1.1Introduction

The sclera, the dense connective tissue that encloses about Þve-sixths of the eye, is remarkable for its strength and the Þrmness with which it maintains the shape of the globe. It aids in the maintenance of intraocular pressure, provides attachment sites for the extraocular muscles, and protects the intraocular structures from trauma and mechanical displacement.

To appreciate these normal functions and understand the pathogenesis of inßammatory and noninßammatory diseases of the sclera, one must acquire some knowledge of the development, anatomy, and physiology of the sclera. A brief description of these areas follows.

into the tissues of the embryo. The cells of the outer cell mass become ßattened; they eventually develop into the trophoblast. The space between inner and outer cell mass forms a central cavity, the blastocystic cavity, after which the embryo is called a blastocyst.

1.2.1.2 Second Week

During the second week of development, some of the cells of the inner cell mass become detached from the inner surface and give rise to a cavity, the primitive yolk sac. The remaining cells give rise to another cavity, the amniotic cavity, and to a bilaminar embryonic disk, consisting of a single upper layer of columnar cells, the epiblast, and a single lower layer of ßattened cells, the hypoblast. The cells of the outer cell mass form the trophoblast which divides into two layers, the inner cytotrophoblast and the outer syncytiotrophoblast.

Ultrastructural Studies

1.2.1.1 First Week

In placental mammals, the fertilized zygote is transformed by cleavage cell division into a solid mass of cells with the appearance of a mulberry called morula. The cells are then rearranged, becoming organized as a group of centrally placed cells, the inner cell mass, completely surrounded by a layer of cells, the outer cell mass. The cells of the inner cell mass are attached at one pole of the morula; they eventually develop

epiblast, called the primitive streak, appears caudally in the midline of the dorsal aspect of the embryonic disk. The cranial end of the primitive streak is swollen and is known as the primitive knot. The primitive streak gives rise to the mesoblast, which spreads to form a layer between the epiblast and hypoblast. This new layer is called the embryonic mesoderm, and the process by which the bilaminar embryonic disk becomes trilaminar is called gastrulation. At the end of gastrulation, the cells that remain in the epiblast form the outer layer or embryonic ectoderm. Some

Fig. 1.1 Diagrams of longitudinal and transverse sections of the fourth-week embryo, showing the neuroectodermal evagination from the ventrolateral aspect of the

neural tube at the level of the forebrain in the diencephalon to form the optic vesicle

mesoblastic cells displace the hypoblastic cells laterally, forming the layer known as the embryonic endoderm. Hence, the epiblast is the source of embryonic ectoderm, embryonic mesoderm, and most, if not all, of embryonic endoderm.

A solid cord of cells grows cranially from the primitive knot to the prochordal plate between ectoderm and endoderm forming a midline cord known as the notochord. The notochord induces the thickening of the overlying ectoderm between the prochordal plate and the primitive knot forming the neural plate. Shortly after its appearance, the neural plate invaginates along the long axis of the embryo to form the neural groove. The lateral walls of the groove are called the neural folds and the edges of the folds form the neural crest. By the end of the third week, the inner neural folds begin to fuse, forming the neural tube which gives rise to the central nervous system. The process of fusion starts in the future embryonic neck and extends toward the cranial and caudal ends of the embryo. The cranial end of the neural tube forms the forebrain, midbrain, and hindbrain; the remainder of the tube forms the spinal cord.

The mesoderm down the center of the embryo differentiates into the paraxial mesoderm, the intermediate mesoderm, and the lateral mesoderm; the paraxial mesoderm divides into dense condensations or somites, each of which differentiates into sclerotome, dermatome, and myotome.

The mesoderm in the head and neck areas (cranial mesoderm) also undergoes differentiation, but the segmentation results in contiguous loose condensations or somitomeres [1, 2]. These mesodermal condensations are located close to neural crest cell population forming a neural crestÐmesoderm interface [1, 2]. The neural crest and mesoderm form the mesenchyme, which is a population of loosely arrayed stellate or Þbro- blast-shaped cells.

1.2.1.4 Fourth Week

The eye develops early in the fourth week as an evagination from the ventrolateral aspect of the neural tube or neuroectoderm, at the level of the forebrain in the diencephalon (Fig. 1.1) [3]. The end of the evagination becomes slightly dilated to form the optic vesicle. Neural crest cells cover the convex surface of the vesicles or neuroectoderm and partially isolate them from the dorsal, cranial, lateral, and ventral surface ectoderm, and from the caudomedial paraxial mesoderm. At the same time, a small area of surface ectoderm, overlying each optic vesicle thickens, forms the lens placode (Fig. 1.2), which invaginates to become the lens vesicle.

1.2.1.5 Fifth Week

Each optic vesicle then invaginates to form the double-layered optic cup of neuroectoderm

Fig. 1.2 Diagrammatic representation of the formation of the lens placode (left transverse section) during the fourth week of embryo development (development of the optic vesicle during week 4 is shown in Fig. 1.1).

Rapid, subsequent, sequential development of the lens vesicle, the optic stalk, and (as shown in greater detail in Fig. 1.3) the double-layered optic cup of neuroectoderm is shown

which is surrounded by neural crest, mesectoderm, or ectomesenchyme. The neuroectoderm gives rise to the pigment layer and the neural layer of the retina, the Þbers and glia of the optic nerve, and the smooth muscle of the iris (Fig. 1.3) (Table 1.1). The surface ectoderm forms the corneal and conjunctival epithelium, lens, lacrimal gland, tarsal glands, and epidermis of the eyelids. The neural crest (or mesectoderm, or ectomesenchyme, also of ectodermal origin) forms the choroid, iris, ciliary musculature, part of the vitreous, corneal stroma, corneal endothelium, trabecular meshwork, optic nerve meninges, and almost all of the sclera. The mesoderm contributes only to the striated extraocular muscles, the vascular endothelia, and a small, temporal portion of the sclera [2, 4]. The sclera, therefore, is of dual origin, reßecting the location of the neural crestÐmesodermal interface. Like the sclera,

other connective tissues are of neural crestÐ mesodermal origin; they include cartilage, bones, ligaments, tendons, dermis, leptomeninges, and perivascular smooth muscle; [5] this may explain, at least in part, the frequent association of sclera and joints in many systemic diseases.

The differentiation of neural crest cells into sclera and choroid is induced by the retinal pigment epithelium [5Ð7]. In developmental colobomas, the defective pigment epithelium fails to induce development of the sclera and the choroid; the sclera remains thin and may develop internal staphylomas. The sclera, as well as the pigment epithelium and the choroid, also requires the presence of the developing lens for normal growth and change in shape, structure, and function [2].

The sclera differentiates from anterior to posterior and from inside to outside [8Ð10].

Fig. 1.3 Further development of the eye (week 5). The neuroectoderm has now given rise to the pigment layer and to the neural layer of the retina, the Þbers and glia of the optic nerve, and the smooth muscle of the iris. The lens vesicle has completely separated and is now a distinct, unattached entity within the developing globe, and the hyaloid artery has developed further throughout the vitreous and to the posterior aspect of the lens vesicle. The vascular plexus of the choroid has now developed, as has the

primative sclera. The surface ectoderm has formed corneal and conjunctival epithelium, lens, lacrimal gland, and tarsal glands, as well as the epidermis of the skin. The neural crest mesectoderm has formed the choroid, the iris, the ciliary musculature, part of the vitreous, the corneal stroma and corneal endothelium, the trabecular meshwork, the optic nerve meninges, and the sclera. The mesoderm contributes only to the striated extraocular muscles and vascular endothelium and to a small temporal portion of the sclera

1.2.1.6 Sixth Week

The differentiation of periocular mesenchymal cells into Þbroblasts has already started by week 6.4 [10]. At this stage, the late mesenchymal cells or very early Þbroblasts do not show pronounced differences between the anterior and posterior portions of the globe, except for the

nuclei, the number of glycogen granules, and the number of lipid vacuoles; the cells in the anterior portion possess elongated nuclei and many glycogen granules and lipid vacuoles, whereas the cells of the posterior portion possess round-to- oval nuclei and few glycogen granules and lipid vacuoles. The late mesenchymal cells or very