Review of Optometry August 1999

The first of a four-part series, this article details the pathophysiology, diagnosis and management of six infectious diseases.

With copious sensory innervation and an essential role in visual refraction, the cornea and anterior segment are critical to visual health and function. For us as optometrists, knowledge of these structures—the most therapeutically accessible area of the eye—and their associated disorders is imperative. This initial installment of the four-part series, "Corneal Atlas," examines the pathophysiology, diagnosis, and management of infections of the cornea. Future articles will address corneal inflammations, trauma and degenerations.

Bacterial keratitis secondary to extended wear of contact lenses.

Bacterial Keratitis
The cornea has many innate defense systems that protect it from bacterial invasion. Corneal trauma, chronic eyelid disease, tear film abnormalities, systemic or iatrogenic immunosuppression, and hypoxic trauma from contact lens wear all threaten the cornea's defenses.1-6 When bacteria breach those defense systems and colonize and proliferate within the stroma, bacterial keratitis results.

In the subsequent inflammatory reaction, polymorphonuclear leukocytes (PMNs) accumulate to form an infiltrate. This reaction in the anterior segment and periorbital region will include lid edema, conjunctival and episcleral injection, and anterior chamber reaction with possible hypopyon formation.7-10

Bacterial keratitis exhibiting profound anterior segment inflammation and eyelid edema.

The patient's immune response will typically neutralize the invading bacteria with subsequent scarring and visual disability. Insufficient immune response, however, may result in cornea perforation with possible infectious endophthalmitis. Common infectious agents implicated in bacterial keratitis include Staphylococcus aureus, S. epidermis, Streptococcus viridans, S. pneumoniae, Neisseria gonorrhoeae, and Pseudomonas aeruginosa.7

The clinical appearance of bacterial keratitis often varies with the virulence of the infective organism. Generally, gram-positive organisms produce a milder appearance, which may result in under-treatment; gram-negative organisms produce more dramatic presentations, and you would expect a greater degree of anterior segment involvement based upon a relatively small corneal lesion. In all cases, there will be a focal accumulation of inflammatory cells within the corneal stroma with an overlying excavation of the epithelium, referred to as a corneal ulcer. Anterior chamber inflammation is also invariably present, but varies depending upon organism's pathogenicity. Secondary uveitic response may be so severe that an inflammatory glaucoma may develop.

Sodium fluorescein staining demonstrating epithelial excavation overly corneal infiltration.

Diagnosis and management begins with clinical suspicion of bacterial keratitis based upon the appearance. Most clinicians begin broad-spectrum antibiosis immediately. For example, many general ophthalmologists decline to routinely culture suspected bacterial corneal ulcers, though the American Academy of Ophthalmology has identified cultures and initial gram stains as standard-of-care.11 For large, visual-axis threatening central, or deep ulcers, we should conduct microbiologic studies before initiating therapy.

Treatment has historically employed fortified antibiotics, commonly gentamicin or tobramicin 1.5 percent combined with cefozalin.1,12 However, they are highly toxic and unstable. Currently, the fluorquinolones ofloxacin (Ocuflox) and ciprofloxacin (Ciloxan) provide excellent broad spectrum antibiotic coverage with minimal toxicity and are as effective at eradicating susceptible organisms as a fortified regimen.13-14 (See "The Role of Corticosteroids.")

Acanthamoeba Keratitis
Two species of free-living soil amoebae can infect the cornea. Naegleria fowleri affects healthy young adults who have a history of exposure to contaminated or brackish water.17 Keratitis from this organism is very uncommon. Acanthamoeba castellanii is the most common cause of amoebic keratitis, and is mostly associated with incorrect contact lens handling and exposure to unsanitary conditions.18-19

The incidence of recognized Acanthamoeba keratitis, though still rare, is rising thanks to correct diagnosis and the increased use of confocal microscopy, which readily identifies Acanthamoeba cysts in the cornea.20-21

Doctors rarely diagnose this chronic disease in its early stages because they often mistake it for herpetic keratitis and bacterial keratitis. It can wax and wane for years before a doctor makes the correct diagnosis.20 In the response to certain antibiotics and preservatives in topical medications, Acanthamoeba will encyst and become dormant, reducing symptoms and clinical signs.20 So it may appear partially responsive to treatment and can assume a very chronic course prior to correct diagnosis. You should strongly suspect Acanthamoeba keratitis in chronic keratitis that does not respond to treatment.

Risk factors include corneal foreign body, contact with non-sterile water, bullous keratopathy, neurotrophic keratopathy, herpes simplex keratitis, radial keratotomy, swimming and scuba diving, basement membrane dystrophy, contact lens wear and bacterial keratitis.18-22 Acanthamoeba keratitis can, however, develop without identifiable risk factors.20 Anything that disrupts the corneal epithelium poses a risk.
The disease initially presents as a non-specific unexplained keratitis or epithelial defect. Roughly half of the patients will report significant pain, the rest only mild irritation and foreign-body sensation. There will always be anterior segment inflammation and injection.20

Though it's historically associated with stromal ring infiltrate formation, only 6 percent of early Acanthamoeba keratitis cases and 16 percent of late cases present this way.20 Most early cases present as non-descript epitheliopathy. However, limbitis occurs as the initial finding in 94 percent of early cases and 84 percent of late cases.20-21 Another common, significant finding is radial keratoneuritis (perineuritis), irregularly thickened corneal nerves in the anterior to mid-stroma with shaggy borders compared to normal nerves.21 Other clinical signs include irregular epithelial defect, corneal microcysts, punctate keratopathy, bullous keratopathy, disciform stromal keratitis, anterior uveitis and a granulomatous stromal reaction.17,21

Acanthamoeba keratitis is often mistakenly treated for HSK. It can initially present as a dendritic keratitis similar to HSK, but there are no herpetic terminal end bulbs in Acanthamoeba dendriform keratitis.20,22

HSK infections and Acanthamoeba keratitis do coexist22 where the latter presents as a secondary opportunistic infection.22-23 The Acanthamoeba organism nestles in the thickened border of the epithelium.22 Consider Acanthamoeba infection in all cases of presumed or actual HSK that don't respond to standard anti-viral therapy.

Diagnosis is often difficult and is often made ex juvantia when all other treatments fail. As with bacteria, corneal scrapings of Acanthamoeba may be cultured for diagnosis. However, the culture must use non-nutrient agar with overlay of either Escherichia coli or Enterobacter. Culturing can take 1-9 days, or longer. Unfortunately, diagnostic yield is low and cultures are frequently negative despite the presence of Acanthamoeba.20-21 Often, cultures reveal the presence of bacteria. This occurs as Acanthamoeba may be both incidental and opportunistic, and frequently coexists with bacterial colonies upon which it feeds. Acanthamoeba frequently exists with other corneal diseases and may not be the primary or most active disease process in a combined keratitis.20 Confocal microscopy has provided a non-invasive, fast, accurate means of diagnosing Acanthamoeba keratitis, but this technology is not widely available.

Medications employed against Acanthamoeba include topical polyhexamethylene biguanide (PHMB), propamidine isethionate (Brolene), chlorhexidine digluconate 0.02 percent, polymixin B, neomycin and clortrimazole 1 percent.20-22,24 In one study of 10 patients, the combination of Brolene and PHMB successfully cured all cases of Acanthamoeba keratitis. Cautious introduction of topical corticosteroids in association with anti-amoebic therapy expedited resolution of the inflammation and provided symptomatic relief.25

Fungal Keratitis
Sixty species of fungus (molds and yeasts) may infect the cornea.26 Molds (filamentary fungi), comprising septate and non-septate organisms, produce feathery colonies that join together to produce hyphae. Yeasts form pseudohyphae.27 The septate filamentary fungi are the most common causes of fungal keratitis, while the non-septate form cause orbital disease but rarely infect the cornea. Fusarium, Aspergillus (both filamentary fungi), and Candida (a yeast) cause the vast majority of fungal corneal infections.26

Risk factors for filamentary fungal keratitis include ocular trauma (particularly if organic vegetative matter is involved), antecedent topical corticosteroid therapy, and pre-existing ocular or systemic immu- nosuppressive diseases.5,27-31 Organic trauma is most significant in initiating filamentary fungal keratitis, but yeast infection is mostly initiated by immunosuppression (through topical steroid use or systemic disease) or alteration of normal epithelial barriers (persistent epithelial defects, neurotrophic keratitis, topical anesthetic use). Candida, an opportunist yeast, is part of the normal human flora. Corneal defense system disruption can readily allow for this yeast infection.27

Once fungi begin colonization, their virulence determines their ability to proliferate within the stroma and to penetrate into deeper layers beyond the reach of typical diagnostic and therapeutic measures. The hyphae make the organisms large enough to preclude their complete ingestion by the host's inflammatory cells.27

Filamentary fungi initially produce a feathery, branching pattern in the cornea. The cornea will appear a dull gray with possible heaping of epithelium and a dry, rough texture.32 There will typically be a plasmoid aqueous with hypopyon. Later, these features are lost and fungal keratitis begins to resemble advanced bacterial keratitis. Subsequent misdiagnosis is likely. It is impossible to differentiate bacterial keratitis from fungal keratitis on clinical judgment alone. Candida infection is more localized with a "button appearance," an expanding stromal infiltrate and a relatively small epithelial ulceration.27

Confirm your clinical suspicion of fungal keratitis either with cultures or corneal biopsy. Standard corneal scraping, with blood and chocolate agar incubated at 37°C for bacteria, is acceptable. However, inoculate additional blood and Sabouraud agar plates at room temperature.27 Anti-fungal sensitivity testing is unreliable compared with antibiotic testing, and correlates poorly with clinical efficacy. Reserve corneal biopsy for cases in which your clinical suspicion is high for fungal infection yet cultures were negative, or for when active ulceration persists despite aggressive antimicrobial therapy.

Treating fungal keratitis is exceptionally frustrating. Most antifungal medications are merely fungistatic and require an intact immune system as well as a prolonged course. Further, all antifungal medications except for natamycin must be adapted for ophthalmic use from systemic antifungal medications. This results in an extreme ophthalmic toxicity. The incidence of fungal keratitis is low, so imminent advances in this area of ophthalmic medical therapy are unlikely.

Table 1: Medical Therapy for Fungal Keratitis

YEASTS

FILIMENTARY FUNGI

First Choice:

First Choice:

Amphotericin B 0.15% gtts &
Flucytosine (1% gtts + 150 mg/kg PO)

Natamycin 5% gtts

Alternative Choice:

Alternative Choice:

Fluconazole (0.5% gtts = 200 mg PO)
& Miconazole 1% gtts

Amphotericin B 0.15% gtts & Flucytosine
Itraconazole (1% cream + 200-400 mg PO) & silver sulfadiazine

All topical medications are delivered hourly around the clock.
(Adapted from Abad JC, Foster CS. Fungal keratitis. Int Ophthalmol Clin 1996;36(3):1-15.)

Drug classes used to treat fungal keratitis include polyene antibiotics (nystatin, amphotericin B and natamycin), pyrimidine analogs (flucytosine), imidazoles (clortrimazole, miconozole, ketoconazole), triazoles (fluconazole and itraconazole) and silver sulfadiazine. Steroids are strictly contraindicated.27 (See Table 1, "Medical Therapy for Fungal Keratitis," above.)

Herpes simplex virus dendrite ulcer (sodium fluorescein staining).

Herpes Simplex Virus Keratitis
Herpes simplex virus takes two forms: HSV type 1 (predominately oral) and HSV type 2 (predominately genital). Ocular HSV is primarily caused by HSV type 1 and is transmitted by direct contact or by exposure to secretions containing active virus cells.33 Ocular HSV presents as primary HSV, neonatal HSV, and recurrent HSV. More specific forms of recurrent HSV include epithelial infectious ulceration and trophic ulceration. (Next month, part two of this series will address other forms that represent stromal involvement.)

Primary HSV infections typically occur before the age 5 and most commonly manifest as an upper respiratory illness. Vesicular skin and oral mucosa eruptions are uncommon. Rarely, the eye will be involved as a follicular conjunctivitis, non-descript epitheliopathy or ulcerative blepharitis. Infants may contact neonatal HSV during delivery, a form that is more commonly caused by HSV type 2. Ocular manifestation can include conjunctivitis, keratitis, stromal immune reaction, and cataract.33

Herpes simplex virus dendrite ulcer (non-stained).

Within days the HSV, which causes the primary infection, travels to the trigeminal ganglia, ciliary ganglia, mesencephalic nucleus or sympathetic ganglia and becomes latent. Once latency occurs, the virus has the potential for future reactivation.34 Systemic illness, local trauma, immunosuppression, sunlight exposure and extreme psychological stress can trigger reactiva- tion.35 Reactivation results in recurrent epithelial and stromal HSV. Infectious corneal epithelial disease manifests as infectious dendritic ulceration and trophic ulceration.

HSV dendritic keratitis typically begins as an irregular, often linear epithelial disruption, which is easy to misdiagnose. The viral cells migrate from their latent resting area and actively replicate within the corneal epithelium. As the disease

Herpes simplex virus geographic ulcer.

progresses, it will assume the classic dendritic ulcer shape with terminal end bulbs. The edges of the ulcer will be slightly raised due to the presence of edematous epithelial cells with live, replicating virus cells.33,35 The devitalized cells in the terminal end bulbs will stain well with rose bengal. Corneal sensation is typically greatly diminished due to recurrence with subsequent accumulated damage to the trigeminal nerve. The patient typically is photophobic with a varying amount of discomfort.

HSV is largely unilateral; bilateral involvement occurs in only 2-7 percent of cases.33,36 If ulceration or edema encroaches upon the visual axis, vision will also be reduced. There may be a mild stromal haze beneath the dendritic ulcer. Typically, this is merely a diffusion of virus cell particles and not a stromal immune response. Most HSV dendritic ulcers are uncomplicated with only a mild stromal reaction that is limited to the anterior stroma and will spontaneously resolve within two weeks. Only after several occurrences will vision or globe integrity be severely threatened. Occasionally, these lesions will become more refractory or have more associated complications. In rare cases, the ulcer will enlarge to form a geographic ulcer. In some cases rather severe anterior uveitis can form.

Herpes simplex virus trophic ulcer.

Recurrent HSV ulceration damages both corneal sensation and basement membrane and can lead to trophic ulceration. Trophic ulcers are oval and vary in size. They occur as an epithelial ulcers that do not completely heal or an area of recurrent epithelial breakdown in a recently healed area. No live virus is present. The edges are often loose and gray. There will be stromal haze, and the lesion will stain poorly with rose bengal.

These defects may persist for months and have the possibility of stromal melting and perforation and secondary opportunistic bacterial infection.33,35

Treatment of HSV dendritic keratitis involves topical antiviral medications such as vidarabine oint- ment (Vira-A) and trifluridine solution (Viroptic). Each medication is effective against HSV.

However, trifluridine solution given nine times a day is currently the drug of choice in the United States due to its effectiveness and ease of use. Use it until its evident the ulcer is resolving, then taper rapidly. Should resolution not occur in 3-4 days, suspect clinical resistance and choose another antiviral medication.

In Europe the drug of choice is topical acyclovir, which is as effective as trifluridine but does not have its high degree of local toxicity.37 Should concurrent anterior uveitis and ocular pain be present, add cycloplegic agents such as homatropine 5 percent or scopolamine 0.25 percent. Avoid topical corticosteroids when active epithelial HSV is present.

Oral acyclovir 400mg five times per day offers specificity, potency and ocular penetration adequate to treat HSV keratitis, and is as effective as trifluridine.35 However, use oral therapy for HSV keratitis only if topical therapy is neither available nor practical.

Oral acyclovir is advocated for use in the management of HSV anterior uveitis in patients receiving topical corticosteroids and trifluridine prophylaxis.38 Oral acyclovir does not assist, though, in preventing stromal keratitis or iritis in patients with HSV epithelial keratitis.39 To date, the most significant role of oral acyclovir is in its prophylactic ability, at 400mg PO BID, to reduce the recurrence of HSV dendritic keratitis.40

Treatment of trophic HSV ulcers involves healing the damaged basement membrane as well as the epithelium. Use copious irrigation at first, often with a bandage contact lens of high water content. Topical prophylactic antibiotics should also be employed. In cases of significant stromal inflammation, you may cautiously introduce low-potency topical corticosteroids with concurrent prophylactic topical antiviral medications.35

Herpes zoster virus skin lesions.

Herpes Zoster Keratitis
Varicella zoster virus (VZV), also known as herpes zoster virus (HZV), causes both varicella (chickenpox) and herpes zoster (shingles), and the recurrent ocular infection herpes zoster ophthalmicus (HZO).33 The virus gains access during primary infection to the sensory ganglia innervating select dermatomes. The thoracic nerves with corresponding dermatomes are the most frequently infected, followed by the cranial nerves.

Of the cranial nerves, the trigeminal nerve is most frequently infected, with the ophthalmic division the most common site. Involvement of the nasociliary branch will give vesicular eruptions on the side of the nose (Hutchinson's sign) and an 85 percent likelihood that the eye will be involved. However, 61 percent of cases with eye involvement do not have Hutchinson's sign.41

Herpes zoster infection begins with a prodromal phase of flu-like illness followed within several days by neuralgia, which may be quite intense. Soon afterward there will be vesicular skin eruptions corresponding to the area of the affected dermatome. In trigeminal involvement, these eruptions will not cross the midline of the face.

Herpes zoster virus epitheliopathy.

Corneal infection by HZV likely represents direct infections by the virus. Often, the keratitis will present years after the original infection. The most common manifestations of HZV corneal infection are punctate keratitis and pseudodendritic ulcers. The pseudodendrites in HZV differ from the true dendrites in HSV by lacking terminal end-bulbs. They are also smaller, more linear and branch less.

Other corneal manifestations of HZV include endothelialitis, stromal infiltrates, disciform keratitis, and exposure keratitis.42 Corneal sensation is even more markedly reduced in HZV than HSV. As a result, neurotrophic keratitis, trophic ulcers and corneal melting with perforation are more significant concerns.

Treatment of HZV epithelial keratitis involves systemic antiviral therapy, gentle debridement with a sterile cotton tip, and prophylactic topical antibiotics. Topical antiviral medications are ineffective. Acyclovir 800mg PO five times per day for 10 days is the traditional treatment for HZV.43 Famciclovir 500mg PO TID for seven days has recently become a more popular option due to an easier dosing schedule.33 Valacyclovir is another new, popular option. It is of utmost importance to begin oral antiviral therapy within 72 hours of skin eruptions. This reduces the incidence and severity of post-herpetic neuralgia.

Subepithelial infiltrates in epidemic keratoconjunctivitis.

Adenoviral Keratoconjunctivitis
Epidemic keratoconjunctivitis (EKC), caused by adenoviral serotypes 8, 19 and 37 is one of the more virulent adenoviral ocular infections.44-45 Modes of transmission include hand-shaking, finger-to-eye contact, medical instruments and waiting room chairs, among others.46 Ocular signs and symptoms include photophobia, ocular irritation, lid edema, preauricular adenopathy, follicular response, pseudomembrane formation, subconjunctival hemorrhage, serous discharge and corneal involvement.

Corneal involvement in EKC manifests as a diffuse superficial punctate keratopathy, when active virus cells replicate within the epithelium. Subepithelial infiltrates eventually develop under areas of epitheliopathy as the immune system attempts to eradicate the organism. Should the visual axis become involved, acuity may fall precipitously.

Follicular reaction indicating adenoviral infection.

Management is supportive. Prophylactic antibiosis is unnecessary as the epithelium is typically not compromised enough to cause concern about secondary bacterial infection. In fact, the risk of antibiotic toxicity outweighs any positive benefit. Some doctors advocate topical steroids in cases where subepithelial infiltration decreases visual acuity. While steroids will ameliorate the signs and symptoms, opponents of this therapy note that steroids will actually prolong the course of the disease by reducing the immune system's ability to suppress live virus cells.47 Topical non-steroidal anti-inflammatory drugs may ameliorate the patient's symptoms without affecting viral clearance.47

A new medication in development heralds much promise. Cidofovir (Vistide) is an antiviral agent that has been used intravenously to treat cytomegalovirus retinitis. A topical form of this drug has been effective against adenoviruses that cause EKC, and has even shown activity against Epstein-Barr virus and herpes (simplex and zoster) virus. This drug should be commercially available in the near future.

Thoroughly understanding the infectious threat to the cornea and the means available to respond to that threat is a crucial component of our optometric practice today. Next month, we'll look at how the cornea typically responds to infection, the corneal inflammatory response.

Dr. Sowka is an associate professor at Nova Southeastern University College of Optometry in Ft. Lauderdale, Fla., where he teaches the courses in glaucoma and retinal disease. Dr. Kabat is an associate professor there where he is director of the college's externship program. They are co-authors of Review of Optometry's Handbook of Ocular Disease Management and are Contributing Editors for Review of Optometry.

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