Total absence of the cornea as an isolated finding without major abnormalities of the surrounding structures has not been reported.

Cryptophthalmos is a rare condition in which the eyelids fail to form. The surface ectoderm component of the cornea is absent in cryptophthalmos; however, the neural crest components are present and make up the external surface of the globe and the anterior segment, even though these tissues may not be normal.¹⁴

Cryptophthalmos may present as an isolated abnormality or may be one of a spectrum of congenital abnormalities. Fraser syndrome is an autosomal recessive multiple malformation syndrome whose major manifestations are cryptophthalmos, syndactyly, laryngeal atresia, and urogenital defects.^15,16,17 Cryptophthalmos is found in 93% of cases. In Fraser syndrome there is a stillborn rate of 26% and a first year mortality of 19%.¹⁸

There are multiple nonspecific types of congenital corneal opacities. Although arrested embryogenesis or intrauterine inflammation may cause the entity, the opacities have the same clinical characteristics as acquired changes following trauma. In order of progressive severity, the degree of opacification is called a facet when only Bowman’s membrane is involved; a nebula when the area of opacification is diffuse, cloudlike, and has indistinct borders; a macula when the area is dense and has a circumscribed border; and a leukoma when the cornea is opaque. Adherent leukoma is a subgroup in which a portion of iris is fused to the posterior surface of the opaque corneal tissue, similar to the findings of some healed acquired corneal perforations (Fig. 2).

Anterior embryotoxin, synonymous with arcus juvenilis, consists of a yellow-white linear deposit central and distinct from the limbus and separated by clear cornea (Fig. 3). The condition, seen most often in men, becomes more intense with age. The adult acquired type of deposit, arcus senilis, has been found to be a clinical characteristic of type II hyperlipidemia and is considered to be a risk factor for coronary heart disease and cardiovascular disease.⁴² The corneal finding is a manifestation of a systemic disease and is not congenital.

Lipid can be shown by special staining methods to be located at the junction of the peripheral cornea and sclera, most densely deposited adjacent to Bowman’s membrane, and next to Descemet’s membrane.

The deposit is more likely due to defective clearing of lipid than excessive deposition of lipid.⁴³

Corneal keloids are hypertrophic scars of the cornea that may be present at birth following intra-uterine trauma. but more often they appear spontaneously or after minor trauma in early childhood. The opacity appears to be an inappropriate repair response of the corneal tissue to trauma. A sector of the cornea or the entire cornea may be involved. The inappropriate repair response usually coexists in the skin. Black persons more commonly are affected than others. Recurrence is the rule, particularly following attempts at surgical excision.⁴⁴ No inheritance pattern has been recognized.

The stromal nodules are composed of proliferating myofibroblasts, activated fibroblasts, and haphazardly arranged fascicles of collagen. Immunohistochemical stains show spindle cells that express immunoreactivity for vimentin and alpha smooth muscle actin.⁴⁵

Keloid formation may be the result of excessive local delivery of amino acids and unknown noxious substances through leaking corneal vessels.⁴⁶ Occasional cases show progression with severe visual loss.⁴⁷

Central dysgenesis of the cornea involves abnormalities of the neural crest mesenchymal derivatives that make up the central cornea posterior to Bowman’s membrane. Bowman’s membrane may be involved secondarily.

Peters’ anomaly includes absence of central corneal endothelium, Descemet’s membrane, and variable amounts of corneal stroma (Fig. 4). In most cases Bowman’s membrane also is absent. Peters’ anomaly may be caused by primary dysgenesis of the corneal endothelial mesoderm, primary dysgenesis of keratocyte and endothelial neural crest mesoderm, or secondary endothelial degeneration due to late anterior displacement of a normally developed crystalline lens.⁴⁸ In addition, it has been suggested that abnormal apposition of an ectopic lens to the developing cornea during the second or third month of gestation may be the cause of exceptional cases of peripheral Peters’ anomaly.⁴⁹

Associated anterior segment anomalies include corectopia, iris hypoplasia, anterior polar cataract or other lens abnormalities, and iridocorneal adhesion. (Fig. 5) Corneal perforations secondary to Peters’ anomaly have been reported at birth.^50,51 Systemic anomalies include Potter’s syndrome (agenesis of the urinary tract) and intestinal malrotation.^52,53,54 Generally, no specific inheritance pattern has been noted, although a family that had an autosomal dominant inheritance pattern has been reported.⁵⁵

Histopathologic findings include absence of Descemet’s membrane, corneal endothelium, and usually Bowman’s membrane, as well as thinning of corneal stroma. The defects in Descemet’s membrane, although usually single and central, may be multiple and isolated to the periphery or may be limited to an area of adhesion of iris.⁵⁶ Descemet’s membrane has been found to have embryonal ultrastructural characteristics combined with attenuated endothelium.⁵⁷ The corneal stromal lamella are more irregular and closely packed when compared with normal. Immunohistochemical markers indicate that a normal complement of collagens type I, III, IV, V, and VI occurs in Peters’ anomaly; however, an increased concentration may occur of the adhesive protein fibronectin, which is known to play a role in the embryologic development of the cornea.^58,59,60

Localized posterior keratoconus, which usually presents as an isolated anomaly, consists of central or paracentral depressions of the posterior contour of the cornea. Descemet’s membrane and the corneal endothelium are present. The mechanism of origin is unknown but may be a mild form of Peters’ anomaly. The condition tends to be unilateral, relatively central in the cornea, and sporadic. No relationship exists with anterior keratoconus. Vision is not affected except in extreme cases in which the anterior corneal curvature is secondarily altered. Associated systemic defects include median facial clefting and severe genitourinary abnormalities, which suggests that the defect occurs early in the gestational period.

Histopathologic changes include disarray of corneal stromal collagen in the area of abnormal posterior curvature. Bowman’s membrane has been absent in some cases. In the area of stromal thinning, an abnormal anterior banding and a multilaminar configuration of Descemet’s membrane occurs. Knoblike excrescences of Descemet’s membrane around the periphery of the corneal defect have been observed, suggesting early embryonic iridocorneal adhesion.^61,62,63

The PAX family of genes is highly conserved throughout species indicating the fundamental nature of function in development. The gene products from the PAX genes are necessary for initiating development of certain tissues and organs. The PAX 6 gene is thought to initiate development of the eye. The following group of disparate entities are part of the anterior segment dysgenesis group as illustrated by the Step ladder classification and linked as they involve mutations in at least three genetic loci. The most important reason for segregating these conditions is that they confer a 50% or greater risk of developing glaucoma.^64,65

Isolated Axenfeld’s anomaly (posterior embryotoxon) consists of a clinically prominent Schwalbe’s line (terminal end of Descemet’s membrane) plus a variable number of iris processes extending from the peripheral iris to Schwalbe’s line (Fig. 6). The condition is most likely a developmental arrest, late in gestation, of tissues derived from neural crest cells.⁶⁶ The line appears as a deep linear opacity of the peripheral cornea of variable prominence and extent and is most often found temporally. The prevalence rate is approximately 15% to 25%.^67,68 No race or sex predilection exists. Although the majority of the eyes are normal, an associated partial iris coloboma and other anomalies may occur.⁶⁸ Axenfeld’s anomaly may be associated with non-ocular abnormalities as part of Axenfeld-Rieger’s syndrome (see later).

Histologically, Axenfeld’s anomaly consists of dense collagen and ground substance covered by a monolayer of flattened endothelial or spindle-shaped cells at the terminal end of Descemet’s membrane. The endothelium is contiguous with the endothelium covering the trabecular beams.⁶⁸ Associated iris processes are composed of normal-appearing iris stroma.

Peripheral dysgenesis (isolated Rieger’s syndrome) encompasses a wide spectrum of developmental abnormalities of anterior chamber angle tissues of neural crest origin associated with systemic anomalies.⁷⁰ This group of abnormalities is important clinically because it is associated with an increased prevalence of glaucoma. The defects are thought to result from a developmental arrest in the third month of gestation. Rieger’s syndrome probably includes those entities sometimes described as mesodermal dysgenesis and anterior chamber cleavage syndrome and most accurately called anterior segment dysgenesis.

Histopathologic changes are characterized by retention of primordial endothelial tissue on the iris and by anterior chamber angle and peripheral iris strands (Fig. 7). Continued contraction of component membranes causes progressive changes of the iris architecture. Glaucoma results from arrested development of the anterior chamber angle structures, characterized by incomplete maturation of the trabecular meshwork and Schlemm’s canal and a high insertion of the peripheral iris.⁷⁰

Because Rieger’s syndrome is often associated with Axenfeld’s anomaly as one of its ocular findings, along with marked anomalous development of the iris and systemic anomalies mainly consisting of facial and dental abnormalities, the clinical term Axenfeld-Rieger syndrome has been suggested.⁶⁶ Corectopia (displacement in the direction of prominent peripheral tissue strands), dyscoria, slit pupil, iris hypoplasia, and prominent iris strands have been reported. Glaucoma eventually may be found in 50% of affected people; however, the glaucoma may not be manifested until childhood or early adulthood. Extraocular abnormalities include enamel hypoplasia, conical and misshapen teeth, hypodontia; impactions, underdevelopment of the maxilla, mandible, and cranial base (anterior and posterior), low-set ears, wide nasal bridge, bilateral microcondyles, and bilateral choanal atresia. Autosomal dominant inheritance patterns in families have been identified.⁷²

Three chromosomal loci have recently been demonstrated to link Axenfeld-Rieger syndrome and related phenotypes. These loci are on chromosomes 4q25, 6p25, and 13q14. The genes at chromosomes 4q25 and 6p25 have been identified as PITX2 and FKHL7, respectively. Mutations in these genes can cause a wide variety of phenotypes that share features with Axenfeld-Rieger syndrome. Axenfeld anomaly, Rieger anomaly, Rieger syndrome, iridogoniodysgenesis anomaly, iridogoniodysgenesis syndrome, iris hypoplasia, and familial glaucoma iridogoniodysplasia all have sufficient genotypic and phenotypic overlap such that they should be considered one condition.⁶⁴

Congenital corneal ectasia is an opaque, ectatic cornea extending between the lids. If the ectactic cornea is lined by adherent iris, the condition is called corneal staphyloma. The cornea then has a blue hue caused by posterior approximation of atrophic iris tissue. Lens opacities are common. The posterior segment is normal. No inheritance pattern is evident. Congenital corneal ectasia is thought to be due to failure of migration of embryonic mesoderm to form corneal endothelium and iris stroma at approximately 7 weeks’ gestation.^73,74

Histologically, the corneal epithelium is normal in thickness but may be keratinized secondary to exposure. Often, local attenuation of Bowman’s membrane occurs. The stroma is thickened, disorganized, hypercellular, and vascularized. A double layer of pigment-containing cells lines the posterior corneal stroma. Usually no sign of an inflammatory infiltrate is present. Descemet’s membrane and corneal endothelium are absent.

Corneal ectasia has become a major concern related to laser-assisted in-situ keratomileusis (LASIK) surgery. Increasing numbers of cases of progressive corneal ectasias have been reported, with many leading to keratoconus.⁷⁵

Sclerocornea is a totally opacified cornea that shows clinical and histologic features of sclera. The condition often is bilateral. Superficial or deep vascularization of the tissue may occur. Associated clinical conditions include nystagmus, strabismus, aniridia, cornea plana, macular hypoplasia, horizontally oval cornea, and glaucoma.⁷⁶ As described in Mieten’s syndrome, sclerocornea may present with congenital cerebral dysfunction, deafness, cryptorchidism, pulmonary disease, brachycephaly, and defects of the face, ears, and skin. Sclerocornea may be inherited in an autosomal dominant pattern. It may result from intrauterine inflammation and other nonspecific causes.

Histologically, increased numbers of collagen fibrils with a variable collagen diameter occur in the normal corneal stroma. Descemet’s membrane appears thin.^77,78 Bowman’s membrane may be absent.⁷⁹

Sclerocornea has been associated with an interstitial deletion of the short arm of chromosome 6(46XY del[6 [p22 p24])⁸⁰ and a microdeletion of Xp22.3.^81,82 Recent evidence supports linkage to mutations in the distal arm of chromosome 6.⁸⁰

Corneal dermoids are choristomas of mesenchymal elements covered by epithelium. The location and extent are variable. Corneal dermoids usually are sporadic; however, autosomal recessive or sex-linked pedigrees have been described.⁸³

The most common location is at the limbus, where the abnormal tissue is present in the peripheral cornea and in the adjacent episclera. Although the majority of limbal dermoids are isolated findings, approximately 30% are associated with Goldenhar’s syndrome (see later). Although most limbal dermoids are superficial, the abnormal tissue occasionally extends into the anterior chamber angle tissue. Central corneal dermoids are the least common (Fig. 8). The posterior cornea and Descemet’s membrane are normal. On rare occasions the entire cornea and anterior segment may be replaced by a dermoid. Descemet’s membrane, iris, anterior chamber, and crystalline lens may be absent. This severe type often is associated with microphthalmos.⁸⁴

Histologically, the corneal epithelium may be keratinized. Bowman’s membrane often is absent. The stroma is replaced to a variable degree by irregularly arranged, dense, vascularized, collagenous connective tissue containing hair follicles, hair shafts, sebaceous glands, fat, smooth muscle, striated muscle, cartilage, teeth, or bone. The mass may be either cystic or solid.

Goldenhar’s syndrome consists of bilateral epibulbar dermoids, accessory auricular appendages, blind pretragal fistulas, and abnormalities of the cervical vertebrae⁸⁵ (Fig. 9). The condition is important because of associated systemic abnormalities, including mandibulofacial dysostosis, phocomelia, and renal malformations. The first and second brachial clefts give rise to the ear, face, and eyelids. Goldenhar’s syndrome is thought to result from a noxious insult during the seventh week of gestation, affecting the brachial clefts and a variable number of other germ tissues of other organ systems, primarily the kidney and skeleton. Associated brachial arch alterations include notching (so-called coloboma) of the upper eyelid, antimongoloid slant of the palpebral fissures, microphthalmos, microcornea, uveal coloboma, hypoplastic upper and lower jaw, microtia, and macrostomia. Nonbrachial arch alterations include anomalies of the cervical vertebrae, heart disease, cleft palate, mental retardation, hydrocephalus, meningioencephalocele, phocomelia, renal hypoplasia, and partially annular pancreas.⁸⁶

Although the eye usually is not involved, a subgroup identified as the Goldenhar-Gorlin syndrome shows diminished visual acuity, tilted optic disc, optic nerve hypoplasia, tortuous retinal vessels, macular hypoplasia and heterotopia, microphthalmia, and anophthalmia. The Goldenhar-Gorlin syndrome may be caused by an asynchrony in the migration of the neural crest cells in the early stages of embryonal development.⁸⁷

Epithelial inflammation often is a part of primary conjunctival inflammation (e.g., almost any form of severe bacterial conjunctivitis). Epithelial inflammatory changes in the form of superficial epithelial punctate keratitis or recurrent erosion syndrome may be secondary to abnormalities of underlying tissue, such as inherited corneal dystrophies (e.g., Reis-Bucklers’ dystrophy and lattice, granular, and macular dystrophies).

Histologically, polymorphonuclear leukocytes are found insinuating among the squamous epithelial cells (exocytosis) associated with intercellular edema (spongiosis) and intracellular edema (primarily of the basalar cell layer). The basement membrane of the epithelium, which usually is inconspicuous by light microscopy, may become very prominent. The orderly maturation of the squamous epithelium may be disturbed, causing various degrees of cellular atypia. In severe and prolonged cases, serous-filled subepithelial bullae may develop. If the integrity of the superficial epithelium is disrupted (recurrent corneal erosion), the anterior corneal stroma may become inflamed and subsequently scarred. With resolution of the edema and bullae, the cells may become maloriented relative to Bowman’s membrane, causing intraepithelial basement membrane formation and intraepithelial cyst formation (epithelial basement membrane syndrome).

Thygeson’s disease is a primary inflammation of the cornea of unknown cause that usually occurs in young people, often between the ages of 20 and 40 years. The patients present with severe symptoms: tearing, foreign body sensation, and photophobia. The initial clinical sign is an outcropping of fine, ground glass–like particles arising from the superficial epithelial layer that mass together as coarse clumps 0.5 to 1 mm in diameter. The lesions usually remain for several weeks to several months and eventually fade, only to recur months or years later. Thygeson’s disease is one of the few corneal epithelial inflammatory conditions that present with an elevation of the epithelial surface, which stains with fluorescein in a negative pattern (i.e., the fluorescein pools around the base of the elevation and the apex stains negatively).

By light microscopy the epithelial cells show a cytopathic effect in the acute stages, suggestive of a viral infection; however, no viral particles have been identified by electron microscopy. Only rarely have viral cultures been positive, and most of these isolated reports have not been confirmed.^88,89

Superior limbic keratoconjunctivitis of Theodore is an idiopathic inflammation of the upper tarsus, superior limbus, and corneal epithelium associated with limbal follicles and the development of recalcitrant filamentary keratitis in one third of cases. Keratoconjunctivitis sicca is a frequent associated finding.⁹⁰ The patients present with fine, papillary, upper tarsal conjunctival reaction in all cases. The superior bulbar conjunctiva often shows positive fluorescein and rose bengal staining. An association with thyroid disease exists in almost 50% of affected individuals.

The corneal alterations are secondary to irritation by the superior tarsal papillary reaction, which results in the disturbance of the superior bulbar conjunctiva, leading to the development of tenacious mucus, which in turn leads to filamentary keratitis. If not treated or in severe cases, the superior bulbar conjunctiva may undergo epidermalization (transformation of mucous membrane to a tissue with the characteristics of skin, primarily keratinization).

Histologic changes of the conjunctiva consist of hyperplasia of the squamous layer and induction of a granular layer that indicates keratin production. The presence of keratinized epithelium either by superficial scraping or full-thickness biopsy supports the clinical diagnosis but is not specific.⁹¹

Epidemic keratoconjunctivitis (EKC) is a highly contagious, self-limited subepithelial inflammatory disease associated most often with adenovirus type 8 and less commonly with adenovirus types 19 and 25.⁹² The disease often occurs as epidemics in factories, schools, or offices of ophthalmologists. The viral particles remain infectious for up to 14 days on metal, glass, or plastic surfaces (e.g., tonometer heads). An incubation period of approximately 8 days occurs between infection and clinical expression in the first eye followed 3 to 7 days later by expression in the second eye. The second eye usually is involved less severely. The onset often is abrupt or explosive, consisting of follicular conjunctivitis associated with tearing, marked swelling and hyperemia of the conjunctiva, and ipsilateral, painful preauricular lymphadenopathy (Fig. 10). In children, EKC can mimic the presentation of orbital cellulitis.⁹³ Conjunctival membranes may develop during the course of EKC, which in turn may lead to filamentary keratitis and/or frank symblepharon formation. Subepithelial keratitis occurs during the second or third week, often reducing visual acuity significantly (20/60).⁹⁴

Historically, very few tissue specimens have been studied. Initially, lymphocytes infiltrate the subepithelial area of the cornea, followed by mild scarring. The resulting nebula may be permanent.

Trachoma is a chronic follicular conjunctivitis caused by a unique class of organisms, Chlamydiaceae, characterized by small size, a gram-negative staining pattern, a biphasic life cycle, and sensitivity to antibiotics.⁹⁵ The metabolically inert, extracellular form of the organism (elementary body) infects specific epithelial cells of the body. Several of the serotypes of Chlamydia trachomatis (A, B, Ba, C) infect only the epithelial cell of the conjunctiva. Other serotypes are known to infect epithelial cells in other parts of the body, causing other specific disease entities (e.g., lymphogranuloma venereum and psittacosis). Once inside the cell, the organism transforms to the metabolically active obligate intracellular parasite (reticulate body), which ultimately forms a microcolony of new elementary bodies. This intracytoplasmic inclusion is typically perinuclear and has been called the Halberstaedter-Prowazek inclusion. The elementary bodies are released at the death of the host cell and infect other epithelial cells.

Corneal blindness caused by this disease has been described in the earliest medical texts and has influenced the history of Europe, North Africa, the Middle East, and Asia. The organism only infects humans. It is spread from person to person, including mother to child, by direct contact with mucous secretions or by the use of common towels or eye makeup. The people most at risk are those living in close quarters, often associated with poor economic, nutritional, and social status. The acute form of trachoma presents in children as the lymphoid tissue of the conjunctiva becomes mature. Extensive mucoid discharge, conjunctival hyperemia, and a myriad of follicles, primarily on the upper tarsal plate, are the initial manifestations. The clinical signs may wax and wane, depending partly on the frequency and severity of secondary bacterial infections. Following a variable period of recurrent episodes of acute or subacute conjunctivitis, the inflammatory phase is replaced by cicatricial changes of the upper tarsal plate, leading to severe trichiasis and entropion. The mechanical trauma from the scarred lid margin on the cornea causes extensive superficial scarring of the cornea beginning with a delicate superior vascular pannus and culminating in a densely opaque, scarred cornea.

Histologically, desquamated epithelial cells or cells sampled by tarsal conjunctival scraping contain discrete, round, densely staining spheroids (initial bodies) that aggregate into a well-defined, paranuclear intracytoplasmic inclusion called the elementary body (Halberstaedter-Prowazek). A distinct rim of cytoplasm between the elementary body and the adjacent nuclear membrane distinguishes the infective agent from crush artifact of the nucleus. The epithelial remnants of cells that have been lysed by the infection often are seen in large phagocytic cells (Leber cells). In the early phases of the disease, the conjunctival subepithelial tissue is markedly expanded by reactive lymphoid hyperplasia, characterized by numerous germinal centers in a polymorphic lymphoid infiltrate. Follicles may form in the paralimbal tissue and ultimately involute to form Herbert’s pits. Corneal neovascularization in the form of an inflammatory pannus begins in the superior cornea in the region of the limbal inflammatory infiltrate.⁹⁶ Associated secondary bacterial conjunctivitis may coexist, as evidenced by an acute, sometimes suppurative, inflammatory reaction. With time, the inflammatory reaction is superseded by an extensive subepithelial tarsal conjunctival fibrovascular reaction, laying down collagen and contracting in a plane just above and parallel to the lid margin (Arlt’s line). The mechanical distortion of the tarsal plate and concurrent destruction of the tarsal plate integrity are noted clinically as entropion and trichiasis. Goblet cells in the conjunctiva are destroyed by the prolonged inflammatory reaction. Subepithelial scarring compromises accessory lacrimal gland tissue and the ducts of the main lacrimal gland. Subsequent anterior surface drying accelerates the scarring process. The scarring of the cornea is a nonspecific degenerative and inflammatory pannus initially, ultimately resulting in the total loss of Bowman’s membrane and scarring of the superficial stroma. The corneal tissue eventually may be substantially replaced by secondary amyloidosis.⁹⁷

Leprosy (Hansen’s disease) is an infectious disease caused by Mycobacterium leprae, a gram-positive, obligate intracellular bacillus of human beings. The disease is characterized by slowly progressive chronic inflammation of the skin, nerves, and eyes. When cell-mediated immunity is maintained (tuberculoid leprosy), the disease is manifested by a small number of cutaneous lesions associated with marked nerve anesthesia and enlargement. Few organisms are seen in histologic sections from tuberculoid leprosy lesions. In individuals who have compromised cell-mediated immunity (lepromatous leprosy), numerous skin lesions occur, associated with less anesthesia. Many organisms are present in mononuclear or epithelioid cells (lepra cells). The lepromatous type is the most contagious. The organism has a particular affinity for nerves and for cooler areas of the body. The cornea, iris, and ciliary body generally are several degrees cooler than core body temperature and are therefore vulnerable to infection.⁹⁸

The anterior segment may be directly infected by M. leprae through the blood stream (chronic anterior uveitis, enlargement of corneal nerves). Inflammation of the facial nerve may lead to exposure keratopathy because of neurogenic lid dysfunction. Immune-complex disturbance may cause episcleritis, scleritis, and iridocyclitis. Impaired corneal sensation disrupts normal corneal metabolism due to lack of substance P and repeated unrecognized trauma. Mechanical abnormalities of the lids may cause direct corneal trauma.⁹⁹

The histologic changes in the cornea are influenced by the immune competence of the host. In the tuberculoid form, the cornea is infiltrated with chronic granulomatous inflammation and minimal scarring unless the cornea has been secondarily infected or severely traumatized. In the lepromatous form, the epithelioid cells of the inflammatory infiltrate are filled with viable organisms, giving the cytoplasm a granular appearance.

Rosacea keratitis is the corneal component of acne rosacea (Fig. 11). The cause of acne rosacea is undetermined but is thought to be a genetically inherited abnormal vasodilation response of the skin, associated with sebaceous hyperplasia and a chronic inflammatory reaction. Approximately 3% of patients with acne rosacea have involvement of the cornea, whereas 20% of patients have eyelid and conjunctival involvement.¹⁰⁰ Corneal changes include peripheral subepithelial scarring, which progresses to the axial cornea, accompanied by stromal vascularization.

Early in the disease, a superficial lymphocytic infiltrate is found in the subepithelial-superficial stromal corneal tissues, leading to sclerosing pannus formation. The process characteristically begins in the inferior peripheral cornea and progresses to the axial cornea.

Lyme disease, named for the Connecticut town in which it was first recognized, is the result of systemic infection by the spirochete Borrelia burgdorferi.¹⁰⁶ There are three stages: primary (erythema chronica migrans)—skin inoculation through bites by the nymphs and hard ticks of the genus Ixodes; secondary—systemic dissemination of the spirochete; and tertiary—involvement of the joints, central nervous system, and cardiovascular system.

Ocular findings are relatively uncommon and include nummular keratitis, uveitis, retinitis, and optic neuritis. It appears that all forms of ocular involvement that have occurred as a manifestation of syphilis also can be caused by B. burgdorferi. However, the organism has never been found inside the eye.¹⁰⁷

Tuberculosis is a granulomatous disease caused by Mycobacterium tuberculosis, which primarily affects the lungs and kidneys. Tuberculosis of the cornea occasionally presents as an extension from conjunctival disease as a superior pannus. Rarely, it may present as an interstitial keratitis. The organism is not found in the cornea. On the other hand, M. chelonae is often found in the cornea, as are several other atypical mycobacteria.¹⁰⁸

Sarcoidosis is a generalized granulomatous inflammation of unknown cause primarily involving the lungs. Sarcoidosis may affect the conjunctiva but rarely affects the cornea directly. Occasional cases occur as an extension from the conjunctiva or uvea.¹⁰⁹

Onchocerciasis is an infectious disease caused by the largest human filarial worm, Onchocerca volvulus. The microfilaria of the worm is transmitted to human subcutaneous tissues by the bite of the blackfly Simulium damnosum. The microfilaria matures in the skin into an adult worm, which may be up to 50 cm in length. The microfilaria discharged from the adult worm migrates through the interstitium of the skin rather than hematogenously to the eye. Alive, the microfilaria are fairly well tolerated and induce only a slight, surrounding lymphocytic or plasma cell reaction. Dead organisms, however, cause a severe inflammatory reaction that is chiefly eosinophilic. The inflammation may cause corneal opacification directly or indirectly by causing secondary iritis with synechia formation and angle closure glaucoma.¹¹⁰

Cogan’s syndrome consists of nonsyphilitic interstitial keratitis and characteristically patchy, bilateral vascularization of the middle and deep corneal stroma, associated with vestibular auditory symptoms, such as hearing loss, dysacousia, and vertigo. The cause of the syndrome is not known. However, there appears to be some form of systemic vasculitis with inflammation found in the dura, gastrointestinal tract, spleen, and kidneys.¹¹⁵ There is no association with immune abnormalities or specific HLA antigen patterns. This disease most frequently is found in young people; however, it can occur in older age groups. The corneal disease tends to be relatively mild, although vascularization can be a significant problem. Approximately 10% of patients exhibit an underlying vasculitis, primarily involving larger vessels (proximal aortitis, aortic insufficiency).¹¹⁶

Other diseases that can cause secondary stromal keratitis are Hodgkin’s disease, lymphogranuloma venereum, hypoparathyroidism, mycosis fungoides, and gold toxicity.

Herpes simplex is the most common cause of viral central corneal ulcers in the United States.¹²⁰ The initial clinical sign may be a cutaneous vesicular rash (Fig. 17) or a corneal epithelial dendrite (Fig. 18). The infection progresses through corneal stromal inflammation (metaherpetic phase) to culminate in central ulceration. The initial epithelial defect is caused by replication of herpes simplex virions in the epithelial cells; the cytopathologic effect of the infection leads to epithelial cell death (rose bengal–positive) and ulceration. The infection is self-limited to an 8- to 10-day course unless shortened by debridement or antiviral therapy. The recurrence rate of initial dendritic infection by herpes simplex (25%) is not influenced by the type of treatment used. Most of the significant complications, such as corneal ulceration (Fig. 19), of herpetic keratitis are related to its tendency to initiate a delayed hypersensitivity type IV reaction, rather than the result of direct infection of the stroma.

By light microscopy, eosinophilic intranuclear inclusions are characteristic of herpes simplex viral infections and represent the result of viral replication (Cowdri type A inclusions).¹²¹ Hypersensitivity type IV reactions in the stroma are characterized by lymphocytic and plasmacytic infiltrates. Intranuclear inclusions are relatively rare and are not found in most specimens. Viral particles occasionally can be found in multinucleated giant cells or within the stroma, especially in keratocytes (Figs. 20 and 21).