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.
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 with iris prolapsing through superior peripheral corneal perforation.
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.
Table 6-1. Treatment of Bacterial, Fungal, or Amebic Keratitis1 ||Download (.pdf)
Table 6-1. Treatment of Bacterial, Fungal, or Amebic Keratitis1
|Organisms||Initial Therapies2||Alternative Therapies2|
|No organisms identified; ulcer suggestiv of bacterial infection||Moxifloxacin, gatifloxacin, or tobramycin with cefazolin||Ciprofloxacin, levofloxacin, gentamicin, ceftazidime, or vancomycin|
|Gram-positive cocci: lancet-shaped with capsule = S pneumoniae||Moxifloxacin, gatifloxacine, or cefazolin||Levofloxacin, penicillin G, vancomycin, or ceftaxidime|
|Gram-positive cocci: methacillin-resistant S aureus (MRSA)||Vancomycin|
|Gram-positive rods: slender and varying in length—Mycobacterium fortuitum, Nocardia species, Actinomyces species||Amikacine, moxifloxacin, or gatifloxacin||Other fluoroquinolones|
|Other gram-positive organisms: cocci or rods||Cefazolin, moxifloxacin, or gatifloxacin||Other fluoroquinolones, penicillin G, vancomycin, or ceftazidime|
|Gram-negative cocci3||Ceftriaxone3||Penicillin G, cefazolin, or vancomycin|
|Gram-negative rods: thin = Pseudomonas||Moxifloxacin, gatifloxacin, ciprofloxaxin, tobramycin, or gentamicin||Other fluoroquinolones, polymyxin B, or carbenicillin|
|Gram-negative rods: large, a square-ended diplobacilli = Moraxella||Moxifloxacin, gatifloxacin, or ciprofloxacin||Tobramyin or getamicin with cefazolin, or penicillin G|
|Other gram-negative rods||Moxifloxacin, gatifloxacin, or tobramycin||Ceftazidime, getamicin, or carbenicillin|
|No organism identified; ulcer suggestive of fungal infection||Natamycin, voriconazole, or posaconazole||Amphotericin B, nystatin, miconazole, or flucytosine|
|Yeast-like organism = Candida species4||Amphotericin B, voriconazole, or posaconazole||Amphotericin B, nystatin, miconazole, or flucytosine|
|Hyphae-like organisms = fungal ulcer||Natamycin, voriconazole, or posaconazole||Amphotericin B or nystatin|
|Cyst, trophozoites = Acanthamoeba||Propamidine and/or polyhexamethylene biguanide||Chlorhexidine or neomycin|
Table 6-2. Drug Concentrations and Dosages for Treatment of Bacterial or Fungal Keratitis ||Download (.pdf)
Table 6-2. Drug Concentrations and Dosages for Treatment of Bacterial or Fungal Keratitis
|Amikacin||50–100 mg/mL||25 mg/0.5 mL/dose||10–15 mg/kg/d IV or IM in two doses|
|Amphotericin B||1.5–3 mg/mL||0.5–1 mg||…|
|Carbenicillin||4 mg/mL||125 mg/0.5 mL/dose||100–200 mg/kg/d IV in four doses|
|Cefazolin||50 mg/mL||100 mg/0.5 mL/dose||15 mg/kg/d IV in four doses|
|Ceftazidime||50 mg/mL||250 mg (0.5 mL)||1 g IV or IM every 8–12 hours (adult dose)|
|Ceftriaxone||…||…||1–2 g/d IV or IM|
|Ciprofloxacin||3 mg/mL||…||500–750 mg orally every 12 hours|
|Flucytosine||1% solution||…||50–150 mg/kg/d orally in four doses|
|Gatifloxacin||3 mg/mL solution||…||…|
|Gentamicin||10–20 mg/mL (fortified)||20 mg/0.5–1 mL/dose||…|
|Miconazole||1% solution or 2% ointment||5–10 mg; 0.5–1 mL/dose||…|
|Moxifloxacin||5 mg/mL solution||…||…|
|Nystatin||50,000 units/mL or cream (100,000 units/g)||…||…|
|Penicillin G||100,000 units/mL||1 million units/dose (painful)||40,000–50,000 units/kg IV in four doses; or continuously, 2–6 million units IV every 4–6 hours|
|Polyhexamethylene biguanide||0.01%–0.02% solution||…||…|
|Polymyxin B||1–2 mg/mL||10 mg/0.5 mL dose||…|
|Posaconazole||1% solution||400 mg orally every 12 hours|
|Propamidine||0.1 mg/mL solution; 0.15% ointment||…||…|
|Tobramycin||10–20 mg/mL (fortified)||20 mg/0.5 mL/dose||…|
|Vancomycin||50 mg/mL||25 mg/0.5mL/dose||…|
|Voriconazole||1% solution||200–300 mg orally every 12 hours; or 200 mg every 12 hours IV|
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.
Pseudomonas ulcer related to 24-hour contact lens wear.
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 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.
Corneal ulcer caused by Candida albicans.
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.
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.
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.
Corneal scar caused by recurrent herpes simplex keratitis. (Courtesy of A Rosenberg.)
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.
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.
Dendritic figures seen in herpes simplex keratitis.
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.
The treatment of HSV keratitis should be directed at eliminating viral replication within the cornea while minimizing the damaging effects of the inflammatory response.
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.
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.
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.
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.
Medical grade cyanoacrylate glue sealing small paracentral corneal perforation.
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 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.
Marginal ulcer of temporal cornea, right eye. (Courtesy of P Thygeson.)
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.
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.
Marginal keratitis. (Courtesy of M Hogan.)
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.
Keratomalacia with ulceration associated with xerophthalmia (dietary) in an infant. (Photo by Diane Beeston.)
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.
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).
Swim goggles are used at night to reduce corneal evaporation.
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 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.