THERAPEUTIC
INSIGHTS
Taming Herpes Simplex Keratitis
What you need to know to recognize, diagnose and treat this recurrent condition.
By Bobby Christensen, O.D., F.A.A.O., Midwest City, Okla.
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Coordinated by Bobby Christensen, O.D., F.A.A.O. |
Two types of herpes simplex virus (HSV) exist: Type I causes cold sores and fever blisters and may involve the eye. Type II is usually sexually transmitted and rarely causes ocular problems. This month we'll investigate the trigger mechanisms related to HSV-1, and we'll discuss other facts you need to know so you can efficiently and effectively recognize, diagnose and treat this virus.
A look at HSV-1
HSV-1 keratitis is estimated to be present in about 500,000 patients per year. Many of these cases are recurrences after the primary ophthalmic infection. The rate of recurrence after the first diagnosis of infectious HSV-1 is estimated to range between 25% and 50% per year. Early and aggressive treatment can reduce healing time and prevent complications. The potential of prophylactic treatment to reduce recurrent episodes of infection is currently under investigation.
Many practitioners have reported a link between topical and oral steroid use and higher incidences of HSV-1 keratitis, with increased severity.
Identifying trigger mechanisms
Environment, trauma and chemical exposure lead to higher recurrence rates of secondary HSV-1. Sunburn, ultraviolet (UV) light exposure and cold wind can increase the incidence of recurrent infection. Trauma accounts for 10% to 20% of the recurrences. These same trigger mechanisms hold true for patients who have recurrent HSV-1 lesions on their lips.
Immune-suppressed patients tend to have more recurrences. This includes patients who have HIV and patients who are undergoing chemotherapy or radiation treatment. Several articles have reported that latanoprost (Xalatan) triggered secondary HSV-1. One study comparing latano-prost to unoprostone (Rescula) found that unoprostone was less of a triggering mechanism for secondary infection. (AM J Ophthmalmol 2001 May;131(5):643-646)
Insufficient data exist on the newer prostaglandin analog glaucoma drugs to tell if they have the same effect. For glaucoma patients who have a history of HSV-1, consider other classes of drugs (beta-blockers or alpha agonists), rather than a prostaglandin analog drug.
Laser vision correction for patients with a history of HSV-1 presents an ethical challenge. Animal studies measuring viral shedding found increased HSV-1 shedding after photorefractive keratectomy and laser-assisted in situ keratomileusis (LASIK) surgery on infected rabbit cor-nea. Both procedures seemed to increase the risk of viral shed-ding equally. Valacyclovir (Valtrex) taken prophylactically before and after surgery decrea-sed the number of virus cells in the tissue and ocular secretions. (J Cataract Refract Surg 2001 Aug;27(8):1288-1293)
Because trauma increases the recurrence rate of HSV-1, you must carefully evaluate laser vision correction risks for this group of patients before proceeding. If the patient insists on laser vision correction after being fully informed of the risk, then you should consider valacyclovir for prophylaxis.
Recognizing subjective clinical presentations
Symptoms of HSV-1 include mild to moderate pain, though the patient more often states that his eye feels scratchy or irritated, rather than painful. Photophobia is usually mild, less than in uveitis or bacterial keratitis. Injection can range from mild (grade 1) to moderate (grade 2), or, rarely, severe (grade 3). Vision is affected if the lesion is on or near the visual axis. Peripheral lesions may not reduce vision. Tearing is usually mild and depends on the level of photophobia.
History may include use of topical steroids, oral steroid treatment, trauma or immune system suppression. A history of previous HSV-1 infections should alert you to a possible recurrence. Recent trips to the beach, ski resorts or other outings where wind and UV light exposure abound are possible triggering incidents.
Establishing an objective clinical presentation
Evaluation with the biomicroscope provides most of the clinical clues. First evaluate the epithelium without dyes. Then, before instilling dyes, measure corneal sensitivity.
If an anesthesiometer isn't available to measure sensitivity, you can still perform an effective test by using a Q-tip as follows:
- Wash your hands, open the Q-tip, wet it with sterile saline and twist a wisp of cotton into a thin strand at the end.
- Explain to the patient that you're going to gently touch the surface of his healthy eye and then you'll touch the surface of his infected eye.
- Before you do this, however, explain that the healthy eye will have a discomfort level of 10. When you touch the infected eye, it may feel the same (10), less uncomfortable (0 to 9) or more uncomfortable (>10).
- Firmly touch the epithelium of the non-infected eye with the wisp. Use a second Q-tip to touch the infected epithelium with the same firmness. A sensitivity reduction in the infected eye of 8 or less is a strong clinical clue of HSV-1 infection.
It's important to remember that corneal sensitivity testing is subjective. In the early stage of infection, the eye may not have lost sensitivity, so don't base your diagnosis on this one test.
- Next, instill fluorescein and evaluate the dye pattern with the biomicroscope. An HSV-1 dendritic lesion stains brightly and the fluorescein absorbs slowly into the surrounding tissue (see middle photo on pg. 49). Rose bengal or lissamine green presents a distinctive stain pattern. Most lesions will stain faintly in the center, darker at the border and again fainter or less dense outside of the border. Note the typical rose bengal stain pattern in the top photo below.
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HSV-1 geographic ulcer staining with rose bengal. |
Dendrite, late fluorescein stain. | Punctate staining after trifluridine treatment for 7 days. |
Typically, cultures aren't initially obtained for suspected HSV-1 ophthalmic infection. If symptoms and diagnostic testing don't present a clear diagnosis of HSV-1, it's prudent to culture the infection. Should initial treatment prove ineffective and you're then suspicious of fungal or Acanthamoeba infections, obtain a culture.
Fungal or Acanthamoeba infections can often mimic HSV-1 and reports of concurrent Acanthamoeba/HSV keratitis have been established. Fluorescein and lissamine green don't diminish the virus in the ocular secretions. Rose bengal is anti-viral and is known to reduce virus in ocular secretions -- therefore don't use it before obtaining a sample for culture.
In my experience, not all HSV-1 presents with the "textbook" dendrite seen in the photos in this article or in the photos we see in textbooks. I've seen small round lesions, areas of concentrated punctate stain and small areas of linear stain. There may also be little decreased corneal sensitivity in eyes that haven't had a recurrent infection or eyes that are in the early stage of infection.
If you're not sure of the cause of the keratitis, remember to always consider HSV-1. With that in mind, stay away from topical steroids until you're sure of the diagnosis. Waiting a few days before starting steroid therapy will seldom negatively affect the outcome when treating infectious keratitis.
Treatment
The following is the typical course of treatment for HSV-1 infections.
First Day
The standard of care in the United States is to prescribe trifluridine (Viroptic). It has proven effective in treating epithelial herpetic lesions. I follow the advice of Dr. Leland Carr, dean of the Pacific College of Optometry. Prescribe trifluridine q.1.h. for 9 hours the first day. Recent studies supply evidence that debridement of the infected tissue helps reduce the recovery time.
Explain to the patient that trifluridine stings and that the eye tends to get more irritated during the course of therapy. I explain that this is a strong medication that kills the virus but also irritates the healthy cells on the front of the eye. Let the patient know that the trifluridine doesn't cause permanent harm -- it just makes the eye uncomfortable.
Until the Lesion Heals
After the first day, I reduce treatment from nine times to eight times per day throughout waking hours. I have the patient return to my office on day three of this dosing frequency. Treatment at eight times per day continues until the lesion has cleared. Most lesions will clear within 4 to 8 days. Depending on the recovery, I usually schedule the next visit for 2 to 3 days after the first follow-up visit.
After the Lesion Heals
When the eye has healed, I reduce the trifluridine dosage to q.i.d., then typically continue treatment at q.i.d. for as many days as it took for the initial lesion to clear. By days 5 to 7 from initiation of treatment, the epithelium usually has generalized stipple staining and the conjunctiva exhibits grade 1 injection from the toxicity of the trifluridine (see bottom photo at left). The epithelial staining and injection subside within a week after discontinuing the trifluridine.
Availability of drug
It may be a good idea to keep a bottle of trifluridine at the office. Start dosage immediately and if it's an after-hours appointment, let the patient take the medication home with him. We've found that some pharmacies don't routinely stock the medication and it takes 24 hours to get it from their distributor.
Educating patients
Patient education is imperative when treating any kind of ocular virus. Follow these pointers when talking to a patient about his condition:
- alert patient of any side effects he may experience while on the medication you prescribe
- discuss the possibility of recurrence
- explain the potential for stromal keratitis with more advanced cases of epithelial HSV-1
- explain the known causes for many of the recurrences
- explain the planned medication dosage and when you expect the patient to return for follow-up evaluation.
Practitioners outside of the United Stated often use acyclovir 3% ointment (Zovirax) to treat HSV-1 keratitis. Clinical trials on rabbits and humans find that recovery outcomes on acyclovir ointment and trifluridine drop are consistently the same.
Studies have been ongoing for many years to determine if taking oral acyclovir prophylactically reduces HSV-1 recurrences. The Herpetic Eye Disease Study Group followed 346 patients for 1 year with latent HSV-1, taking no preventive anti-viral (oral acyclovir). This group of patients had a rate of recurrence of 32%. The second group of 357 patients received 800 mg/d of oral acyclovir. The incidence of recurrence was 19%. (Arch Ophthalmol 2000 Aug;118(8):1030-1036)
An interesting study with rabbits with latent HSV-1 infection measured the shedding of HSV-1 virus after LASIK. Sixty-seven percent of the rabbits that didn't receive valacyclovir before LASIK had HSV-1 shedding following the procedure. The rabbits that were administered 150 mg/kg/day of valacyclovir before and after the surgery had 0% shedding of HSV-1. (Trans Am Ophthalmol Soc 2000;98:285-305)
In comparison, trials to establish drug efficacy showed that trifluridine, cidofovir, acyclovir and pencyclovir were relatively the same when it came to healing lesions. Idoxuridine (Herplex) was found to be less effective than the other drugs. ((1) Invest Ophthalmol VisSci 1999 Feb;40(2);378-384 (2) Arch Ophthalmol 1998 June;116(6);777-780 (3) Trans Am Ophthalmol Soc 2000:98:505-532)
RESEARCH ROUNDUP |
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For 1 year, the Herpetic Eye Disease Study Group followed 346 patients who had latent HSV-1 and who weren't taking any preventive anti-viral, such as oral acyclovir (Zovirax). This group had a 32% recurrence rate. A second group of 357 patients received 800 mg/d of oral acyclovir and experienced only a 19% rate of recurrence. Other study findings indicate that topical and oral steroid use increases the severity of HS keratitis in rabbits. Many practitioners report that it's linked to higher incidences of infectious keratitis with increased severity. |
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A study from Italy used heat shock-inactivated HSV-1 as a vaccination. The authors noted a significant reduction in recur-rences and that the average duration of the keratitis was reduced in the study group receiving the vaccination. (Cornea 1999 Jan;18(1):47-51)
Penciclovir ointment and ganciclovir ophthalmic gel 0.15% (Virgan) are two other anti-virals that have been and continue to be evaluated in studies for ocular use. One study found trifluridine and cidofovir to be statistically more effective than penciclovir for treatment of HSV-1 keratitis. Arch Ophthalmol 1998 Jun;116(6):777-780) Another study comparing acyclovir 3% and ganciclovir found the healing rates to be slightly better with ganciclovir than with acyclovir. The healing rates were 85% with ganciclovir and 72% with acyclovir. (Cornea 1997 Jul: 16(4):393-399)
Polyhexamethylene biguanide (PHMB) 0.02% is used in conjunction with other medications to treat Acanthamoeba keratitis. PHMB is a close relative to preservatives used in some soft contact lens solutions. It was found effective against HSV in vitro activity, but it didn't slow viral shedding in vivo. It was concluded that the concentration wasn't strong enough to be effective against HSV-1. (Cornea 1997 Sep:16(5):556-559)
Stromal herpetic keratitis has been successfully treated with cyclosporin A instilled in the eye b.i.d. as an adjunct to steroid therapy. For patients who are steroid responders, cyclosporin offers another option to help fight the stromal inflammation. Cyclosporin combined with corticosteroid treatment may offer a more aggressive treatment to help patients who have persistent stromal keratitis. This approach may allow discontinuance of the steroids earlier with slow tapering of the cyclosporin. (1) Ophthalmic Res 1997:29(6):405-408 (2) Graefes Arch Clin Exp Ophthalmol 1999 May;237(5):435-438
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CODING CUES |
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Code HS keratitis as: infectious keratitis Use these codes for office visits: 99203 or 99213 |
HSV-1 conclusions
HSV-1 is a complex disease that usually responds to aggressive treatment. We'll probably see some new medications in the future, and preventive therapy may be more important than was initially thought. Prevention of recurrent episodes by avoiding the triggering mechanisms is a part of the education and treatment plan for the patient. Be aggressive with the initial treatment plan to try to reduce the chance of secondary stromal keratitis. When you're unsure of the diagnosis, be judicious in your use of steroids.
Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.