Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

520 CHAPTER 26 Diseases of the Cornea

or concurrent use of steroids, a compromised immune system, recent ocular surgery, dry eyes, epithelial damage, neuroparalytic keratopathy,Bell’s palsy,rheumatoid arthritis, patching, and malnutrition.

If CIE is diagnosed, treatment should be directed at resolving any underlying etiology such as blepharitis and/or conjunctivitis (see Chapters 23 and 25). Topical 1% prednisolone acetate or 0.1% fluorometholone four times a day is the mainstay treatment to reduce inflammation and aid resolution of the infiltrates. Antibiotic drops such as tobramycin are recommended four times a day as prophylaxis, particularly if there is any associated epithelial staining. Alternatively, a steroid–antibiotic combination product may be used to assist patient compliance. The patient should be reexamined in 2 to 3 days and should exhibit definite improvement in both signs and symptoms.The topical steroid should be tapered,with the goal of discontinuing the drug in approximately 2 weeks.

If a definitive diagnosis between CIE and bacterial keratitis cannot be made, corneal cultures should be obtained before starting antibiotic or steroid therapy. If multiple risk factors are present, treat the condition as a bacterial keratitis and reevaluate within 24 hours to assess any changes in corneal health.

Bacterial Corneal Ulcers

Etiology

Bacterial corneal ulcers, also known as bacterial keratitis, most often occur in eyes susceptible to infection by preexisting conditions. There are many predisposing risk factors, and their incidence in patients with bacterial ulcers varies over time, with patient characteristics, and from region to region. Studies worldwide continue to show contact lens wear, particularly extended contact lens wear, and trauma to be the leading risk factors for the development of bacterial keratitis. Other reported predisposing factors include a history of HSV, ocular surface disease, dry eye, systemic disease (diabetes mellitus, rheumatoid arthritis), steroid use, smoking, alcoholism, malnutrition, immunocompromised status, and low socioeconomic status. Males are more likely to have corneal ulceration than females. Ultimately, any condition that causes epithelial damage, such as bullous keratopathy, RCE, eyelid abnormalities, and neurotrophic keratitis, may increase the risk of infectious corneal ulcers. Furthermore, prolonged use of prophylactic antibiotics can cause corneal ulcers due to an overgrowth of resistant bacteria.

Corneal ulcers are bimodal in occurrence, with the highest incidence in patients in their twenties and those in their sixties to seventies. This pattern can be attributed to the increased incidence of trauma and contact lens wear in the younger group and to ocular surface disease and eyelid disease in the older group.

The type of bacteria isolated from corneal ulcers is influenced by several factors, including the presence of

predisposing conditions, the examiner’s technique, the media used for isolation and culture, the patient’s age, and the patient’s geographic location. Frequent isolates from bacterial corneal ulcers include Pseudomonas aeruginosa, Staphylococcus aureus, Moraxella, Streptococcus pneumoniae, α-hemolytic Streptococcus, Staphylococcus epidermidis (coagulase-negative Staphylococcus), Klebsiella, Proteus, and Serratia. The main bacterial isolates in children vary somewhat among studies, but most commonly include gram-positive organisms such as Staphylococcus and α-hemolytic streptococci and gram-negative organisms such as Pseudomonas in large numbers.

The clinical appearance of bacterial corneal ulcers is similar irrespective of the causative organism, and laboratory studies are needed to make a definitive diagnosis. It can be useful, however, to evaluate the clinical appearance as an aid in choosing the initial antibiotic (Table 26-5). In general, ulcers caused by gram-negative organisms are diffuse and gray-white, have a “wet’’ or “soupy’’ appearance, and have abundant mucopurulent discharge. The central cornea often is involved and the ulcer spreads rapidly. Gram-positive organisms cause more discrete round or oval ulcers. These are also graywhite but are “drier’’ in appearance. Some of the grampositive organisms can cause a severe anterior chamber reaction.

A rare microbial keratitis known as infectious crystalline keratitis, characterized by branching intrastromal crystalline opacities that appear like cracked glass or needles in the anterior and mid-corneal stroma, has been reported. It presents with minimal inflammation due to the presence of biofilm, which is involved in phagocytosis suppression and interferes with polymorphonuclear chemotaxis. Predisposing factors may include previous corneal surgery;herpetic keratitis;neurotrophic keratopathy; topical, periocular, and intravitreal corticosteroids; and topical anesthetic abuse. Although it progresses slowly, it responds poorly to treatment with antibiotics because of the existence of biofilm produced by the causative organisms. Streptococcus viridans is most commonly associated with infectious crystalline keratitis; however, Staphylococcus epidermidis, Pseudomonas, Haemophilus, Enterococcus, Mycobacterium, Candida, and Alternaria have also been implicated. No significant clinical features differentiate the different pathogens, so laboratory evaluation is highly suggested to guide antimicrobial or antifungal therapy.

Diagnosis

Patients with infectious corneal ulcers present with similar symptoms regardless of the causative agent. These symptoms include photophobia, decreased visual acuity, redness, swelling of the lids, discharge, reports of a “white spot’’ on the eye, and variable degrees of pain. Patients with ulcers caused by Moraxella are less likely to report pain, as are patients who have corneal hypoesthesia.

Slit-lamp examination typically reveals moderate to severe edema and inflammation of the lid and conjunctiva, a purulent discharge, and ulceration of the corneal epithelium (Figure 26-43). As previously described, these ulcerations can take on many appearances, usually accompanied by surrounding corneal edema and stromal infiltration beneath the ulcer. A mild to severe anterior chamber reaction, which can cause hypopyon, cataracts,

Figure 26-43 Bacterial corneal ulcer with a hypopyon. (Courtesy of Pat Caroline.)

synechiae, and elevated IOP, also is frequently associated with corneal ulcers. Descemetoceles, perforation, and scarring have been reported.

A thorough history should be performed on all patients with corneal ulcers to determine which risk factors, if any, are present. The severity of the corneal ulcer should be determined by performing a detailed clinical examination, including slit-lamp biomicroscopy. The initial antibiotic regimen should be selected based on patient history and clinical appearance. For instance, a patient who wears extended-wear soft contact lenses and presents with a very large ulcer of short duration is more likely to have a Pseudomonas infection and should be treated with agents known to be effective against this organism (Figure 26-44). Photodocumentation or detailed corneal diagramming, including size, location, neovascularization, depth of hypopyon, and depth of the ulcer, should also be performed to allow accurate monitoring of the lesion.

The role of culturing in the management of corneal ulcers is a topic of ongoing debate in the ophthalmic literature. Advantages of performing smears include immediate determination of the presence of bacterium in the ocular tissues and whether the organism is gram-positive or gramnegative. Cultures can help determine the actual pathogen and may be useful in determining an alternative antibiotic if initial therapy is ineffective. Organism sensitivities allow

522 CHAPTER 26 Diseases of the Cornea

Figure 26-44 Pseudomonas corneal ulcer. (Courtesy of Pat Caroline.)

selection of the most appropriate antibiotic and prevent overuse of ineffective antibiotics, which can cause corneal toxicity. Studies have shown that appropriate initial therapy is a very important influence on the outcome of severe corneal ulcers. An additional advantage to culturing is that it allows ocular microbiologists to identify varying patterns of responsible microorganisms and to detect emerging resistance. Continual observation of keratitis isolates and their vulnerability provides guidelines for developing treatment recommendations.

Although many authors and corneal specialists advocate microbiologic studies before the treatment of ulcerative keratitis, surveys show that many general ophthalmologic practices are likely to forgo scrapings and cultures for ulcers that appear less severe. Common reasons for not culturing before treatment include the high cost in time, equipment, and financial resources; the poor isolation rate; and the high success rate of treating empirically. Studies have shown that patients treated in general ophthalmology clinics tend to have smaller more peripheral ulcers that did not require culture data for modification of therapy because they typically respond to empiric broad-spectrum antibiotics.

Until controlled studies are undertaken to determine the true costs, risks, and benefits of corneal cultures, consensus about the need for cultures before treating corneal ulcers is unlikely. Conservative management supports the use of corneal cultures before treatment of any infectious corneal ulcer. Other options include reserving microbiologic studies for severe or sightthreatening ulcers or those suspected of being nonbacterial. Looking at the characteristics of patients for which medical therapy is more likely to fail may be helpful in determining which ulcers need to be cultured under this model. These characteristics include older patients, individuals treated with topical steroids, those with a past history of ocular surgery, or those who have very poor visual acuity at presentation. Ulcer characteristics which increase the risk of failure include a central location, a larger size at presentation, limbal involvement,

and hypopyon. Culturing would also be indicated for patients who are monocular, have trauma from vegetable matter, or have ulcers that are not responding to therapy.

Microbiologic evaluation of a corneal ulcer is aimed at determining the causative organism and instituting appropriate treatment. It has been demonstrated that more positive cultures are obtained by using a calcium alginate swab instead of a platinum spatula (better for retrieval of fungi). Culture specimens of the conjunctiva and eyelid margins are acquired with a calcium alginate swab moistened with thioglycolate or trypticase soy broth.The specimens are directly plated onto solid blood and chocolate agar plates using an “R’’ and “L’’ pattern for the lids and a horizontal and vertical line for the conjunctiva. A new swab is used for each area cultured. These specimens are collected without anesthesia because the preservative in the anesthetic can inhibit bacterial growth. Rayon, Dacron, and cotton swabs are not recommended because they also may inhibit the growth of some bacteria, although Dacron has been reported to be acceptable. Moistening the swab increases patient comfort and the number of bacteria that are collected and released when plated.

For the second step, a topical nonpreserved anesthetic solution is instilled and a sterile platinum spatula is used to obtain material from the corneal ulcer for Gram and Giemsa staining. This material should be smeared onto clean glass slides, heat fixed with an alcohol lamp for gram staining and air dried for Giemsa staining, and then stained following each stain manufacturer’s suggestions. Gram stains are useful for determining if the most prevalent organism is gram-positive or gram-negative, but it is important to realize that the topical anesthetic can cause damage to the cell walls of gram-positive bacteria, causing them to stain more like gram-negative organisms. Gram stains correlate with culture results in approximately 65% to 77% of cases. Giemsa stains are useful for determining the type of inflammatory cell present and, more importantly, can reveal fungal components.

In the third step a sterile platinum spatula is used to scrape the corneal ulcer and, without cutting into the media, two blood agar plates, one chocolate agar plate, and a Sabouraud’s dextrose agar plate without cycloheximide are inoculated with one row of “C’s’’ each. One blood agar plate is stored at 37°C. The other blood agar plate and the Sabouraud’s agar are stored at 25°C to improve the chances of fungal growth. Aerobic and facultatively anaerobic bacteria, such as Neisseria and Haemophilus, are more likely to grow on the chocolate agar plate.

The next step is to gently rub the ulcer with a sterile calcium alginate swab moistened with thioglycolate broth or trypticase soy broth and inoculate three rows of “C’’ on each of the blood, chocolate, and Sabouraud’s plates. This swab is placed in a tube of thioglycolate broth medium to isolate anaerobes. A freshly moistened swab should then be rubbed across the corneal ulcer and used

to reinoculate the same “C’’ streaks on the agar plates. This swab should then be placed in trypticase soy broth. If there are any indications that the corneal ulcer may be caused by Acanthamoeba, cultures also should be performed on non-nutrient agar with an Escherichia coli overgrowth. The use of both the swab and the spatula has been suggested because filamentous bacteria or fungi may be cultured more easily with the spatula.

Twenty-four to 48 hours are needed to obtain information from cultures. From 28% to 93% will be culture positive, with an average around 50%. If a fungal ulcer is suspected, 2 to 6 weeks are necessary before the cultures should be declared negative. Some of the bacteria recently considered pathologic instead of normal flora also take longer to grow on cultures. These include Diphtheroids, which require 1 week to grow, and Mycobacterium, which may require as long as 8 weeks to grow on routine culture media.

A recent study compared the microbiological yield of cultures established by direct inoculation of media versus indirect inoculation by means of Amies without charcoal transport medium. For bacterial ulcers, all cultures that were positive after direct plating were also positive after passage through transport medium at either 4 to 8 or 24 hours. Additionally,all cultures that were negative after direct plating were also negative after both 4 to 8 and 24 hours in transport medium.Thus it was concluded that cultures obtained by means of Amies medium held for up to 24 hours appear to produce positive cultures at a rate comparable with direct plating for bacterial ulcers. The results of this study provide encouraging data that clinicians can comfortably use an Amies transport medium to culture bacterial corneal ulcers as an alternative to in-office direct plating.

Once an organism has grown on culture, sensitivity testing can be performed to determine which antibiotics are the most effective.The most commonly used method, the Kirby-Bauer diffusion disc system, usually takes 48 hours to perform. Unfortunately, it can be inaccurate because of the lower concentrations of antibiotic on the test discs compared with levels that can be achieved in the cornea through topical application. In addition, some topical ocular preparations are not available on discs for sensitivity testing.

Management

Treatment of microbial keratitis is started immediately irrespective of whether microbiologic evaluation has been performed. The best antimicrobial agent or agents to use initially is debated in the ophthalmic literature. The two main choices for initial antibiotic treatment are the combination of two fortified antibiotics, such as cefazolin and tobramycin, or monotherapy with topical fluoroquinolones. Just as with the decision to culture, the choice of antibiotic is often influenced by history and clinical presentation. Milder presentations, in low-risk

patients, are often treated successfully with fluoroquinolone monotherapy.

Initial treatment has traditionally included broadspectrum antibiotics that were chosen based on the Gram stain results, history, and clinical impression. If no organisms or multiple organisms are seen on the Gram stain or if there are risk factors that differ from the Gram stain result,treatment is initiated with cefazolin (50 mg/ml), one drop every 15 to 30 minutes, and gentamicin or tobramycin (13.6 mg/ml),one drop every 15 to 30 minutes. This is the most common fortified antibiotic treatment suggested for sight-threatening infections and is often considered the standard against which other treatments are compared. When initiating treatment, it is important to give a loading dose by instilling five drops of each of the suggested antibiotics, 1 minute apart.

The advantages to using fortified antibiotics include broad-spectrum coverage when the pathogen is not clearly identified and the use of a specific antimicrobial known to be effective against the type of organism identified by staining. The disadvantages to this method include the need to have the fortified drops prepared by the pharmacy (few pharmacies do sterile compounding), expense, the use of multiple drops, corneal toxicity, stinging upon instillation, and the need to keep cefazolin refrigerated to prevent discomfort from a change in pH. Prepared solutions of fortified tobramycin and cefazolin also have a short shelf-life of 4 weeks.

The fluoroquinolones have advantages over combined fortified antibiotic therapy.They are considered by many to be an excellent choice for initial treatment of non–sight-threatening ulcerative keratitis.They are readily available as commercially prepared medications that do not need to be fortified to be effective. As a result, there is less chance of contamination and less epithelial toxicity compared with fortified drops. Their wide spectrum of activity allows the patient to use only one medication, and, when compared with fortified antibiotics, they cause less discomfort upon instillation and are also less expensive.These attributes may increase patient compliance.

The second-generation fluoroquinolones, ciprofloxacin and ofloxacin, are approved by the U.S. Food and Drug Administration (FDA) for the treatment of bacterial corneal ulcers.The use of ciprofloxacin and ofloxacin has provided successful coverage against most of the frequently encountered gram-positive and gram-negative pathogens; however, the increasing number of bacterial strains resistant to these fluoroquinolones is becoming a concern when they are used as monotherapeutic agents. Reports have shown an increased resistance of

Staphylococcus aureus, coagulase-negative Staphylococcus species, Streptococcus, and aerobic gram-positive rods. Additionally, several centers have reported emerging resistance of Pseudomonas aeruginosa. Moxifloxacin and gatifloxacin are two fourth-generation fluoroquinolones introduced for topical ophthalmic use. In vitro studies have confirmed these medications have enhanced

524 CHAPTER 26 Diseases of the Cornea

activity against S. aureus isolates, coagulase-negative

Staphylococcus, and Streptococcus and certain strains of atypical mycobacteria. Other potentially beneficial features of these compounds include enhanced drug delivery into the anterior segment and lower likelihood of selecting for resistant bacterial strains.

Despite the aforementioned benefits to the fourthgeneration fluoroquinolones, both moxifloxacin and gatifloxacin are only FDA approved for bacterial conjunctivitis. A study conducted in India was among the first to validate the benefits of the fourth-generation fluoroquinolones by clinical trial on human eyes. This study compared the bacteriologic and clinical efficacy of gatifloxacin and ciprofloxacin for the treatment of bacterial keratitis. A significantly higher proportion of ulcers that had been treated with gatifloxacin exhibited complete healing compared with those that had been treated with ciprofloxacin; however, the mean time to healing of the ulcers was similar in both groups. Additionally, gatifloxacin had a significantly better action against grampositive cocci both in vitro and in vivo when compared with ciprofloxacin. Despite the generally promising results, further clinical trials are indicated on human eyes to definitively establish the role of the newer fourthgeneration fluoroquinolones as first-line monotherapy in bacterial keratitis, particularly in infections resulting from

P. aeruginosa.

Ciprofloxacin, which is available in an aqueous 0.3% ophthalmic solution and an ointment form, has a broad spectrum of action. Ciprofloxacin has been shown to be at least as successful in treating corneal ulceration as fortified antibiotics;however,as mentioned earlier,there appears to be an increasing number of resistant strains since its introduction. The usual dosage of ciprofloxacin solution for the treatment of bacterial ulcers is two drops every 15 minutes for 6 hours, then two drops every 30 minutes for 18 hours, followed by two drops every hour for 24 hours. Ciprofloxacin is then used every 4 hours for the next 12 days. Ciprofloxacin ointment also is effective in the treatment of bacterial keratitis. It is applied every 1 to 2 hours in the first 2 days and then every 4 hours for the next 12 days.

When ciprofloxacin is used in either form, a white corneal precipitate may develop in patients.This deposit, which is actually ciprofloxacin in precipitate, usually occurs at the ulcer site from 1 to 7 days after initiating treatment. Its presence makes it more difficult to evaluate the corneal ulcer and may decrease the patient’s visual acuity. Anecdotal information suggests that this decrease in visual acuity may be severe enough for alternative pharmacotherapy to be chosen in a monocular patient. The white precipitate may disappear spontaneously even with continued treatment and resolves without adverse effect once ciprofloxacin therapy is discontinued.

Ofloxacin 0.03% ophthalmic solution has also been shown to be effective in the treatment of corneal ulcers. Studies demonstrate that ofloxacin causes less burning

and stinging and less corneal toxicity than the fortified antibiotics. However, data suggest an increased risk of corneal perforation after fluoroquinolone treatment of bacterial keratitis, particularly ofloxacin, when compared with treatment with fortified antibiotics. Until further studies are conducted, extra care should be exercised in the use of these drugs.

Cycloplegic agents, such as 5% homatropine instilled three times a day or 1% atropine two times a day, may help decrease the iritis associated with infectious keratitis and decrease patient discomfort.

In situations in which patient compliance is questionable, subconjunctival injections of traditional antibiotics such as cefazolin, gentamicin, and penicillin G may be necessary. The risks of subconjunctival injections should be weighed against the benefit of constant and high corneal drug levels achieved by this method. The use of corneal collagen shields as drug delivery devices can often achieve corneal antibiotic levels significantly higher than those obtained by subconjunctival injection. The use of a collagen shield as a method for drug delivery may reduce the frequency of antibiotic instillation by maintaining a more uniform drug concentration. It also has been suggested that collagen shields may compete for the collagen-damaging enzymes released by Pseudomonas. When considering the use of corneal collagen shields with combination drug therapy, drug compatibility must be considered. For example, vancomycin and gentamicin have been combined effectively; however, gentamicin and cefazolin precipitate and penicillins inactivate aminoglycosides. Unfortunately, collagen shields are often uncomfortable, and many patients do not tolerate them well.

It is important to determine whether hospitalization is necessary by evaluating the likelihood of corneal perforation as well as the patient’s ability to comply with the frequency of drop instillation and the follow-up schedule. The patient must be examined at least daily to evaluate the size and depth of the ulcer, the degree of anterior chamber reaction, the development of satellite lesions, and the amount of pain the patient is experiencing. Ulcers caused by gram-negative organisms often appear worse in the first 24 hours after initiation of therapy, even if treatment is successfully decreasing the bacterial count. In milder ulcers it is possible to see subtle signs of improvement after 18 to 24 hours of appropriate therapy. If the ulcer is no worse, the original antibiotics are continued for at least 36 to 48 hours. If the ulcer appears worse, therapy should be changed based on the culture results, which usually are available after 48 hours. As the cornea is assessed, it is important to consider the potential for toxicity caused by the antibiotics. If performed, the results from sensitivity testing can be used to alter the medication schedule, to discontinue the less effective drug if two are being administered, or to substitute equally effective medications if the patient is experiencing an adverse reaction to the original antibiotic(s).

As the corneal ulcer responds to antibiotics, the frequency of instillation can be tapered slowly. Patients with ulcers caused by gram-negative rods must be tapered very slowly and may be on medications for as long as 2 to 4 weeks. Patients should continue to use antibiotics for 1 week after resolution of the ulcer. If the ulcer is not responding to treatment, the possibility of nonbacterial causes must be considered, and corneal scraping may need to be repeated. If possible, antimicrobial therapy is discontinued for 24 to 48 hours before the scraping and culturing.

The use of topical steroids for the treatment of bacterial corneal ulcers is controversial. Because some of the damage that occurs with bacterial corneal ulcers is inflammatory in nature, some authors believe topical steroids may be used if adequate bacteriocidal drugs are instilled concurrently. However, the efficacy and safety for the use of topical steroids in bacterial keratitis have not been determined. Conservative therapy advocates that steroids should not be used until the infecting organism and the most effective antibiotic have been identified through microbiologic evaluation. Furthermore, steroids should not be used until progressive improvement of the ulcer has been noted for 2 to 3 days.At that time, 1% prednisolone acetate, loteprednol, or 0.1% dexamethasone might be considered if the infiltrate is compromising the visual axis. If topical steroids are used, they are typically administered two to four times a day, and the antibiotic must be instilled more frequently than the steroid. Additionally, it is important to monitor the patient very closely because steroids decrease the host response to bacteria.

The use of steroids is contraindicated in eyes in which there is a threat of perforation, because the steroid negatively affects collagen synthesis. When a penetrating keratoplasty is necessary, steroids may be used up to 24 hours before surgery to lessen postsurgical inflammation and improve the chances of success.

VIRAL KERATITIS

Epidemic Keratoconjunctivitis

Etiology

As its name implies, epidemic keratoconjunctivitis (EKC) is highly contagious and communicable. It is typically caused by adenoviruses, with types 8, 19, and 37 most commonly reported. Adenoviruses can cause severe epidemics and can be spread by finger-to-eye contact, medical instruments such as tonometers, and possibly chairs, magazines, and other articles found in the practitioner’s reception area.The contagious period may last as long as 3 weeks,and the virus is recoverable from all body secretions the first 10 days after ocular involvement occurs.

It has been shown that adenovirus type 8 survives up to 4 days on a metal tonometer; type 19 has been recovered

up to 8 days from paper and 35 days from dry plastic. The incubation period from exposure to onset of symptoms is 4 to 18 days, with a mean of 10 days.

Diagnosis

Patients usually present with complaints of acute onset of ocular redness, foreign body sensation, burning, profuse tearing, lid swelling, photophobia, and lid matting, especially in the morning. The symptoms typically are unilateral, with the second eye becoming involved over time. Because of systemic immune responses, the second eye usually is affected less severely than the first.

History often elicits an acquaintance, family member, or coworker with similar signs or symptoms. These symptoms are usually more severe in adults. Rarely, the patient reports a low-grade fever and upper respiratory symptoms.

Examination typically reveals a marked conjunctivitis with a primarily follicular and papillary response of the palpebral conjunctiva.The follicles typically are worse in the inferior palpebral conjunctiva, with papillae more common in the superior. Preauricular lymphadenopathy is present in about 64% of patients at presentation and lasts approximately 1 week. Small subconjunctival hemorrhages are not an uncommon characteristic.

The conjunctivitis and symptoms last 7 to 16 days, with a mean between 8.6 and 10 days. A diffuse superficial epithelial keratitis usually develops in the first week and may be caused by proliferation of live virus within the corneal epithelium. In approximately 1 week this fine keratitis progresses to become deeper, positively staining, slightly elevated focal epithelial lesions. These epithelial lesions fade slowly, usually disappearing by 4 weeks.

Granular or fluffy subepithelial opacities typically develop under the focal epithelial lesions 11 to 15 days after the onset of symptoms (Figure 26-45).These lesions likely represent antigen-antibody complexes that form in response to the viral antigen. Subepithelial infiltrates occur in 10% to 90% of cases depending on the serotype of the causative agent. Severe subepithelial infiltrates may decrease the patient’s visual acuity to 20/200 or worse. They can last from 3 months to 2 years and may cause permanent focal anterior stromal scars.

Additional findings in EKC can include pseudomembrane formation (Figure 26-46) and corneal epithelial sloughing. Symblepharon, scleritis, and anterior uveitis rarely develop. Nasolacrimal system obstruction due to inflammation or adhesion of opposing surfaces, as occurs in symblepharon formation, also is a rare complication.

Confirmatory laboratory testing has been limited to viral cultures with subsequent immunoassay testing, which has limited its use, making reliance on history and clinical signs for diagnosis. A new in-office test for the adenovirus has been marketed. The RPS Adeno Detector is a 10-minute, in-office, lateral flow immunoassay that detects the presence of adenovirus in suspected

adenoviral conjunctivitis. The test possesses both good sensitivity and specificity for the detection of adenovirus.

Management

Treatment of EKC is primarily supportive. It is very important to inform the patient of the expected course of the disease, including the likelihood that the symptoms will increase in severity for several days and then

Figure 26-46 Pseudomembrane (arrow) located in inferior fornix of an EKC patient. (Courtesy of Pat Caroline.)

spontaneously resolve in 2 to 4 weeks. Artificial tears or lubricants, topical ophthalmic decongestants, and cold compresses may be used for symptomatic relief. Cleaning mucus from the lids and lashes and the use of oral analgesics and sunglasses also may increase patient comfort.

It is equally important to warn the patient of the contagious nature of EKC.The patient should be instructed to wash his or her hands frequently, to use separate towels and soap, to dispose of facial tissues, and to avoid direct contact with others. It may be necessary to instruct the patient to remain at home for up to 2 weeks after the onset of symptoms. To avoid spreading EKC to other patients and staff members in the practitioner’s office, it is important to minimize the number of return visits, isolate affected patients from others by using a single room for examining these patients when possible, and disinfecting one’s hands and instruments carefully between each patient. EKC can be cultured from the hands of approximately 50% of patients with this condition. Conventional hand washing has been shown to be an unreliable method of removing adenovirus from contaminated hands, so gloves should be used whenever examining these patients.

There are promising new drugs,such as N-chlorotaurine, in FDA trials as potential treatments for adenoviral infections. N-chlorotaurine has demonstrated good efficacy in vitro in treating adenovirus and is now currently being investigated as a potential treatment for patients with adenoviral infections.

The appropriate use of topical anti-inflammatory agents to control patient symptoms poses a clinical challenge in the management of patients with EKC. The use of topical ophthalmic steroids is not recommended by most authors as a general course; however, their use to enhance patient comfort and reduce severe inflammation during the acute phase of EKC is fairly widespread in clinical practice. As a result of their effective anti-inflamma- tory and anti-immune activity, topical ophthalmic steroids may be necessary if central infiltrates are affecting visual acuity or if signs and symptoms are particularly severe. When necessary, a mild steroid such as 0.5% loteprednol or 0.1% fluorometholone alcohol two to four times a day is usually sufficient.Tapering can be started as soon as the patient becomes more comfortable and is continued for 2 to 4 weeks. When steroids are used, the formation of subepithelial infiltrates may be suppressed, but they usually reappear when the steroids are discontinued.

No controlled studies have been performed to determine whether NSAIDs are helpful in providing symptom relief in EKC. However, in animal studies there is a suggestion that treatment of EKC using topical NSAIDs may be a safer alternative to using potent topical steroids (e.g., 1% prednisolone acetate) to control symptoms during the acute phase.

The use of topical ophthalmic antiviral agents such as idoxuridine and adenine arabinoside generally has been found to be ineffective in the treatment of EKC. However, 1% trifluridine has been shown to decrease replication of adenovirus types 8, 13, and 19 in vitro, though no strong evidence exists for its use in EKC patients.

Pharyngoconjunctival fever and acute hemorrhagic conjunctivitis are similar to EKC in presentation except for a recent history of upper respiratory problems and fever in pharyngoconjunctival fever and development of large subconjunctival hemorrhages in acute hemorrhagic conjunctivitis. The cornea typically is less involved in each of these conditions, but they are treated in the same manner as EKC.

Herpes Simplex Keratitis

Etiology

Humans are the only natural host for HSV, and more than 80% of the population carries systemic antibodies to them. However, ocular manifestation afflicts less than 1% of those exposed to the virus.The primary, or initial, HSV infection usually occurs by the age of 5 and often goes unnoticed or is too mild for the parent to seek medical attention for the child. After the primary infection, the virus settles into the central nervous system and localizes in the nerve ganglia. Latency of the virus persists for life in the innervating sensory ganglia.

Typically, but not universally, HSV type 1 infects tissue above the waist, including the oral and ocular areas. It is transmitted by kissing or other close contact with individuals who are shedding the virus in active lesions.

The virus remains latent in the trigeminal nerve, may remain in the cornea, and has been reported in tears. HSV type 2 usually infects the genital area and is transmitted sexually but can cause ocular infection if transmitted to the eye via infected genital secretions. This most commonly occurs in neonates who are exposed to the virus in the birth canal. In neonates, herpes simplex can cause a fatal systemic infection.

Both types of latent HSV are thought to be reactivated by many factors, including UV exposure, trauma, stress, extreme temperatures, immunosuppression, and menstruation.When activated, the virus travels along the sensory nerve to peripheral tissue to cause recurrent HSV infection. An estimated 300,000 cases of primary and recurrent HSV infections develop each year.

Herpes simplex keratitis (HSK) is caused by HSV type 1 in adults and is one of the most common infectious etiologies of blindness. It is second only to trauma as a cause of corneal blindness in the United States, where an estimated 50,000 new or recurrent cases are seen each year. Recurrent HSK can be reactivated by many factors in addition to those listed above. Reactivation has been reported in patients after penetrating keratoplasty, argon laser trabeculoplasty, Nd:YAG laser peripheral iridotomy, or treatment with excimer lasers, including cases in which ocular herpes had not occurred previously. It is important to realize that because most patients have latent HSV it is possible for a reactivation to occur despite a negative history of a primary infection.

The severity of HSK is related to the viral strain as well as host factors. Most published HSK studies show a male prevalence; however, when evaluating keratoplasties due to HSK, a male preponderance is not always seen. This finding suggests that females may be more likely to acquire a more severe form of HSK or more readily seek surgical intervention. Additionally, the status of the immune system plays a key role with regard to HSK severity.

Diagnosis

Although pain, photophobia, and decreased vision are reported by patients with both primary and secondary HSV ocular infection, these symptoms are usually mild during the primary infection and are accompanied by signs and symptoms similar to an upper respiratory infection such as mild rhinitis, pharyngitis, fever, malaise, and a generalized skin rash.An ulcerative or vesicular blepharitis (see Chapter 23) or an acute follicular conjunctivitis often occurs in patients with primary HSV infection. Although the preauricular lymph node often is swollen, the patient frequently reports no node tenderness.

Corneal involvement in the form of epithelial keratitis or dendrites occurs in up to 63% of initial clinical HSV infections.These tend to be small, late in onset, and transitory, lasting only 1 to 3 days. Stromal disciform keratitis, which manifests as a round area of stromal edema with an overlying intact epithelium, is much less frequent in

528 CHAPTER 26 Diseases of the Cornea

patients with initial clinical HSV infection, occurring in about 6%.

Unrecognized primary HSV keratoconjunctivitis is most commonly misdiagnosed as EKC because of the follicular conjunctivitis, lymphadenopathy, and corneal changes. One clinical feature that is helpful in making the diagnosis is the tendency for primary HSK to be unilateral and EKC to be bilateral.

After the primary infection the predominant form of recurrent ocular HSV infection is epithelial and stromal keratitis.A history of epithelial keratitis is not a significant risk factor for recurrent epithelial keratitis. In contrast, a previous episode of stromal keratitis significantly increases the probability of subsequent stromal keratitis. The Herpetic Eye Disease Study Group (HEDS) showed that a patient with at least one previous episode of stromal keratitis is 10 times more likely to have a subsequent episode of stromal keratitis during the subsequent 18 months. Furthermore, it was found that a progressive increase in the number of previous episodes of stromal keratitis correlated with an increasing risk of recurrent stromal keratitis. Additionally, HEDS found that stromal keratitis may occur in the absence of a history of superficial ocular HSV. The patient is usually most symptomatic during the first episode of recurrent HSK, with symptoms decreasing with each subsequent episode due to reduced corneal sensitivity. This corneal hypoesthesia is a classic but not pathognomonic sign of HSK.

Recurrent HSK has accompanying lid and conjunctival involvement in about 31% of cases.This involvement typically appears as unilateral follicular conjunctivitis with moderate to severe diffuse conjunctival hyperemia. The initial epithelial lesions of HSK are small vesicles that are generally described as punctate epithelial keratopathy. Although dendritic or ameboid keratitis is the most common manifestation of HSK (Figure 26-47), a diffuse

Figure 26-47 Typical branching pattern of dendritic epithelial herpes simplex keratitis. (Courtesy of Pat Caroline.)

punctate keratitis often develops first. This keratitis is caused by a swelling of the epithelial cells from intracellular replication of HSV and a contiguous cell-to-cell spread of the virus in the corneal epithelium. Initially, this swelling causes NaFl to pool around the cells, but within 24 hours the cells die and a coarse punctate or stellate keratitis develops. As these areas of punctate keratitis coalesce, they develop into the typical branching dendritic or ameboid herpes simplex keratitis.

Dendritic ulcers from herpes simplex stain brightly with NaFl and have dichotomous branching, terminal end bulbs, and a delicate pattern. The edges of these lesions are formed by swollen opaque cells that stain well with rose bengal. Although these lesions are typical of HSK and often suggest the diagnosis, it is important to rule out other causes of dendritiform lesions.These include pseudodendrites caused by contact lens wear, herpes zoster ophthalmicus, healing epithelial defects, Epstein-Barr, medicamentosus primarily from antivirals, corneal dystrophy, Acanthamoeba keratitis, systemic tyrosinemia type II, and Thygeson’s SPK (TSPK). Herpes simplex dendritic lesions can enlarge to form an amoeboid (geographic) shape. Stromal edema and subepithelial infiltrates can develop under the dendrite in just a few days.These infiltrates can leave faint scars in the superficial stroma, which can be useful for diagnosing previous episodes of HSK.

Noninfectious indolent epithelial ulcers also can occur in HSK.These ulcers, formerly referred to as metaherpetic lesions, tend to be ovoid, 2 to 8 mm in size, with smooth rolled edges. They may be caused by damage to the epithelial basement membrane due to inflammation, tear film abnormalities, neurotropic cornea, or toxicity from antiviral medications. These ulcers may be recalcitrant, resulting in neovascularization and scarring.

Disciform or stromal keratitis may develop beneath a dendrite in recurrent HSK, can occur months after the initial episode, or may develop without a history of epithelial keratitis or blepharoconjunctivitis. The 5- to 7-mm disc-shaped area of edema in the corneal stroma can cause folds in Descemet’s membrane. Disciform keratitis occurs in approximately 20% to 48% of patients with recurrent HSK.

Epithelial bullae can be found in some cases of disciform keratitis, as can a Wessley ring, which is composed of immune cells surrounding the discoid edema.A mild to moderate uveitis with keratic precipitates is usually present, although it may not be visible due to corneal edema. Secondary glaucoma can also develop, primarily the result of intraocular inflammation (trabeculitis).

The diagnosis of herpes simplex disciform keratitis is usually based on clinical appearance. If a history of previous episodes, ghost scars, or decreased corneal sensation is found,herpes simplex is the likely cause,but it is important to rule out other etiologies such as herpes zoster, varicella, vaccinia, mumps, and syphilis.

Necrotizing IK, a chronic form of HSK, may occur after multiple attacks. It is characterized by a white, dense,

cottage cheese–like infiltrate of the stroma with epithelial ulceration.Anterior uveitis, secondary glaucoma, vascularization, scarring, corneal thinning, and perforation can all occur with necrotizing IK.

Although not typically used, laboratory tests are available to help diagnose HSK in equivocal cases. One of the most reliable and fastest tests is the Herpchek®, which is an enzyme immunoassay test that yields results in 1 day. Additional laboratory tests include viral culture microbiologic studies, enzyme-linked virus inducible system, and polymerase chain reaction detection.

Management

Treatment of HSK is primarily based on whether the corneal condition is caused solely by active virus, as is found in epithelial dendritic keratitis, or has an immune component, as is typical of disciform keratitis. No treatment has been proven to remove the virus from the ganglia, so treatment is designed to stop the replication of the virus, eradicate live virus, reduce the rate of recurrence, and maintain visual acuity.

Treatment for corneal epithelial disease is typically started with 1% trifluridine ophthalmic drops every 2 hours, not to exceed nine times a day.Trifluridine is the drug of choice in the United States because it is the only commercially available topical ophthalmic antiviral.

If the corneal lesions are superficial, the patient is an adult, and no topical steroids have been used, minimalwipe corneal debridement can be performed as an adjunct to the use of antivirals. Gentle debridement is performed by instilling topical anesthetic drops such as proparacaine and using a sterile cotton-tipped applicator to remove the lesions.

If there is an anterior chamber reaction or if debridement has been performed, a cycloplegic agent such as 5% homatropine or 0.25% scopolamine should be used two to three times a day. Topical steroids should be tapered or discontinued in any patient using them, because they are contraindicated in the presence of active HSV corneal epithelial disease.Antibiotics have no benefit in the treatment of herpes simplex epithelial disease but can be used prophylactically if the epithelial defect is greater than 6 mm in size.

Antivirals are toxic to the corneal epithelium and may delay healing, so their frequency of use should be decreased after the first week to five times a day.Therapy should be continued for several days after healing to allow time for the dormant virus to be shed. Some authors suggest tapering antiviral medications.

Within 2 weeks of using 1% trifluridine solution, 97% of cases resolve. Although drug-resistant HSV is rare, it is possible and should be considered if there is no improvement within the first few days. If there is no improvement or an adverse reaction occurs, use of a different antiviral is indicated. Acyclovir 3% ointment, although not commercially available for ophthalmic use in the United States, has been shown to be effective and well tolerated

for treatment of HSK when used five times per day. Alternative agents such as cyclosporin A, ganciclovir gel, and cidofovir have also been shown to be useful in the treatment of HSK.

Unlike dendritic keratitis, indolent ulcers are typically very difficult to treat. Instillation of a prophylactic antibiotic, such as polymyxin B-bacitracin ointment two to four times a day, and a cycloplegic agent, such as 5% homatropine two to three times a day, is indicated.Therapeutic soft contact lens use with appropriate antibiotic therapy can also be considered as alternatives. These patients must be monitored carefully to ensure that no secondary infection develops. If the ulcer deepens, a new infiltrate forms, or if there is an increase in the anterior chamber reaction while the patient is being treated, cultures should be performed to rule out bacterial or fungal infection. Cyanoacrylate glue,conjunctival flap surgery,or tarsorrhaphy may be required if healing does not occur.

Although there may be an active viral component in disciform keratitis, treatment is typically directed toward controlling inflammation. If the disciform keratitis is very mild and off the visual axis, control of uveitis with cycloplegics such as 5% homatropine three times a day and lubricating drops for comfort are all that is needed. If the disciform keratitis is affecting vision because of its severity or location, topical steroids are indicated to shorten the duration of the stromal keratitis as shown in the HEDS. Topical antivirals should be administered concurrently any time steroids are used for this condition. Although many clinicians choose to use antivirals at the same frequency as the topical steroid, another report by HEDS suggests that antiviral use four times a day is adequate prophylaxis. Because of the possibility of active virus in disciform keratitis, it is prudent to use the lowest dose of topical steroid that will resolve the inflammation. It is also prudent to postpone the use of steroids to allow antiviral drugs to work, because this delay has been shown to have no effect on visual outcome at 6 months.

Improvement occurs quickly in disciform keratitis with topical corticosteroids, but the steroid must be tapered very slowly. It is common for the patient to instill a drop of 1% prednisolone acetate every day or every other day after 3 months of treatment. It is not uncommon to have the patient use lower concentrations of topical steroids, such as prednisolone 0.12%, every other day for more than a year. Topical antiviral agents can be discontinued when steroids are used no more than once a day. If the steroid is tapered too quickly and the disciform keratitis recurs, the topical steroid and antiviral agent should both be reinstituted at a higher frequency of instillation. Disciform keratitis generally leaves a scar after resolution of the acute inflammation (Figure 26-48). Although some success in removing herpetic scarring has been reported with PTK, penetrating keratoplasty may be necessary for the patient to regain useful vision. Unfortunately, recurrence of herpetic disease in corneal grafts can be as high as 44% in 2 years.