The cornea is the principal refractive element of the eye (Fig. 1-8). Its anterior surface is covered by a layer of non-keratinized stratified squamous epithelium five or six cells in thickness. The inconspicuous basement membrane of the epithelium rests on the Bowman membrane, a felt-work of modified stroma. The bulk of the cornea is composed of paucicellular collagenous stroma that contains keratocytes and artifactual clefts. The posterior surface of the cornea is lined by the corneal endothelial cells. This delicate monolayer of cells rests on a thick PAS-positive basement membrane called the Descemet membrane, which it secretes.

The corneal epithelium is derived embryologically from surface ectoderm. The corneal endothelium and stroma are derived from successive waves of migrating neural crest cells.

Developmental anomalies of the cornea include microcornea, defined as <11 mm in greatest diameter, and megalocornea, which is >13 mm. Cornea plana is a bilateral familial trait (autosomal dominant or recessive) characterized by corneal flattening and peripheral opacification. The autosomal recessive variant is caused by mutations in the gene for keratocan. The cornea in sclerocornea resembles sclera. The epithelium is thickened, the Bowman membrane is absent, and the anterior third of the stroma is scarred and vascularized. Solid dermoids and complex choristomas are discussed in Chapter 5.

The Axenfeld-Rieger syndrome is a spectrum of developmental anomalies that affects the peripheral cornea, the iris, and the angle and has associated systemic findings. In the past, the terms angle cleavage syndrome and mesodermal dysgenesis were commonly applied to this disorder. Axenfeld-Rieger syndrome is important because about half of affected patients develop glaucoma. Prominence and anterior displacement of the Schwalbe line into clear cornea, which is called posterior embryotoxon of Axenfeld, occurs in many patients (Fig. 6-1). Processes of iris stroma often bridge the angle and insert onto the posterior embryotoxon (Axenfeld anomaly). Patients may have iris stromal abnormalities including hypoplasia and slit, multiple (polycoria), and false pupils (pseudocoria). Posterior embryotoxon is a common finding in Alagille syndrome (Fig. 6-1D,E).

Axenfeld/Rieger syndrome is inherited as an autosomal dominant trait. Mutations in the FOXC1, PITX2, and RIEG2 genes have been found in the syndrome. Affected patients can have developmental defects of the face (maxillary hypoplasia) and teeth (anodontia, oligodontia, microdontia and peg-like incisors) and redundant periumbilical skin. Shields have postulated that the ocular abnormalities in Axenfeld-Rieger syndrome are consistent with a developmental arrest, occurring late in gestation, of certain anterior ocular structures derived from neural crest.

Congenital corneal opacities occur in Peters anomaly, a developmental anomaly characterized by a concave defect in the central cornea that includes posterior stroma, Descemet membrane, and endothelium (Fig. 6-2). Histopathology shows a central concave defect in the posterior corneal stroma that often contains abnormal thickened lamellae. The endothelium and Descemet membrane are absent within the posterior ulcer, and there is a corresponding area of stromal edema and opacification. The Bowman layer may be thickened or absent. The crystalline lens adheres to or is incarcerated within the posterior ulcer in some cases of Peters anomaly (Fig. 6-2C,D), and iridocorneal adhesions often insert into the periphery of the posterior corneal defect. Peters anomaly can be caused by mutations in PAX6, PITX2, CYP1B1, or FOXC1 genes and also occurs in fetal alcohol syndrome.

This spectrum of developmental anomalies includes the posterior ulcer of von Hippel and posterior keratoconus. A concave defect in the posterior cornea is lined by the Descemet membrane and endothelium in posterior keratoconus. Caused by mutations in the B3GALTL gene, autosomal recessively inherited Peters plus syndrome includes Peters anomaly plus short stature, developmental delay, and lip abnormalities.

About 45% of patients with aniridia develop a progressive keratopathy that has characteristic histopathologic features. Probably related to limbal stem cell (LSC) deficiency, the keratopathy includes conjunctival metaplasia of the corneal epithelium with goblet cells and an inflamed vascularized pannus (Fig. 6-3).

Herpes simplex virus (HSV) keratitis (Fig. 6-9) is the most common corneal infection that causes visual loss in the United States and Europe. Most cases of herpetic keratitis are caused by HSV type I, which causes infection above the waist. The classic clinical manifestation of early ocular herpesvirus infection is dendritic keratitis, a superficial ulcerating infection of the corneal epithelium that has a characteristic branching configuration (Fig. 6-9A). Viral cultures are positive in 75% of cases, and smears show Cowdry type A intranuclear viral inclusions in the infected epithelial cells. The primary epithelial infection tends to be self-limited lasting 7 to 10 days with complete recovery and disappearance of the virus from the primary site of infection. However, recurrences are quite common because the virus remains in a latent state in the trigeminal ganglion where its DNA has been incorporated into the genome of the neurons. Poorly understood trigger mechanisms reactivate the virus, which travels down the sensory nerve to cause overt recurrent disease. One in four cases of primary HSV keratitis recurs. The recurrence rate rises to 50% after an initial recurrence.

A more serious, potentially blinding form of ocular herpesvirus infection affects the corneal stroma. Although the pathogenesis of herpes stromal keratitis is not entirely understood, an immunological response to viral antigens shed from infected corneal epithelial or endothelial cells probably is basis for nonulcerative HSV disciform keratitis. The necrotizing form of HSV stromal keratitis actually may involve viral invasion and low-grade replication in the stroma.

Light microscopy of corneal buttons with chronic herpes stromal keratitis typically reveals scarring and vascularization of the stroma and infiltration by chronic inflammatory cells (Fig. 6-9C). The presence of lymphocytes, plasma cells, and histiocytes in the inflammatory infiltrate in many cases provides evidence for an immunological response. The inflammatory infiltrate frequently includes epithelioid histiocytes. These can occur anywhere in the stroma, but they characteristically coalesce to form giant cells near the Descemet membrane (Fig. 6-9D,E). A giant cell reaction to the Descemet membrane is not pathognomonic for chronic HSV keratitis, but it is highly suggestive. In many cases, there is thinning and scarring of the chronically inflamed cornea with loss of the Bowman membrane and anterior stroma. Progressive stromal loss can lead to corneal perforation in chronic herpetic keratitis. Compensatory hyperplasia of the corneal epithelium is often found in areas of extensive stromal loss (Fig. 6-8F). Viral inclusions are not found light microscopically in the stroma in herpes stromal keratitis. Virions and viral antigens have been detected electron microscopically and immunocytochemically, however.

Varicella-zoster virus (VZV), another member of the herpesvirus family, also causes a dendritic keratitis. Zoster
dendrites lack the rounded terminal bulbs that typically occur at the end of the branches of HSV dendrites and are not full-thickness epithelial ulcerations as HSV dendrites are (Fig. 6-8B).

Focal subepithelial infiltrates occur in the corneas of patients who have epidemic keratoconjunctivitis or EKC, which generally is caused by adenovirus types 8 and 19. The subepithelial infiltrates develop in the later noninfectious
stage of the disease and are thought to be composed of lymphocytes attracted by viral antigens. EKC is often a severe, temporarily incapacitating infection, which is highly contagious. Ophthalmologists should take care to avoid infecting themselves and other patients. Patients with EKC usually have preauricular adenopathy.

In a generic sense, the term interstitial keratitis refers to any nonulcerative inflammation of the corneal stroma. (HSV disciform keratitis is a form of interstitial keratitis). Other causes of stromal or interstitial keratitis include tuberculosis and leprosy; protozoan parasites like Acanthamoeba; onchocercal microfilaria; systemic disorders like sarcoidosis, Hodgkin disease, and mycosis fungoides; foreign bodies such as caterpillar setae and plant material; and drugs including gold and arsenic.

In common parlance, however, the term interstitial keratitis generally connotes the severe stromal keratitis that affects patients with congenital syphilis during the first or second decade. Acute luetic interstitial keratitis is marked clinically by a “salmon patch” of intense stromal vascularization and severe photophobia. Lymphocytes infiltrate the edematous stroma. The late sequelae of old syphilitic interstitial keratitis can be relatively subtle: they include a faint diffuse nebulous opacification of the stroma and residual nonperfused ghost vessels located deep in the corneal stroma (Fig. 6-10A). The ghost vessels are best disclosed by the biomicroscopic technique of sclerotic scatter.

Histopathologically, the Bowman membrane usually is absent. The stroma is free of inflammation, and fine vessels that usually do not contain blood are seen in the posterior third of the stroma, often just anterior to the Descemet membrane (Fig. 6-10B). Part of the stroma may have a rarefied vacuolated appearance and will stain intensely for acid mucopolysaccharide. The Descemet membrane is often thickened and may be studded with irregular guttate excrescences. The thickening of the Descemet membrane may be massive. Relucent strands and networks of basement membrane material are found on the posterior corneal surface in exceptional cases (Fig. 6-10C,D).

Luetic interstitial keratitis occasionally develops in acquired syphilis, in which corneal involvement is typically
unilateral and sectoral. The association of nonluetic interstitial keratitis and vestibuloauditory symptoms is called Cogan syndrome. Cogan syndrome is thought to be an autoimmune disorder.

Protozoan parasites including microsporidians and the freshwater amoebas Acanthamoeba castellanii and A. polyphaga cause unusual corneal infections. Originally reported in patients with HIV/AIDS, microsporidial keratoconjunctivitis has occurred in immunocompetent individuals as well. The parasite can infect the epithelium of the cornea and conjunctiva or the corneal stroma (Fig. 6-11). Extensive interlamellar colonies of microsporidia with scant inflammation reminiscent of infectious crystalline keratopathy are found in some cases. The microsporidial spores are focally birefringent, especially in Gram stains, which helps to differentiate them from yeast and bacteria (Fig. 6-11C).

Acanthamoeba keratitis was initially reported in 1974 and is closely linked to the development and widespread use of soft contact lenses. Acanthamoeba keratitis classically afflicts soft contact lens wearers who use contaminated homemade saline solutions or wear their lenses while swimming or bathing in hot tubs. The keratitis is usually severely painful. Although many cases respond to medical therapy, penetrating keratoplasty (corneal transplantation) may be necessary. The initial stages of Acanthamoeba keratitis can be confused with herpetic keratitis if clinical suspicion is low. A ring or annular infiltrate is a characteristic feature of Acanthamoeba keratitis, but usually develops in
the later stages of the disease. Radial keratoneuritis also is found in some cases (Fig. 6-12 A,B).

Microscopically, Acanthamoeba keratitis is often marked by focal detachment or desquamation of the corneal epithelium. In contrast to bacterial or fungal keratitis, the anterior stroma in many cases contains only a relatively sparse infiltrate of inflammatory cells, mainly polys and macrophages (Fig. 6-12E,F). Stromal necrosis is usually inconspicuous, and stromal vascularization generally is not observed despite a lengthy course that may last months prior to keratoplasty. Amoebic cysts in the stroma and epithelium are readily found in routine hematoxylin and eosin-stained sections or smears (Fig. 6-12C-H). The chitinous walls of the Acanthamoeba cysts are round or oval and stain with PAS, GMS, and Giemsa. The cytoplasm typically retracts from the cyst wall in tissue sections (Fig. 6-12D,G). The cysts contain a small round nucleus with a distinct nucleolus. Trophozoites are usually difficult to identify because they resemble macrophages. Intense stromal keratitis with localized abscess formation and palisading granulomatous inflammation can be observed in the late stages of the disease.

Acanthamoeba keratitis can be diagnosed using corneal smears, biopsies, or confocal microscopy. In smears, the organisms are most readily found within sheets of epithelial cells and are readily detected in sections stained with hematoxylin and eosin, which has been shown to be superior to special stains including calcofluor white (Fig. 6-12H). Previously touted as a diagnostic aid for Acanthamoeba, calcofluor white currently is unavailable in many hospitals. In addition, it is nonspecific, is subject to false positives, and requires an ultraviolet fluorescent microscope. Acanthamoebas are cultured on agar plates overlain with a layer of Escherichia coli. The amebas produce diagnostic linear tracks on the surface of the plates as they graze on the bacteria.

Onchocerciasis is a major cause of blindness in parts of Africa and South and Central America. This infestation by the parasite Onchocerca volvulus is called river blindness because its vector, the black simulium fly, breeds in swift-running mountain streams. Pairs of adult Onchocerca breed in characteristic nodules in the skin of infested individuals. The female worm releases myriad microfilariae that migrate to all parts of the body. Necrotic microfilariae incite focal inflammation. Microfilariae are often found in the corneal stroma where they produce keratitis with a characteristic nummular (coin-shaped) pattern. Secondary closed-angle glaucoma caused by anterior uveitis is a major cause of blindness in endemic areas. Chorioretinal degeneration, also an allergic reaction to the parasite, is another important cause of blindness. Slit-lamp examination may disclose microfilariae in the anterior chamber in heavily infested patients. The tiny worms are photophobic, and they quickly swim behind the iris when the lamp is turned on. Patients are treated by the surgical removal of parasitic nodules, the antihelminthic drug ivermectin and doxycycline. Doxycycline kills Wolbachia bacterial endosymbionts that are required for the survival of Onchocerca microfilariae and for embryogenesis.

Although bacterial and fungal ulcers usually involve the central cornea, a variety of ulcerations affect its periphery. Most important are the peripheral corneal ulcerations that may herald the presence of a systemic vasculitis such as granulomatosis with polyangiitis (Wegener’s), periarteritis nodosa, systemic lupus erythematosus, or rheumatoid arthritis.

A rapidly progressive, painful, ulcerative keratitis, Mooren ulcer begins peripherally and extends across the cornea. The margin of the ulcer has a characteristic
overhanging configuration (Fig. 6-13). Mooren ulcer usually is a unilateral disease of elderly patients in the United States. A severe, bilateral form of the disease affects young individuals in Africa. Some cases have been linked to chronic hepatitis C infection. An autoimmune response to calgranulin, a normally hidden antigen expressed by keratocytes may be involved in the pathogenesis of Mooren ulcer.

Terrien ulcer is a slowly progressive bilateral trough-like thinning of the stroma that begins as superiorly in males. The epithelium remains intact, but the Bowman membrane and the superficial stroma are lost. Vascularization and occasional lymphocytes and plasma cells are found in the ectatic stroma.

Toxins produced by Staphylococci cause infiltrates and superficial ulcerations in the peripheral cornea.

Pterygium (Fig. 6-14) is a degenerative disease of the cornea characterized by a wedge-shaped ingrowth of conjunctival tissue that slowly invades the peripheral cornea. The nasal limbus is usually affected, and both eyes are often involved. The name pterygium reflects the fanciful resemblance of the vascularized ingrowth to the membranous wing of an insect (pter is the Greek word for wing). Pterygium initially is a cosmetic blemish, but it can cause visual loss if it invades the pupillary axis.

Pterygia occur more often in southern latitudes and are twice as common in men who work outdoors and typically have greater UV exposure. Other environmental factors such as wind or dust may play a pathogenic role. Pterygia probably are caused by damage to LSCs by chronic exposure to UV light. Focal LSC deficiency is thought to be an important factor in the transdifferentiation of cornea epithelium into conjunctival-like tissue that invades the cornea. Pterygia arise from the part of the limbal conjunctiva exposed to light in the interpalpebral fissure. A phenomenon called peripheral light focusing may concentrate the UV light on the nasal limbus where the LSCs reside. Presumably, the chronic UV exposure activates and/or mutates LSC resulting in clonal expansion, local cell proliferation, and corneal invasion, or alternatively, the focused UV radiation severely damages or destroys the repository of LSC allowing the conjunctival epithelium to invade the cornea. Small clusters of primitive stem-like cells called Fuchs flecks have been found in the advancing head of some pterygia. These clusters of primitive cells, which are immunoreactive for stem cell markers CK15, CK19, and p63A, might be activated to proliferate, forming an invasive pterygium. As they invade the cornea, the cells use matrix metalloproteinases to dissolve Bowman membrane.

Histopathologically, pterygia resemble an ingrowth of benign conjunctiva onto the periphery of the cornea (Fig. 6-14B). Bowman membrane is absent, and the stroma shows increased vascularity. Actinic elastosis of collagen is often present, but may be relatively inconspicuous or absent in some cases. The epithelium usually resembles conjunctival epithelium. Epithelial hyperplasia and even dysplasia occur rarely. Pterygia should be examined
histopathologically to exclude the possibility of an unsuspected neoplasm. In addition to ocular surface squamous neoplasms, amelanotic melanomas occasionally are misdiagnosed clinically as pterygia. Definitive therapy is surgical removal, often with conjunctival autografts or amnionic membrane grafts.

Calcific band keratopathy is a superficial opacity that extends across the part of the cornea exposed in the interpalpebral fissure (Fig. 6-15). It is caused by calcification of the Bowman membrane and the anterior stroma. A clear interval separates the band of superficial calcification from the limbus, and the opacity usually contains small circular holes. Calcific band keratopathy can complicate chronic uveitis or long-standing glaucoma and also complicates systemic disorders of calcium metabolism including hypercalcemia, vitamin D intoxication, milk-alkali syndrome, hypophosphatemia, and Fanconi syndrome. Histopathology discloses basophilic granules in the Bowman membrane and the superficial stroma. The alizarin red and von Kossa stains for calcium are positive. The chelating agent EDTA is often used to treat calcific band keratopathy. A noncalcific form of band keratopathy related to chronic actinic keratopathy also occurs. The granules are larger and stain positively with the Verhoeff-van Gieson elastic stain.

Chronic actinic keratopathy (Fig. 6-16) and climatic droplet keratopathy are two of many names applied to a degenerative disorder that is marked by the deposition of multiple spherules of yellow hyaline material in the anterior cornea. The disorder is also called spheroidal degeneration and Labrador keratopathy. The degeneration is particularly prevalent in areas where intense glare is reflected from ice (Labrador) or sand (the Dahlak Islands in the Red Sea). Other synonyms such as oleoguttate dystrophy and degeneratio sphaerularis elaoides stress the resemblance of the corneal deposits to droplets of olive oil (Fig. 6-16C). In H&E-stained sections the drop-like deposits
of amorphous hyaline material usually are amphophilic or light gray in color. The material stains intensely with the Verhoeff-van Gieson elastic stain, and the positive reaction is not abolished by pretreatment with elastase, a characteristic it shares with the elastotic degeneration in pinguecula and pterygium. The hyaline deposits autofluoresce under ultraviolet light and are said to behave similarly when illuminated with the slit lamp’s cobalt blue filter. In some cases, tiny globules of hyaline material are concentrated in the Bowman membrane mimicking calcific band keratopathy. Concurrent corneal scarring can severely decrease visual acuity in advanced cases.

Salzmann nodular degeneration was once called Salzmann nodular dystrophy. It is now recognized that this typically unilateral disorder is not heritable and is best classified as a secondary degenerative process of uncertain cause. Clinically, the corneal epithelium is focally elevated by deposits of dense collagenous connective tissue that appear white clinically. Salzmann nodular degeneration resembles a massive focal pannus histopathologically. Mounds of relatively acellular hyaline connective tissue elevate the corneal epithelium anterior to the plane of the Bowman membrane, which may be destroyed.

Lipid deposition occurs in the peripheral corneal stroma in arcus senilis or gerontoxon, a relatively common aging change (Fig. 6-35A). Fat stains performed on frozen sectioned tissue disclose a concurrent deposit in the perilimbal sclera, which is inapparent clinically. Similar corneal deposition in a male less than age forty may signify a hyperlipemic state that can predispose to cardiovascular disease. Lipid keratopathy is a secondary phenomenon caused by lipid deposition in a heavily vascularized stroma.

A corneal keloid is a hypertrophic scar that massively thickens the corneal stroma. Elevated and exposed, the corneal epithelium on the surface of the keloid typically undergoes epidermalization and transforms into opaque skin-like tissue. Large corneal keloids frequently develop in patients who have corneal staphylomas (Fig. 6-17). In such cases, the posterior surface of the cornea is lined by atrophic remnants of iris, mainly iris pigment epithelium. A staphyloma is an ectasia (area of thinning) lined by uveal tissue. The term uveal is derived from the Latin word uva meaning grape. Staphyle means a “bunch of grapes” in Greek. The latter prefix signifies the involvement of uveal tissue. Corneal staphylomas and keloids are common sequelae of keratomalacia and measles keratitis in underdeveloped countries.

The tear film functions as the true anterior surface of the cornea, whose health depends on an adequate supply of properly constituted tears. Disorders of tear production and composition include deficiencies in the aqueous component, the mucinous wetting agent produced by the goblet cells, or abnormalities in the most superficial layer of lipid. Minor degrees of ocular drying are encountered often in clinical practice. If an eye is totally dry, the cornea becomes opaque.

Keratoconjunctivitis sicca is marked by corneal drying, superficial punctate keratopathy (punctate staining), and filamentary keratitis composed of strands of detached corneal epithelium and mucus. Keratoconjunctivitis sicca and xerostomia are characteristic features of the autoimmune disorder Sjögren syndrome. Drying of the mouth and eyes is caused by infiltration and destruction of the acini of the salivary and the main and accessory lacrimal glands by T lymphocytes. Myoepithelial islands persist in the lymphoid infiltrate (lymphoepithelial lesion of Godwin). About 10% of affected patients develop malignant lymphoma.

Corneal epithelial keratinization and epidermalization occur in severe vitamin A deficiency. Patients have xerophthalmia and night blindness caused by deficient rod photopigment. A process of bland corneal melting called keratomalacia frequently leads to corneal perforation (Fig. 6-18). Malnourished children in underdeveloped
countries and vitamin A-deficient alcoholics in the United States are at risk. The Bitot spot, a clinical marker for xerophthalmia, is an elevated dry area of epithelium with a foamy appearance.

A corneal delle (pl. dellen) is a focal area of corneal thinning with superficial surface ulceration, which is located central to an elevated lesion at the limbus. Dellen probably are caused by focal dehydration of the corneal stroma related to deficient focal corneal wetting.

Neurotrophic or neuroparalytic keratopathy is a corneal epitheliopathy that may complicate 5th nerve lesions or corneal hypesthesia caused by herpetic eye disease or herpes zoster ophthalmicus. The keratopathy develops rapidly after surgical sectioning of the trigeminal nerve interrupts poorly understood trophic factors. Patients with neurotrophic or neuroparalytic keratopathy can develop sterile corneal ulcers or melts. Compared to those in infected corneas, the walls and bed of sterile ulcers contain a paucity of inflammatory cells, and there often is extensive loss of keratocytes and faint stromal basophilia as well.

The term pannus is applied to a flat superficial scar of the anterior cornea (Fig. 6-19). Two types of pannus are recognized histopathologically. The paradigmatic inflammatory pannus occurs in trachoma and is marked by a subepithelial ingrowth of inflamed fibrovascular tissue from the limbus, which destroys the Bowman membrane. Degenerative pannus occurs in chronically edematous corneas with bullous keratopathy. Microscopically, a layer of connective tissue is found interposed between the base of the epithelium and the Bowman membrane, which remains intact. In contrast to an inflammatory pannus, the subepithelial scar of degenerative pannus does not necessarily grow in from the limbus. Cells, which probably are stromal fibroblasts, migrate into the space between the Bowman membrane and the detached epithelium and synthesize collagen. This fibrous scar forms the pannus and may alleviate the painful bullous keratopathy at the expense of visual acuity. In rare instances, amyloid is deposited secondarily beneath the epithelium.

Keratoconus is an enigmatic bilateral degenerative disorder characterized by progressive thinning or ectasia of the central stroma that imparts a conical configuration to the cornea (Figs. 6-20 and 6-21). Keratoconus usually presents around puberty with visual loss caused by severe astigmatism. Most cases of keratoconus do not appear to be inherited, but there is a positive family history in 10% of cases and the disease is more prevalent in the first-degree relatives of affected individuals. Most cases are sporadic, however, and there is no evidence of a genetic basis for the disease. Keratoconus can complicate several systemic disorders including trisomy 21, Ehlers-Danlos syndrome, Leber congenital amaurosis, and atopic dermatitis. Keratoconus occurs in ˜5% of patients with Down syndrome and frequently is associated with the acute onset of severe corneal edema called corneal hydrops. Keratoconus in patients with atopic dermatitis, Down syndrome, and Leber congenital amaurosis, an early-onset retinal dystrophy, could

be related to forceful eye rubbing or the oculodigital reflex. The latter is a common behavioral pattern seen in visually and mentally handicapped children who repeatedly strike their eyes with their thumbs in order to mechanically induce flashes of light or phosphenes. However, the incidence of keratoconus is much higher in children blind from Leber congenital amaurosis (29%) compared to other disorders, suggesting that it might be due to genetic factors.

The consistency of the cornea in keratoconus is abnormal; the sectioned cornea almost invariably assumes an irregular wavy configuration on a microslide, which immediately suggests the diagnosis (Fig. 6-20). Higher magnification discloses central or apical thinning of the stroma, which can be reduced to less than one-tenth normal thickness in exceptional cases. Characteristic dehiscences, which typically have a wavy configuration, occur in the Bowman membrane. These probably are pathognomic for keratoconus and serve to confirm the diagnosis histopathologically (Figs. 6-20D and 6-21). Some cases exhibit apical scarring with increased fibroblastic activity and new collagen production. The corneal epithelium usually is intact and irregular in caliber with areas of both thinning and compensatory hyperplasia. The Descemet membrane usually is thin, and the endothelium is well preserved. A rupture in the Descemet membrane is found if acute hydrops has occurred. If the hydrops had resolved prior to corneal transplantation, the gap in Descemet membrane is lined by a thin layer of new Descemet membrane synthesized by endothelial cells that have migrated into the defect. Special stains show iron deposition in the corneal epithelium encircling the cone. This deposit is evident clinically as a Fleischer ring, one of the several eponymic iron lines of the cornea (Fig. 6-20E-G). Other iron lines unassociated with keratoconus include the Hudson-Stähli line (across the low third of the cornea), the Stocker line (in front of a pterygium), and the Ferry line (next to a filtering bleb). The basic defect in keratoconus is uncertain but may be related to abnormal degradation of the corneal extracellular matrix. Abnormal levels of tissue metalloproteinase inhibitors and alcohol dehydrogenase have been identified in some cases.

Pellucid degeneration of the cornea resembles keratoconus histopathologically but is located in the periphery of the cornea

In classic ophthalmic usage, the term dystrophy usually denotes an inherited, relatively symmetric bilateral disease that is slowly progressive, unassociated with vascularization or inflammation in its early stages, and unrelated to environmental or systemic factors. The pathology is or appears to be localized to an ocular tissue. Dystrophies usually are not evident at birth, but become clinically evident later in life. The etymological derivation of the word dystrophy is outdated because it refers to poor nutrition. The term usually is applied to hereditary diseases of the cornea and macula.

Advances in molecular biology have markedly increased our understanding of these rare, interesting disorders. Several corneal dystrophies are now known to be caused by allelic mutations in the gene encoding a single corneal protein. Macular corneal dystrophy (MCD) appears to be the ocular manifestation of an otherwise innocuous systemic enzyme deficiency. Meesmann epithelial dystrophy is caused by an abnormality in the genes for proteins that are only expressed in the corneal epithelium.

In the past, corneal dystrophies were classified anatomically as superficial, stromal, and endothelial based on the location of the clinical and pathologic findings. The second edition of the IC3D Classification of Corneal Dystrophies, published in 2015, incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. This new classification will be continually upgraded in the future as our understanding of molecular genetics increases. The IC3D classification contains a wealth of clinical, pathologic, and genetic information and illustrations and is highly recommended.