Clinically, the conjunctiva is an extremely valuable ally of the ophthalmic surgeon and diagnostician. The bulbar surface, because of its loosely adherent properties, is used to great advantage in glaucoma surgery. Its capacity to heal rapidly ensures the success of many surgical procedures. A conjunctival flap placed over a nonhealing or infected cornea promotes healing and preserves corneal integrity.⁴ Autologous conjunctival transplantation has been carried out from one eye to the other to repair leaky filtration blebs and to hasten corneal epithelial covering after chemical burns have destroyed the corneal surface.⁵ Characteristic conjunctival changes occur in many systemic diseases. For example, pathognomonic vascular signs are present in the conjunctival vessels in sickle cell anemia, scleral icterus is an early sign of jaundice, distinctive pigmentary changes are present in ochronosis, Bitot's spot appears in the conjunctiva in vitamin A deficiency, and typical crystalline deposits are present in the conjunctiva in cystinosis.^6,7 Another exceptional advantage of the conjunctiva is the ease with which conjunctival biopsy material can be obtained, causing little discomfort to the patient and producing virtually no loss of tissue integrity.

Under normal circumstances, the mucocutaneous junction is a well-defined border. As the epidermis approaches the conjunctiva, the cornified acellular layer becomes thinner, and at the junction the superficial cells of the epidermis are no longer present in large numbers in the border region. Only a few keratohyalin granules remain.⁸ The superficial cells in the border region retain only a few well-defined nucleated cells. In the conjunctiva proper, however, all cells are nucleated and contain many cytoplasmic organelles. The superficial cells begin to show microvilli, contain numerous mucous granules, and have wider intercellular spaces. Goblet cells are also apparent. The conjunctiva becomes keratinized only in certain diseases, such as the Stevens-Johnson syndrome, cicatricial pemphigoid, and vitamin A deficiency.⁹

At the posterior end of the eyelid margin at the mucocutaneous junction, the skin epidermis of the eyelid abruptly transforms into the palpebral conjunctiva and continues on the posterior aspect of the eyelid.¹¹ The palpebral conjunctiva is markedly adherent to the tarsal plate of the lids. The palpebral conjunctiva is an area where reactive pathology of the conjunctiva may be seen clinically. There are two types of changes that can occur in this region: follicle formation and papilla formation. Follicles are thought to be identical to lymphoid follicles found elsewhere in the body (Fig. 5).⁷ Follicle formation is characteristic of viral and chlamydial infections as well as toxic conjunctivitis due to application of certain topical medications.¹² Papillae are composed of chronic inflammatory cells such as lymphocytes and plasma cells and are distinguished from follicles by the presence of blood vessels at their center.⁸ Giant papillae are found in certain allergic diseases (e.g., vernal catarrh) and after long-term use of contact lenses, keratoprostheses, ocular postenucleation prostheses, and cosmetic shells (Fig. 6).^7,13

The bulbar conjunctiva extends from the limbus to the forniceal area. It is so thin and translucent that the underlying sclera can be seen through it. The bulbar conjunctiva is loosely adherent to the sclera to allow the eye free movement in all directions. It is attached to the tendons of the rectus muscles, which in turn are covered by Tenon's capsule. Approximately 3 mm from the limbus, the bulbar conjunctiva, Tenon's capsule, and sclera become firmly attached, and the conjunctiva cannot be easily picked up.¹⁴ This attachment is routinely encountered during the dissection of a limbal-based conjunctival flap in ocular surgery.

The glands of Wolfring are also accessory lacrimal glands. There are two to five on the upper lid along the upper border of the tarsus.¹⁰ Two glands are present along the inferior edge of the lower tarsus. The excretory duct is lined with basal cuboidal epithelial cells, similar to the conjunctival epithelium onto which it opens. The fine structure of Krause's gland is essentially the same as that of the lacrimal gland in the orbit (Fig. 7A and B). Manz's glands, which produce mucinous secretions and are present at the superior limbus, have been identified in the pig, calf, and ox, but they are thought to be absent in humans.^10,15

At the corneal periphery, the conjunctival epithelium and stroma form rete pegs and papillae. The limbal stroma, with its overlying epithelium, is arranged in radial fibrovascular elevations termed the palisades of Vogt. These palisades alternate with epithelial rete ridges. Palisades are present all around the cornea, but are most defined superiorly and inferiorly. Small nerves, vessels, and lymphatics run the length of the papillae. The nerves are unmyelinated and branch considerably on entering the conjunctival stroma and basal epithelial layer. The epithelial layer becomes increasingly similar to corneal epithelium. Furthermore, limbal epithelial cells contain the stem cell population for corneal epithelial cellular proliferation and differentiation,^20–23 which is evidenced by the following: (1) Limbal cells migrate centripetally during healing of large corneal epithelial defects; (2) human corneal epithelium has a lower proliferative capacity in cell culture than limbal epithelium; (3) limbal basal cells do not express the differentiation marker keratin 3; (4) only limbal basal cells retain [³H] thymidine for extended periods; and (5) the limbal basal cells express unique proteins including α-enolase (Fig. 9).^23–28

The structure of the conjunctival epithelium can be related to its functions. Smaller interepithelial openings measure 1 to 3 μm, which can be appreciated with a scanning electron microscope (Fig. 10), and these are openings of interepithelial goblet cells. Larger openings (10 to 60 μm) are the openings of the epithelial rugae, which are produced by numerous interepithelial glands. At the surface, the intercellular spaces are completely closed by tight junctions. Beneath the surface, extensions of the cytoplasm (microvilli) protrude into the intercellular spaces, which are occasionally connected by desmosomes.²⁰ These microvilli can also be seen on the epithelial cell surface. The basal epithelial cells are attached to the quite thick basement membrane by hemidesmosomes.²⁰

One function of the conjunctival epithelium is resorption. One study showed that in patients with occluded efferent tear ducts, 30% of the technetium placed in the conjunctival sac was absorbed within 15 minutes.²⁹ Superficial application of medication is also absorbed by the conjunctiva.³⁰ These properties are attributed to phagocytic capabilities of the conjunctival epithelium and the leakiness of the tight junctions. Another important function of the epithelium is its contribution to the tear film. Histochemical and immunochemical studies have shown that the conjunctival epithelium is capable of producing protein and cytokines.^31,32 In addition, the conjunctival epithelium synthesizes MUC1 mucin, a membrane spanning mucin that may anchor the tear film and MUC4 mucin, a secreted mucin that may form a portion of the mucous layer of the tear film.^33,34 The contribution of the conjunctiva to the tear film is also indicated by the findings that many substances, including proteolytic and glycolytic enzymes, various antibiotic glycoproteins, and glucose, are less concentrated in reflex tear secretions than in basic tear secretions.^31,32 Reflex tear secretion affects only the volume secreted by the lacrimal and accessory lacrimal glands, so that the above substances are probably of conjunctival origin.

Ultrastructures at the surface of the epithelium can be imaged by scanning electron microscope. The surface cells are hexagonal and completely covered with microvilli (Fig 11). The diameter and height of the microvilli are 0.5 μm and 1 μm, respectively. These structures are important not only for enlarging the resorption surface of the epithelium, but also for stabilizing and anchoring the tear film.^17,22,28 The anchoring of the tear film may also be aided by a mucin-like protein, which has been shown to localize in these microvilli.³⁵ Many believe that the conjunctival microvilli play an important role in absorbing viral particles during infection.¹⁹ These microvilli have a high alkaline phosphatase activity. Branched microvilli with or without giant papillary conjunctivitis can also be appreciated. Scanning electron microscope further differentiates surface epithelium into light-, medium-, and dark-colored cells. These qualities are also found in the corneal epithelial surface. The light-colored cells are most numerous. The medium- and dark-colored cells are less frequent, and they have more compact microvilli than the light-colored cells.

Surface epithelial cells can be further divided into five different cell types in the conjunctiva. These differentiations are based on the number and kind of organelles found in the cells and on the arrangement of these organelles in the cytoplasm.

Type I cells are the goblet cells. These cells produce the mucinous layer of the tear film. Thus, these cells' cytoplasm is filled with large, electron-dense granules. In most cases, a well-differentiated Golgi system is found in the perinuclear spaces of cells of this type.¹⁸ Goblet cells are found throughout the conjunctiva except at the limbus. They are most frequently found in the fornix. Goblet cells appear to be derived from epithelial stem cells.³⁶ Although the site of conjunctival stem cells is not as well defined as the site of the corneal epithelial stem cells, the available data indicate that they are concentrated in the fornix.³⁷

Type II cells are defined by the numerous 60- to 300-nm electron-dense granules. These large granules are usually present in the apical cytoplasm of the cells. Rough endoplasmic reticulum (rER) and Golgi material also define these cells.¹⁸ In the apical area of the cells, the vesicles partly coalesce with the cell membrane and release their contents onto the surface of the epithelium. Type II cells are the most common cells in the human conjunctiva, and they are distributed throughout the conjunctiva. The highest amount is found in the tarsal and forniceal conjunctiva.

Type III cells are recognizable by their welldeveloped Golgi complex.¹⁸ Numerous vesicles are often collected on the concave or convex side of the Golgi complexes. It is well known that polysaccharides and proteins combine to form glycoproteins within the Golgi system.³⁸ On the concave side of a Golgi complex, the finished product is then presented in the form of vacuoles that can reach the epithelial surface. Here the contents of the vesicles are released outward through fusion of the vesicle membrane with the plasma membrane. For this reason, it is thought that type III cells also belong to the functional complex that contributes to the mucinous secretions of the tear film. Type III cells are equally distributed throughout the conjunctival epithelium.

Large quantities of rER characterize type IV cells.¹⁸ These cells are most frequent in the nasal part of the tarsal conjunctiva; they constitute 35% to 40% of epithelial surface cells, slightly more in subjects who are more than 60 years old. A small amount of mitochondria and Golgi apparatus is present in these cells, but they do not determine the cellular structure. From previous studies, it is known that protein content of up to 20 g/L is present in the aqueous layer of tear film.¹⁸ Human tear fluid contains a specific tear albumin, immunoglobulins, plasminogen activators, proteases, lysozymes, complement factors, and lactoferrin.³⁹ At this point, further studies are needed to identify the proteins secreted by type IV cells.

Type V cells are identified by the high content of mitochondria, which are typically located in the apical part of the cell. These cells are most frequent among epithelial surface cells in the bulbar and upper limbal region. They constitute more than 50% of the epithelial cells in the upper limbus. Resorption of substances requires active transport processes, which in turn require energy. Because type V cells contain numerous mitochondria, it can be deduced that these cells provide a morphologic basis for such processes. This theory is supported by the fact that animal species with high numbers of mitochondria-rich epithelial cells have accelerated rates of absorption of horseradish peroxidase.¹⁸ The cytoplasm of these cells are often more electron dense than that of their neighboring epithelial cells. Other cells, including lymphocytes, Langerhans' cells, and melanocytes can also be found in the conjunctival epithelium.

Conjunctiva-associated lymphoid tissue is similar to mucosa-associated lymphoid tissue of the gut and respiratory tract. Mucosa-specific lymphocytes (CD8 T-cells) are found maximally in epithelium of epibulbar conjunctiva and in the lacrimal glands.⁴⁰ Such mucosa-specific lymphocytes express the human mucosal lymphocyte (HML-1) antigen. HML-1 antigen is a membrane antigen expressed on more than 95% of intraepithelial CD8 lymphocytes. Lymphoid follicles containing CD4 and CD8 T-cells are found within the lamina propria. Modified epithelium (M-cells) overlie these follicles and are specialized to capture and present antigens to underlying immune cells.⁴¹

In chronic inflammation or normal aging, conjunctival concretions that appear as yellow spots are found in the upper tarsal conjunctiva.⁴² These concretions are composed of finely granular material and membranous debris. Histochemically they stain strongly for phospholipid and elastin. Plasmin and phosphate are absent, suggesting that the concretions are products of cellular degeneration without any calcific deposits. Other changes seen in the epithelium with increasing age include flatter epithelium, intracellular hyaline substance deposit, and decreased number of microvilli.⁴³

Langerhans' cells are found in the basal and -suprabasal portion of the limbal epithelium. These cells have dendritic processes and characteristic granules. They have no desmosomal connections with the epithelial cells. Melanocytes are scattered in the basal layer of both limbal and bulbar epithelium (Fig. 12).⁴⁴ A conjunctival melanoma is uncommon but potentially lethal. The ascent of atypical melanocytes to the surface of the conjunctival epithelium is indicative of malignancy.⁴⁵

Goblet cells are relatively large cells and can measure up to 25 by 25 μm. The entire cell is composed of membrane-bound mucus packets that may or may not be filled with mucin. A welldeveloped Golgi system can be found in the perinuclear space of these cells. Here, the Golgi apparatus assembles mucus packets. These mucin packets fill the cell and give the cell its goblet-shaped appearance. The organelles and nucleus of a fully developed goblet cell are pushed into the marginal—especially basal—region by the numerous mucus packets. Lysosomes, microsomes, and mitochondria are also found in the cytoplasm.

Ultrastructural studies of goblet cells suggest an apocrine secretory mechanism that releases mucus in the form of packets; however, this has not been demonstrated conclusively (Fig. 14A and B).⁵⁰ This secreted mucus forms the posterior layer of the tear film. Other layers of the tear film include an aqueous layer containing soluble proteins and mucins and a thin anterior layer consisting of meibomian gland oil.⁵¹ Mucus is released rapidly in response to surface irritants, trauma, or toxins. This reflexive response is necessary to replenish the mucous layer and to protect the ocular surface. Recent evidence indicates that parasympathetic and sympathetic nerves are located adjacent to the goblet cells. It is not clear whether the cells are directly innervated (Figs. 15 and 16).^52,53 However, corneal debridement causes goblet cell secretion,⁵⁴ suggesting that ocular damage stimulates the reflex sensory nerves of the cornea to activate a local reflex arc. In turn, the efferent neurons in the conjunctiva activate and release neurotransmitters, which stimulate the goblet cells. This is supported by the fact that topical application of vasoactive intestinal peptide (VIP), serotonin, epinephrine, dopamine, or phenylephrine stimulates conjunctival goblet cell mucus secretions.^52,54

Goblet cells normally appear to be present in the middle and superficial layer of the epithelium. Most if not all goblet cells, however, are attached to the basement membrane by a thin cytoplasmic stalk.³⁷ Goblet cells are attached to neighboring epithelial cells by desmosomes. The question of whether goblet cells and the stratified conjunctival epithelial cells share a common stem cell precursor or derive from two separate stem cell pools is unclear. Morphologic data suggest, however, that the basal epithelial cells of the conjunctiva may differentiate into mucin-producing goblet cells, since immature goblet cells with few mucus packets in the cytoplasm can be observed in the basal cell layer among other squamous epithelial cells. As the goblet cell fills with mucous, the apical portion of the cell moves upward to the epithelial surface, where it secretes mucus. Although it takes approximately 3 to 6 days for basal epithelial cells to reach the surface of the conjunctival epithelium, it appears that goblet cells have a much longer life span. This may allow these cells to secrete their mucus and then refill with newly synthesized mucin several times during their life span.³⁷

Goblet cells are most numerous in the lower nasal fornix, lower middle fornix, and lower palpebral site; goblet cells are scarce in the bulbar conjunctiva temporal to the cornea and usually absent adjacent to the cornea.^18,48,55 The density of the goblet cells is variable in different age groups. In adults older than 37 years, the number of goblet cells remains fairly constant, but it can be modified by external factors that may cause either an increase or a decrease in cell count at any age. After an initially rapid period of development during the first year of life, the density of goblet cells slowly decreases through childhood and then reaches a fairly constant level (30 to 70 goblet cells per 0.1 mm² mucosal surface). Qi⁵⁶ demonstrated that in the nasal inferior fornix conjunctiva, the mean number of goblet cells per 100 epithelial cells was 10.17 ± 2.81 in the younger group (average age 25 years) and 5.27 ± 3.38 in the older group (average age 62 years). Although little is known about the factors that influence normal conjunctival goblet cell density and distribution, the degree of conjunctival hydration has been proposed as a significant exogenous factor. Some believe that gravitation of aqueous tears into the lower conjunctival sac, formation of a lacrimal lake, and accumulation of tears at the median canthus results in maximal hydration of the lower nasal fornix and lower nasal palpebral conjunctiva, therefore resulting in maximal density of goblet cells.⁵⁵ This is also supported by the fact that the goblet cell count in patients with keratitis sicca has been found to be significantly lower than similar counts in normal patients.^9,57

It has been known for more than 140 years that goblet cells produce mucus secretions.⁴⁸ We now know that goblet cells may produce up to 2.2 μL of mucus daily.⁵⁸ Mucus is crucial for ocular surface integrity because it lubricates and protects the epithelial cells. Mucin acts to reduce the surface tension of the tear film to ensure its stability. The normal preocular tear film comprises a complex mixture of lipids, polysaccharides, and proteins that continually bathe the ocular surface. The lipid component also reduces the surface tension of the tear film for stability, and it also prevents desiccation of the underlying epithelium.^18,59,60

Goblet cell mucus has many other functions in addition to preserving the stability of the tear film. It contributes to local immunity by providing a medium for adherence of immunoglobulins (IgA) and microbicidal lysozyme.⁵⁵ Mucus also aids in the cleansing mechanism of the eye. The mucus network arrangement traps cell debris, foreign bodies, and bacteria. Upon blinking, this network apparently collapses into mucous strands that are then moved to the medial canthus, where it dries out on the skin. Mucus also plays a role in the inflammatory response. The mucus thread that lies in the inferior fornix in normal persons contains a superoxide-producing system. Peroxidase activity has also been reported in rat conjunctival goblet cells.⁶¹

Biochemical and histochemical analysis have shown that the secreted material of goblet cells consists of high-molecular-weight sulfated and nonsulfated glycoproteins. These glycoproteins include sialomucins and sulphomucins.^62,63 Recently one of these mucins has been identified as MUC5 mucin. In situ hybridization data suggest that this mucin is made only in goblet cells.³³ Neuraminidase, chondro-6-sulfatase, and hyaluronidase can digest most mucin. Mucin can also be differentiated into acidic and neutral mucin. In the newborn, the majority of mucin is acidic; the amount of neutral mucin increases with postnatal development.⁵⁵ This is important to know because the different biochemical compositions of mucin may have different functional implications. It is also important to note that sequential staining reactions with aldehyde fuchsin and Alcian blue also demonstrate that goblet cells from different organ systems of the same organism may not be chemically similar to the goblet cell of the conjunctiva.

In many ocular surface disorders, the normal epithelium—secretory or nonsecretory—is modified and becomes nonsecretory keratinized epithelium. This pathologic transition is called squamous metaplasia.⁶⁴ The decrease in goblet cell density is associated with a decrease in tear mucin; the tear film becomes unstable and causes keratoconjunctivitis sicca (dry eye syndrome).^65–67 “Snake-like” nuclear chromatin and other nuclear changes are also seen in conjunctival nonsecretory cells from patients with dry eyes.⁶⁸ These nuclear changes are also seen in normal subjects who wear contact lenses. A deficiency of either the aqueous or mucin components of tears causes a drying of the conjunctiva and cornea. A deficiency of the aqueous component is seen in keratoconjunctivitis sicca, whereas the mucin component is deficient in conditions causing loss of goblet cells (e.g., chemical burns, Stevens-Johnson syndrome, hypovitaminosis A, ocular pemphigoid, Sjögren's syndrome, acute alkali burns).^9,18,59

A recent study has shown that asymptomatic wearers of soft contact lenses who had been using their lenses for several years have a decreased density of goblet cells.⁵⁷ Medications such as topical beta-blockers also cause a pronounced reduction of goblet cells. For this reason, patients who must be treated with this drug should undergo regular checks of tear secretions and stability of their tear film. Although a decrease of mucin content has been used to indicate the severity of various mucin deficiency disorders, goblet cell density may be a better indicator of ocular surface integrity,^55,69,70 especially in determining the severity of keratoconjunctivitis sicca. In this condition, patients may have an excess of mucus as well as a relative decrease in goblet cell density. Other conditions associated with increased mucous production are lagophthalmos and blepharitis. Decreased mucus production is associated with pemphigoid and infectious conjunctivitis.

Non-goblet cell epithelium is another important source of mucus production by the conjunctiva.^62,63,71 Electron microscopy of human and rat conjunctiva reveals numerous small granules that stain specifically for mucopolysaccharides, but not for lysosomes (Figs. 17 and 18). The non-goblet cells' secretory vesicles contain sulfomucin, sialomucin, and neutral mucins,⁶³ a mucin profile similar to that of goblet cells. Although goblet cells are the main source of the conjunctival mucin, non-goblet cell epithelium is also an important source of mucin. This epithelial source may be responsible for the tenacious or sticky mucus found in patients who have giant papillary conjunctivitis or ocular allergies, or who wear contact lenses, ocular prostheses, or cosmetic shells.¹³ This tenacious mucus is also seen in diseases such as keratoconjunctivitis sicca, Stevens-Johnson syndrome, and ocular pemphigoid, where goblet cell density is below normal.^72,73

The substantia propria is divided into two layers: a superficial lymphoid layer and a deeper fibrous layer. The lymphoid layer is not present at birth, but is formed a few months afterward. The lymphocytes in this layer are aggregated into nodules, but they are not true lymphoid follicles. The deeper fibrous layer consists of thick, collagenous, elastic tissue and contains the vessels and nerves of the conjunctiva in addition to Krause's glands.

In many persons, localized, elevated, yellowish-white excrescences are observed medially and laterally, close to the limbal margin. These elevations are called pingueculae, and histologically they are very similar to pterygia, which also exist in the same perilimbal area but involve the cornea as well. Both pingueculae and pterygia show senile elastotic degeneration—a process involving a breakdown of the collagen. The breakdown products stain with elastin but are not sensitive to elastase.⁷⁷

Biomicroscopic examination of the peripheral bulbar conjunctiva in many persons has revealed lipid nodules that vary in diameter from 30 to 80 nm.⁷⁸ These lipid deposits are conjunctival and episcleral, and the number of deposits increases with age. They are present nasally and temporally; they usually are found adjacent to blood vessels, but occasionally they occur in more isolated foci.

Papillae are small (less than 1 mm), fairly regular, hyperemic projections that develop in areas where the conjunctiva is firmly attached to the underlying tissue by connective tissue septa. These fibrous attachments are present on the tarsus and semilunar fold and at the limbus. Papillae contain a central fibrovascular core of vessels that branch in a spoke-like pattern upon reaching the surface. The valleys between the projections are pale and relatively avascular. Papillae confer a slightly irregular or velvety appearance to the tarsal conjunctiva.⁸¹ Histologically, papillae are covered with hyperplastic epithelium. The stromal tissue surrounding the vascular core is edematous and infiltrated with chronic inflammatory cells.⁸² Papillae are a nonspecific sign of inflammation and may result from virtually any etiologic agent.

Large or giant papillae have a more specific clinical significance. Moderately severe conjunctival inflammation may disrupt the connective tissue anchoring septa in the tarsal and limbal areas. This allows small papillae to coalesce and form larger projections (greater than 1 mm).⁷⁹ The appearance of giant papillae varies according to their cause. In atopic and palpebral vernal keratoconjunctivitis, giant papillae are frequently large, polygonal, and flat-topped.^13,83 They bestow a cobblestone appearance to the tarsal conjunctiva. In limbal vernal conjunctivitis, giant papillae assume a smooth, round gelatinous appearance and are frequently associated with Trantas dots (clumps of eosinophils or degenerated epithelial cells).⁸⁴ The giant papillae on the upper tarsal conjunctiva associated with contact lens use (giant papillary conjunctivitis) range from slightly raised, symmetric, pale lesions to large, polygonal, flat-topped lesions.^81,85

Another common feature of conjunctival inflammation is follicle formation. Follicles are frequently seen in the fornix and have little clinical significance in this area. Follicular hypertrophy is significant when it involves the bulbar or palpebral conjunctiva. Most follicles are small (0.5 to 1.5 mm), pale, round-oval, elevated structures.^79,81 Unlike papillae, which have a central vascular tuft, follicles are avascular lesions; however, they are often bypassed or encircled by small conjunctival vessels. Histologically, follicles consist of aggregated lymphocytes in the superficial substantia propria. Some are organized into germinal centers and contain histiocytic cells with phagocytized nuclear debris. The stromal tissues surrounding the follicles are frequently infiltrated with lymphocytes and plasma cells.⁷⁹ Follicle formation is most commonly associated with viral and chlamydial infections.

Another sign of conjunctival inflammation that may suggest a specific cause is membrane formation. True membranes consist of fibrin, fibrinous byproducts, leukocytes, and necrotic debris, which become firmly interlaced around superficial epithelial cells. Clinically, they have a translucent and porcelain-like appearance. When true membranes are removed, strands of fibrin tear away the epithelium, resulting in bleeding.⁸¹ True membrane formation may be seen in diphtheria conjunctivitis, Neisseria gonorrhoeae conjunctivitis, β-hemolytic streptococcal conjunctivitis, and Stevens-Johnson syndrome.^82,85 Pseudomembranes are similar in composition and appearance to true membranes, but they are much less adherent to the underlying epithelium and bleeding usually does not occur when they are removed. Important causes of pseudomembranous conjunctivitis include viral conjunctivitis, bacterial conjunctivitis, and alkali burns. Ligneous conjunctivitis is an unusual childhood form of membranous conjunctivitis. It typically presents as a thick, whitish, wood-like induration on the upper tarsal conjunctiva. Histologic examination reveals a thickened and sometimes dyskeratotic epithelium. The subepithelial tissue contains fibrin, acute and chronic inflammatory cells, and amorphous eosinophilic material.⁸²

Conjunctivitis may present with various types of cellular exudate. Examination of Giemsa-stained conjunctival scrapings may help suggest or confirm a specific diagnosis. A polymorphonuclear leukocytic response is seen in bacterial or fungal conjunctivitis, neonatal inclusion conjunctivitis, acute toxic drug reactions, and any conjunctivitis with inflammatory membranes or necrosis. Viral infections such as adenoviral or herpes simplex conjunctivitis, as well as molluscum contagiosum and chronic toxic drug reactions, usually provoke a mononuclear response. A mixed response consisting of both polymorphonuclear and mononuclear cells is characteristic of conjunctivitis caused by chlamydial or trachomatous infection or chemical burns. The presence of eosinophils can be demonstrated on cytologic examination in conjunctival allergic responses to allergens such as dust and pollen. Multinucleated giant cells are elicited by herpes, trachoma, chlamydia, and neoplasia.⁸⁵

Persistent or recurrent inflammation of the conjunctiva causes a series of reactive and degenerative changes. Initially, the epithelium and goblet cells undergo hyperplasia. Focal crypt-like infoldings of the proliferated epithelium and goblet cells (pseudoglands of Henle) may develop.⁷⁹ The surface openings of these pseudoglands may become clogged with cellular debris, chronic inflammatory cells, and mucin, forming clear or yellow cysts called pseudoretention cysts.⁸² Eventually, in-flam-mation will cause atrophy and epidermalization of the conjunctival epithelium. Epidermalization consists of goblet cell loss, keratinization, and the formation of rete ridges. It imparts a white, plaque-like appearance (leukoplakia) to the conjunctival epithelium. Ectropion of the lower lid is commonly associated with epidermalization of the palpebral conjunctiva. Vitamin A deficiency, dry eye syndrome, and various conjunctival neoplasms can provoke keratinization of the bulbar conjunctiva.⁷⁹

The wound healing response in the conjunctival stroma is similar to vascularized tissue in other body sites. Stromal wound healing can be divided into four phases: (1) clot phase; (2) proliferation phase; (3) granulation phase; and (4) collagen phase.⁸⁶ The clot phase occurs almost immediately after surgical or traumatic injury to the conjunctiva. It is characterized by blood vessel constriction and the leakage of blood cells and plasma proteins (fibrinogen, fibronectin, and plasminogen). A fibrin-fibronectin matrix or clot forms when the extravascular blood or plasma is exposed to certain tissue factors. During the proliferative phase, fibroblasts, new capillaries, and various inflammatory cells such as monocytes and macrophages migrate into the clot and replicate. Inflammatory cells degrade the fibrin-fibronectin clot. Fibroblasts originate from the wound margins, subconjunctival tissue, and episclera.⁸⁷ Monkey studies suggest that fibroblast proliferation begins at about the 5th day after surgical injury. Fibroblasts synthesize fibronectin, interstitial collagen and glycosamino-glycans to form fibrovascular connective tissue or granulation tissue. The granulation phase occurs by day 10 in the monkey model. Finally, the collagen phase is characterized by the aggregation of tropocollagen molecules to form immature soluble collagen fibrils which then undergo cross-linking to form mature collagen.⁸⁶ Initially, type III collagen is synthesized; this is replaced by type I collagen as the wound matures.⁸⁸ With time, capillaries and fibroblasts largely disappear, leaving a dense, collagenous scar.⁸⁷

The conjunctival response to corneal wounding has been known since Mann first observed that peripheral corneal abrasions heal by the sliding of limbal cells to cover the epithelial defect.⁸⁹ This response should be split into two phases: (1) the response of the limbal epithelium, which is the source of the corneal epithelial stem cells; and (2) the response of the conjunctival epithelium itself. Under normal circumstances, the limbal epithelium acts as a barrier and is able to exert an inhibitory growth pressure that prevents migration of conjunctival epithelial cells onto the cornea.⁸⁹ Like the rest of the body surface, the conjunctiva and cornea are in a constant state of turnover. Corneal epithelial cells are continuously shed into the tear pool and simultaneously replenished by cells moving centrally from the limbus and anteriorly from the basal layer of the epithelium. Movement from the basal to superficial layers is relatively rapid, requiring 7 to 10 days; however, movement from the limbus to the center of the cornea is slow and may require months.

This normal physiologic process is exaggerated in the case of a corneal abrasion. During corneal healing of a lesion, corneal epithelial cells flatten, spread, and actually move across the defect until it is completely covered.⁹⁰ Cell proliferation, which is independent of cell migration, begins to occur approximately 24 hours after the injury has been inflicted.⁹¹ Stem cells from the limbus also respond to heal the corneal defect by proliferating to give rise to daughter cells termed transient amplifying cells.⁹² These cells migrate to heal the wound and also undergo proliferation to replenish the wound area.⁹² Further evidence of this was provided by observation of migrating limbal pigment onto the clear cornea.⁹⁰ The concept that the limbal cells form a barrier to conjunctival cells was further supported by the observation that rabbit eyes treated for 120 seconds with n-heptanol, which removed both the corneal and conjunctival epithelium but left the limbal basal cells intact, healed with corneal epithelium and had unvascularized corneas. However, when the entire limbal zone was surgically removed along with n-heptanol treatment, corneal vascularization and conjunctivalization was observed.⁹³ Demonstration of the centripetal migration of limbal cells (marked by India ink) provided more direct evidence of this concept.^94,95 The rate of migration has been established to be 17 μm/day in the mouse⁹⁴ and 64 μm/h in the rabbit model.⁹⁶ These cells migrate in masses as a continuous, coherent sheet with most cells retaining their positions relative to each other, much like the movement of a “herd of cattle.”⁹⁵

Rearrangement of intracellular actin filaments plays a role in movement. Cell migration can be inhibited by blocking polymerization of actin, indicating that actin filaments actively participate in the mechanism of cell motion.⁹⁷ Some authors believe that conjunctival as well as limbal epithelial cells may contribute to the regeneration of corneal epithelium. Marked proliferative responses in the conjunctiva after a central corneal epithelium abrasion have been described.^98,99 Why the conjunctival epithelium should proliferate in response to a central corneal wound is unknown. One possibility is that the proliferation acts to replenish the goblet cell number, which decreases by up to 50% after corneal wounding.⁵² However, proliferation occurs at high levels in the bulbar conjunctiva, which contains few if any goblet cells. Also, the apparent decrease in cell number is more likely the result of mucin secretion, rather than actual loss of goblet cells. Alternately, conjunctival cells may migrate into the limbus or cornea to help replenish the wound area. No firm data exist, however, that conjunctival epithelium migrates onto the corneal surface in the presence of intact limbal epithelium. Finally, the corneal epithelial wound healing is not complete until the newly regenerated epithelium has anchored itself firmly to the underlying connective tissue. Permanent anchoring units are not formed until the wound defect is completely covered. Epithelial cells migrate rapidly and develop strong, permanent adhesions within 1 week when the basement membrane is intact. When this membrane is disrupted, the cells must secrete new membrane, and then normal adhesions are established. Although transient attachments are regularly formed and released during the cell migration process, according to Dua and associates⁹⁰ it takes 6 weeks for the formation of normal adhesions. Their study suggests that tiny buds of corneal epithelium are present all along the contact line between the normal corneal epithelium and the migrating conjunctival epithelium. They observed these buds arising from the corneal epithelium and reported that normal corneal epithelium appears to replace the conjunctival epithelium by gradually pushing it toward the limbus.⁹⁰ The magnitude and extent of both the conjunctival and corneal regenerative responses to a corneal abrasion correlate with the size of the wound. Larger erosions were reported to induce a more pronounced response in the epithelial cell migration and mitotic rate at the limbus.²⁹ Insults caused by chemical injuries, Stevens-Johnson syndrome, contact lens-induced keratopathy, and aniridia result in limbal damage. These insults cause delayed healing of the cornea, recurrent epithelial erosions, corneal vascularizations, and conjunctival epithelial ingrowth.⁹³

The stability of the wound healing response differs when the replacement cells are conjunctival versus corneal in origin. Experiments indicate that healing accomplished by conjunctival cells results in erosion or regression of healing in many eyes, whereas corneal cells proceed smoothly to cover the corneal defect.¹⁰⁰ Epithelial growth factor receptors are present on the conjunctival and corneal epithelial cells and are an indispensable agent in corneal wound healing.^101,102 Epithelial growth factor is found in the tear film. Further investigation is needed to fully understand the regulatory mechanism by which stem cells differentiate and proliferate.

A subconjunctival accumulation of aqueous called a filtering bleb is commonly seen after successful glaucoma filtering surgery. The diameter, elevation, and vascularity of filtering blebs are highly variable. Functioning blebs may be thin and polycystic, or they may have a flatter, thicker, and more diffuse appearance. Nearly all functioning blebs are relatively avascular and contain small cystic spaces (microcysts).⁸⁶ Microcysts are best seen with indirect illumination and probably represent channels for the passage of aqueous humor. Histologically, functioning blebs show normal conjunctival epithelium with no junctions between the cells that would limit fluid movement. The subepithelial connective tissue is loosely organized and contains many histologically clear spaces. The clear spaces probably correspond to the microcysts seen clinically.¹⁰³

In failed blebs, the conjunctiva is scarred to the underlying episcleral tissue.⁸⁷ Failed blebs are typically low to flat and heavily vascularized with no microcysts. Both light and electron microscopy of failed blebs reveals normal epithelium, but abnormally dense and thickened subepithelial connective tissue due to large amounts of collagen. Also, fibroblasts and blood vessels are present in the bleb wall.¹⁰³ Failed blebs must be differentiated from encapsulated blebs (Tenon's capsule cysts). Encapsulated blebs are smooth, dome-shaped, conjunctival elevations with large vessels separated by avascular spaces. Microcysts are not usually present. Encapsulated blebs trap aqueous over the filtering site, thereby raising intraocular pressure. Unlike failed blebs, however, most of these blebs will recover function within a few months.⁸⁶ Histologically, encapsulated blebs consist of thin, almost avascular sheets of fibrous connective tissue with areas of proliferating fibroblasts. The inner surfaces of the bleb walls are lined with acellular material (probably fibrin).⁸⁷

Pharmacologic agents that inhibit fibroblast proliferation have been shown to decrease the risk of bleb failure in high-risk patients.¹⁰⁴ 5-Fluorouracil (5-FU) and mitomycin-C (MMC) have been studied most extensively. 5-FU is a pyrimidine analogue that blocks DNA synthesis by inhibiting thymidylate synthesis.⁸⁶ 5-FU has been shown to inhibit fibroblast proliferation in tissue culture and animal models. Additional studies have demonstrated that subconjunctival injections of 5-FU improve the success rate of filtering surgery in high-risk eyes.⁸⁷ A major disadvantage of 5-FU is the need for frequent postoperative injections. Complications associated with 5-FU administration include corneal epithelial defects, conjunctival wound leaks, suprachoroidal hemorrhages, subepithelial scarring, and endophthalmitis.¹⁰⁴ MMC is an antibiotic derived from the fermentation of Streptomyces caespitosus. MMC appears to have greater inhibitory effects on fibroblasts than 5-FU.⁸⁸ A single intraoperative application of MMC is effective in increasing the success rate of filtering surgery in high-risk eyes. Disadvantages associated with its use include conjunctival wound leaks, choroidal detachments, and prolonged hypotony.¹⁰⁴ A recent randomized clinical trial compared the efficacy and complication rate of 5-FU versus MMC in high-risk eyes. Patients were followed for nearly 3 years after glaucoma filtering surgery. Eyes treated with MMC had lower intraocular pressure and required fewer medications than eyes treated with 5-FU. Apart from an increased incidence of Tenon's cyst formation in the MMC treated eyes, late postoperative complications were similar in the two groups.¹⁰⁴

The second major source of supply, the anterior ciliary arteries, travel along the tendon of the rectus muscles and give off anterior conjunctival arteries just before piercing the globe. These arteries send branches to the pericorneal plexus and to the neighboring regions of the bulbar conjunctiva in the limbal area. In this region, there is free anastomosis in the subconjunctival and episcleral tissue between the anterior conjunctival vessels and terminal branches of the posterior conjunctival vessels, resulting in the zone of palisades of Busacca. Thus, the superficial and deep systems in the limbal area are closely connected. Clinically, this is an area of diagnostic importance. With inflammation and infections of the conjunctiva, the superficial posterior vessels are engorged; in deep keratitis or iritis, the deeper ciliary vessels are hyperemic.

The conjunctival veins are more numerous than the arteries.¹⁰ For the most part, the major portion of the drainage from the tarsal conjunctiva and the bulbar conjunctiva is directed to the palpebral veins. Some of the tarsal veins empty independently into the superior and inferior ophthalmic veins. Outflow is from the circum-corneal region to the veins that serve the extraocular muscles.

Small blood vessels of the bulbar conjunctiva have arteriovenous communications.¹⁴ The communicating vessels may be tortuous and uneven in caliber, but they usually are larger in diameter than capillaries. Each gives off capillary branches proximally and receives capillaries distally. They are not true arteriovenous anastomoses because they do not possess muscular walls that would render them capable of responding to chemical agents. Occasionally, the conjunctival blood vessels may become damaged, causing a spontaneous subconjunctival hemorrhage. These hemorrhages have very few associations with systemic diseases and usually absorb in a matter of a week or two. Electron microscopy has revealed that a majority of the capillaries often have a thick, continuous wall but few fenestrations (Fig. 20). Larger vessels with smooth muscles are also present.

The superficial plexus receives lymphatic drainage from the limbal area. It has larger collector channels that run circumferentially 7 to 8 mm behind the limbus, forming an incomplete pericorneal lymphatic ring. Its other lymphatic drainage channels include a recurrent nasal group that drains the upper nasal quadrant and a descending temporal group. Both groups drain by way of the medial canthus. A large collecting vessel from the inferior fornix empties by way of the lateral canthus. Laterally placed lymph vessels flow to the preauricular lymph nodes; medially placed vessels flow to the submaxillary lymph nodes. Clinically, these vessels may be visible with a biomicroscope in certain conditions such as scleredema adultorum, and some of these lymph vessels may fill with blood and look like dilated veins.^107,108 Electron microscopy reveals that these lymphatics differ from blood capillaries in some respects. For example, the endothelium is very thin but has no fenestrae, the intercellular junctions are less well formed than in capillaries, the basement membrane is interrupted or absent, and pericytes are usually absent (Fig. 22).

Also present in the conjunctiva are the end bulbs of Krause, which are specialized, compact nerve endings 0.2 to 0.1 mm in length and surrounded by a connective tissue capsule. The bulb itself may be single but of complex structure, or it may be compound. These end bulbs are relatively rare and vary in distribution. Their exact function remains unknown. One theory is that they are really a stage in the growth cycle of specialized nerve end organs.¹⁰

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