Foundation Volume 1, Chapter 29. Conjunctiva

2/7/15, 3:00 PMFoundation Volume 1, Chapter 29. Conjunctiva

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Chapter 29ConjunctivaJ. ERIC PEPPERL, TOM GHUMAN, KULJIT S. GILL, JAMES D.ZIESKE and STEFAN D. TROCMEMain Menu Table Of Contents

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ANATOMYCONJUNCTIVAL GLANDSCONJUNCTIVAL EPITHELIUMEPITHELIAL CYSTSGOBLET CELLSSUBSTANTIA PROPRIACONJUNCTIVAL INFLAMMATIONCONJUNCTIVAL WOUND HEALINGCONJUNCTIVAL HEALING IN GLAUCOMA FILTERING SURGERYARTERIESVEINSLYMPHATICSNERVE SUPPLYTHE CARUNCLEPLICA SEMILUNARISREFERENCES

The conjunctiva is a vascularized mucous membrane that covers the anterior surfaceof the globe (bulbar and forniceal conjunctiva) and the posterior surface of the upperand lower eyelids (palpebral conjunctiva). Its superficial layer, the conjunctivalepithelium, is continuous with the epidermis of the lids and the outermost layer ofthe cornea, the corneal epithelium. The conjunctiva is responsible for the productionof mucous, which is essential for tear film stability and corneal transparency.1 Theconjunctiva also has enormous potential for combating infection for four reasons: (1)it is highly vascular; (2) the different cell types contained in it can initiate andparticipate in defensive inflammatory reaction; (3) it has many immunocompetentcells that contribute a rich supply of immunoglobulins; and (4) the surface anatomy(microvilli) and biochemistry (enzymatic activity) of the conjunctival cells enable thattissue to engulf and neutralize foreign particles, such as viruses.2,3

Clinically, the conjunctiva is an extremely valuable ally of the ophthalmic surgeonand diagnostician. The bulbar surface, because of its loosely adherent properties, isused to great advantage in glaucoma surgery. Its capacity to heal rapidly ensuresthe success of many surgical procedures. A conjunctival flap placed over anonhealing or infected cornea promotes healing and preserves corneal integrity.4Autologous conjunctival transplantation has been carried out from one eye to theother to repair leaky filtration blebs and to hasten corneal epithelial covering afterchemical burns have destroyed the corneal surface.5 Characteristic conjunctivalchanges occur in many systemic diseases. For example, pathognomonic vascularsigns are present in the conjunctival vessels in sickle cell anemia, scleral icterus is anearly sign of jaundice, distinctive pigmentary changes are present in ochronosis,Bitot's spot appears in the conjunctiva in vitamin A deficiency, and typical crystallinedeposits are present in the conjunctiva in cystinosis.6,7 Another exceptional

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advantage of the conjunctiva is the ease with which conjunctival biopsy material canbe obtained, causing little discomfort to the patient and producing virtually no loss oftissue integrity.

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

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ANATOMYThe conjunctiva lines the posterior surface of the upper and lower lids and the anterior surface ofthe globe. From the inner surface of the lid it is reflected forward onto the globe above and below,forming two recesses: the superior and inferior fornix. The superior fornix is located at the level ofthe orbital margin 8 to 10 mm from the limbus (Fig. 1A, B, and C). The inferior fornix isapproximately 8 mm from the limbus (Fig. 2A, B, and C). On the medial side, the fornicealstructures are replaced by the caruncle and the plica semilunaris (Fig. 3). The absence of the fornixon the medial side is necessary in order to allow the inferior punctum to dip and drain from thesuperficial tear fluid layer.10 Laterally, the fornix extends just behind the equator of the globe (Fig.4). It is quite deep and approximately 14 mm from the limbus.

Fig. 1.Low-powerview ofthe globe.A. Arrowpointingto theregion ofthesuperiorfornix. B.

Superior fornix (F) showing epithelium and substantia propria. Conjunctival sac (CS). C. Higher-power view of epithelium showing goblet cells on the surface (arrows). (B, 50; C, 170)

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Fig. 2. A. Region of the inferior fornix (arrow). B. Inferior fornix showing epithelium, goblet cells,and a follicle (F). C. Inferior fornix showing Mller's muscle (MM) in the substantia propria. (B, 60; C, 80)

Fig. 3. Medical region of the eye showing the caruncle (C) and plicasemilunaris (P).

Fig. 4. Region of the lateral fornix (arrow).

At the posterior end of the eyelid margin at the mucocutaneous junction, the skin epidermis of theeyelid abruptly transforms into the palpebral conjunctiva and continues on the posterior aspect ofthe eyelid.11 The palpebral conjunctiva is markedly adherent to the tarsal plate of the lids. Thepalpebral 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 papillaformation. 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 toxicconjunctivitis due to application of certain topical medications.12 Papillae are composed of chronicinflammatory cells such as lymphocytes and plasma cells and are distinguished from follicles by thepresence 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 postenucleationprostheses, and cosmetic shells (Fig. 6).7,13

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Fig. 5. Follicles on the upper tarsal surface.

Fig. 6. Giant papillae present on the upper tarsal surface of apatient who wore a cosmetic shell.

The bulbar conjunctiva extends from the limbus to the forniceal area. It is so thin and translucentthat the underlying sclera can be seen through it. The bulbar conjunctiva is loosely adherent to thesclera to allow the eye free movement in all directions. It is attached to the tendons of the rectusmuscles, which in turn are covered by Tenon's capsule. Approximately 3 mm from the limbus, thebulbar conjunctiva, Tenon's capsule, and sclera become firmly attached, and the conjunctiva cannotbe easily picked up.14 This attachment is routinely encountered during the dissection of a limbal-based conjunctival flap in ocular surgery.

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CONJUNCTIVAL GLANDSKrause's glands are accessory lacrimal glands found in the deep subconjunctivalconnective tissue of the upper fornix. There are 42 in the upper fornix andapproximately 6 to 8 in the lower fornix. Because accessory lacrimal glands presentin this region may be inadvertently excised, causing a dry eye problem, the integrityof the superior border of the upper tarsus is extremely important to preserve duringoperations (e.g., Fasanella-Servat procedure for upper lid ptosis).

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

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Fig. 7. A. Inferior fornix showing papillary projection (P). B.Inferior fornix demonstrating Krause's glands (KG). (A, 40;B, 80)

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CONJUNCTIVAL EPITHELIUMThe conjunctiva, like other mucous membranes, is composed of two layers: thestratified epithelial layer and the substantia propria layer, which is composed of anadenoid fibrous layer (Fig. 8). The lid margins are covered anteriorly by dry,keratinized epithelium, which merges into the moist, nonkeratinized epitheliumposteriorly covering the tarsus. In many ocular surface disorders, the normalepithelium is modified and becomes nonsecretory and keratinized. This pathologictransition is called squamous metaplasia. The severity of ocular surface alteration isparallel to the degree of metaplasia.16 The stratified epithelium varies in thicknessfrom 2 to 4 layers in the upper tarsal portion, to 6 to 8 layers at the corneoscleraljunction, to 8 to 10 layers at the conjunctival margins.17 Epithelial cells are columnarin the fornix and tend to be cuboidal on the bulbar and tarsal conjunctiva.18,19Because of the increased mechanical pressure on the limbal and marginal epithelialzones, these superficial cells at the limbus have adapted by producing a flat surfacecell layer.19

Fig. 8. Bulbar conjunctival epithelium, composed of irregularlypiled polygonal epithelial cells. The surface is uneven andbeset with microvilli. The basal line also is undulated. GC,goblet cells; ST, stroma. ( 4300)

At the corneal periphery, the conjunctival epithelium and stroma form rete pegs andpapillae. The limbal stroma, with its overlying epithelium, is arranged in radialfibrovascular elevations termed the palisades of Vogt. These palisades alternate withepithelial rete ridges. Palisades are present all around the cornea, but are mostdefined superiorly and inferiorly. Small nerves, vessels, and lymphatics run thelength of the papillae. The nerves are unmyelinated and branch considerably onentering the conjunctival stroma and basal epithelial layer. The epithelial layer

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becomes increasingly similar to corneal epithelium. Furthermore, limbal epithelialcells contain the stem cell population for corneal epithelial cellular proliferation anddifferentiation,2023 which is evidenced by the following: (1) Limbal cells migratecentripetally during healing of large corneal epithelial defects; (2) human cornealepithelium has a lower proliferative capacity in cell culture than limbal epithelium;(3) limbal basal cells do not express the differentiation marker keratin 3; (4) onlylimbal basal cells retain [3H] thymidine for extended periods; and (5) the limbalbasal cells express unique proteins including -enolase (Fig. 9).2328

Fig. 9. Immunolocalization of -enolase in thebasal cell layer of human limbal epithelium.(Courtesy of James D. Zieske)

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

Fig. 10. Middle layer of bulbar conjunctival epitheliumshowing widened intercellular spaces, into which smallcytoplasmic processes are protruding. Relatively fewdesmosomes are shown. Tonofilaments (t) tend to formbundles. IS, intercellular space; d, desmosomes; p,cytoplasmic processes. ( 20,800)

One function of the conjunctival epithelium is resorption. One study showed that inpatients with occluded efferent tear ducts, 30% of the technetium placed in theconjunctival sac was absorbed within 15 minutes.29 Superficial application ofmedication is also absorbed by the conjunctiva.30 These properties are attributed tophagocytic capabilities of the conjunctival epithelium and the leakiness of the tightjunctions. Another important function of the epithelium is its contribution to the tearfilm. Histochemical and immunochemical studies have shown that the conjunctival

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epithelium is capable of producing protein and cytokines.31,32 In addition, theconjunctival epithelium synthesizes MUC1 mucin, a membrane spanning mucin thatmay anchor the tear film and MUC4 mucin, a secreted mucin that may form aportion of the mucous layer of the tear film.33,34 The contribution of the conjunctivato the tear film is also indicated by the findings that many substances, includingproteolytic and glycolytic enzymes, various antibiotic glycoproteins, and glucose, areless concentrated in reflex tear secretions than in basic tear secretions.31,32 Reflextear secretion affects only the volume secreted by the lacrimal and accessorylacrimal glands, so that the above substances are probably of conjunctival origin.

Ultrastructures at the surface of the epithelium can be imaged by scanning electronmicroscope. The surface cells are hexagonal and completely covered with microvilli(Fig 11). The diameter and height of the microvilli are 0.5 m and 1 m,respectively. These structures are important not only for enlarging the resorptionsurface of the epithelium, but also for stabilizing and anchoring the tear film.17,22,28The anchoring of the tear film may also be aided by a mucin-like protein, which hasbeen shown to localize in these microvilli.35 Many believe that the conjunctivalmicrovilli play an important role in absorbing viral particles during infection.19 Thesemicrovilli have a high alkaline phosphatase activity. Branched microvilli with orwithout giant papillary conjunctivitis can also be appreciated. Scanning electronmicroscope further differentiates surface epithelium into light-, medium-, and dark-colored cells. These qualities are also found in the corneal epithelial surface. Thelight-colored cells are most numerous. The medium- and dark-colored cells are lessfrequent, and they have more compact microvilli than the light-colored cells.

Fig. 11. Transmission electron micrographs ofthe microvilli (mv) in the bulbar conjunctivalepithelial surface (A) and in the fornicealconjunctival epithelial surface (B), showingthe length difference. They are short in theformer and long and slender in the latter. mg,mucous granulesthose in B exhibitfibrillogranular contents. (A, 26,000; B, 26,000)

Surface epithelial cells can be further divided into five different cell types in theconjunctiva. These differentiations are based on the number and kind of organellesfound 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 tearfilm. Thus, these cells' cytoplasm is filled with large, electron-dense granules. Inmost cases, a well-differentiated Golgi system is found in the perinuclear spaces ofcells of this type.18 Goblet cells are found throughout the conjunctiva except at thelimbus. They are most frequently found in the fornix. Goblet cells appear to bederived from epithelial stem cells.36 Although the site of conjunctival stem cells isnot as well defined as the site of the corneal epithelial stem cells, the available dataindicate that they are concentrated in the fornix.37

Type II cells are defined by the numerous 60- to 300-nm electron-dense granules.

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These large granules are usually present in the apical cytoplasm of the cells. Roughendoplasmic reticulum (rER) and Golgi material also define these cells.18 In theapical area of the cells, the vesicles partly coalesce with the cell membrane andrelease their contents onto the surface of the epithelium. Type II cells are the mostcommon cells in the human conjunctiva, and they are distributed throughout theconjunctiva. The highest amount is found in the tarsal and forniceal conjunctiva.

Type III cells are recognizable by their welldeveloped Golgi complex.18 Numerousvesicles are often collected on the concave or convex side of the Golgi complexes. Itis well known that polysaccharides and proteins combine to form glycoproteinswithin the Golgi system.38 On the concave side of a Golgi complex, the finishedproduct is then presented in the form of vacuoles that can reach the epithelialsurface. Here the contents of the vesicles are released outward through fusion of thevesicle membrane with the plasma membrane. For this reason, it is thought thattype III cells also belong to the functional complex that contributes to the mucinoussecretions of the tear film. Type III cells are equally distributed throughout theconjunctival epithelium.

Large quantities of rER characterize type IV cells.18 These cells are most frequent inthe nasal part of the tarsal conjunctiva; they constitute 35% to 40% of epithelialsurface cells, slightly more in subjects who are more than 60 years old. A smallamount of mitochondria and Golgi apparatus is present in these cells, but they donot determine the cellular structure. From previous studies, it is known that proteincontent of up to 20 g/L is present in the aqueous layer of tear film.18 Human tearfluid contains a specific tear albumin, immunoglobulins, plasminogen activators,proteases, lysozymes, complement factors, and lactoferrin.39 At this point, furtherstudies are needed to identify the proteins secreted by type IV cells.

Type V cells are identified by the high content of mitochondria, which are typicallylocated in the apical part of the cell. These cells are most frequent among epithelialsurface 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 activetransport processes, which in turn require energy. Because type V cells containnumerous mitochondria, it can be deduced that these cells provide a morphologicbasis for such processes. This theory is supported by the fact that animal specieswith high numbers of mitochondria-rich epithelial cells have accelerated rates ofabsorption of horseradish peroxidase.18 The cytoplasm of these cells are often moreelectron dense than that of their neighboring epithelial cells. Other cells, includinglymphocytes, Langerhans' cells, and melanocytes can also be found in theconjunctival epithelium.

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

In chronic inflammation or normal aging, conjunctival concretions that appear as

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yellow spots are found in the upper tarsal conjunctiva.42 These concretions arecomposed of finely granular material and membranous debris. Histochemically theystain strongly for phospholipid and elastin. Plasmin and phosphate are absent,suggesting that the concretions are products of cellular degeneration without anycalcific deposits. Other changes seen in the epithelium with increasing age includeflatter epithelium, intracellular hyaline substance deposit, and decreased number ofmicrovilli.43

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

Fig. 12. Basal portion of the epithelium of bulbarconjunctiva, showing bundles of tonofilaments (t) inthe epithelial cells and a melanocyte (M) containingmelanin granules (arrow). Note also a long process(P) extending from the melanocyte betweenepithelial cells. Although epithelial cells are joined bydesmosomes (d), the melanocyte has nodesmosomes around the cell. hd =hemidesmosome; bm = basement membrane (12,700)

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EPITHELIAL CYSTSEpithelial cysts found in the conjunctiva under normal circumstances are classifiedaccording to their location. Intraepithelial cysts, such as cystic goblet cells, occurexclusively in the upper quadrant of the bulbar conjunctiva. Cystic subepithelial cystsoccur on the semiluminar fold. Solitary subepithelial cysts occur in the lower andupper fornix.46 Polycystic mucous cysts are found mainly in the upper fornix. Varioustheories have been proposed to account for their presence. These cysts are generallythought to arise from (1) dilatation of extra ducts of accessory lacrimal glands; (2)lumen formation in epithelium that has grown into the substantia propria after aninflammatory process; (3) agglutination of mucosal infoldings in inflammatorydiseases; or (4) a traumatic injury leading to the formation of implantation cysts.Clinically, these cysts vary in size and may produce a mucoid substance.47

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GOBLET CELLSGoblet cells are present in the middle and superficial layers of the epithelium andconstitute 15% of human epithelial surface cells (Fig. 13).18 Intraepithelialcollections of goblet cells, known as Manz's glands, are located 3 to 7 mm nasallyfrom the corneal limbus on the bulbar conjunctiva.48 The presence of Manz's glandsin humans is controversial. Another structure formed by goblet cells is Henle'scrypts, which are 0.5-mm appendix-shaped invaginations.48 These large structures

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contain goblet cells and are most prominently developed in the nasal half of thetarsal area. In 1867, Steida49 described conjunctival crypts with elaboratemorphology. He described them as net-shaped, saccular, branched crypts lying in thetarsal regions, especially temporally in the upper tarsal areas, and lined with gobletcells. Kessing described mucus crypts that were strictly intraepithelial.48 Theseintraepithelial crypts were more numerous on the nasal side, particularly in thebulbar and inferior forniceal region. In the elderly, these crypts often show mucinstagnation, which forms small cystic structures of various shapes.

Fig. 13. Conjunctival epithelium of fornix, showingmany goblet cells (GC); one goblet cell protrudesabove the epithelial surface (arrow). n, nucleus of agoblet cell; mv, microvilli. ( 4000)

Goblet cells are relatively large cells and can measure up to 25 by 25 m. The entirecell is composed of membrane-bound mucus packets that may or may not be filledwith mucin. A welldeveloped Golgi system can be found in the perinuclear space ofthese cells. Here, the Golgi apparatus assembles mucus packets. These mucinpackets fill the cell and give the cell its goblet-shaped appearance. The organellesand nucleus of a fully developed goblet cell are pushed into the marginalespeciallybasalregion by the numerous mucus packets. Lysosomes, microsomes, andmitochondria are also found in the cytoplasm.

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

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Fig. 14. A. Low-power SEM of the epithelialsurface of bulbar conjunctiva, showingrelatively distinct cell borders. Large whitespots (arrows) are the mucous substancesecreted by goblet cells representing the sitesof the openings of these cells. The tissue wastreated with 20% acetylcysteine for 10minutes, but mucoid substance still remainedin places on the other epithelial surface aswell. B. Higher-power SEM of the sameepithelial surface as shown in A. The entiresurface is covered with microvilli, but the cellborders are clearly distinguished from theadjacent areas because of differentdistribution densities of microvilli. Arrowsindicate the surface of goblet cells; anabundant mucous substance still remains hereafter treatment with 20% acetylcysteine for10 minutes. (A, 2300; B, 6500)

Fig. 15. Immunolocalization of vasoactive intestinalpeptide in conjunctival flat mount. Fluorescencemicrographs are a montage of sections imagedparallel to the conjunctival surface at 1-m intervalswith a confocal microscope. Vasoactive intestinalpeptide-containing nerves appear as green lines.

Fig. 16. Fluorescence micrograph of sectionfrom inferior conjunctiva showing tyrosinehydroxylase (TH)-containing nerve fibers.Presence of TH indicates that sympatheticnerve fibers surround individual goblet cells.(Original magnification; 600. Dartt DA,McCarthy DM, Mercer HJ et al: Localization ofnerves adjacent to goblet cells in ratconjunctiva. Curr Eye Res 14:993, 1995)

Goblet cells normally appear to be present in the middle and superficial layer of theepithelium. Most if not all goblet cells, however, are attached to the basementmembrane by a thin cytoplasmic stalk.37 Goblet cells are attached to neighboringepithelial cells by desmosomes. The question of whether goblet cells and the

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stratified conjunctival epithelial cells share a common stem cell precursor or derivefrom 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 thecytoplasm can be observed in the basal cell layer among other squamous epithelialcells. As the goblet cell fills with mucous, the apical portion of the cell moves upwardto the epithelial surface, where it secretes mucus. Although it takes approximately 3to 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 cellsto secrete their mucus and then refill with newly synthesized mucin several timesduring their life span.37

Goblet cells are most numerous in the lower nasal fornix, lower middle fornix, andlower palpebral site; goblet cells are scarce in the bulbar conjunctiva temporal to thecornea and usually absent adjacent to the cornea.18,48,55 The density of the gobletcells is variable in different age groups. In adults older than 37 years, the number ofgoblet cells remains fairly constant, but it can be modified by external factors thatmay cause either an increase or a decrease in cell count at any age. After an initiallyrapid period of development during the first year of life, the density of goblet cellsslowly decreases through childhood and then reaches a fairly constant level (30 to70 goblet cells per 0.1 mm2 mucosal surface). Qi56 demonstrated that in the nasalinferior fornix conjunctiva, the mean number of goblet cells per 100 epithelial cellswas 10.17 2.81 in the younger group (average age 25 years) and 5.27 3.38 inthe older group (average age 62 years). Although little is known about the factorsthat influence normal conjunctival goblet cell density and distribution, the degree ofconjunctival hydration has been proposed as a significant exogenous factor. Somebelieve that gravitation of aqueous tears into the lower conjunctival sac, formation ofa lacrimal lake, and accumulation of tears at the median canthus results in maximalhydration of the lower nasal fornix and lower nasal palpebral conjunctiva, thereforeresulting in maximal density of goblet cells.55 This is also supported by the fact thatthe goblet cell count in patients with keratitis sicca has been found to be significantlylower than similar counts in normal patients.9,57

It has been known for more than 140 years that goblet cells produce mucussecretions.48 We now know that goblet cells may produce up to 2.2 L of mucusdaily.58 Mucus is crucial for ocular surface integrity because it lubricates and protectsthe epithelial cells. Mucin acts to reduce the surface tension of the tear film toensure its stability. The normal preocular tear film comprises a complex mixture oflipids, polysaccharides, and proteins that continually bathe the ocular surface. Thelipid component also reduces the surface tension of the tear film for stability, and italso prevents desiccation of the underlying epithelium.18,59,60

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

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

In many ocular surface disorders, the normal epitheliumsecretory or nonsecretoryis modified and becomes nonsecretory keratinized epithelium. This pathologictransition is called squamous metaplasia.64 The decrease in goblet cell density isassociated with a decrease in tear mucin; the tear film becomes unstable and causeskeratoconjunctivitis sicca (dry eye syndrome).6567 Snake-like nuclear chromatinand other nuclear changes are also seen in conjunctival nonsecretory cells frompatients with dry eyes.68 These nuclear changes are also seen in normal subjectswho wear contact lenses. A deficiency of either the aqueous or mucin components oftears causes a drying of the conjunctiva and cornea. A deficiency of the aqueouscomponent is seen in keratoconjunctivitis sicca, whereas the mucin component isdeficient in conditions causing loss of goblet cells (e.g., chemical burns, Stevens-Johnson syndrome, hypovitaminosis A, ocular pemphigoid, Sjgren's syndrome,acute alkali burns).9,18,59

A recent study has shown that asymptomatic wearers of soft contact lenses who hadbeen using their lenses for several years have a decreased density of goblet cells.57Medications such as topical beta-blockers also cause a pronounced reduction ofgoblet cells. For this reason, patients who must be treated with this drug shouldundergo regular checks of tear secretions and stability of their tear film. Although adecrease of mucin content has been used to indicate the severity of various mucindeficiency disorders, goblet cell density may be a better indicator of ocular surfaceintegrity,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 relativedecrease in goblet cell density. Other conditions associated with increased mucousproduction are lagophthalmos and blepharitis. Decreased mucus production isassociated with pemphigoid and infectious conjunctivitis.

Non-goblet cell epithelium is another important source of mucus production by theconjunctiva.62,63,71 Electron microscopy of human and rat conjunctiva revealsnumerous small granules that stain specifically for mucopolysaccharides, but not forlysosomes (Figs. 17 and 18). The non-goblet cells' secretory vesicles containsulfomucin, sialomucin, and neutral mucins,63 a mucin profile similar to that ofgoblet cells. Although goblet cells are the main source of the conjunctival mucin,non-goblet cell epithelium is also an important source of mucin. This epithelialsource may be responsible for the tenacious or sticky mucus found in patients whohave giant papillary conjunctivitis or ocular allergies, or who wear contact lenses,ocular prostheses, or cosmetic shells.13 This tenacious mucus is also seen in

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diseases such as keratoconjunctivitis sicca, Stevens-Johnson syndrome, and ocularpemphigoid, where goblet cell density is below normal.72,73

Fig. 17. Superficial layer of epithelium of bulbarconjunctiva showing numerous mucous granules(arrows) of the epithelial cells and granules (g) ofgoblet cells. mv, microvilli. ( 24,700)

Fig. 18. Forniceal epithelium showing a goblet cell(GC) protruding into the epithelial surface(conjunctival sac). Numerous mucous granules(mg) are found near the epithelial cell surface.Finely fibrillar substance within the goblet cellgranules (g) is often partially condensed inbundles and exhibits a faint fingerprint-likepattern. mv, long microvilli cut in cross-sections.( 9000)

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SUBSTANTIA PROPRIAThe conjunctival epithelium rests on a connective tissue layer called the substantiapropria. This tissue has enormous anti-infectious potential. Numerous mast cells(6000/mm3), lymphocytes, plasma cells, and neutrophils are normally present inthis layer.7476 Extracellular IgG, IgA, and IgM were found in the substantia propriaof conjunctivas of 16 persons without ocular disease.3

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

In many persons, localized, elevated, yellowish-white excrescences are observedmedially and laterally, close to the limbal margin. These elevations are calledpingueculae, and histologically they are very similar to pterygia, which also exist inthe same perilimbal area but involve the cornea as well. Both pingueculae andpterygia show senile elastotic degenerationa process involving a breakdown of thecollagen. The breakdown products stain with elastin but are not sensitive toelastase.77

Biomicroscopic examination of the peripheral bulbar conjunctiva in many persons has

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revealed lipid nodules that vary in diameter from 30 to 80 nm.78 These lipid depositsare conjunctival and episcleral, and the number of deposits increases with age. Theyare present nasally and temporally; they usually are found adjacent to blood vessels,but occasionally they occur in more isolated foci.

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CONJUNCTIVAL INFLAMMATIONInflammation of the conjunctiva or conjunctivitis may be induced by a large varietyof exogenous and endogenous infectious and toxic agents. The clinical andhistopathologic findings in conjunctivitis are highly variable and depend on theseverity, duration, and inciting agent.79 Nonetheless, hyperemia, edema (chemosis),and formation of papillae are almost always features of conjunctival inflammation.Clinically, hyperemia presents as increased conjunctival redness or injection.Hyperemia occurs when neurogenic mechanisms or vasoactive substances produceblood vessel dilatation. Inflammatory edema results from direct endothelial cellinjury or the release of vasoactive substances. Vasoactive mediators, such ashistamine, serotonin, and bradykinin, increase vascular permeability by causingendothelial cells to contract.80 This contraction probably involves only thoseepithelial cells that line postcapillary venules.79 Clinically, conjunctival edema ischaracterized by swelling of the bulbar conjunctiva, rugae (folds) in the fornices, andformation of papillae.81

Papillae are small (less than 1 mm), fairly regular, hyperemic projections thatdevelop in areas where the conjunctiva is firmly attached to the underlying tissue byconnective tissue septa. These fibrous attachments are present on the tarsus andsemilunar fold and at the limbus. Papillae contain a central fibrovascular core ofvessels that branch in a spoke-like pattern upon reaching the surface. The valleysbetween the projections are pale and relatively avascular. Papillae confer a slightlyirregular or velvety appearance to the tarsal conjunctiva.81 Histologically, papillaeare covered with hyperplastic epithelium. The stromal tissue surrounding thevascular core is edematous and infiltrated with chronic inflammatory cells.82 Papillaeare a nonspecific sign of inflammation and may result from virtually any etiologicagent.

Large or giant papillae have a more specific clinical significance. Moderately severeconjunctival inflammation may disrupt the connective tissue anchoring septa in thetarsal and limbal areas. This allows small papillae to coalesce and form largerprojections (greater than 1 mm).79 The appearance of giant papillae variesaccording to their cause. In atopic and palpebral vernal keratoconjunctivitis, giantpapillae are frequently large, polygonal, and flat-topped.13,83 They bestow acobblestone appearance to the tarsal conjunctiva. In limbal vernal conjunctivitis,giant papillae assume a smooth, round gelatinous appearance and are frequentlyassociated with Trantas dots (clumps of eosinophils or degenerated epithelialcells).84 The giant papillae on the upper tarsal conjunctiva associated with contactlens use (giant papillary conjunctivitis) range from slightly raised, symmetric, palelesions to large, polygonal, flat-topped lesions.81,85

Another common feature of conjunctival inflammation is follicle formation. Folliclesare frequently seen in the fornix and have little clinical significance in this area.Follicular hypertrophy is significant when it involves the bulbar or palpebral

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conjunctiva. Most follicles are small (0.5 to 1.5 mm), pale, round-oval, elevatedstructures.79,81 Unlike papillae, which have a central vascular tuft, follicles areavascular lesions; however, they are often bypassed or encircled by smallconjunctival vessels. Histologically, follicles consist of aggregated lymphocytes in thesuperficial substantia propria. Some are organized into germinal centers and containhistiocytic cells with phagocytized nuclear debris. The stromal tissues surroundingthe follicles are frequently infiltrated with lymphocytes and plasma cells.79 Follicleformation is most commonly associated with viral and chlamydial infections.

Another sign of conjunctival inflammation that may suggest a specific cause ismembrane formation. True membranes consist of fibrin, fibrinous byproducts,leukocytes, and necrotic debris, which become firmly interlaced around superficialepithelial 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 diphtheriaconjunctivitis, Neisseria gonorrhoeae conjunctivitis, -hemolytic streptococcalconjunctivitis, and Stevens-Johnson syndrome.82,85 Pseudomembranes are similar incomposition and appearance to true membranes, but they are much less adherent tothe underlying epithelium and bleeding usually does not occur when they areremoved. Important causes of pseudomembranous conjunctivitis include viralconjunctivitis, bacterial conjunctivitis, and alkali burns. Ligneous conjunctivitis is anunusual childhood form of membranous conjunctivitis. It typically presents as athick, whitish, wood-like induration on the upper tarsal conjunctiva. Histologicexamination reveals a thickened and sometimes dyskeratotic epithelium. Thesubepithelial tissue contains fibrin, acute and chronic inflammatory cells, andamorphous eosinophilic material.82

Conjunctivitis may present with various types of cellular exudate. Examination ofGiemsa-stained conjunctival scrapings may help suggest or confirm a specificdiagnosis. A polymorphonuclear leukocytic response is seen in bacterial or fungalconjunctivitis, neonatal inclusion conjunctivitis, acute toxic drug reactions, and anyconjunctivitis with inflammatory membranes or necrosis. Viral infections such asadenoviral or herpes simplex conjunctivitis, as well as molluscum contagiosum andchronic toxic drug reactions, usually provoke a mononuclear response. A mixedresponse consisting of both polymorphonuclear and mononuclear cells ischaracteristic of conjunctivitis caused by chlamydial or trachomatous infection orchemical burns. The presence of eosinophils can be demonstrated on cytologicexamination in conjunctival allergic responses to allergens such as dust and pollen.Multinucleated giant cells are elicited by herpes, trachoma, chlamydia, andneoplasia.85

Persistent or recurrent inflammation of the conjunctiva causes a series of reactiveand degenerative changes. Initially, the epithelium and goblet cells undergohyperplasia. Focal crypt-like infoldings of the proliferated epithelium and goblet cells(pseudoglands of Henle) may develop.79 The surface openings of thesepseudoglands 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 conjunctivalepithelium. Epidermalization consists of goblet cell loss, keratinization, and theformation of rete ridges. It imparts a white, plaque-like appearance (leukoplakia) tothe conjunctival epithelium. Ectropion of the lower lid is commonly associated withepidermalization of the palpebral conjunctiva. Vitamin A deficiency, dry eye

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syndrome, and various conjunctival neoplasms can provoke keratinization of thebulbar conjunctiva.79

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CONJUNCTIVAL WOUND HEALINGSurgical incisions and traumatic lacerations of the conjunctiva provoke a rapidhealing response. The conjunctival epithelium heals by migration of cells and mitoticproliferation. The bare sclera, tarsus, or residual subepithelial tissue provides thescaffold for epithelial wound healing. Initially, epithelial cells from the suprabasallayers migrate and slide inward to cover the defect. Subsequently, the basal cellslose their desmosomal attachments and slide inward. Proliferation of the basal layerreestablishes the normal thickness of the epithelium. In this way, conjunctivalwounds as large as 1 cm2 can be re-epithelialized within 48 to 72 hours.79,82

The wound healing response in the conjunctival stroma is similar to vascularizedtissue in other body sites. Stromal wound healing can be divided into four phases:(1) clot phase; (2) proliferation phase; (3) granulation phase; and (4) collagenphase.86 The clot phase occurs almost immediately after surgical or traumatic injuryto the conjunctiva. It is characterized by blood vessel constriction and the leakage ofblood cells and plasma proteins (fibrinogen, fibronectin, and plasminogen). A fibrin-fibronectin matrix or clot forms when the extravascular blood or plasma is exposedto certain tissue factors. During the proliferative phase, fibroblasts, new capillaries,and various inflammatory cells such as monocytes and macrophages migrate intothe clot and replicate. Inflammatory cells degrade the fibrin-fibronectin clot.Fibroblasts originate from the wound margins, subconjunctival tissue, andepisclera.87 Monkey studies suggest that fibroblast proliferation begins at about the5th day after surgical injury. Fibroblasts synthesize fibronectin, interstitial collagenand glycosamino-glycans to form fibrovascular connective tissue or granulationtissue. The granulation phase occurs by day 10 in the monkey model. Finally, thecollagen phase is characterized by the aggregation of tropocollagen molecules toform immature soluble collagen fibrils which then undergo cross-linking to formmature collagen.86 Initially, type III collagen is synthesized; this is replaced by typeI collagen as the wound matures.88 With time, capillaries and fibroblasts largelydisappear, leaving a dense, collagenous scar.87

The conjunctival response to corneal wounding has been known since Mann firstobserved that peripheral corneal abrasions heal by the sliding of limbal cells to coverthe epithelial defect.89 This response should be split into two phases: (1) theresponse of the limbal epithelium, which is the source of the corneal epithelial stemcells; and (2) the response of the conjunctival epithelium itself. Under normalcircumstances, the limbal epithelium acts as a barrier and is able to exert aninhibitory growth pressure that prevents migration of conjunctival epithelial cellsonto the cornea.89 Like the rest of the body surface, the conjunctiva and cornea arein a constant state of turnover. Corneal epithelial cells are continuously shed into thetear pool and simultaneously replenished by cells moving centrally from the limbusand anteriorly from the basal layer of the epithelium. Movement from the basal tosuperficial layers is relatively rapid, requiring 7 to 10 days; however, movement fromthe 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.

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During corneal healing of a lesion, corneal epithelial cells flatten, spread, andactually move across the defect until it is completely covered.90 Cell proliferation,which is independent of cell migration, begins to occur approximately 24 hours afterthe injury has been inflicted.91 Stem cells from the limbus also respond to heal thecorneal defect by proliferating to give rise to daughter cells termed transientamplifying cells.92 These cells migrate to heal the wound and also undergoproliferation to replenish the wound area.92 Further evidence of this was provided byobservation of migrating limbal pigment onto the clear cornea.90 The concept thatthe limbal cells form a barrier to conjunctival cells was further supported by theobservation that rabbit eyes treated for 120 seconds with n-heptanol, whichremoved both the corneal and conjunctival epithelium but left the limbal basal cellsintact, healed with corneal epithelium and had unvascularized corneas. However,when the entire limbal zone was surgically removed along with n-heptanoltreatment, corneal vascularization and conjunctivalization was observed.93Demonstration 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 beenestablished to be 17 m/day in the mouse94 and 64 m/h in the rabbit model.96These cells migrate in masses as a continuous, coherent sheet with most cellsretaining their positions relative to each other, much like the movement of a herd ofcattle.95

Rearrangement of intracellular actin filaments plays a role in movement. Cellmigration can be inhibited by blocking polymerization of actin, indicating that actinfilaments actively participate in the mechanism of cell motion.97 Some authorsbelieve that conjunctival as well as limbal epithelial cells may contribute to theregeneration of corneal epithelium. Marked proliferative responses in the conjunctivaafter a central corneal epithelium abrasion have been described.98,99 Why theconjunctival epithelium should proliferate in response to a central corneal wound isunknown. One possibility is that the proliferation acts to replenish the goblet cellnumber, which decreases by up to 50% after corneal wounding.52 However,proliferation occurs at high levels in the bulbar conjunctiva, which contains few if anygoblet cells. Also, the apparent decrease in cell number is more likely the result ofmucin secretion, rather than actual loss of goblet cells. Alternately, conjunctival cellsmay migrate into the limbus or cornea to help replenish the wound area. No firmdata exist, however, that conjunctival epithelium migrates onto the corneal surface inthe presence of intact limbal epithelium. Finally, the corneal epithelial wound healingis not complete until the newly regenerated epithelium has anchored itself firmly tothe underlying connective tissue. Permanent anchoring units are not formed until thewound defect is completely covered. Epithelial cells migrate rapidly and developstrong, permanent adhesions within 1 week when the basement membrane is intact.When this membrane is disrupted, the cells must secrete new membrane, and thennormal adhesions are established. Although transient attachments are regularlyformed and released during the cell migration process, according to Dua andassociates90 it takes 6 weeks for the formation of normal adhesions. Their studysuggests that tiny buds of corneal epithelium are present all along the contact linebetween the normal corneal epithelium and the migrating conjunctival epithelium.They observed these buds arising from the corneal epithelium and reported thatnormal corneal epithelium appears to replace the conjunctival epithelium bygradually pushing it toward the limbus.90 The magnitude and extent of both theconjunctival and corneal regenerative responses to a corneal abrasion correlate with

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the size of the wound. Larger erosions were reported to induce a more pronouncedresponse in the epithelial cell migration and mitotic rate at the limbus.29 Insultscaused by chemical injuries, Stevens-Johnson syndrome, contact lens-inducedkeratopathy, and aniridia result in limbal damage. These insults cause delayedhealing of the cornea, recurrent epithelial erosions, corneal vascularizations, andconjunctival epithelial ingrowth.93

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

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CONJUNCTIVAL HEALING IN GLAUCOMA FILTERING SURGERYGlaucoma filtering surgery is the primary surgical procedure for the treatment ofglaucoma. Unlike cataract surgery, the success of glaucoma filtering surgery dependspartly on the inhibition of conjunctival wound healing. The basic mechanism offiltering surgery is the creation of a fistula between the anterior chamber and thesubconjunctival space, thereby avoiding the pathologic obstruction to aqueousoutflow.86 Aqueous that enters the subconjunctival space has two possible routes ofegress: (1) reabsorption by blood vessels or conjunctival lymphatics, or both; and/or(2) movement through the conjunctival epithelium into the tears.87

A subconjunctival accumulation of aqueous called a filtering bleb is commonly seenafter successful glaucoma filtering surgery. The diameter, elevation, and vascularityof filtering blebs are highly variable. Functioning blebs may be thin and polycystic, orthey may have a flatter, thicker, and more diffuse appearance. Nearly all functioningblebs are relatively avascular and contain small cystic spaces (microcysts).86Microcysts are best seen with indirect illumination and probably represent channelsfor the passage of aqueous humor. Histologically, functioning blebs show normalconjunctival epithelium with no junctions between the cells that would limit fluidmovement. The subepithelial connective tissue is loosely organized and containsmany histologically clear spaces. The clear spaces probably correspond to themicrocysts seen clinically.103

In failed blebs, the conjunctiva is scarred to the underlying episcleral tissue.87 Failedblebs are typically low to flat and heavily vascularized with no microcysts. Both lightand electron microscopy of failed blebs reveals normal epithelium, but abnormallydense and thickened subepithelial connective tissue due to large amounts ofcollagen. Also, fibroblasts and blood vessels are present in the bleb wall.103 Failedblebs must be differentiated from encapsulated blebs (Tenon's capsule cysts).Encapsulated blebs are smooth, dome-shaped, conjunctival elevations with largevessels separated by avascular spaces. Microcysts are not usually present.Encapsulated blebs trap aqueous over the filtering site, thereby raising intraocularpressure. Unlike failed blebs, however, most of these blebs will recover functionwithin a few months.86 Histologically, encapsulated blebs consist of thin, almost

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avascular sheets of fibrous connective tissue with areas of proliferating fibroblasts.The inner surfaces of the bleb walls are lined with acellular material (probablyfibrin).87

Pharmacologic agents that inhibit fibroblast proliferation have been shown todecrease the risk of bleb failure in high-risk patients.104 5-Fluorouracil (5-FU) andmitomycin-C (MMC) have been studied most extensively. 5-FU is a pyrimidineanalogue that blocks DNA synthesis by inhibiting thymidylate synthesis.86 5-FU hasbeen shown to inhibit fibroblast proliferation in tissue culture and animal models.Additional studies have demonstrated that subconjunctival injections of 5-FUimprove the success rate of filtering surgery in high-risk eyes.87 A majordisadvantage of 5-FU is the need for frequent postoperative injections. Complicationsassociated with 5-FU administration include corneal epithelial defects, conjunctivalwound leaks, suprachoroidal hemorrhages, subepithelial scarring, andendophthalmitis.104 MMC is an antibiotic derived from the fermentation ofStreptomyces caespitosus. MMC appears to have greater inhibitory effects onfibroblasts than 5-FU.88 A single intraoperative application of MMC is effective inincreasing the success rate of filtering surgery in high-risk eyes. Disadvantagesassociated with its use include conjunctival wound leaks, choroidal detachments, andprolonged hypotony.104 A recent randomized clinical trial compared the efficacy andcomplication rate of 5-FU versus MMC in high-risk eyes. Patients were followed fornearly 3 years after glaucoma filtering surgery. Eyes treated with MMC had lowerintraocular pressure and required fewer medications than eyes treated with 5-FU.Apart from an increased incidence of Tenon's cyst formation in the MMC treatedeyes, late postoperative complications were similar in the two groups.104

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ARTERIESThe conjunctival arteries are derived from two sources: (1) the palpebral branches ofthe nasal and lacrimal arteries of the lid; and (2) the anterior ciliary artery. Bothvessels are derived from the ophthalmic artery, which is derived from the internalcarotid artery (Fig. 19).14 The post-tarsal plexus of the lid, which is supplied by themarginal and peripheral artery of the upper lids, supplies the palpebral conjunctiva.The perforating arteries from the marginal palpebral arcade pass through the tarsus,reaching the subconjunctival space in the region of the subtarsal sulcus to form themarginal and tarsal vessels. The perforating vessels from the peripheral palpebralarcade perforate Mller's muscle and supply most of the forniceal conjunctiva. Thisarcade sends descending branches to supply the tarsal conjunctiva and alsoanastomoses with vessels from the marginal arcade and ascending branches thatpass into the superior or inferior fornix to continue around the fornices to the bulbarconjunctiva as the posterior conjunctival arteries.

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Fig. 19. Arterial supply of the conjunctiva. AC,anterior ciliary artery; C, palpebral conjunctiva; IPA,inferior (marginal) palpebral arcade; L, limbus; PC,posterior conjunctival arteries; SF, superior fornix;SPA, superior palpebral arcade. (Modified from Duke-Elder S: System of Ophthalmology, Vol II, p 547. StLouis, CV Mosby, 1976)

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

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VEINSOn close surface examination of the conjunctiva, it may be possible to see aqueousveins originally described by Ascher.105,106 These veins vary in diameter from 0.01to 0.1 mm and are easily identifiable. They are usually found near the limbus, mostoften nasally, and appear hook shaped when they first come off the sclera. Theycontain a clear fluid and run a short course for approximately 1 cm. They are joinedby an episcleral vein, the blood of which may become diluted; alternatively, the clearfluid and the blood may run side by side unmixed, forming a laminated vein. Theseaqueous veins are the exit channels of the aqueous.

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 bulbarconjunctiva is directed to the palpebral veins. Some of the tarsal veins emptyindependently into the superior and inferior ophthalmic veins. Outflow is from thecircum-corneal region to the veins that serve the extraocular muscles.

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

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Larger vessels with smooth muscles are also present.

Fig. 20. A blood capillary in the stroma of bulbarconjunctiva. This is a nonfenestrated type, butthere also is a fenestrated type in the conjunctivalstroma. Both endothelium (E) and pericytes (P)are surrounded by a basement membrane (bm),and the lumen contains erythrocytes (RC). (6300)

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LYMPHATICS

The lymphatic channels in the conjunctiva14 are arranged in two plexuses: (1) asuperficial plexus consisting of small vessels placed below the capillaries; and (2) adeeper plexus consisting of larger vessels in the fibrous portion of the substantiapropria (Fig. 21A and B). These vessels are important in the mediation ofimmunologic reactions that occur in certain ocular diseases and surgical conditions.

Fig. 21. A. Photomicrograph of bulbarconjunctival epithelium. Note goblet cells(arrow). The substantia propria is composed ofloose connective tissue and diverse cellularelements. B. A lymph channel (L) in thesubstantia propria. The channel is lined withendothelial cells (arrows). (A and B, 240)

The superficial plexus receives lymphatic drainage from the limbal area. It has largercollector channels that run circumferentially 7 to 8 mm behind the limbus, formingan incomplete pericorneal lymphatic ring. Its other lymphatic drainage channelsinclude a recurrent nasal group that drains the upper nasal quadrant and adescending temporal group. Both groups drain by way of the medial canthus. A largecollecting vessel from the inferior fornix empties by way of the lateral canthus.Laterally placed lymph vessels flow to the preauricular lymph nodes; medially placedvessels flow to the submaxillary lymph nodes. Clinically, these vessels may be visiblewith a biomicroscope in certain conditions such as scleredema adultorum, and someof these lymph vessels may fill with blood and look like dilated veins.107,108 Electronmicroscopy reveals that these lymphatics differ from blood capillaries in somerespects. For example, the endothelium is very thin but has no fenestrae, theintercellular junctions are less well formed than in capillaries, the basementmembrane is interrupted or absent, and pericytes are usually absent (Fig. 22).

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Fig. 22. A lymphatic capillary in the substantiapropria of bulbar conjunctiva. Endothelium (E)is thin, its basement membrane is often notwell developed (as in this picture), and thelumen (L) usually contains no erythrocytes. (13,700)

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NERVE SUPPLYThe nerve supply to the conjunctiva is derived entirely from the first division of thetrigeminal nerve.10 The nerves to the lid supply most of the conjunctiva. Thesenerves comprise the infratrochlear branch of the nasociliary nerve, the lacrimalnerve, the supratrochlear and supraorbital branches of the frontal nerve, and theinfraorbital nerve from the maxillary division of the trigeminal nerve. The limbal areais supplied by branches from the ciliary nerves. All nerves form a network in theconjunctiva and terminate either peripherally in various forms of specialized endingsor on blood vessels and epithelial cells. The majority of nerve endings in theconjunctiva are free, unmyelinated nerve endings (Figs. 23 and 24). They form asub-epithelial plexus in the superficial part of the substantia propria. Many of thesefibers end on blood vessels, and others form an intraepithelial plexus around thebase of epithelial cells and send free nerve endings between cells.10

Fig. 23. A nerve fiber bundle in conjunctivalstroma (substantia propria) composed ofseveral unmyelinated nerve fibers (arrows)surrounded by a layer of perineurium (P);there are also intervening collagen fibrils (c).Each unmyelinated nerve fiber is composed ofaxons (A) wrapped with Schwann's cells (SC).( 13,700)

Fig. 24. Substantia propria of bulbar conjunctiva, showingmyelinated (MN) and unmyelinated (UN) nerve fibers. Inboth fibers, axons (A) are wrapped with Schwann's cells(SC) that have a basement membrane (bm). However,the axons are single and have a myelin sheath (ms) inthe former; they are multiple and have no myelin sheathin the latter. nf, neurofilament; nt, neurotubule; m,mitochondria. ( 20,800). Inset. Higher power of aportion (arrow) of the myelin sheath, showing thelamellar structure. ( 40,000)

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 connectivetissue capsule. The bulb itself may be single but of complex structure, or it may be

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compound. These end bulbs are relatively rare and vary in distribution. Their exactfunction remains unknown. One theory is that they are really a stage in the growthcycle of specialized nerve end organs.10

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THE CARUNCLEThe caruncle is a small, flesh-like body that lies in the lacus lacrimalis and to themedial side of the plica semilunaris. It is part of the margin of the lower lid thatbecomes cut off by the development of inferior canaliculus. The caruncle is coveredby a stratified squamous epithelium similar to skin, but it does not undergokeratinization. Like skin, it contains hair as well as sebaceous and sweat glands, butunlike skin, it contains accessory lacrimal glands similar to Krause's glands. Thedeep connective tissue in the caruncle is made up of parts of the septum orbitaleand the medial check ligament. Numerous goblet cells can be found singly or ingroups (Fig. 25). The blood supply of the caruncle comes only from the superiorpalpebral arteries. Because the supply is so abundant to this tissue, bleeding may beprofuse if the caruncle is inadvertently damaged. Nerve supply is provided by theinfratrochlear nerve. The lymphatics from here drain along with the rest of themedial part of the conjunctiva into the submaxillary lymph nodes.

Fig. 25. Epithelium of caruncle. It has many goblet cells(GC), some protruding toward the conjunctival sac. mv,microvilli of goblet cells. ( 12,200)

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PLICA SEMILUNARISThe plica semilunaris is a fold of conjunctiva lying lateral to the caruncle. It is moreor less vertical, with its concavity facing laterally. Because the lateral border is free,a cul-de-sac of approximately 2 mm in depth is formed when the globe is adducted.It is practically nonexistent when the globe is abducted. The plica corresponds to thenictitating membrane in lower vertebrates. In humans, it is a vestigial structureconsisting of a mere fold of conjunctiva. There are 8 to 10 layers of epithelial cellscontaining many goblet cells. Langerhans' cells may also be present in theepithelium. The substantia propria may have some nonstriated muscle supplied bysympathetic nerves and may contain fatty tissue. The connective tissue stroma ofthe plica is loose and highly vascular (Fig. 26).

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Fig. 26. Plica semilunaris showing goblet cells(arrows), epithelium and fibrovascularconnective tissue ( 50). (Fine BS, Yanoff M:Ocular Histology, 2nd ed, p 315. Hagerstown,Harper & Row, 1979)

Portions of the original chapter, including many of the illustrations, have beenretained in this revision.The authors, editors, and publisher wish to recognize the work of B. D. Srinivasan,Frederick A. Jakobiec, and Takeo Iwamoto for their contributions from the originalchapter.

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REFERENCES1. Holly RJ: Formation and stability of the tear film. Int Ophthalmol 13:73, 1973

2. Pfister RR: The normal surface of conjunctiva epithelium: A scanning electronmicroscopic study. Invest Ophthalmol 14:267, 1975

3. Allansmith MR, O'Connor GR: Immunoglobulins: Structure, function and relationto the eye. Surv Ophthalmol 14:367, 1970

4. Gundersen T, Pearlson HR: Conjunctival flaps for corneal disease: Their usefulnessand complications. Trans Am Ophthalmol Soc 67:78, 1969

5. Thoft RA: Conjunctival transplantation. Arch Ophthalmol 95:1425, 1977

6. Nagpal KC, Asdourian GK, Goldbaum MH: The conjunctival sickling sign,hemoglobin S, and irreversibly sickled erythrocytes. Arch Ophthalmol 95:808, 1977

7. Duke-Elder S: Diseases of the Outer Eye, Vol 8, p 1061. St Louis, CV Mosby, 1965

8. Parakkal PF, Alexander NJ: Keratinization, pp 4445. New York, Academic Press,1972

9. Ralph RA: Conjunctival goblet cell density in normal subjects and in dry eyesyndromes. Invest Ophthalmol 14:299, 1975

10. Warwick R: Eugene Wolff's Anatomy of the Eye and Orbit, Seventh Edition.Philadelphia, WB Saunders, 1976

11. Kurpakus MA, Maniaci MT, Esco M: Expression of keratins K12, K4 and K14during development of ocular surface epithelium. Curr Eye Res 13:805, 1994

12. Spinak M: Cytological changes of the conjunctiva in immunoglobulin-producingdyscrasias. Ophthalmology 88:1207, 1981

13. Trocme SD, Raizman MB, Bartley GB: Medical therapy for ocular allergy. MayoClin Proc 67:557, 1992

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14. Duke-Elder S: System of Ophthalmology, Vol 2, p 543. St Louis, CV Mosby, 1961

15. Jordan DR, Anderson RB, Mamalis N: Accessory lacrimal glands. Ophthalmic Surg21:146, 1990

16. Rivas L, Oroza MA, Perez-Esteban A, Murube-delCastillo J: Topographicaldistribution of ocular surface cells by the use of impression cytology. ActaOphthalmol 69:371, 1991

17. Oduntan AO: The inferior conjunctiva of the monkey. Acta Anat 143:178, 1992

18. Steuhl KP: Ultrastructure of the conjunctival epithelium. Dev Ophthalmol 19:1,1989

19. Weingeist TA: Fine structure and function of ocular tissues: The conjunctiva. IntOphthalmol Clin 13(3):85, 1973

20. Nicolaissen B Jr, Eidal K, Haaskjold E et al: Outgrowth of cells from humanconjunctival explants onto cornea in vitro. Acta Ophthalmol 69:723, 1991

21. Sandvig KU, Haaskjold E, Bjerknes R et al: Cell kinetics of conjunctival andcorneal epithelium during regeneration of different-sized corneal epithelial defects.Acta Ophthalmol 72:43, 1994

22. Tseng SC, Tsai RJ: Limbal transplantation for ocular surface reconstructionareview. Fortschr Ophthalmol 88:236, 1991

23. Zieske JD: Perpetuation of stem cells in the eye. Eye 8:163, 1994

24. Zieske JD, Bukusoglu G, Yankauckas MA: Characterization of a potential markerof corneal epithelial stem cells. Invest Ophthalmol Vis Sci 33:143, 1992

25. Schermer A, Galvin S, Sun T-T: Differentiation-related expression of a major 64Kcorneal keratin in vivo and in culture suggests limbal location of corneal epithelialstem cells. J Cell Biol 103:49, 1986

26. Cotsarelis G, Cheng S-Z, Dong G et al: Evidence of slow-cycling limbal epithelialbasal cells that can be preferentially stimulated to proliferate: Implications onepithelial stem cells. Cell 57:201, 1989

27. Lindberg K, Brown ME, Chaves HV et al: In vitro propagation of human ocularsurface epithelial cells for transplantation. Invest Ophthalmol Vis Sci 34:2672, 1993

28. Sandvig KU, Haaskjold E: The proliferative response during regeneration of aringshaped defect in the corneal epithelium. Acta Ophthalmol 71:39, 1993

29. Sorensen

Documents

Foundation Volume 1, Chapter 29. Conjunctiva