Chapter 6. Cornea

The cornea functions both as a protective barrier and as a “window” through which light rays pass to the retina. Its transparency is due to its uniform structure, avascularity, and deturgescence (see Chapter 1). Deturgescence, or the state of relative dehydration of the corneal tissue, is maintained by the bicarbonate “pump” provided by the endothelium and the barrier function of the epithelium and endothelium. The endothelium is more important than the epithelium in the mechanism of dehydration, and damage to the endothelium is far more serious than damage to the epithelium. Destruction of the endothelial cells causes edema of the cornea and loss of transparency, which is more likely to persist because of the limited potential for recovery of endothelial function. Damage to the epithelium usually causes only transient, localized edema of the corneal stroma that clears with the rapid regeneration of epithelial cells. Evaporation of water from the precorneal tear film produces hypertonicity of the film. Together with direct evaporation, this draws water from the superficial corneal stroma in order to maintain the state of dehydration.

Penetration of the intact cornea by drugs is biphasic. Fat-soluble substances can pass through intact epithelium, and water-soluble substances can pass through intact stroma. Therefore, to pass through the cornea, drugs must be soluble in both lipids and water.

Corneal Resistance to Infection

The epithelium is an efficient barrier to the entrance of microorganisms into the cornea. If the epithelium is defective, the avascular stroma and Bowman's layer become susceptible to infection with a variety of organisms, including bacteria, Acanthamoeba, and fungi. Streptococcus pneumoniae (the pneumococcus) is a true bacterial corneal pathogen; other pathogens require a heavy inoculum, compromised barrier function, or a relative immune deficiency to produce infection.

Moraxella liquefaciens, which occurs mainly in alcoholics (as a result of pyridoxine depletion), is a classic example of the bacterial opportunist, and in recent years a number of new corneal opportunists have been identified. Among them are Serratia marcescens, Mycobacterium fortuitum-chelonei complex, viridans streptococci, Staphylococcus epidermidis, and various coliform and proteus organisms, along with viruses, Acanthamoeba, and fungi.

Local or systemic corticosteroids modify the host immune reaction in several ways and may allow opportunistic organisms to invade and flourish.

Physiology of Symptoms

Since the cornea has many pain fibers, most superficial or deep corneal lesions cause pain and photophobia. The pain of epithelial disease is worsened by movement of the lids (particularly the upper lid) over the cornea and usually persists until healing occurs. Since the cornea serves as the “window” of the eye and refracts light rays, corneal lesions usually blur vision, especially if centrally located.

Photophobia in corneal disease is the result of painful contraction of an inflamed iris. Dilation of iris vessels is a reflex phenomenon caused by irritation of the corneal nerve endings. Photophobia, severe in most corneal disease, is minimal in herpetic keratitis because of the hypesthesia associated with the disease, which can be a valuable diagnostic sign.

Although tearing and photophobia commonly accompany corneal disease, there is usually no discharge except in purulent bacterial ulcers.

Investigation of Corneal Disease

Symptoms & Signs

Obtaining a thorough history is important. A history of trauma can often be elicited, foreign bodies and abrasions being the two most common corneal lesions, and eliciting any history of corneal disease in the patient or the family can be critical. The keratitis of herpes simplex infection is often recurrent, but since recurrent erosion is extremely painful and herpetic keratitis is not, these disorders can be differentiated by their symptoms. The patient's use of topical medications should be investigated, since corticosteroids may have been used and may have predisposed to bacterial, fungal, or viral disease, especially herpes simplex keratitis. Immuno-suppression also occurs with systemic diseases, such as diabetes, AIDS, and malignant disease, as well as with specific immunosuppressive therapy. All medications and preservatives can cause contact dermatitis or corneal toxicity; the importance of toxicity as a cause of corneal and conjunctival disease should not be underestimated.

The keys to examination of the cornea are adequate illumination and magnification. The slitlamp is essential in proper examination of the cornea; in its absence, a loupe and bright illumination can be used for gross inspection. Examining the light reflection, while moving the light carefully over the entire cornea, will identify rough areas indicative of epithelial defects. Fluorescein staining can highlight superficial epithelial lesions that might otherwise not be apparent. Examination, particularly after trauma, is often facilitated by instillation of a local anesthetic, but sterile drops must be used. Confocal microscopy assists diagnosis, particularly in suspected Acanthamoeba or fungal infection.

Laboratory Studies

To select the proper therapy for corneal infections, especially due to bacteria, fungi, or Acanthamoeba laboratory aid is essential. Since a delay in identifying the correct organism may severely compromise the ultimate visual result, it should be achieved as soon as possible. Examination of corneal scrapings, stained with Gram's and Giemsa's stains, may allow identification of the organism, particularly bacteria, while the patient waits. Polymerase chain reaction (PCR) may provide rapid identification of herpes viruses, Acanthamoeba, and fungi. Cultures for bacteria are usually obtained in all cases at first presentation. Cultures for fungi, Acanthamoeba, or viruses may be undertaken if the clinical features are typical or there is lack of response to treatment for bacterial infection. Appropriate therapy is instituted as soon as the necessary specimens have been obtained. It is important that therapy is not withheld if an organism cannot be identified on microscopic examination of corneal scrapings, although it may have to be empirical based upon the clinical features.

Morphologic Diagnosis of Corneal Lesions

Epithelial Keratitis

The corneal epithelium is involved in most types of conjunctivitis and keratitis and in rare cases may be the only tissue involved (eg, in superficial punctate keratitis). The epithelial changes vary widely from simple edema and vacuolation to minute erosions, filament formation, partial keratinization, etc. The lesions vary also in their location on the cornea. All of these features have important diagnostic significance (Figure 6–1), and slitlamp examination with and without fluorescein staining should be a part of every external eye examination.

Subepithelial Keratitis

There are a number of important types of discrete subepithelial lesions, often secondary to epithelial keratitis (eg, the subepithelial infiltrates of epidemic keratoconjunctivitis, caused by adenoviruses 8 and 19).

Stromal Keratitis

The responses of the corneal stroma to disease include infiltration, representing accumulation of inflammatory cells; edema manifested as corneal thickening, opacification, or scarring; “melting” or necrosis, which may lead to thinning or perforation; and vascularization. The patterns of these responses are less specific for disease entities than those seen in epithelial keratitis, and the clinician often must rely on other clinical information and laboratory studies for clear identification of causes.

Endothelial Keratitis

Dysfunction of the corneal endothelium results in corneal edema, initially involving the stroma and later the epithelium. Stromal edema often produces “folds” or “wrinkles” in Descemet's membrane. This contrasts with corneal edema due to raised intraocular pressure, in which the epithelium is affected before the stroma. As long as the cornea is not too edematous, it is often possible to visualize morphologic abnormalities of the corneal endothelium with the slitlamp. Inflammatory cells on the endothelium (keratic precipitates or “KPs”) are less commonly an indication of endothelial disease, when they are usually localized, than due to anterior uveitis, which may or may not accompany stromal keratitis, when they tend to be more generally distributed.

Cicatrization due to corneal ulceration is a major cause of blindness and impaired vision throughout the world (see Chapter 20). Most of this visual loss is avoidable by early diagnosis and prompt appropriate treatment, but also by minimizing predisposing factors.

Infectious Corneal Ulcers

Central ulcers usually are infectious ulcers secondary to corneal epithelial damage. The lesion is situated centrally, away from the vascularized limbus. It is often accompanied by hypopyon, a collection of inflammatory cells seen as a pale layer in the inferior anterior chamber that also occurs in severe anterior uveitis (see Chapter 7). Although hypopyon is sterile in bacterial corneal ulcers unless there has been a rupture of Descemet's membrane, in fungal ulcers it may contain fungal elements.

Central suppurative ulceration was once caused almost exclusively by S pneumoniae infection complicating corneal trauma, particularly occurring in patients with obstructed nasolacrimal ducts. The commonest predisposing factor in developed countries has become contact lens wear, being particularly associated with Pseudomonas and Acanthamoeba keratitis. More widespread use of compromising systemic and local medications has increased the incidence of corneal ulcers due to opportunistic bacteria, fungi, and viruses.

Bacterial Keratitis

Many types of bacterial corneal ulcers look alike and vary only in severity. This is especially true of ulcers caused by opportunistic bacteria (eg, alpha-hemolytic streptococci, Staphylococcus aureus, S epidermidis, Nocardia, and M fortuitum-chelonei), which often cause indolent corneal ulcers that tend to spread slowly and superficially.

Streptococcus Pneumoniae (Pneumococcal) Corneal Ulcer (Figure 6–2)

Pneumococcal corneal ulcer usually manifests 24–48 hours after inoculation of an abraded cornea. It typically produces a gray, fairly well-circumscribed ulcer that tends to spread erratically from the original site of infection toward the center of the cornea. The advancing border shows active ulceration and infiltration as the trailing border begins to heal. (This creeping effect gave rise to the term “acute serpiginous ulcer.”) The superficial corneal layers become involved first, and then the deep parenchyma. The cornea surrounding the ulcer is often clear. Hypopyon is common. Scrapings from the leading edge of a pneumococcal corneal ulcer usually contain gram-positive lancet-shaped diplococci. Drugs recommended for use in treatment are listed in Tables 6–1 and 6–2. Concurrent dacryocystitis and nasolacrimal duct obstruction should also be treated.

Pseudomonas Aeruginosa Corneal Ulcer

Pseudomonas corneal ulcer begins as a gray or yellow infiltrate at the site of a break in the corneal epithelium (Figure 6–3). Severe pain is common. The lesion tends to spread rapidly in all directions because of the proteolytic enzymes produced by the organisms. Although superficial at first, the ulcer may quickly affect the entire cornea with devastating consequences, including corneal perforation and severe intraocular infection. There is often a large hypopyon that tends to increase in size as the ulcer progresses. The infiltrate and exudate may have a bluish-green color. This is due to a pigment produced by the organism and is pathognomonic of P aeruginosa infection.

Today, especially in developed countries, Pseudomonas corneal infection often is associated with soft contact lenses—especially extended-wear lenses. The organism has been shown to adhere to the surface of soft contact lenses. Some cases have been reported following the use of contaminated fluorescein solution or eye drops. It is mandatory that the clinician use sterile medications and sterile technique when caring for patients with corneal injuries.

Scrapings from the ulcer may contain long, thin Gram-negative rods that are often few in number. Drugs recommended for use in treatment are listed in Tables 6–1 and 6–2.

Moraxella Liquefaciens Corneal Ulcer

M liquefaciens (diplobacillus of Petit) causes an indolent oval ulcer that usually affects the inferior cornea and progresses into the deep stroma over a period of days. There is usually no hypopyon or only a small one, and the surrounding cornea is usually clear. M liquefaciens ulcer often occurs in a patient with alcoholism, diabetes mellitus, or other causes of immunosuppression. Scrapings may contain large, square-ended Gram-negative diplobacilli. Drugs recommended for use in treatment are listed in Tables 6–1 and 6–2. Treatment can be difficult and prolonged.

Group a Streptococcus Corneal Ulcer

Central corneal ulcers caused by beta-hemolytic streptococci have no identifying features. The surrounding corneal stroma is often infiltrated and edematous, and there is usually a moderately large hypopyon. Scrapings often contain gram-positive cocci in chains. Drugs recommended for use in treatment are listed in Tables 6–1 and 6–2.

Staphylococcus Aureus, Staphylococcus Epidermidis, & Alpha-Hemolytic Streptococcus Corneal Ulcers

Central corneal ulcers caused by these organisms are now being seen more often, many of them in corneas compromised by topical corticosteroid use. The ulcers are often indolent, but may be associated with hypopyon and some surrounding corneal infiltration. They are often superficial, and the ulcer bed feels firm when scraped. Scrapings may contain Gram-positive cocci—singly, in pairs, or in chains. Infectious crystalline keratopathy (in which the cornea has a crystalline appearance) has been described in patients receiving long-term therapy with topical corticosteroids; the disease is often caused by alpha-hemolytic streptococci as well as nutritionally deficient streptococci. Tables 6–1 and 6–2 show recommended drug regimens.

Mycobacterium Fortuitum-Chelonei & Nocardia Corneal Ulcers

Ulcers due to M fortuitum-chelonei and Nocardia are rare. They often follow trauma and are often associated with contact with soil. The ulcers are indolent, and the bed of the ulcer often has radiating lines that make it look like a cracked windshield. Hypopyon may or may not be present. Scrapings may contain acid-fast slender rods (M fortuitum-chelonei) or gram-positive filamentous, often branching organisms (Nocardia). See Tables 6–1 and 6–2 for recommended drug regimens.

Fungal Keratitis

Fungal corneal ulcers once were seen only in agricultural settings, but with the advent of contact lenses, immunosuppressive disease and corticosteroid use, these infections are seen in a variety of populations. The use of corticosteroids is not indicated in fungal disease; by altering the natural immune response and enhancing collagenase activity, these drugs are counterproductive.

Fungal ulcers are indolent and have a gray infiltrate with irregular edges, often a hypopyon, marked inflammation of the globe, superficial ulceration, and satellite lesions (usually infiltrates at sites distant from the main area of ulceration) (Figure 6–4). Underlying the principal lesion—and the satellite lesions as well—there is often an endothelial plaque associated with a severe anterior chamber reaction. Corneal abscesses frequently occur.

Most fungal ulcers are caused by opportunists such as Candida, Fusarium, Aspergillus, Penicillium, Cephalosporium, and others. There are no identifying features that help to differentiate one type of fungal ulcer from another.

Scrapings from fungal corneal ulcers, except those caused by Candida, contain hyphal elements; scrapings from Candida ulcers usually contain pseudohyphae or yeast forms that show characteristic budding. Tables 6–1 and 6–2 list the drugs recommended for the treatment of fungal ulcers.

Viral Keratitis

Herpes Simplex Keratitis

Herpes simplex keratitis occurs in two forms: primary and recurrent. It is the most common cause of both corneal ulceration and corneal blindness in the United States. The epithelial form is the ocular counterpart of labial herpes, with which it shares immunologic and pathologic features as well as having a similar time course. The only difference is that the clinical course of the keratitis may be prolonged because of the avascularity of the corneal stroma, which retards the migration of lymphocytes and macrophages to the lesion. Herpes simplex virus (HSV) ocular infection in the immunocompetent host is often self-limited, but in the immunologically compromised host, including patients treated with topical corticosteroids, its course can be chronic and damaging. Stromal and endothelial disease has previously been thought to be a purely immunologic response to virus particles or virally induced cellular changes. However, there is increasing evidence that active viral infection can occur within stromal and possibly endothelial cells as well as in other tissues within the anterior segment, such as the iris and trabecular endothelium. This highlights the need to assess the relative role of viral replication and host immune responses prior to and during therapy for herpetic disease. Topical corticosteroids may control damaging inflammatory responses but at the expense of facilitation of viral replication. Thus, whenever topical corticosteroids are to be used, antivirals are likely to be necessary. Any patient undergoing topical corticosteroid therapy for herpetic eye disease must be under the supervision of an ophthalmologist.

Serologic studies suggest that most adults have been exposed to the virus, although many do not recollect any episodes of clinical disease. Following primary infection, the virus establishes latency in the trigeminal ganglion. The factors influencing the development of recurrent disease, including its site, have yet to be unraveled. There is increasing evidence that the severity of disease is at least partly determined by the strain of virus involved. Most HSV infections of the cornea are still caused by HSV type 1 (the cause of labial herpes), but in both infants and adults, a few cases caused by HSV type 2 (the cause of genital herpes) have been reported. The corneal lesions caused by the two types are indistinguishable.

Scrapings of the epithelial lesions of HSV keratitis and fluid from skin lesions contain multinucleated giant cells. The virus can be cultivated on the chorioallantoic membrane of embryonated hens' eggs and in many tissue cell lines—for example, HeLa cells, on which it produces characteristic plaques. In most cases, however, diagnosis can be made clinically on the basis of characteristic dendritic or geographic ulcers and greatly reduced or absent corneal sensation. PCR methods are used for accurate identification of HSV from tissue and fluid as well as from corneal epithelial cells.

Clinical Findings

Primary ocular herpes simplex is infrequently seen, but manifests as a vesicular blepharoconjunctivitis, occasionally with corneal involvement, and usually occurs in young children. It is generally self-limited, without causing significant ocular damage. Topical antiviral therapy may be used as prophylaxis against corneal involvement and as therapy for corneal disease.

Attacks of the common recurrent type of herpetic keratitis (Figure 6–5) are triggered by fever, overexposure to ultraviolet light, trauma, the onset of menstruation, or some other local or systemic source of immunosuppression. Unilaterality is the rule, but bilateral lesions develop in 4%–6% of cases and are seen most often in atopic patients.

1. Symptoms— The first symptoms of an HSV infection are usually irritation, photophobia, and tearing. When the central cornea is affected, there is also some reduction in vision. Since corneal anesthesia usually occurs early in the course of the infection, the symptoms may be minimal and the patient may not seek medical advice. There is often a history of fever blisters or other herpetic infection, but corneal ulceration can occasionally be the only sign of a recurrent herpetic infection.

2. Lesions— The most characteristic lesion is the dendritic ulcer, which occurs in the corneal epithelium, has a typical branching, linear pattern with feathery edges, and has terminal bulbs at its ends (Figure 6–6). Fluorescein staining makes the dendrite easy to identify, but unfortunately herpetic keratitis can also simulate many corneal infections and must be considered in the differential diagnosis of many corneal lesions.

Geographic ulceration is a form of chronic dendritic disease in which the delicate dendritic lesion takes a broader form. The edges of the ulcer lose their feathery quality. Corneal sensation, as with dendritic disease, is diminished. The clinician should always test for this sign.

Other corneal epithelial lesions that may be caused by HSV are a blotchy epithelial keratitis, stellate epithelial keratitis, and filamentary keratitis. All of these are usually transitory, however, and often become typical dendrites within a day or two.

Subepithelial opacities can be caused by HSV infection. A ghost-like image, corresponding in shape to the original epithelial defect but slightly larger, can be seen in the area immediately underlying the epithelial lesion. The “ghost” remains superficial but is often enhanced by the use of antiviral drugs, especially idoxuridine. As a rule, these subepithelial lesions do not persist for more than a year.

Disciform keratitis is the most common form of stromal disease in HSV infection. The stroma is edematous in a central, disk-shaped area, without significant infiltration and usually without vascularization. The edema may be sufficient to produce folds in Descemet's membrane. Keratic precipitates may lie directly under the disciform lesion but may also involve the entire endothelium because of the frequently associated anterior uveitis. The pathogenesis of disciform keratitis is generally regarded as an immunologic reaction to viral antigens in the stroma or endothelium, but active viral disease cannot be ruled out. Like most herpetic lesions in immunocompetent individuals, disciform keratitis is normally self-limited, lasting weeks to months. Edema is the most prominent sign, and healing can occur with minimal scarring and vascularization. A similar clinical appearance is seen with primary endothelial keratitis (endothelitis), which can be associated with anterior uveitis together with raised intraocular pressure and a focal inflammation of the iris. This is thought to be due to viral replication within the various anterior chamber structures.

Stromal HSV keratitis in the form of focal areas of infiltration and edema, often accompanied by vascularization, is likely to be predominantly due to viral replication. Corneal thinning, necrosis, and perforation may develop rapidly, particularly if topical corticosteroids are being used. If there is stromal disease in the presence of epithelial ulceration, it may be difficult to differentiate bacterial or fungal superinfection from herpetic disease. The features of the epithelial disease need to be carefully scrutinized for herpetic characteristics, but a bacterial or fungal component may be present and the patient must be managed accordingly. Stromal necrosis also may be caused by an acute immune reaction, again complicating the diagnosis with regard to active viral disease. Hypopyon may be seen with necrosis as well as secondary bacterial or fungal infection.

Peripheral lesions of the cornea can also be caused by HSV. They are usually linear and show a loss of epithelium before the underlying corneal stroma becomes infiltrated. (This is in contrast to the marginal ulcer associated with bacterial hypersensitivity, for example, to S aureus in staphylococcal blepharitis, in which the infiltration precedes the loss of the overlying epithelium.) Separation of the two disorders is important since the treatment of marginal immune ulcers can include use of corticosteroids, a medication not indicated the treatment of active viral infection. Testing for corneal sensation is unreliable in peripheral herpetic disease. The patient is apt to be far less photophobic than a patient with nonherpetic corneal disease.

Treatment

The treatment of HSV keratitis should be directed at eliminating viral replication within the cornea while minimizing the damaging effects of the inflammatory response.

1. Debridement— An effective way to treat dendritic keratitis is epithelial debridement, since the virus is located in the epithelium and debridement will also reduce the viral antigenic load to the corneal stroma. Healthy epithelium adheres tightly to the cornea, but infected epithelium is easy to remove. Debridement is accomplished with a tightly wound cotton-tipped applicator. A cycloplegic/mydriatic agent such as homatropine 5% is then instilled into the conjunctival sac, and a pressure dressing is applied. The patient should be examined daily and the dressing changed until the corneal defect has healed, usually within 72 hours. Adjunctive therapy with a topical antiviral accelerates epithelial healing. Topical drug therapy without epithelial debridement for epithelial keratitis offers the advantage of not requiring patching but involves a hazard of drug toxicity.

2. Drug therapy—The topical antiviral agents used in herpetic keratitis are idoxuridine, trifluridine, vidarabine, ganciclovir, and acyclovir. (Topical acyclovir for ophthalmic use is not approved in the United States.) Ganciclovir and acyclovir are much more effective in stromal disease than the others. Idoxuridine and trifluridine are frequently associated with toxic epitheliopathy. Oral antivirals like acyclovir are of critical importance in the treatment of herpetic eye disease, particularly in atopic individuals who are susceptible to aggressive ocular and dermal (eczema herpeticum) herpetic disease. Dosage for active disease is 400 mg five times daily in nonimmunocompromised patients and 800 mg five times daily in compromised and atopic patients. Prophylactic dosage in recurrent disease is 400 mg twice daily. Famciclovir or valacyclovir may also be used.

   Viral replication in the immunocompetent patient, particularly when confined to the corneal epithelium, usually is self-limited and scarring is minimal. It is thus unnecessary and potentially highly damaging to use topical corticosteroids. Regrettably, particularly when there is stromal disease, concerns about permanent scarring due to the corneal inflammation often result in the use of topical corticosteroids, but this is based on the misconception that reducing inflammation reduces disease severity. Even when the inflammatory response is thought to be purely immunologically driven, such as in disciform keratitis, topical corticosteroids are often best avoided if the episode is likely to be self-limited. Once topical corticosteroids have been used, this usually commits the patient to requiring the drug to control further episodes of keratitis, with the potential for uncontrolled viral replication and other steroid-related side effects, such as bacterial and fungal superinfection, glaucoma, and cataract. Topical corticosteroids may also accelerate corneal thinning, thus increasing the risk of corneal perforation. If it becomes necessary to use topical corticosteroids because of the severity of the inflammatory response, it is absolutely essential that appropriate antiviral therapy be used to control viral replication. Problems in the management of HSV keratitis are often due to inappropriate use of multiple topical treatments, including antivirals, antibiotics, and corticosteroids, resulting in adverse effects including epithelial toxicity. Frequently, using oral antivirals and tapering the corticosteroids will result in marked improvement.

3. Surgical treatment— Penetrating keratoplasty may be indicated for visual rehabilitation in patients with severe corneal scarring, but it should not be undertaken until the herpetic disease has been inactive for many months. Postoperatively, recurrent herpetic infection may occur as a result of the surgical trauma and the topical corticosteroids necessary to prevent corneal graft rejection. It may also be difficult to distinguish corneal graft rejection from recurrent stromal disease. Systemic antiviral agents should be used for several months after keratoplasty to cover the use of topical corticosteroids.

   Corneal perforation due to progressive herpetic stromal disease or superinfection with bacteria or fungi may necessitate emergency penetrating keratoplasty. Cyanoacrylate glue can be used to seal a small perforation (Figure 6–7), and lamellar “patch” grafts have been successful in selected cases. Lamellar keratoplasty has the advantage over penetrating keratoplasty of reduced potential for corneal graft rejection. A therapeutic soft contact lens, tarsorrhapy, or amniotic membrane may be required to heal persistent epithelial defects in HSV keratitis.

4. Control of trigger mechanisms that reactivate HSV infection—Recurrent HSV infections of the eye are common, occurring in about one-third of cases within 2 years after the first attack. A trigger mechanism can often be discovered by careful questioning of the patient. Once identified, the trigger can often be avoided. Aspirin can be used to avoid fever, excessive exposure to the sun or ultraviolet light can be avoided, and aspirin can be taken just prior to the onset of menstruation.

Varicella-Zoster Viral Keratitis

Varicella-zoster virus (VZV) infection occurs in two forms: primary (varicella) and recurrent (herpes zoster). Ocular manifestations are uncommon in varicella but common in ophthalmic zoster. In varicella (chicken-pox), the usual eye lesions are pocks on the lids and lid margins. Rarely, keratitis occurs (typically a peripheral stromal lesion with vascularization), and still more rarely, epithelial keratitis occurs with or without pseudodendrites. Disciform keratitis, with uveitis of varying duration, has been reported.

In contrast to the rare and benign corneal lesions of varicella, the relatively frequent ophthalmic herpes zoster is often accompanied by keratouveitis that varies in severity according to the immune status of the patient. Thus, although children with zoster keratouveitis usually have benign disease, the aged have severe and sometimes blinding disease. Corneal complications in ophthalmic zoster often occur if there is a skin eruption in areas supplied by the branches of the nasociliary nerve.

Unlike recurrent HSV keratitis that usually affects only the epithelium, VZV keratitis affects the stroma and anterior uvea at onset. The epithelial lesions are blotchy and amorphous except for an occasional linear pseudodendrite that only vaguely resembles the true dendrites of HSV keratitis. Stromal opacities consist of edema and mild cellular infiltration and initially are subepithelial. Deep stromal disease can follow with necrosis and vascularization (Figure 6–8). A disciform keratitis sometimes develops and resembles HSV disciform keratitis. Loss of corneal sensation, with the risk of neurotrophic keratitis (see later), is always a prominent feature and often persists for months after the corneal lesion appears to have healed. The associated uveitis tends to persist for weeks or months, but with time it eventually heals. Scleritis (sclerokeratitis) can be a serious feature of VZV ocular disease.

Intravenous and oral antivirals have been used successfully for the treatment of herpes zoster ophthalmicus, particularly in immunocompromised patients. The oral dosage for acyclovir is 800 mg five times daily for 10–14 days; for valacyclovir, 1 g three times daily for 7–10 days; for famciclovir, 500 mg every 8 hours for 7–10 days. Therapy needs to be started within 72 hours after appearance of the rash. The role of topical antivirals is less certain. Topical corticosteroids may be necessary to treat severe keratitis, uveitis, and secondary glaucoma. The use of systemic corticosteroids is controversial. They may be indicated in reducing the incidence and severity of postherpetic neuralgia, but the risk of steroid complications is significant. Unfortunately, systemic acyclovir has little influence on the development of postherpetic neuralgia. However, the condition is self-limited, and reassurance can be helpful as a supplement to analgesics. Patients with facial and scalp lesions should be seen for several months after the skin lesions arise because the onset of keratitis can be delayed.

Acanthamoeba Keratitis

Acanthamoeba is a free-living protozoan that thrives in polluted water containing bacteria and organic material. Corneal infection with Acanthamoeba is usually associated with soft contact lens wear, including silicone hydrogel lenses, or overnight wear of rigid (gas-permeable) contact lenses to correct refractive errors (orthokeratology). There have been cases associated with a particular contact lens solution, probably related to insufficient anti-Acanthamoeba efficacy. It may also occur in non–contact lens wearers after exposure to contaminated water or soil.

The initial symptoms are pain out of proportion to the clinical findings, redness, and photophobia. The characteristic clinical signs are indolent corneal ulceration, a stromal ring, and perineural infiltrates, but patients often present with changes confined to the corneal epithelium.

The diagnosis is established by culturing on specially prepared media (non-nutrient agar with an overlay of E scherichia coli). Better results are obtained by corneal biopsy than corneal scraping, since histopathologic examination for amebic forms (trophozoites or cysts) can also be undertaken. Impression cytology and confocal microscopy are newer diagnostic techniques. Contact lens cases and solutions should be cultured. Often the amebic forms can be identified in the contact lens case fluid.

The differential diagnosis includes herpetic keratitis, with which it is frequently confused, fungal keratitis, mycobacterial keratitis, and Nocardia infection of the cornea.

In the early stages of the disease, epithelial debridement may be beneficial. Medical treatment is usually started with intensive topical propamidine isethionate (1% solution) and either polyhexamethylene biguanide (0.01%–0.02% solution) or fortified neomycin eyedrops (Tables 6–1 and 6–2). Acanthamoeba species may have variable drug sensitivities and may acquire drug resistance. Treatment is also hampered by the organisms' ability to encyst within the corneal stroma, necessitating prolonged treatment. Corticosteroids are not indicated in the treatment of Acanthamoeba corneal disease unless required to control severe inflammation.

Keratoplasty may be necessary in advanced disease to arrest progression of the infection or after resolution and scarring to restore vision. Amniotic membrane transplants may be helpful for persistent epithelial defects. If the organism reaches the sclera, medical and surgical treatments are usually fruitless.

Noninfectious Corneal Ulcers

Marginal Infiltrates & Ulcers

The majority of marginal corneal ulcers are benign but extremely painful. They are secondary to acute or chronic bacterial conjunctivitis, particularly staphylococcal blepharoconjunctivitis and less often Koch-Weeks (Haemophilus aegyptius) conjunctivitis. They are not an infectious process, however, and scrapings do not contain the causal bacteria. They are the result of sensitization to bacterial products, antibody from the limbal vessels reacting with antigen that has diffused through the corneal epithelium.

Marginal infiltrates and ulcers (Figure 6–9) start as oval or linear infiltrates, separated from the limbus by a lucid interval, and only later may ulcerate and vascularize. They are self-limited, usually lasting from 7 to 10 days, but those associated with staphylococcal blepharoconjunctivitis usually recur. Treatment for blepharitis (shampoo scrubs, antimicrobials) usually will clear the problem; topical corticosteroids may be needed for severe cases. Topical corticosteroid preparations shorten their course and relieve symptoms, which are often severe, but treatment of the underlying blepharoconjunctivitis is essential if recurrences are to be prevented. Before starting corticosteroid therapy, great care must be taken to distinguish this entity from marginal herpetic keratitis. Marginal herpetic keratitis is usually almost symptomless because of corneal anesthesia, whereas hypersensitivity-type marginal ulcer is painful.

Mooren's Ulcer (Figure 6–10)

The cause of Mooren's ulcer is still unknown, but an autoimmune origin is suspected. It is a marginal ulcer, unilateral in 60%–80% of cases and characterized by painful, progressive excavation of the limbus and peripheral cornea that often leads to loss of the eye. It occurs most commonly in old age but does not seem to be related to any of the systemic diseases that most often afflict the aged. It is unresponsive to both antibiotics and topical corticosteroids. Surgical excision of the limbal conjunctiva in an effort to remove sensitizing substances has recently been advocated. Lamellar tectonic keratoplasty has been used with success in selected cases. Systemic immunosuppressive therapy often is necessary to control moderate or advanced disease.

Phlyctenular Keratoconjunctivitis

Phlyctenules are localized accumulations of lymphocytes, monocytes, macrophages, and also neutrophils. They appear first at the limbus, but in recurrent attacks they may involve the bulbar conjunctiva and cornea. Corneal phlyctenules, often bilateral, cicatrize and vascularize, but conjunctival phlyctenules leave no trace.

Phlyctenular keratoconjunctivitis is a delayed hypersensitivity response, in most cases in developed countries to S aureus or other bacteria that proliferate on the lid margin in association with blepharitis. It may also occur in response to Mycobacterium tuberculosis, which was formerly a major cause of visual loss in the United States, particularly among Native Americans. The attack may be triggered by an acute bacterial conjunctivitis but is associated typically with a transient increase in the activity of childhood tuberculosis. Phlyctenules, rarely causing visual disability, also occur in San Joaquin Valley fever, a result of hypersensitivity to a primary infection with Coccidioides immitis.

Untreated phlyctenules spontaneously regress after 10–14 days. Topical corticosteroid therapy shortens their duration and decreases scarring and vascularization. In the staphylococcal type, the acute staphylococcal infection and chronic blepharitis need to be treated.

Marginal Keratitis in Autoimmune Disease (Figure 6–11)

The peripheral cornea receives its nourishment from the aqueous humor, the limbal capillaries, and the tear film. It is contiguous with the subconjunctival lymphoid tissue and the lymphatic arcades at the limbus. The perilimbal conjunctiva appears to play an important role in the pathogenesis of corneal lesions that arise both from local ocular disease and from systemic disorders, particularly those of autoimmune origin. There is a striking similarity between the limbal capillary network and the renal glomerular capillary network. On the endothelial basement membranes of the capillaries of both networks, immune complexes are deposited and immunologic disease results. Thus, the peripheral cornea often participates in such autoimmune diseases as rheumatoid arthritis, polyarteritis nodosa, systemic lupus erythematosus, scleroderma, midline lethal and Wegener's granulomatosis, ulcerative colitis, Crohn's disease, and relapsing polychondritis. The corneal changes are secondary to scleral inflammation, with or without scleral vascular closure (see Chapter 7). The clinical signs include vascularization, infiltration and opacification, and peripheral guttering that may progress to perforation. Mooren's ulcer may be an example of advanced marginal keratitis. Treatment is directed toward control of the associated systemic disease; topical therapy usually is ineffective, and systemic use of potent immunosuppressive drugs often is required. Corneal perforation may require cyanoacrylate glue (Figure 6–7), lamellar patch grafting, or a full-thickness keratoplasty.

Corneal Ulcer Due to Vitamin A Deficiency

The typical corneal ulcer associated with avitaminosis A is centrally located and bilateral, gray and indolent, with a definite lack of corneal luster in the surrounding area (Figure 6–12). The cornea becomes soft and necrotic (hence the term “keratomalacia”), and perforation is common. The epithelium of the conjunctiva is keratinized, as evidenced by the presence of a Bitot's spot. This is a foamy, wedge-shaped area in the conjunctiva, usually on the temporal side, with the base of the wedge at the limbus and the apex extending toward the lateral canthus. Within the triangle the conjunctiva is furrowed concentrically with the limbus, and dry flaky material can be seen falling from the area into the inferior cul-de-sac. A stained conjunctival scraping from a Bitot's spot will show many saprophytic xerosis bacilli (Corynebacterium xerosis; small curved rods) and keratinized epithelial cells.

Avitaminosis A corneal ulceration results from dietary lack of vitamin A or impaired absorption from the gastrointestinal tract and impaired utilization by the body. It may develop in an infant who has a feeding problem; in an adult who is on a restricted or generally inadequate diet; or in any person with a biliary obstruction, since bile in the gastrointestinal tract is necessary for the absorption of vitamin A, or other causes of mal-absorption. Lack of vitamin A causes a generalized keratinization of the epithelium throughout the body. The conjunctival and corneal changes together are known as xerophthalmia. Since the epithelium of the air passages is affected, many patients, if not treated, will die of pneumonia. Avitaminosis A also causes a generalized retardation of osseous growth. This is extremely important in infants; for example, if the skull bones do not grow and the brain continues to grow, increased intracranial pressure and papilledema can result.

Mild vitamin A deficiency should be treated in adults with a dose of 30,000 U/d for 1 week. Advanced cases will require much higher doses initially (20,000 U/kg/d). Sulfonamide or antibiotic ointment can be used locally in the eye to prevent secondary bacterial infection. The average daily requirement of vitamin A is 1500–5000 IU for children, according to age, and 5000 IU for adults. Highly pigmented vegetables are the best source of dietary vitamin A.

Neurotrophic Keratitis

Trigeminal nerve dysfunction, due to trauma, surgery, tumor, inflammation, or any other cause, may result in corneal anesthesia with loss of the blink reflex, one of the cornea's defense mechanisms, as well as lack of trophic factors important for epithelial function. In the early stages of neurotrophic keratitis, there is diffuse blotchy epithelial edema. Subsequently there is loss of the epithelium (neurotrophic ulcer), which may extend over a large area of the cornea.

In the absence of corneal sensation, even a severe keratitis may produce little discomfort. Patients must be warned to look out for redness of the eye, reduced vision, or increased conjunctival discharge and to seek ophthalmic care as soon as any of these develop. Keeping the cornea moist with artificial tears and lubricant ointments may help to protect it. Swim goggles may be useful at night (Figure 6–13).

Once neurotrophic keratitis develops, it must be treated promptly. The most effective management is to keep the eye closed by careful horizontal taping of the eyelids, by tarsorrhaphy, or by means of ptosis induced with botulinum toxin. Secondary corneal infection must be treated promptly.

Exposure Keratitis

Exposure keratitis may develop in any situation in which the cornea is not properly moistened and covered by the eyelids. Examples include exophthalmos from any cause, ectropion, floppy lid syndrome, the absence of part of an eyelid as a result of trauma, and inability to close the lids properly, as in Bell's palsy. The two factors at work are the drying of the cornea and its exposure to minor trauma. The uncovered cornea is particularly subject to drying during sleeping hours and swim goggles may be useful at night (Figure 6–13). If an ulcer develops, it usually follows minor trauma and occurs in the inferior third of the cornea. Exposure keratitis is sterile but can become secondarily infected.

The therapeutic objective is to provide protection and moisture for the entire corneal surface. The treatment method depends on the underlying condition: eyelid surgery, correction of exophthalmos, an eye shield, or the options mentioned above in the discussion of neurotrophic keratitis. The combination of corneal anesthesia and exposure is particularly likely to result in severe keratitis.

Chlamydial Keratitis

All five principal types of chlamydial conjunctivitis (trachoma, inclusion conjunctivitis, primary ocular lymphogranuloma venereum, parakeet or psittacosis conjunctivitis, and feline pneumonitis conjunctivitis) may be accompanied by corneal lesions. Only in trachoma and lymphogranuloma venereum, however, are they blinding or visually damaging. The corneal lesions of trachoma have been extensively studied and are of great diagnostic importance. In order of appearance, they consist of (1) epithelial microerosions affecting the upper third of the cornea; (2) micropannus; (3) subepithelial round opacities, commonly called trachoma pustules; (4) limbal follicles and their cicatricial remains, known as Herbert's peripheral pits; (5) gross pannus; and (6) extensive, diffuse, subepithelial cicatrization. Mild cases of trachoma may have only epithelial keratitis and micropannus and may heal without impairing vision.

The rare cases of lymphogranuloma venereum have far fewer characteristic changes but are known to have developed blindness secondary to diffuse corneal scarring and total pannus. The remaining types of chlamydial infection cause only micropannus, epithelial keratitis, and, rarely, subepithelial opacities that are not visually significant. Several methods of identifying chlamydia are available through any competent laboratory.

Chlamydial keratoconjunctivitis responds to systemic tetracyclines, for example, doxycycline, erythromycin, and azithromycin (see Chapter 5). Topical sulfonamides, tetracyclines, erythromycin, and rifampin are also effective.

Drug-Induced Epithelial Keratitis

Epithelial keratitis is not uncommonly seen in patients using antiviral medications (idoxuridine and trifluridine) and several of the broad-spectrum and medium-spectrum antibiotics, such as neomycin, gentamicin, and tobramycin. It is usually a coarse superficial keratitis affecting predominantly the lower half of the cornea and interpalpebral fissure and may cause permanent scarring. The preservatives in eyedrops, particularly benzalkonium chloride (BAK) and thimerosal, are common causes of toxic keratitis.

Keratoconjunctivitis Sicca (Including Sjögren's Syndrome)

Epithelial filaments in the lower half of the cornea are the cardinal signs of this autoimmune disease, in which secretion of the lacrimal and accessory lacrimal glands is diminished or eliminated. There is also a blotchy epithelial keratitis that affects mainly the lower half. Severe cases develop mucous pseudofilaments that stick to the corneal epithelium.

This pattern of keratitis also occurs in cicatrizing conjunctival diseases such as ocular pemphigoid, in which destruction of goblet cells of the conjunctiva results in mucus deficiency, such that any tears fail to wet the corneal epithelium effectively.

Treatment of keratoconjunctivitis sicca calls for the frequent use of tear substitutes and lubricating ointments, of which there are many commercial preparations. Fish or flaxseed oil has been found to be helpful (1000 mg bid). Mucus deficiency requires treatment with mucus substitutes in addition to artificial tears. Topical vitamin A may help to reverse epithelial keratinization. Moisture chambers or swim goggles may be required (Figure 6–13). Lacrimal punctal plugs and punctal occlusion are important in the management of advanced cases, as are room humidifiers. Cyclosporine (a T-cell inhibitor), 0.05% applied topically, occasionally can reestablish goblet cell (mucin) density. Preservative-free artificial tears are often indicated.

Adenovirus Keratitis

Keratitis usually accompanies all types of adenoviral conjunctivitis, reaching its peak 5–7 days after onset of the conjunctivitis. It is a fine epithelial keratitis best seen with the slitlamp after instillation of fluorescein. The minute lesions may group together to make up larger ones.

The epithelial keratitis is often followed by subepithelial opacities. In epidemic keratoconjunctivitis (EKC), which is due to adenovirus types 8 and 19, the subepithelial lesions are round and grossly visible (see Figure 5–6). They appear 8–15 days after onset of the conjunctivitis and may persist for months or even (rarely) for several years. Similar lesions occur very exceptionally in other adenoviral infections, eg, those caused by types 3, 4, and 7, but tend to be transitory and mild, lasting a few weeks at most.

Although the corneal opacities of adenoviral keratoconjunctivitis tend to fade temporarily with the use of topical corticosteroids so that the patient is temporarily more comfortable, corticosteroid therapy can prolong the corneal disease and is therefore not recommended.

Other Viral Keratitides

A fine epithelial keratitis may be seen in other viral infections, such as measles (in which the central cornea is affected predominantly), rubella, mumps, infectious mononucleosis, acute hemorrhagic conjunctivitis, Newcastle disease conjunctivitis, and verruca of the lid margin. A superior epithelial keratitis and pannus often accompany molluscum contagiosum nodules on the lid margin, which is a feature of HIV infection.

Keratoconus

Keratoconus is an uncommon degenerative bilateral disease that may be inherited as an autosomal recessive or autosomal dominant trait. Unilateral cases of unknown cause occur rarely. Symptoms appear in the second decade of life. The disease affects all races. Keratoconus has been associated with a number of diseases, including Down's syndrome, atopic dermatitis, retinitis pigmentosa, aniridia, vernal catarrh, Marfan's syndrome, Alport's syndrome, and Ehlers–Danlos syndrome. Pathologically, there are disruptive changes in Bowman's layer with keratocyte degeneration and ruptures in Descemet's membrane.

Blurred vision is the only symptom. Many patients present with rapidly increasing myopic astigmatism. Signs include cone-shaped cornea (Figure 6–14A); linear narrow folds centrally in Descemet's membrane (Vogt's lines), which are pathognomonic; an iron ring around the base of the cone (Fleischer's ring); and, in extreme cases, indentation of the lower lid by the cornea when the patient looks down (Munson's sign). There is an irregular or scissor reflex on retinoscopy and a distorted corneal reflection with Placido's disk or the keratoscope even early in the disease. Color-coded topography provides earlier and more accurate information on the degree of corneal distortion (Figure 2–24). Early topographic signs of keratoconus (forme fruste) suggests an unstable cornea and possibly an unsuitable candidate for laser refractive surgery. Often, the fundi cannot be clearly seen because of corneal astigmatism.

Acute hydrops of the cornea may occur, manifested by sudden diminution of vision associated with central corneal edema (Figure 6–14B). This arises as a consequence of rupture of Descemet's membrane. Usually it clears gradually without treatment but often leaves apical and Descemet membrane scarring.

Rigid contact lenses will markedly improve vision in the early stages by correcting irregular astigmatism. Keratoconus is one of the most common indications for corneal transplantation, traditionally penetrating keratoplasty but possibly deep lamellar keratoplasty (DLK), which avoids the risk of endothelial rejection. Surgery is indicated when a contact lens can no longer be effectively worn or when peripheral thinning will affect the surgery.

Keratoconus is often slowly progressive between the ages of 20 and 60, although an arrest in progression of the keratoconus may occur at any time. If a corneal transplant is done before extreme corneal thinning occurs, the prognosis is excellent; good best-corrected vision is achieved in over 85% of eyes after 4 years and in over 70% of eyes after 14 years. Best vision after deep lamellar or penetrating keratoplasty often will require use of a rigid contact lens. Insertion of intracorneal (stromal) ring segments (Intacs) may delay the need for corneal transplantation, being suitable for patients with moderate keratoconus intolerant of contact lenses.

Corneal Degeneration

The corneal degenerations are a rare group of slowly progressive, bilateral, degenerative disorders that usually appear in the second or third decades of life. Some are hereditary. Other cases follow ocular inflammatory disease, and some are of unknown cause.

Terrien's Disease

Terrien's disease is a rare bilateral symmetric degeneration characterized by marginal thinning of the upper nasal quadrants of the cornea. Men are more commonly affected than women, and the condition occurs more frequently in the third and fourth decades. There are no symptoms except for mild irritation during occasional inflammatory episodes, and the condition is slowly progressive. The clinical picture consists of marginal thinning and peripheral vascularization with lipid deposition. Perforation is a complication, especially from trauma. Tectonic (structural) keratoplasty may be required. Histopathologic studies of affected corneas have revealed vascularized connective tissue with fibrillary degeneration and fatty infiltration of collagen fibers. Because the course of progression is slow and the central cornea is spared, the prognosis is reasonably good.

Band (Calcific) Keratopathy (Figure 6–15)

Band keratopathy is characterized by the deposition of calcium salts in a band-like pattern in the anterior layers of the cornea. The keratopathy is usually limited to the interpalpebral area. The calcium deposits are noted in the basement membrane, Bowman's layer, and anterior stromal lamellas. A clear margin separates the calcific band from the limbus, and clear holes may be seen in the band, giving a Swiss-cheese appearance. Symptoms include irritation, injection, and blurring of vision.

Calcific band keratopathy has been described in a number of inflammatory, metabolic, and degenerative conditions. It is characteristically associated with juvenile idiopathic arthritis. It has been described in long-standing inflammatory conditions of the eye, glaucoma, and chronic cyclitis. Band keratopathy may also be associated with hyperparathyroidism, vitamin D intoxication, sarcoidosis, and leprosy. The standard method of removing band keratopathy consists of removal of the corneal epithelium by curettage under topical anesthesia followed by irrigation of the cornea with a sterile 0.01-molar solution of ethylenediaminetetraacetic acid (EDTA) (edetate calcium) or application of EDTA with a cotton-tip applicator. The rigid sheets of calcium deposits can be lifted and dissected away with a sharp blade. Final smoothing of the area is accomplished best with the excimer laser (photo-therapeutic keratectomy—PTK).

Climatic Droplet Keratopathy (Labrador Keratopathy, Spheroid Degeneration of the Cornea) (Figure 6–16)

Climatic droplet keratopathy affects mainly people who work out of doors. The corneal degeneration is thought to be caused by exposure to ultraviolet light and is characterized in the early stages by fine subepithelial yellow droplets in the peripheral cornea. As the disease advances, the droplets become central, with subsequent corneal clouding causing blurred vision. Treatment in advanced cases is corneal transplantation.

Salzmann's Nodular Degeneration

This disorder is usually preceded by corneal inflammation, particularly phlyctenular keratoconjunctivitis or trachoma. Symptoms include redness, irritation, and blurring of vision. There is degeneration of the superficial cornea that involves the stroma, Bowman's layer, and epithelium, with superficial whitish-gray elevated nodules sometimes occurring in chains.

Rigid contact lenses will significantly improve visual acuity in most cases. Corneal transplantation is rarely required, but superficial lamellar keratectomy or photo-therapeutic (excimer laser) keratectomy (PTK) may be necessary.

Arcus Senilis

Arcus senilis is an extremely common, bilateral, benign peripheral corneal degeneration. Its prevalence is strongly associated with age. It is also associated with hypercholesterolemia and hypertriglyceridemia. Blood lipid studies should be performed in affected individuals under age 50.

Pathologically, lipid droplets involve the entire corneal thickness but are more concentrated in the superficial and deep layers, being relatively sparse in the corneal stroma.

There are no symptoms. Clinically, arcus senilis appears as a hazy gray ring about 2 mm in width and with a clear space between it and the limbus (Figure 6–17). No treatment is necessary, and there are no complications.

Hereditary Corneal Dystrophies

This is a group of rare hereditary disorders of the cornea of unknown cause characterized by bilateral abnormal deposition of substances and associated with alteration in the normal corneal architecture that may or may not interfere with vision. These corneal dystrophies usually manifest themselves during the first or second decade but sometimes later. They may be stationary or slowly progressive throughout life. Corneal transplantation, when indicated, improves vision in most patients with hereditary corneal dystrophy.

Anatomically, corneal dystrophies may be classified as epithelial, stromal, or posterior-limiting membrane dystrophies.

Epithelial Corneal Dystrophies

Meesmann Dystrophy

This slowly progressive disorder is characterized by microcystic areas in the epithelium. The onset is in early childhood (first 1–2 years of life). The main symptom is slight irritation, and vision is slightly affected. The inheritance is autosomal dominant.

Epithelial Basement (Anterior) Membrane Dystrophy

Microcysts, dots, or map or fingerprint patterns, hence the older names Cogan's microcystic dystrophy and map-dot-fingerprint dystrophy, are seen at the level of the epithelial basement membrane. Confocal microscopy demonstrates abnormal epithelial basement membrane protruding into the epithelium, as well as epithelial cell abnormalities and microcysts. Recurrent erosion is common. Vision usually is not significantly affected.

Others

Reis–Bückler dystrophy is a dominantly inherited dystrophy affecting primarily Bowman's layer. The disease begins within the first decade of life with symptoms of recurrent erosion. Opacification of Bowman's layer gradually occurs, and the epithelium is irregular. No vascularization is usually noted. Vision may be markedly reduced.

Vortex dystrophy, or cornea verticillata, is characterized by pigmented lines or whorls occurring in Bowman's layer or the underlying stroma and spreading over the entire corneal surface. Visual acuity is not markedly affected. Such a pattern of radiating pigmented lines may also be seen in patients treated with chlorpromazine, chloroquine, indomethacin, or amiodarone as well as in Fabry's disease.

Stromal Corneal Dystrophies

There are three primary types of stromal corneal dystrophies.

Granular Dystrophy

This usually asymptomatic, slowly progressive corneal dystrophy most often begins in early childhood. The lesions consist of central, fine, whitish “granular” lesions in the stroma of the cornea. The epithelium and Bowman's layer may be affected late in the disease. Visual acuity is slightly reduced. Histologically, the cornea shows uniform deposition of hyaline material. Corneal transplantation is not needed except in very severe and late cases. The inheritance is autosomal dominant.

Macular Dystrophy

This type of stromal corneal dystrophy is manifested by a dense gray central opacity that starts in Bowman's layer. The opacity tends to spread toward the periphery and later involves the deeper stromal layers. Recurrent corneal erosion may occur, and vision is severely impaired. Histologic examination shows deposition of acid mucopolysaccharide in the stroma and degeneration of Bowman's layer. Penetrating or deep keratoplasty is often required. The inheritance is autosomal recessive.

Lattice Dystrophy

Lattice dystrophy starts as fine, branching linear opacities in Bowman's layer in the central area and spreads to the periphery. The deep stroma may become involved, but the process does not reach Descemet's membrane. Recurrent erosion often occurs. Histologic examination reveals amyloid deposits in the collagen fibers. Corneal transplantation, usually penetrating keratoplasty but possibly deep lamellar keratoplasty, is common, as is recurrence of the dystrophy in the graft. The hereditary pattern for lattice dystrophy is autosomal dominant.

Posterior Corneal Dystrophies

Fuchs' Dystrophy

This disorder begins in the third or fourth decade and is slowly progressive throughout life. Women are more commonly affected than men. There are central wart-like deposits on Descemet's membrane, thickening of Descemet's membrane, and defects of size and shape of the endothelial cells. Decompensation of the endothelium may occur, particularly after cataract surgery, and leads to edema of the corneal stroma and epithelium, causing blurring of vision. Corneal haze is slowly progressive. Histologic examination of the cornea reveals the wart-like excrescences, which are secreted by the endothelial cells, over Descemet's membrane. Thinning and pigmentation of the endothelium and thickening of Descemet's membrane are characteristics. Penetrating keratoplasty, generally combined with cataract surgery if this has not been performed previously, was the standard treatment once corneal decompensation has developed, but overall has become required less frequently with improvements in cataract surgery and is largely being replaced by deep lamellar endothelial keratoplasty (DLEK), in which the endothelium with only a thin layer of stroma is transplanted.

Posterior Polymorphous Dystrophy

This is a common disorder with onset in early childhood. Polymorphous plaques of calcium crystals are observed in the deep stromal layers. Vesicular lesions may be seen in the endothelium. Edema occurs in the deep stroma. The condition is asymptomatic in most cases, but in severe cases, epithelial and total stromal edema may occur. The inheritance is autosomal dominant.

Thygeson's Superficial Punctate Keratitis

Superficial punctate keratitis is an uncommon chronic and recurrent bilateral disorder more common in females. It is characterized by discrete and elevated oval epithelial opacities that show punctate staining with fluorescein, mainly in the pupillary area. The opacities are not visible grossly but can be easily seen with the slitlamp or loupe. Subepithelial opacities underlying the epithelial lesions (ghosts) are often observed as the epithelial disease resolves.

No causative organism has been identified, but a virus is suspected. A varicella-zoster virus has been isolated from the corneal scrapings of one case.

Mild irritation, slight blurring of vision and photophobia are the only symptoms. The conjunctiva is not involved.

Epithelial keratitis secondary to staphylococcal blepharoconjunctivitis is differentiated from superficial punctate keratitis by its involvement of the lower third of the cornea and lack of subepithelial opacities. Epithelial keratitis in trachoma is ruled out by its location in the upper third of the cornea and the presence of pannus. Many other forms of keratitis involving the superficial cornea are unilateral or are eliminated by their histories.

Short-term instillation of corticosteroid drops will often cause disappearance of the opacities and subjective improvement, but recurrences are the rule. The ultimate prognosis is good since there is no scarring or vascularization of the cornea. Untreated, the disease runs a protracted course of 1–3 years. Long-term treatment with topical corticosteroids may prolong the course of the disease for many years and lead to steroid-induced cataract and glaucoma. Therapeutic soft contact lenses have been used to control symptoms in especially bothersome cases. Cyclosporine topical drops, 1% or 2%, have been effective as a substitute for corticosteroids.

Recurrent Corneal Erosion

This is a fairly common and serious mechanical corneal disorder that presents some classic signs and symptoms but may be easily missed if it is not looked for specifically. The patient is usually awakened during the early morning hours by a pain in the affected eye. The pain is continuous, and the eye becomes red, irritated, and photophobic. When the patient attempts to open the eyes in the morning, the lid pulls off the loose epithelium, resulting in pain and redness.

Three types of recurrent corneal erosions can be recognized:

1. Acquired recurrent erosion (traumatic): The patient usually gives a history of previous corneal injury. It is unilateral, it occurs with equal frequency in men and women, and the family history is negative. The recurrent erosion occurs most frequently in the center below the pupil regardless of the location of the previous injury.

2. Recurrent erosion associated with corneal disease: After corneal ulceration heals, the epithelium may break down in a recurrent fashion (as in HSV “metaherpetic” ulcer).

3. Recurrent erosion associated with corneal dystrophies: Recurrent erosions of the cornea may be observed in patients with epithelial basement membrane dystrophy, lattice dystrophy, and ReisBückler's corneal dystrophy.

Recurrent corneal erosion is due to a defect in anchoring of the corneal epithelium between the epithelial basement membrane and Bowman's layer, due to faulty hemidesmosome connections. The epithelium is loose and vulnerable to separation.

Instillation of a local anesthetic relieves the symptoms immediately, and fluorescein staining will show the eroded area, typically a small area in the lower central cornea. Healed erosions often exhibit subepithelial debris.

Treatment consists of a pressure bandage on the eye to promote healing. Mechanical denuding of the loose corneal epithelium may be necessary. The other eye should be kept closed most of the time to minimize movement of the lid over the affected eye. Bed rest is desirable for 24 hours. The cornea usually heals in 2–3 days. To reduce the risk of and promote continued healing, a bland ophthalmic ointment at bedtime is used for several months. In more severe cases, artificial tears are instilled during the day. The use of hypertonic ointment (glucose 40% or sodium chloride 5%) drops is often of value. Therapeutic soft contact lenses, needle micropuncture of Bowman's layer, and PTK have been useful in cases that do not respond to more conservative management.

Interstitial Keratitis Due to Congenital Syphilis

This self-limited inflammatory disease of the cornea, also known as immune stromal keratitis, characteristically is a late manifestation of congenital syphilis, but overall other causes are now more prevalent (see below), partly because of the reduction in incidence of congenital syphilis. Interstitial keratitis rarely occurs in acquired syphilis, of which the incidence has increased markedly in association with HIV infection.

Interstitial keratitis due to congenital syphilis occasionally starts unilaterally, but almost always becomes bilateral weeks to months later. It affects all races and is more common in female than male patients. Symptoms appear between the ages of 5 and 20. Pathologic findings include edema, lymphocytic infiltration, and vascularization of the corneal stroma. It is probably a delayed immune response to stromal antigen retained from passage of Treponema pallidum organisms through the cornea before or at birth, because the organisms are not found in the cornea during the acute phase.

Clinical Findings

Symptoms and Signs

Hutchinson's triad comprises interstitial keratitis, deafness, and notched upper central incisors. Saddle nose is another sign of congenital syphilis. The patient complains of pain, photophobia, and blurring of vision. Physical signs include conjunctival injection, corneal edema, vascularization of the deeper corneal layers, and miosis. There is an associated severe anterior granulomatous uveitis and blepharospasm due to photophobia. The grayish-pink appearance of the cornea (due to edema and vascularization) that occurs in the acute phase is sometimes referred to as a “salmon patch.”

Laboratory Findings

Serologic tests for syphilis are positive.

Complications & Sequelae

Corneal scarring and vascularization occur if the process has been particularly severe and prolonged. Secondary glaucoma may result from the uveitis.

Treatment

Topical cycloplegic/mydriatic agents to dilate the pupils are important to prevent formation of posterior synechiae. Corticosteroid drops often relieve the symptoms dramatically but must be continued for long periods to prevent recurrence of symptoms. Dark glasses and a darkened room may be necessary if photophobia is severe. Treatment should be given for systemic syphilis, even though this usually has little effect on the ocular condition. Corneal scarring may necessitate corneal transplant, and glaucoma, if present, may be difficult to control.

Course & Prognosis

The severity of corneal disease is not affected by treatment, which is aimed at prevention of complications. The inflammatory phase lasts 3 or 4 weeks. The corneas then gradually clear, leaving ghost vessels and scars in the corneal stroma.

Interstitial Keratitis Due to Other Causes

In the United States, unilateral interstitial (immune stromal) keratitis is usually due to herpes simplex virus and occasionally due to varicella-zoster virus. Commonly no cause is found for active bilateral interstitial keratitis, but congenital syphilis remains the most commonly identified cause of inactive bilateral disease. Tuberculosis, leprosy, cytomegalovirus, measles virus, mumps virus, and Lyme disease are rare causes of interstitial keratitis. Treatment is usually symptomatic, but it is important to establish the cause whenever possible.

Cogan syndrome is a rare disorder generally believed to be a vascular hypersensitivity reaction of unknown origin. It is a disease of young adults and is characterized by nonsyphilitic interstitial keratitis and a vestibuloauditory disturbance, usually sudden hearing loss. Corticosteroids are reputed to be of value, but some degree of visual impairment and complete nerve deafness usually supervene. Rarely patients die due to vasculitis, such as aortitis.

Corneal Pigmentation

Pigmentation of the cornea may occur with or without ocular or systemic disease. There are several distinct varieties.

Krukenberg Spindle

In pigment dispersion syndrome, brown uveal pigment is deposited bilaterally upon the central endothelial surface in a vertical spindle-shaped fashion (Krukenberg spindle). It occurs in a small percentage of people over age 20, usually in myopic women. It can be seen grossly in severe cases, but is best observed with the slitlamp. The visual acuity is only slightly affected, and the progression is extremely slow. Pigmentary glaucoma must be ruled out by regular examination of both intraocular pressures and optic discs.

Blood Staining

This disorder occurs occasionally as a complication of traumatic hyphema with secondary glaucoma and is due to hemosiderin in the corneal stroma. The cornea is golden brown, and vision is decreased. In most cases the cornea gradually clears in 1–2 years.

Kayser–Fleischer Ring

This is a bilateral pigmented ring whose color varies widely from ruby red to bright green, blue, yellow, or brown. Composed of fine granular deposits of copper, each ring is 1–3 mm in diameter and located just inside the limbus at the level of Decemet's membrane. In exceptional cases, there is a second ring.

Kayser–Fleischer rings are almost always due to Wilson's disease (hepatolenticular degeneration) and are an important clinical finding as their presence may obviate the need for liver biopsy in patients with suggestive clinical features and abnormal copper studies. They have been described in chronic liver disease not due to Wilson's disease. In Wilson's disease, the intensity of the pigmentation can be reduced by treatment of the abnormal copper metabolism, such that the corneal signs may be an indicator of response to treatment.

Iron Lines (Hudson–Stähli Line, Fleischer's Ring, Stocker's Line, Ferry's Line)

Localized deposits of iron within the corneal epithelium may occur in sufficient quantity to become visible clinically. The Hudson–Stähli line is a horizontal line at the junction of the middle and lower thirds of the cornea, corresponding to the line of lid closure, in otherwise normal elderly patients. Fleischer's ring surrounds the base of the cone in keratoconus. Stocker's line is a vertical line associated with pterygia, and Ferry's line develops adjacent to limbal filtering blebs. Similar iron deposits are seen at the site of corneal scars.

Glass contact lenses were first described in 1888 by Adolf Fick and were then used for the treatment of keratoconus by Eugene Kalt. Poor results were achieved until 1945, when Kevin Tuohy of Los Angeles produced a plastic precorneal lens with a diameter of 11 mm. Since that time, advances in contact lens technology have produced several different varieties of lenses, which are broadly divided into two types: rigid and soft lenses. The basic requirement for success of contact lenses is to overcome the effect on oxygen supply to the cornea from wearing an occlusive lens. The optical features of contact lenses are discussed in Chapter 21.

Rigid Lenses

Standard Hard Lenses

These direct descendants of Tuohy's lens are made of polymethylmethacrylate (PMMA; Perspex). They are impervious to oxygen and thus rely on pumping of tears into the space between the lens and the cornea during blinking to provide oxygen to the cornea. They are smaller than the corneal diameter. Always for daily wear, these lenses are easy to care for, are relatively inexpensive, and correct vision efficiently, particularly if there is significant astigmatism. Unfortunately, many persons cannot tolerate them. Corneal edema due to corneal hypoxia and spectacle blur (poor vision with spectacle correction after a period of contact lens wear) are common complaints, and they are now rarely used.

Rigid Gas-Permeable Lenses

These are rigid lenses made from cellulose acetate butyrate, silicone acrylate, or silicone combined with polymethylmethacrylate. They have the advantage of high oxygen permeability, thus improving corneal metabolism, and greater comfort while retaining the optical properties of rigid lenses, although they are not as easy to tolerate as soft lenses. They are generally used on a daily-wear basis but can be used on an extended-wear (24-hour) basis in exceptional circumstances. Gas-permeable lenses are particularly suitable for correction of keratoconus and astigmatism and when bifocal or multifocal lenses are required.

Orthokeratology is the overnight wear of rigid gas-permeable lenses to correct myopia or astigmatism by reshaping the cornea. It is advocated as a safer, less expensive alternative to refractive surgery, but there is risk of corneal infection. Most ophthalmologists recommend not wearing any type of refractive contact lens through the night.

Soft Lenses

Cosmetic Soft Lenses

Hydrogel lenses, based on hydroxymethyl methacrylate (HEMA) or silicone, of which the latter provides greater oxygen permeability, are considerably more comfortable than rigid lenses but are flexible and thus conform to the surface of the cornea. Regular astigmatism can be partially corrected by incorporating cylinder into the soft lens; irregular astigmatism is poorly corrected. They are cheaper to purchase but are less durable and complications are more common than with rigid lenses, including ulcerative keratitis (particularly if the lenses are worn overnight), immune corneal reactions to deposits on the lenses, giant papillary conjunctivitis, reactions to lens-care solutions (especially those containing the preservative thimerosal), corneal edema, and corneal vascularization.

Cosmetic soft contact lenses are usually removed each day, to be cleaned, disinfected, and then stored overnight in solution. With care, a pair of such lenses will last for 1 year but then should be discarded. Disposable soft contact lenses for daily wear are readily available, but are more expensive. Soft lenses replaced every 2 to 4 weeks, if properly worn and cared for, are quite safe. Disposable soft contact lenses for overnight (extended) wear, usually to be worn for 1 week and then replaced but potentially to be worn for up to 30 days, are strongly promoted by contact lens manufacturers but generally are not recommended by ophthalmologists because of the increased risk of corneal infection. For aphakic correction, it is occasionally necessary to resort to extended wear because of difficulties with insertion, removal, and care of the lenses.

Therapeutic Soft Lenses

The use of therapeutic soft contact lenses has become an indispensable part of the ophthalmologist's management of external eye disease. The lenses form a soft barrier over the cornea, providing protection against trichiasis and exposure. Lenses with high water content can act as a “stent” for epithelial healing, such as in the treatment of recurrent erosions. Patients with pain due to epithelial disease, such as in bullous keratopathy, particularly benefit from therapeutic soft contact lenses. Lenses with low water content can be used to seal small corneal perforations or wound leaks. In all cases of therapeutic contact lens wear, infection can occur. Antimicrobial coverage may be indicated if there is an epithelial defect.

Contact Lens Care

It is essential that all contact lens wearers be made aware of the risks associated with contact lens wear—particularly those patients choosing the high-risk varieties such as extended-wear lenses for cosmetic optical correction purely on the grounds of convenience. All wearers must be under the regular care of a contact lens practitioner. Many of the chronic complications of contact lens wear are asymptomatic in their early and easily treated stages. Any contact lens should be removed immediately if the eye becomes uncomfortable or inflamed, and ophthalmic attention must be sought immediately if symptoms do not rapidly resolve.

Except for daily disposables, contact lenses require regular cleaning and disinfecting, and particularly in the case of soft lenses, removal of protein deposits is required. Disinfection regimens include heat, chemical soaking, and hydrogen peroxide systems. All are effective if used according to the manufacturer's instructions, but some seem to be insufficiently effective against resistant organisms such as Acanthamoeba and Fusarium.

For contact lens wearers who have developed hypersensitivity reactions to preservatives in their contact lens solutions, there are contact lens care systems that do not contain preservatives. It is important that such individuals are aware of the ability of organisms such as Pseudomonas and Acanthamoeba to survive in nonpreserved saline solutions. The use of nonpreserved contact lens solutions requires much greater vigilance in the regular disinfection of lenses and lens storage cases. Even with standard contact lens care systems, deposits in contact lens storage cases may prevent effective disinfection. Tap water, which may harbor organisms such as Acanthamoeba, should not be used for rinsing contact lenses or contact lens storage cases. Contact lenses should not be worn when bathing in a hot tub or swimming.

Corneal transplantation (keratoplasty) is indicated for a number of serious corneal conditions, for example, scarring, edema, thinning, and distortion. Penetrating keratoplasty (PK) means full-thickness corneal replacement. Lamellar keratoplasty is a partial-thickness procedure to replace the anterior cornea with a variable amount of stroma, extending to deep lamellar keratoplasty (DLK), in which almost the entire cornea except the endothelium is replaced. The reverse procedure is deep lamellar endothelial keratoplasty (DLEK), of which there are a number of variants such as Descement's stripping automated endothelial keratoplasty (DSAEK), in which the endothelium with only a thin layer of stroma is transplanted.

Younger donors are preferred for penetrating and deep lamellar endothelial keratoplasties, because there is a direct relationship between age and the health and number of the endothelial cells, but older corneas (50–65 years) are acceptable if the endothelial cell count is adequate. Because of the rapid endothelial cell death rate, the eyes should be enucleated soon after death and refrigerated immediately. Whole eyes should be used within 48 hours, preferably within 24 hours. Modern storage media allow for longer storage. Corneoscleral caps stored in nutrient media may be used up to 6 days after donor death, and preservation in tissue culture media allows storage for as long as 6 weeks.

For lamellar and deep lamellar keratoplasty, corneas can be frozen, dehydrated, or refrigerated for several weeks; the endothelial cells are not important in these partial-thickness procedures involving the anterior cornea.

Diseases, like chemical injuries (see Chapter 19), in which loss of limbal stem cells leads to failure of corneal epithelialization, may benefit from limbal stem cell transplants, from the fellow eye or a donor eye, or amniotic membrane transplants, particularly in preparation for corneal transplantation. For severe corneal disease unsuitable for corneal transplantation, various artificial corneas (keratoprostheses) have been attempted with increasing success.

Techniques

For penetrating or lamellar keratoplasty, the recipient eye is prepared by a partial-thickness cutting of a circle of diseased cornea, such as with a suction trephine (cookie-cutter action), and full-thickness removal with scissors or partial-thickness removal with dissection. For deep lamellar endothelial keratoplasty, the recipient endothelium is removed using instruments inserted into the anterior chamber.

For penetrating keratoplasty, the donor corneoscleral cap is placed endothelium up on a suction Teflon block; the trephine (Figure 6–18) is pressed down into the cornea, and a full-thickness button is punched out. For lamellar, deep lamellar, and deep lamellar endothelial keratoplasty, the process is adapted, using mechanical or possibly laser-cutting devices, to remove the required portion of cornea from a corneoscleral cap or whole globe. Precut tissue for endothelial keratoplasty is now available from eye banks in developed countries.

Developments in sutures (Figure 6–19), instruments, and microscopes, as well as changes in surgical techniques, have significantly improved the prognosis in all patients requiring corneal transplants. Reducing and managing postoperative astigmatism and corneal graft rejection continue to be major problems, particularly after penetrating keratoplasty (see Chapter 16). The use of an intraoperative hand-held keratometer and early suture removal guided by topographical mapping has proved useful in trying to minimize post-graft astigmatism. A large and lengthy multi-institutional study has revealed that the only antigens identified with transplant rejection are those of the ABO blood-type group. For this reason, some surgeons are matching donor and recipient ABO types before surgery, especial in high-risk patients (prior rejection, vascularized corneas, etc).

The inconvenience of spectacles to many wearers and the complications associated with contact lenses have resulted in a search for surgical solutions to the problem of refractive error.

Radial Keratotomy

Developed initially by Sato of Japan and later by Fyodorov of the USSR, the central cornea is flattened by almost full-thickness radial incisions. The procedure is now rarely performed.

Keratomileusis

In 1961, Barraquer of Colombia reported on the technique of myopic keratomileusis in which a lamellar corneal autograft is removed, shaped with a cryolathe (flattened), and sutured back into position. The procedure, also now rarely performed, was a precursor to laser in situ keratomileousis (LASIK).

Procedures to Correct Astigmatism

Astigmatism continues to be a problem following most corneal operations, especially penetrating keratoplasty, and after cataract surgery. Astigmatism after keratoplasty may be improved by various surgical procedures, including relaxing incisions, compression sutures, and wedge resections. Laser procedures, such as LASIK or surface ablation techniques (LASEK, PRK, epi-LASIK) (see below), may be helpful. Refinements of incision, including adjustment of location according to preoperative corneal astigmatism, are useful in preventing postoperative astigmatism after cataract surgery.

Alloplastic Corneal Implants

Various plastic discs and rings (eg, Intacs) have been placed in the corneal stroma to correct refractive errors but with limited success.

Clear Lens Removal & Phakic Lens Implants

Removal of the crystalline lens (clear lens removal) is widely advocated for treatment of high myopia and presbyopia, but there are significant risks, notably retinal detachment in highly myopic eyes. Insertion of an intraocular lens without removal of the crystalline lens (phakic lens implant) is also undertaken, but corneal endothelial damage and development of cataract are worrisome.

Lasers

An advanced approach to refractive corneal surgery involves the use of lasers (see Chapter 23). The excimer laser has received the most publicity, but the femtosecond laser is also proving useful.

In LASIK, a motorized microkeratome or the femtosecond laser is used to cut a thin lamellar corneal disk, which is folded back. Laser of the stromal bed produces the desired carefully programmed reshaping of the cornea, and then the flap is repositioned. The surface ablation techniques are photorefractive keratectomy (PRK), laser epithelial keratectomy (LASEK), and epi-LASIK. In PRK, only the corneal epithelium is removed prior to the laser treatment. In LASEK and epi-LASIK, the epithelium is removed, with dilute alcohol and a microkeratome respectively, and replaced after the laser treatment. When necessary, the laser delivery in all these techniques can be further refined by wavefront guided technology to take account of the optical aberrations of individual eyes.

Laser refractive surgery is mostly used for myopia, but can also treat astigmatism or hyperopia. Long-term visual results are about the same for the various techniques, but each has its advantages and disadvantages. Surface ablation (PRK, LASEK) and LASIK now are being used for up to 10 diopters (or more) of myopia with good results. In large ablations, especially with LASIK, the threat of ecstasia must be considered. LASIK produces the most rapid recovery, both visually and in terms of discomfort, but surface ablation has become much less uncomfortable, mostly due to effective nonsteroidal anti-inflammatory drugs. Surface haze also is less of a problem than before due to proper cooling of the corneal surface both during and immediately after ablation. The surface ablation techniques are particularly indicated for thin corneas and patients at risk of corneal trauma. Complications of laser refractive corneal surgery include unexpected refractive outcome, fluctuating refraction, irregular astigmatism, regression, epithelial, flap, or interface problems, stromal haze, corneal ectasia, and infection. Previous laser refractive corneal surgery results in particular difficulties when determining intraocular lens power for cataract surgery.

Other Refractive Techniques

Conductive keratoplasty (CK) shows promise along with safety in the treatment of hypermetropia and possibly presbyopia. Laser thermokeratoplasty (LTK) is also being studied for the treatment of low hyperopia.