Iridotrabeculodysgenesis (aniridia)

B.Associated with phakomatoses and hamartomas

1.Neurofibromatosis (Von Recklinghausen’s disease)

2.Encephalotrigeminal angiomatosis (Sturge–Weber syndrome)

3.Angiomatosis retinae (von Hippel-Lindau syndrome)

4.Oculodermal melanocytosis (Nevus of Ota)

C.Associated with metabolic disease

1.Oculocerbrorenal syndrome (Lowe’s syndrome)

2.Homocystinurea

D.Associated with inflammatory disease

1.Maternal rubella syndrome (congenital rubella)

2.Herpes simplex iridocyclitis

E.Associated with mitotic disease

1.Juvenile xanthogranuloma (nevoxanthoendothelioma)

2.Retinoblastoma

F.Associated with other congenital disease

1.Trisomy 13-15 syndrome (Patau’s syndrome)

2.Rubinstein–Taybi syndrome

3.Persistent hyperplastic primary vitreous

An anatomic classification of the developmental glaucomas has been proposed by Hoskins, Shaffer, and Hetherington (1984).6 Clinically identifiable anatomical defects of the eye were chosen as the basis for this classification because they were readily apparent on examination of the patient (Table 2.3). This system categorizes developmental glaucoma more precisely, but does not apply to glaucomas that occur in the absence of a developmental anomaly of the eye. Certain cases, however, can only be described by anatomical defects. In addition, this classification does have prognostic implications. Isolated trabeculodysgenesis, for example, responds more favorably to surgical intervention compared with trabeculodysgenesis associated with iris or corneal anomalies.

In the Hoskins–Shaffer–Hetherington system, defects are classified anatomically according to the three major anterior chamber structures affected: the trabecular meshwork, the iris, and the cornea. Trabeculodysgenesis is defined as maldevelopment of the trabecular meshwork, including the iridotrabecular junction, since the trabecular meshwork is

Table 2.3 Hoskins–Shaffer–Hetherington (1984) classification of the developmental glaucomas

I.Isolated trabeculodysgenesis (malformation of trabecular meshwork in the absence of iris or corneal anomalies)

A.Flat iris insertion

1.Anterior insertion

2.Posterior insertion

3.Mixed insertion

B.Concave (wrap-around) iris insertion

C.Unclassified

II.Iridotrabeculodysgenesis (trabeculodysgenesis with iris anomalies)

A.Anterior stromal defects

1.Hypoplasia

2.Hyperplasia

B.Anomalous iris vessels

1.Persistence of tunica vasculosa lentis

2.Anomalous superficial vessels

C.Structural anomalies

1.Holes

2.Colobomata

3.Aniridia

III.Corneoiridotrabeculodysgenesis (malformation of trabecular meshwork with iris and corneal anomalies)

A.Peripheral

B.Midperipheral

C.Central

D.Corneal size

formed during separation of the iris from the cornea. Isolated trabeculodysgenesis7 occurs in the absence of developmental anomalies of the iris or cornea. This is the hallmark of primary developmental glaucoma (primary congenital glaucoma) and is the only detectable ocular anomaly in approximately 50% of the infants and juvenile patients with glaucoma.

Trabeculodysgenesis

Trabeculodysgenesis occurs in two major forms, distinguished primarily by the appearance of the iridotrabecular junction: flat iris insertion and concave (‘wrap-around’) iris insertion. In the flat iris insertion, patients have an iridotrabecular junction in which the iris appears to insert flatly and abruptly into a thickened trabecular meshwork. The plane of the iris is flat, and the iris tissue stops abruptly where the iris joins the trabeculum. The level of iris insertion may vary along the angle circumference, even posterior to the scleral spur.

An anterior insertion, into the trabecular meshwork or anterior to the scleral spur, is the most common type of developmental glaucoma. An anterior insertion usually obscures the view of the ciliary body, although it is possible to see pigmented portion of the anterior ciliary body through a thickened trabecular meshwork when the angle is viewed obliquely from above. Small iris processes may extend onto

the trabecular surface, and the surface of the trabecular meshwork may have a stippled, orange peel appearance. The peripheral anterior iris stroma may be thinned, but the corneal stroma and the iris collarette appear normal.

In the concave (‘wrap-around’) iris insertion, the plane of iris is well posterior to the normal position of the scleral spur. However, the anterior iris stroma continues upward and over the trabecular meshwork, obscuring the scleral spur and ending just short of Schwalbe’s line. Thus, the iris sweeps around the angle, forming a concave or ‘wrap-around’ insertion. This is most easily recognized in brown irides, and is much less common than flat iris insertion.

The trabeculodysgenesis in some eyes cannot be classified because of corneal clouding or previous surgery. There is no evidence of other iris or corneal malformation in isolated trabeculodysgenesis. The elevated intraocular pressure, however, may cause secondary stretching of these structures.

Iridotrabeculodysgenesis

In iridotrabeculodysgenesis, malformation of the trabecular meshwork is accompanied by maldevelopment of the iris. Iridodysgenesis or maldevelopment of the iris is subdivided into anterior stromal defects, anomalous iris vessels, and structural anomalies.

The anterior stromal defect category includes hypoplasia of the anterior iris stroma, which is the most common iris defect associated with developmental glaucoma. Because the normal infant eye has some peripheral thinning of the iris and because stretching of the iris from pressure can further thin the anterior stroma, diagnosis of true hypoplasia of the anterior stroma should be made only when there is clearly a malformation of the collarette with absence or marked reduction of the crypt layer.

The defect, when present, is easily recognized. The sphincter muscle is quite obvious, whereas the iris collarette is either absent or is formed only in the far periphery. Twigs of iris stroma may be seen scattered over the surface of the iris. The iris may insert anteriorly at the level of the scleral spur, and the trabecular meshwork may appear to be thickened. An absent or poorly developed anterior iris stroma has been described as a common finding in Axenfeld’s anomaly and Rieger ’s anomaly.2,8 This defect, when occurring by itself, is typical of familial hypoplasia of the iris with glaucoma.1,9,10 It should not be confused with primary congenital glaucoma since the hypoplastic iris syndrome is dominantly inherited.

In hyperplasia of the anterior iris stroma, excessive anterior iris stroma appears as a diffuse thickening of the brown iris covered with abundant small nodules, giving the iris surface a cobblestone appearance. In the series reported by Hoskins et al,6 there were only two cases, both of which were associated with Sturge–Weber syndrome and developmental glaucoma.

Vascular anomalies of the iris are divided into those with some form of persistence of the tunica vasculosa lentis, and those with irregularly wandering anomalous superficial vessels. Persistence of tunica vasculosa lentis is characterized by the regular arrangement of the vessels looping into the

pupillary axis either in front of or behind the lens. The normal radial vessels of the iris surface are also prominent because this condition is usually accompanied by hypoplasia of the anterior iris stroma. In anomalous superficial vessels, the vessels wander irregularly over the iris surface, and the pupil is usually distorted. The iris surface has a whorled appearance because of the curving of the radial fibers of the iris. The anterior iris stroma is often hypoplastic.

These vascular patterns must be differentiated from exposure of the radial iris vessels that may exist in normal blue-eyed infants or in eyes with hypoplasia of the anterior iris stroma. In such eyes, there is no vascular anomaly even though the vessels are easily seen. Also, the term rubeosis does not apply, because the vessels exist at birth and do not represent neovascularization. Anomalous vessels of the iris are seen most frequently in eyes presenting with glaucoma and cloudy corneas at birth and represent a more severe malformation of the anterior segment. These eyes behave quite differently from eyes whose only structural defect is trabeculodysgenesis. These patients have a poor prognosis for initial surgical treatment and usually require multiple surgeries.

The type of iridodysgenesis characterized by structural anomalies or structural iris defects is easily identified by clinical examination. The anatomic defect may present in several different ways. Holes present as a full thickness opening in the iris without sphincter involvement, as seen in Rieger ’s anomaly. Colobomata cause full-thickness defects of the sphincter. In aniridia, most of the iris and all of the sphincter is missing.

Corneoiridotrabeculodysgenesis

Although the cornea certainly changes under the influence of elevated intraocular pressure, it may also be the site of a primary malformation. Usually a combination of iris, corneal, and trabecular dysgeneses results in glaucoma. Most commonly there are iridocorneal adhesions, hypoplasia of the anterior iris stroma, and some form of corneal opacity or structural change. For classification purposes, corneal defects are grouped according to their location as peripheral lesions, midperipheral lesions, and central lesions. Glaucoma may also be associated with abnormalities of corneal size, including microcornea and macrocornea.

Peripheral corneal lesions occur adjacent to and concentric with the limbus and extend no more than 2 mm into clear cornea. Generally, these changes involve the entire circumference of the cornea and are often seen as posterior embryotoxon with adherent iris tissue (e.g., Axenfeld’s anomaly). Midperipheral lesions usually involve a sector of the cornea and are almost always opacities with iris adhesions. The iris is quite dysgenetic, manifested by hypoplasia of the stroma, hole formation, and pupillary abnormalities (e.g., Rieger ’s anomaly). Central corneal anomalies are usually opacities, often with central stromal thinning. Hoskins et al (1984)6 reported two cases with a hole through the cornea, draining aqueous. Most central lesions are round, with associated iris adhesions between the collarette and the margin of the opacity, and have a clear zone separating the lesion from

the limbus (e.g., Peters anomaly). Occasionally, maldevelopment of the central portion of the cornea causes adhesions between the lens, iris, and cornea with no anterior chamber formation (e.g., anterior chamber cleavage syndrome, anterior staphyloma). This is an extreme form of central iridocorneodysgenesis.

Patients with developmental glaucoma may have microcornea or macrocornea. Microcornea may occur as an isolated defect or may be associated with rubella syndrome, persistent hyperplastic primary vitreous (PHPV), Rieger ’s anomaly, and nanophthalmos. Because increased intraocular pressure may stretch these glaucomatous eyes, corneal enlargement is not always a developmental defect. It is important to distinguish megalocornea from the corneal stretching that occurs as a part of the glaucomatous process. Megalocornea may occur as a primary defect or in association with other defects such as Axenfeld syndrome. X-linked recessive megalocornea may be associated with glaucoma, which may occur later in life. The prognosis for control of glaucoma in eyes with corneodysgenesis is not as good as in eyes with isolated trabeculodysgenesis.

Advantages of anatomical classification

Classification by syndromes and eponyms is important because it allows a few words to describe a constellation of characteristics that are frequently found together. However, an anatomical classification has certain advantages over eponym or syndrome nomenclature when dealing with developmental anomalies. Often the anomalies are varied and do not fit particular syndrome or eponym patterns. Occasionally, a form not previously seen needs to be categorized and treated. Correct classification according to eponym or syndrome may require knowledge of factors not yet known about a particular patient, such as future inheritance pattern, response to therapy, or histopathologic examination.

The anatomical classification is helpful because it does not require knowledge of the histopathologic findings, time of onset, response to treatment, inheritance pattern, or any other factor. Patients may be classified according to more than one classification system, and the anatomical classification has been useful as a supplement to the more traditional nomenclature. The anatomical classification improves communication among researchers in this field, because it allows greater precision in describing patients and predicting surgical outcome.

At the present time, we recognize the excellent surgical prognosis in patients with isolated trabeculodysgenesis. In patients who have additional developmental defects of the anterior segment, the prognosis is worse compared with isolated trabeculodysgenesis. Patients with associated iris anomalies, especially those with anomalous iris vessels, respond poorly to primary surgical intervention and represent either a more severe form of primary congenital glaucoma or perhaps a different development defect altogether. Those with corneal dysgenesis associated with anomalous superficial iris vessels or other iris abnormalities appear to benefit least from primary surgery.

Neurocristopathies

It has been recognized that neural crest-derived mesenchymal cells make a major contribution to the development of the tissues of the anterior segment. Therefore, one would expect that a group of ocular diseases exists that involves the cornea, iris, and trabecular meshwork, either singly or in combination and often in association with glaucoma. In some patients, these disorders would also be accompanied by abnormalities of non-ocular tissues that are also derived from neural crest cells, including craniofacial abnormalities, dental malformation, middle ear deafness, and malformation of the base of the skull. Clinical syndromes such as Axenfeld– Rieger syndrome, Peters anomaly, Sturge–Weber syndrome, and other phakomatoses can be interpreted based on their neural crest cell derivation. All of these disorders are believed to provide possible clinical evidence either of abnormalities in the migration of neural crest cells or of terminal interference with cellular interactions.11 These diseases and malformations of cells derived from the neural crest have been grouped together under the term neurocristopathies.12

Conclusion

Different classification systems with varying terminology have been used to lump and split the large number of disorders associated with glaucoma affecting infants and children. Many patients with classical clinical presentation may be described according to traditional eponyms and syndromes. Hoskins and associates have advocated a shift away from eponyms and syndrome names towards an emphasis on descriptive terminology. Noting that the trabecular meshwork, iris, and cornea are the three major structures involved in these conditions, they suggested the terms

‘trabeculodysgenesis,’ ‘iridodysgenesis,’ and ‘corneodysgenesis’ or a combination thereof, as a system of classifying the developmental glaucomas.

While there is value in categorizing disorders on the basis of anatomical descriptions and mechanisms, the wide range of manifestations and the limited understanding of disease mechanisms may make it difficult to apply such a system in all cases of developmental glaucomas. However, more precise terminology should be used whenever possible.

References

1.Jerndal T. Dominant goniodysgenesis with late congenital glaucoma. Am J Ophthalmol 1972; 74:28–33.

2.Shaffer RN, Weiss DI. Congenital and paediatric glaucomas. CV Mosby: St. Louis; 1970.

3.Worst JG. Congenital glaucoma: remarks on the aspect of chamber angle, ontogenetic and pathogenetic background and mode of action goniotomy. Invest Ophthalmol 1968; 7:127–134.

4.Hoskins HD Jr, Kass MA. Becker-Shaffer ’s diagnosis and therapy of the glaucomas, 6th edn. CV Mosby: St. Louis; 1989:356.

5.DeLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19.

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

7.Hoskins HD Jr, Hetherington J, Shaffer RN, Welling AM. Developmental glaucoma: diagnosis and classification. In: Proceedings of the New Orleans Academy of Ophthalmology Glaucoma Symposium. CV Mosby: St. Louis; 1981:172–190.

8.Hoskins HD, Shaffer RN. Rieger ’s syndrome. A form of irido-corneal mesodermal dysgenesis. Pediatr J Ophthalmol 1972; 9:26.

9.Martin JP, Hart CT. Familial glaucoma. Br J Ophthalmol 1974; 58:536–542.

10.Weatherill JR, Hart CT. Familial hypoplasia of the iris stoma associated with glaucoma. Br J Ophthalmol 1969; 53:433–438.

11.Kupfer C, Datilies MB, Kaiser-Kupfer M. Development of the anterior chamber of the eye: embryology and clinical implications.

In: Lutjen-Drecoll E, ed. Basic aspects of glaucoma research: international symposium held at the Department of Anatomy, University ErlangenNürnberg, September 17 and 18, 1981. Schattauer: Stuttgart; 1982.

12.Bolande RP. The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 1974; 5:409.

Introduction

Concepts of anterior ocular segment development Normal development of the anterior segment

Theories of abnormal development in primary congenital glaucoma

Embryologic basis of other angular neurocristopathies

Embryologic basis of different iris anomalies

Developmental genetics

Conclusion

Introduction

During embryonic development, the human eye is derived from both ectoderm (surface and neural ectoderm, including neural crest) and paraxial mesoderm. Many structures that were originally believed to have been derived from mesoderm are now considered to be of neural crest origin. A basic understanding of normal development, particularly related to structures of the anterior ocular segment and theories of abnormal development, is helpful preparation for an understanding of developmental glaucomas.

Concepts of anterior ocular segment development

In the classic germ-layer theory of development of the human body, there are three layers in the developing embryo: ectoderm, endoderm, and mesoderm. According to this theory, the ectoderm gives rise to surface epithelia and to the nervous system, the endoderm forms the gut, and the mesoderm gives rise to all other structures that are not derived from either the ectoderm or endoderm.

Early studies on the development of the eye1–4 depicted the epithelium of the cornea, the retina, and the neural components of the uveal tract as derived from ectoderm, and the remainder of the ocular structures as developed from the mesoderm. Mesenchymal cells are described as a dispersed population of undifferentiated embryonic cells that are stellateshaped and loosely arranged. Although it still may be true that the non-ectodermal portions of the eye stem from the mesenchymal cells, it is now apparent that these cells differ in their embryonic origin. The importance of this realization lies in the fact that a number of congenital anomalies and other pathologic entities, especially disorders of the anterior

ocular segment, can be more thoroughly understood with consideration of the embryonic lineage of the cells involved.5,6 Recent experimental studies, most using animal models, have shown that a major portion, if not all, of the ocular mesenchyme is derived from neural crest cells.7–13 Neural crest cells may be defined as those neuroectodermal cells that proliferate from the crest of the neural folds at about the time the folds fuse to form the neural tube (Fig. 3.1). The neural crest cells that remain attached to the neural tube eventually differentiate into the cerebral and spinal ganglia and the roots of the dorsal nerves. However, many of the neural crest cells migrate away from the neural tube and form secondary mesenchyme, which differentiates into various body

structures (Table 3.1).

Normal development of the anterior segment

General development

The earliest development of the optic vesicle in humans appears as paired outpouchings, one on each side of the developing neural tube in the region that ultimately will form the diencephalon or forebrain.1,3,14,15 As the optic vesicles extend toward the surface ectoderm, the superior and the inferior walls of the neural tube constrict, so that each optic vesicle is connected to the wall of the forebrain by the so-called optic stalk.

E

NT

NC

Figure 3.1 Embryonic formation of neural crest cells (NC). These cells are derived from neuroectoderm located at the crest of the neural folds when the folds fuse to form the neural tube (NT). The cells migrate under the ectoderm (E).

Table 3.1 Contributions of neural crest-derived mesenchyme and mesodermal mesenchyme to human ocular structures

A Neural crest cell derivatives

1 Sclera (except caudal portion)

2 Cornea

a Endothelium

b Keratocytes

3 Uveal tract

a Fibroblasts of choroid b Ciliary body muscles c Stromal cells of iris

d Melanocytes

4Iridocorneal angle

a Trabecular meshwork endothelium

5Vascular system a ? Pericytes

BMesodermal cell derivatives 1 Caudal region of sclera

2 Vascular endothelium, including Schlemm’s canal

3 Extraocular muscles

Induction of the lens is first seen as a thickening of the surface ectodermal cells (the lens placode) at about the 3rd week of gestation. As the lens vesicle forms, the optic vesicle is developing into the optic cup (Fig. 3.2). By the 4th week, differential growth and movement of the cells of the optic vesicle cause the temporal and lower walls of the vesicle to

Retina

Optic cup

Optic stalk

Lens vesicle

Embryonic

fissure

move inward against the upper and posterior walls. The two laterally growing edges of the cup eventually meet and fuse. This process also involves the optic stalk and results in the formation of embryonic or optic fissure.

The lens vesicle separates from the surface ectoderm by the 6th week.3 At this time, the optic cup, which arises from neural ectoderm, has reached the periphery of the lens. A triangular mass of undifferentiated cells overrides the rim of the cup and surrounds the anterior periphery of the lens. From this tissue mass will arise portions of the cornea, iris, and the anterior chamber angle. The undifferentiated cells are derived from cranial neural crest cells origin.7–13

The anterior chamber is formed by three waves of tissue derived from the mass of undifferentiated (neural crest) cells, which grow in between the surface ectoderm and lens (Fig. 3.3). The first wave (avascular) differentiates into the primordial corneal endothelium by the 6th to 7th week and subsequently produces Descemet’s membrane. The second wave (vascular) insinuates between the primordia of the cornea and the lens and gives rise to the pupillary membrane and the stroma of the iris (7th week). In the later months, the pigment epithelial layer of the iris develops from neural ectoderm. The third (avascular) wave grows between the corneal endothelium and epithelium to produce keratocytes, which form the stroma of the cornea. 16,17

Development of anterior chamber angle

The aqueous outflow structures in the anterior chamber angle appear to arise from the mesenchymal cells of neural crest cell origin. The precise details of this development, however, are not fully understood. At the 22 to 24 mm stage (7th to 8th week), the anterior chamber angle is undifferentiated and is occupied by loosely arranged mesenchymal cells, and the anterior chamber itself is a slit-like opening. Several hypotheses have been advanced in the attempt to explain the formation of anterior chamber angle, including atrophy3 or resorption18 (progressive disappearance of portion of fetal tissue), cleavage19 (separation of two pre-existing

I

II

Lens

Figure 3.2 Formation of the optic cup. After the optic vesicle extends to the lens placode, the lens pit develops and the optic cup is formed at the end of the optic stalk. The lens pit develops into the lens vesicle within the optic cup. The retina is developed from the inner layers of the optic cup.

The embryonic fissure of the optic cup and optic stalk is located inferiorly in this sagittal view. (Modified with permission from reference 7.)

Retina

Figure 3.3 Ingrowth of neural crest cells. Three successive waves of ingrowth of neural crest cells are associated with differentiation of the anterior chamber. The first wave (I) forms the corneal endothelium. The second wave (II) forms the iris and pupillary membrane. The third wave (III) develops into keratocytes, which form the corneal stroma.

tissue layers due to differential growth rate), and rarefaction20 (mechanical distention due to growth of the anterior ocular segment). More recent work, however, suggests that none of these concepts are completely correct.

Anderson21 studied 40 normal fetal and infant eyes by light and electron microscopy and found that the anterior surface of the iris at 5 months gestation inserts at the edge of the corneal endothelium, covering the cells that are destined to become trabecular meshwork. This appears to be what Worst22 called the fetal pectinate ligament, separating the corneoscleral meshwork primordium from the anterior chamber angle. The developmental process does not consist of simple cleavage or atrophy, for with either process the uveal tract would simply split away from the corneoscleral shell and the trabecular tissue. The result would be that the ciliary muscle would extend into the perpheral iris and the ciliary processes would be on the posterior surface of the peripheral iris.

The trabecular meshwork later becomes exposed to the anterior chamber as the angle recess deepens and moves posteriorly (Fig. 3.4). Anderson noted a posterior repositioning of the anterior uveal structures in progressively older tissue specimens, presumably due to differential growth rates. The repositioning process is not just the sliding of the uveal tract along the inner side of the sclera but there is also repositioning of the various layers within the uveal tract in relation to one another.

At birth, the insertion of the iris and ciliary body is near the level of the scleral spur, and usually posterior to it. On gonioscopy of a normal newborn eye, the insertion of the iris into the angle wall will be seen posterior to the scleral spur in most cases, with the anterior extension of the ciliary body seen as a band anterior to the iris insertion. The iris insertion into the angle wall is rather flat, as the angle recess has not yet formed. Continued posterior sliding of the uveal tissue occurs during the first 6 to 12 months of life, which is apparent gonioscopically as formation of the angle recess. Thus, the adult angle configuration in which the iris turns slightly posteriorly before inserting into the ciliary body is not normally present at birth but develops in the first year of life.

There is some difference of interpretation regarding the innermost layer of the trabecular meshwork primordium as it is uncovered by the posteriorly receding iris. Anderson21 felt that the smooth surface represents the multilayered mesenchymal tissue, which begins to cavitate by the 7th fetal month. Others have suggested, however, that a true endothelial layer covers the meshwork during gestation. Hansson and Jerndal23 studied human fetal eyes by scanning electron microscopy and described a single layer of endothelium, continuous with that of the cornea, extending over the primitive anterior chamber angle and iridopupillary structures, creating a closed cavity at the beginning of the 5th fetal month. Worst22 observed a similar sheet of flat endothelial cells on the pupillary membrane and felt that the disappearance of this layer progresses centrifugally toward the anterior chamber angle.

Hansson and Jerndal23 noted that the anterior chamber angle portion of the endothelial layer begins to flatten, with loss of clear-cut borders, by the 7th fetal month. During the final weeks of gestation and the first weeks after birth, the endothelial layer undergoes fenestration with migration of cells into the underlying uveal meshwork. Van Buskirk24 also observed intact endothelium completely lining the anterior chamber angle by the second gestational trimester in macaque monkey eyes studied by scanning electron microscopy. He noted that fenestration and gradual retraction of this tissue occurs in the 3rd trimester and progresses in a posterior-to- anterior direction.

As the endothelium of the cornea and anterior chamber angle begins to differentiate, a distinct demarcation line develops at the primordium of Schwalbe’s line.23 It has also been suggested, based on transmission electron microscopy of eyes from premature infants with gestational ages of 24 to 42 weeks, that formation of the trabecular meshwork begins on the anterior chamber side and progresses toward Schlemm’s canal.25 This is thought to be consistent with some cases of primary congenital glaucoma in which the site of obstruction to aqueous outflow appears to be a thickened tissue adjacent to the inner wall of Schlemm’s canal.25,26

Shields combined various observations into a unified concept of anterior chamber angle development.27 At 5 months

gestation, a continuous layer of endothelium creates a closed cavity, and the anterior surface of the iris inserts in front of the primordial trabecular meshwork. In the third trimester, the endothelial membrane progressively disappears from the pupillary membrane, iris, and anterior chamber angle, possibly incorporated into the trabecular meshwork. The peripheral uveal tissue begins to slide posteriorly in relation to the anterior chamber angle structures. Development of the trabecular meshwork begins in the inner, posterior aspect of the primordial tissue and progresses toward Schlemm’s canal and Schwalbe’s line. The normal anterior chamber angle is not fully developed until approximately one year of life.

Theories of abnormal development in primary congenital glaucoma

Although it is generally agreed that the intraocular pressure elevation in primary congenital glaucoma is due to an abnormal development of the anterior chamber angle that leads to reduced facility of aqueous outflow, there is no universal agreement as to the nature of the developmental alteration. Theories of mechanism parallel the basic concepts regarding the normal development of the anterior chamber angle, most of which are no longer accepted as being entirely correct. The major theories that have been proposed in the past will be reviewed and the current understanding of the developmental abormality of primary congenital glaucoma will be described.

Mann (1928)2 proposed that the anterior chamber angle is formed by atrophy of the mesenchyme and arrest of this process results in retention of abnormal tissue that blocks aqueous outflow in primary congenital glaucoma. Allen, Burian, and Braley (1955)19 postulated that incomplete cleavage of mesoderm results in absent angle recess in primary congenital glaucoma, although the cleavage theory for normal development has not been proved. Barkan (1955)18 suggested that incomplete resorption of the mesodermal cells by adjacent tissue led to the formation of a membrane across the anterior chamber angle. This membrane became known as ‘Barkan’s membrane,’ although its existence has not been proved histologically using light as well as electron

microscopy.21,23,26,28–31

Maumenee (1958)28 demonstrated abnormal anterior insertion of the ciliary muscle over scleral spur in infantile glaucoma eyes. He noted that the longitudinal and circular fibers of the ciliary muscle inserted into the trabecular meshwork rather than into the scleral spur, and that the root of the iris can insert directly into the trabecular meshwork. He postulated that these changes might compress the scleral spur forward and externally, thus narrowing Schlemm’s canal. Maumenee (1963)31 also noted the absence of Schlemm’s canal in some histopathologic specimens and suggested that this might be a cause of aqueous outflow obstruction in congenital glaucoma, although others feel this may be a secondary change.32

Worst (1966)22 proposed a combined theory, which included elements of the atrophy and resorption concepts, but rejected the cleavage theory. He suggested that incomplete

development of the scleral spur leads to a high insertion of the longitudinal portion of the ciliary muscle on the trabeculum. In addition, he felt that a single layer of endothelial cells cover the anterior chamber angle during gestation, and that its abnormal retention in primary congenital glaucoma constitutes ‘Barkan’s membrane.’ Worst claimed that ‘though histopathological proof of this structure is almost completely lacking... this has little influence on the probability that this concept is valid.’33

Smelser and Ozanics (1971)20 explained primary congenital glaucoma as a failure of anterior chamber angle mesoderm to become properly rearranged into the normal trabecular meshwork. Subsequent light and electron microscopic studies favor this theory.25,26,32,34–36 Kupfer and associates (1978)5 suggested that abnormal neural crest cell migration and a defect of terminal induction by embryonic inducers is the cause of several forms of congenital glaucoma.37,38

Anderson (1981)21,39 provided histopathological support for the high insertion of the anterior uvea into the trabecular meshwork, suggesting that this is due to a developmental arrest in the normal migration of the uvea across the meshwork in the third trimester of gestation. He stated that, in eyes with primary congenital glaucoma, the iris and the ciliary body have the appearance of an eye in the seventh or eighth month of gestation rather than one at full term development. The iris and ciliary body have failed to recede posteriorly, and thus the iris insertion and anterior ciliary body overlap the posterior portion of the trabecular meshwork. Anderson believed that, in infantile glaucoma, the thickened trabecular beams have prevented the normal posterior migrations of ciliary body and iris root.

Beauchamp and co-workers (1985)40 have postulated that abnormal extracellular matrix and glycoproteins lead to abnormal anterior segment development by interfering with adductors, inductors, receptors and specific time sequencing. They state that, in primary congenital glaucoma, the defects in morphogenesis and differentiation (capacitation) can be seen as mild, requiring only a minor ‘remodeling’ by, for example, goniotomy to become functional. McMenamin (1991) observed a marked increase in the volume of extracellular matrix during development.41 Tawara and Inomata (1994) found extensive accumulations of basal lamina-like material containing heparan sulfate-type proteoglycans in the thick subcanalicular tissue in trabeculectomy specimens from patients with developmental glaucoma.42

In summary, primary congenital glaucoma appears to result from a developmental abnormality of anterior chamber angle tissue derived from neural crest cells, leading to aqueous outflow obstruction by one or more of several mechanisms. Developmental arrest may lead to an anterior insertion of iris, insertion of the ciliary muscle directly into trabecular meshwork, and only rudimentary development of the scleral spur (Fig. 3.5). The high insertion of the ciliary body and iris into the posterior portion of the trabecular meshwork may compress the trabecular beams, and the extracellular matrix may be abnormal. In addition, there may be primary developmental defects at various levels of the meshwork and, in some cases, of Schlemm’s canal. However, a true

Figure 3.5 Meridional representation of the anterior chamber angle showing the embryonic configuration. The features include an anterior insertion of the iris (I), a rudimentary scleral spur (II), insertion of the ciliary muscle directly into the trabecular meshwork (III), and undifferentiated trabecular meshwork (IV). These features also may be observed in eyes with primary congenital glaucoma. SC = Schlemm’s canal. (Adapted with permission from reference 7.)

membrane over the meshwork does not appear to be a feature of this disorder.

Embryologic basis of other angular neurocristopathies

It has been recognized that neural crest derived mesenchymal cells make a major contribution to the tissues of the anterior ocular segment. Although major developmental events leading to iridocorneal angle formation occur during the third trimester, embryonic insult much earlier in human gestation can induce an abnormal sequence of events leading to anterior segment dysgenesis.43

The neurocristopathies are a group of ocular diseases that involve the cornea, iris and trabecular meshwork (either singly or in combination), often are associated with glaucoma, and are frequently accompanied by abnormalities of nonocular tissue that are also derived from neural crest cells (e.g., craniofacial and dental malformation, middle ear deafness, malformation of the base of the skull).5 These diseases include Axenfeld–Rieger syndrome, Peters anomaly, and Sturge–Weber syndrome or other phakomatoses.

Based on clinical and histopathologic observations and the current concepts of normal anterior segment development, a developmental arrest, late in gestation, of certain anterior segment structures derived from neural crest cells, has been postulated as the mechanism of Axenfeld–Rieger syndrome.27,44 This leads to abnormal retention of the primordial endothelial layer on portions of the iris and anterior chamber angle, and alterations in the aqueous outflow structures. The retained endothelium with associated basement membrane is believed to create the iridocorneal strands, while contraction of the tissue layer on the iris leads to the iris changes, which sometimes continue to progress after birth. The developmental arrest also may account for the high insertion of the

anterior uvea into the posterior trabecular meshwork, similar to the alterations seen in primary congenital glaucoma, and result in incomplete maturation of the trabecular meshwork and Schlemm’s canal.

Neural crest cells also give rise to most of the mesenchyme related to the forebrain and pituitary gland, bones and cartilages of the upper face, and dental papillae.7,38,45 This could explain the developmental anomalies involving the pituitary gland, the facial bones, and teeth. Other defects, however, such as those of the umbilicus and genitourinary system, are more difficult to associate with a primary defect of cranial neural crest cells.

Peters anomaly is characterized by a spectrum of changes in anterior segment structures, including the lens, the cornea, and the anterior chamber angle.46–48 These changes include defects in the posterior stroma of the cornea, Descemet’s membrane, and endothelium, with or without extension of iris tissue strands from the iris collarette to the edge of the corneal leukoma. They may also include a central keratolenticular stalk and cataract. The corneal abnormalities may result from incomplete migration of the neural crestderived mesenchymal cells during early embryogenesis. Incomplete migration of the first wave may leave a central defect in endothelium and Descemet’s membrane, which may couple with a stromal defect because of incomplete migration of the second wave. An anterior staphyloma represents a more severe degree of failure of mesenchyme to differentiate properly so that a thin, ectatic, leukoma lined by uveal tissue replaces the cornea.

Numerous theories have been devised to account for the raised intraocular pressure in patients with phakomatoses,49–51 including Sturge–Weber syndrome and neurofibromatosis. Several investigators have reported primary defects in the structures of the aqueous outflow pathways in patients with these syndromes. The abnormalities include malformation or absence of Schlemm’s canal, persistence of embryonic tissue in the trabecular meshwork, or incomplete ‘cleavage’ of the iridocorneal angle.52–56 Abnormalities of neural crest cells could explain the pathogenesis of the associated glaucoma in these patients who have no secondary obstruction to aqueous outflow.

Embryologic basis of different iris anomalies

At about the 7th week of gestation a vascular wave insinuates between the primordia of the cornea and the lens to form the anterior portion of the vascular tunic of the lens (pupillary membrane), which later becomes the superficial layer of iris stroma. At the same time, the hyaloid artery has grown through the embryonic fissure of the optic stalk and across the vitreous cavity to the posterior aspect of the lens, where it ramifies as the posterior portion of the vascular tunic of the lens. The annular vessel which forms circumferentially around the mouth of the optic cup sends branches posteriorly (between the rim of the optic cup and the equator of the lens) to anastomose with branches of the hyaloid vessel. These