Review of Cornea
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An Overview of Ocular Herpetic Disease

Oral antivirals are the cornerstone of therapy for ocular herpetic disease, but careful diagnosis and judicious comanagement play essential roles as well.

By William B. Potter, O.D.

Release Date: MAy 2010
Expiration Date: MAY 31, 2013

Goal Statement:

Ocular herpes is a challenge for both the optometrist and the patient. Current licensure generally allows the optometrist to prescribe the full range of anti-herpetic agents, yet many cases remain unresolved and may require subspecialty care. This course explains how to identify and treat cases of ocular herpetic disease, and when to refer patients for further care.

Faculty/Editorial Board:

William B. Potter, O.D.

Credit Statement:

This course is COPE approved for 2 hours of CE credit. COPE ID is 28164-SD. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Potter is on the speakers bureau for Alcon.


fig1The presentation of ocular herpes is a challenge for both optometrists and patients. Although current licensure generally allows the optometrist to prescribe a full range of anti-herpetic agents, many cases remain unresolved and may require subspecialty care.

The major herpes viruses that cause ocular disease—simplex and zoster—often cause ongoing immunologic reactions that outlive the active infection. Other members of the herpes family, such as Epstein Barr and cytomegalovirus, are less frequent causes of ocular pathology. So, in this article, I’ll limit the discussion to herpes simplex and herpes zoster.

The Herpes Virus

We know herpes infections have been recognized for many centuries, from Hippocrates’ description of skin lesions that “creep and crawl” to Shakespeare’s reference to “blister plagues.” More scientifically, Vidal noted human-to-human transmission in 1893, and Lowenstein found transmission in a laboratory setting in 1919.1

Patients often misunderstand the origins of herpes infections, assuming that it’s a sexually transmitted disease. Because this is true in only a minority of ocular cases, a good history and proper counseling at initial diagnosis can help overcome this notion and reduce the patient’s anxiety.

fig2

The herpes viruses are classified as DNA viruses, meaning that their genetic material is in the form of DNA, which is double-stranded. This is an important concept in understanding the therapy for herpetic infection because both topical and oral agents rely on their anti-DNA transcription properties to achieve effectiveness. Therapeutic agents prevent the viral DNA from being “read,” thereby stopping protein synthesis and replication.

The hallmark of the herpes virus family is its ability to remain latent in the sensory ganglia. The viral genome, or genetic sequence, is retained in an inactive form until the host organism’s immune system is weakened.2 While not all humans manifest herpes infection, more than 90% carry the latent virus.

An individual’s genetic makeup and immunologic status, as well as the strength of the infecting virus, determine ongoing latency or active infection. The nerve cell itself may employ peptides and hormones that keep the viral activity in check.2

Virus and Inflammation

The inflammatory phase of herpes infections can be especially damaging and difficult to manage. This may be explained by the concept of molecular mimicry, where the herpes virus causes coding of proteins that are similar to those of normal tissue. For example, it is thought that the herpes simplex virus has a coat protein called UL6, which is similar to proteins found in the human cornea. This presents an obvious problem: As the human immune system becomes conditioned to attack the offending virus, it will also tend to attack normal tissue.2 When this happens, white blood cells known as CD4+ T cells are activated, which release chemokines and Th1 cytokines, triggering a destructive inflammatory cascade.

Another possible source of inflammation in herpes simplex infection is a viral protein known as glyco-protein K. This protein apparently induces other white blood cells, known as CD8+ T cells, to come to the inflammatory site. CD8+ cells are thought to be responsible for the corneal scarring that is so familiar to the eye practitioner for its devastating visual consequences.3

fig3Identifying Ocular Herpes

Herpes simplex is the leading cause of infectious corneal blindness in the United States.4 In its epithelial form, dendritic keratitis is the most common presentation to the primary care optometrist. Confusion of these lesions with pseudodendrites is a common problem that can best be solved by remembering the two key features of the classic dendritic lesion: True dendritic lesions show arborization and terminal end bulbs.

Secondarily, the clinician can be tipped to the possibility of prior herpes infection if there exists unexplained corneal scarring, corneal hypoesthesia or iris atrophy. Pseudodendrites can be caused by contact lenses and their solutions, trauma, dry eye, and other infections, especially herpes zoster. A good history can be a key tool in differentiating such lesions.



Topical Treatment

We have a couple options for topical treatment of herpetic keratitis:

Viroptic. Viroptic (trifluridine, GlaxoSmithKline) is the cornerstone of topical treatment for herpes simplex keratitis. It is given one drop every two hours for one week in the affected eye until the corneal epithelium is sufficiently healed. Further treatment is then suggested at four times daily for another week.

This drug interferes with viral replication by blocking DNA transcription. It is very effective, though toxicity is a significant risk. Increased redness, pain, infiltrates and corneal staining, despite improvement in the dendritic lesion, suggest drug toxicity. Although the literature expresses caution at treatment periods longer than 21 days, we have seen toxicity reactions to trifluridine in as early as five to seven days.

Vira-A. Another popular topical drug, the ointment Vira-A (vidarabine, Monarch Pharmaceuticals), was used in conjunction with Viroptic, but it has been off the market for several years. Another topical antiviral, acyclovir, is used in Europe, but does not have approval for herpes simplex keratitis here in the United States.

Zirgan. In September 2009, the FDA approved Zirgan (ganciclovir gel 15%, Sirion Therapeutics) for acute herpetic keratitis (dendritic ulcers). European practitioners have had access to ganciclovir ophthalmic gel for more than 10 years. Its dosage is one drop five times daily until resolution of the ulcer, then three times daily for another seven days. Research and clinical experience will hopefully prove the effectiveness of this product now that it is available in the United States.

Oral Treatment

Oral Dosing for Herpes Simplex

If an oral agent is appropriate, a prescription for herpes simplex should be administered as follows:

  • Zovirax (acyclovir, GlaxoSmithKline) 400mg five times daily for seven to 10 days
  • Valtrex (valacylovir, GlaxoSmithKline) 500mg three times daily for seven to 10 days
  • Famvir (famciclovir, Novartis) 250mg three times daily for seven to 10 days.

Oral treatment for acute herpes simplex keratitis, though not without controversy, has become common practice. (See “Oral Dosing for Herpes Simplex,” right.) Such treatment may at least reduce the viral load in the ciliary ganglion and associated nerves, even if there isn’t a large effect in the corneal epithelium.

On the other hand, some researchers have suggested that an orals only approach is clinically effective in the absence of the potentially toxic topical drugs.5 Incontrovertible research on this topic is lacking. Because the cornea has no blood supply, the orals only approach relies on the knowledge that oral acyclovir achieves supratherapeutic levels in the precorneal tear film.6

Our treatment choice is to use topical trifluridine or the newer ganciclovir, with conservative monitoring, as well as the oral agent. Hopefully, a large sample study will vindicate the orals only approach to herpes simplex keratitis. We’ve had some success with the no topicals method in patients whose epithelium is compromised by self-treatment with over-the-counter agents or excessive topical antibiotics. While acyclovir has been a mainstay herpetic treatment for years, we tend to prefer the newer prodrug valacyclovir. Prodrugs are compounds that are converted to a more active form of the drug once introduced into the patient’s system. In this case, valacyclovir is converted to acyclovir in the patient’s intestine and liver, and it achieves effective therapeutic levels in the serum with a smaller quantity of drug required. It is then phosphorylated to its most active form within virus infected cells. Famciclovir is converted to penciclovir upon ingestion and is similarly phosphorylated within infected cells.

While these drugs are not high in systemic toxicity, patients often have mild upset stomach or headache upon starting treatment. Reassure patients in advance that these symptoms may occur, and that they generally pass. As always, take extra caution with patients who have kidney or liver dysfunction, or who are taking multiple medications. Consultation with the patient’s internist is always a wise approach.

Controversies in HSV Treatment

There are several myths that need to be debunked about herpes simplex treatment.

  • “Don’t treat the first episode.”

Although poorly referenced in the literature, some practitioners believe that it’s beneficial to defer treatment the first time a patient has an episode of systemic herpes simplex. The rationale is that the immune system mounts a better long-term response if it’s permitted to respond to the unchecked infection.

In interviewing local specialists in pediatric ophthalmology and infectious disease, I found that the no-treatment notion is disputed as dangerous because the possible manifestations of disseminated herpes outweigh the risk of a suppressed immune response. Appropriate antiviral treatment does not imply that the patient’s immune response will be underdeveloped.

  • “Don’t treat dry eye and herpes simultaneously.”

At least one study has reported favorable results when treating herpes simplex keratitis in patients who concurrently suffer from dry eye.9 The combination of punctal cautery and Restasis (cyclosporine, Allergan) therapy reduced the recurrence rate of herpes simplex stromal keratitis in a sample of 42 patients. This study is interesting because it suggests that dry eye is a stressor that may contribute to stromal keratitis in the herpes patient.

More importantly, it should prove reassuring that Restasis can indeed be used in patients who have suffered herpes simplex keratitis, albeit with close monitoring. Since its introduction, our practice has successfully prescribed Restasis for dry eye patients who have a history of herpes simplex keratitis, provided that there are no active epithelial lesions. However, we continue to respect Allergan’s comment that the product has not been studied for safety on these patients.

  • “Don’t treat herpetic eyes with topical steroids or you’ll make them worse.”

Traditional optometric teaching may have inadvertently discouraged proper usage in the early years of ocular therapeutic education. In addition, opposition to optometric drug laws had painted steroid use as inappropriate, with herpetic exacerbation as the feared endpoint.

However, topical steroid use is a required element in the treatment of several forms of ocular herpes simplex. Disciform keratitis and other stromal inflammations (to the viral coat proteins described earlier) will go unresolved without immunosuppression. Herpetic iritis is also treated with aggressive steroid use, including hourly prednisolone acetate and cycloplegia as cornerstone therapies. Similarly, Posner-Schlossman syndrome, with its elevated IOP and mild anterior chamber reaction, benefits from steroid treatment even though it may be herpetic in etiology.

The common requirements for initiating steroids are that any dendritic lesions should be reasonably healed and, if there is corneal involvement, antiviral coverage (both topical and oral) should be maintained.

Sometimes herpes simplex keratitis episodes are unresolved at seven days. So, we frequently extend the oral therapeutic regimen to 10 to 14 days, based on the individual patient’s response. Systemic toxicity is not a great concern with a conservatively longer dosage period. Unfortunately, the drawn-out cases are more likely to have stromal involvement in the form of disciform keratitis, which represents a deeper immunologic response. Subspecialty corneal consultation and comanagement are suggested here, as guidance with steroid therapy and extended periods of antiviral therapy may be indicated.

A major breakthrough in the treatment of herpes simplex keratitis came from the National Eye Institute’s Herpetic Eye Disease Study (HEDS) in 1999. Completed in several sections, HEDS gave authoritative results for the oral treatment and prevention of ocular herpes simplex. HEDS I showed that topical prednisone was helpful in treating patients with stromal keratitis. It also demonstrated that there is no benefit to adding oral acyclovir in stromal keratitis if the patient is already taking topical steroids and antivirals.7

fig4


HEDS II demonstrated results that are more relevant to the primary care optometrist. This study showed that oral acyclovir in a prophylactic dosage of 400mg b.i.d. reduced the rate of recurrence of any form of ocular herpes in the following year by 41%. Further, HEDS II showed a 50% reduction in the recurrence of severe forms of ocular herpes, such as disciform keratitis, if acyclovir is taken for a year as described.

This data is very important to the eye practitioner because it’s critical to initiate the preventative therapy as a team approach with the patient’s family doctor. In our experience, family practitioners may not have an acute awareness of this treatment method, and should be educated on its importance and safety.

Another feature included in the HEDS II study was its evaluation of oral acyclovir’s efficacy in preventing epithelial herpes simplex from developing into stromal disease or iritis. The study found no added benefit to oral acyclovir if the patient was already taking topical trifluridine.8

However, informal discussion with corneal specialists shows that oral antiviral therapy is currently popular as an adjunct therapy in treating epithelial disease. One could speculate that there is doubt on the study results, or that the oral therapy speeds resolution of the epithelial disease itself. Further, we find that patients with signs of acute ocular herpes may show symptoms of systemic inflammation, such as fever, and may benefit from oral treatment.

Herpes Zoster Ophthalmicus

Oral Dosing for Herpes Zoster

Oral agents for herpes zoster ophthalmicus should be administered as follows:

  • Zovirax (acyclovir, GlaxoSmithKline) 800mg five times daily for seven to 10 days.
  • Valtrex (valacylovir, GlaxoSmithKline) 1,000mg three times daily for seven to 10 days
  • Famvir (famciclovir, Novartis) 500mg three times daily for seven to 10 days.

Note that the Physician’s Desk Reference indicates higher oral antiviral doses for herpes zoster than for herpes simplex. This may be due to the longer duration

The herpes zoster virus is the same varicella agent that causes chicken pox in its initial infection. As with herpes simplex, herpes zoster has been recognized for more than a century. Zoster’s features were elaborated by William Heberden in the late 1700s, differentiating it from the simplex virus. In 1888, Janus Von Bokay was the first researcher to suggest that chicken pox and shingles were caused by the same virus.10

Because the human immune system is unable to eradicate the virus, it remains latent in sensory ganglia until an episode of immunologic compromise. Activation of the zoster virus causes hyperesthesia in the affected sensory nerves within two to three days, with the characteristic papillovesicular rash soon to follow.11

Fifty percent to 70% of patients have ocular involvement if the first division of the fifth cranial nerve is involved.11 Viral infection and subsequent inflammation can affect all ocular structures. Corneal scarring and uveitis with secondary cataract, glaucoma and macular edema are especially worrisome possibilities. Corneal staining and mucoid plaques may serve as signals that these serious involvements are on the way.12 Upon presentation of herpes zoster ophthalmicus, it is critical to initiate systemic treatment with oral antiviral agents (see “Oral Dosing for Herpes Zoster,” above). Research has shown the benefit of systemic therapy if instituted within 48 hours of vesicular outbreak.13 Beyond 72 hours, its efficacy is diminished though it may still be helpful. Topical antiviral agents have not been shown to be effective, but they are sometimes used if there is clinical uncertainty in considering zoster vs. simplex. For example, it may be justified to start topical antivirals if a patient manifests lid vesicles and early, poorly differentiated dendrites, thus blurring the lines between simplex and zoster.

However, potential toxicity of topical trifluridine requires cautious follow-up care. Follow-up on herpes zoster ophthalmicus should be undertaken at least on alternate days until the inflammation subsides and the patient perceives better comfort. Also, be sure to consult with the patient’s family physician to rule out any underlying immunosuppression as a cause for the zoster outbreak. A particular challenge to the clinician: the patient who presents with symptoms, but no signs of herpes zoster ophthalmicus. We’ve had several patients who presented with malaise, tingling and pain along the first division of the fifth cranial nerve (i.e., discomfort radiating from the superior ocular area to the scalp). A low-grade blepharoconjunctivitis accompanied these symptoms, which was treated topically with antibiotic-steroid combination. The absence of vesicular eruption on the scalp led to the diagnosis of herpes zoster sine herpetum, as creeping lesions were missing despite classic symptomatology. We started oral Valtrex at 1,000mg three times daily for 10 days, with confidence and justification in the principle that the risk of therapy well outweighed the risk of the disease process itself.

Herpes zoster is a greater risk to our patients as they age. As primary care doctors, we can recommend that patients consult with their family physicians about vaccination against this disease. Zostavax (Merck), a herpes zoster vaccine, has been shown to reduce herpes zoster episodes by 51% in patients 60 to 69 years old.14 It also reduces the chances of post-herpetic neuralgia by 67%. This vaccine is given in the form of an attenuated live virus, which stimulates the immune system to fight off the herpes zoster infection. Patients who are highly allergic, immune compromised, or who suffer from tuberculosis are excluded from this new vaccine.

Simplex vs. Zoster

Viral illness, herpes simplex and herpes zoster share some features in common—all can cause systemic illness and vesicular lesions, for instance. So, it is critical to distinguish some of the subtle features. For example, simplex tends to cause true dendritic corneal lesions, while zoster causes pseudodendrites or simpler diffuse staining. Simplex can follow multiple nerve branches, while zoster tends to follow a single nerve branch, such as the first division of the fifth cranial nerve.

There are also differences in terms of the timelines of each disease. Simplex often causes recurrently acute disease, while zoster consequences are more chronic.15 Herpes simplex keratitis often responds well to treatment within a week, though repeated episodes are common and increase the risk of scarring. Our experience with zoster keratitis, as well as uveitis, is that episodes that can go on for weeks or longer. However, recurrence is usually much less frequent.

When Things Don’t Go Well

Keratitis from both herpes simplex and herpes zoster can have prolonged clinical courses. Their tendency to cause corneal scarring requires close attention, as the visual axis can be threatened rapidly by white blood cell infiltration.

Judicious use of steroids is the key to success, and many cases merit consultation with a corneal specialist. Soft steroids, such as fluorometholone, can be started at four to six times daily when the corneal epithelium is reasonably closed. Viral suppression by oral and/or topical agents should be maintained, because steroids suppress the eye’s ability to fight the herpes virus.

As a rule of thumb, I seek corneal consultation if a herpetic corneal infiltrate is anticipated to cause a patient to lose acuity, or if the patient shows no improvement after several days of treatment.

Uveitis is another complication of herpes infections that may present after the initial visit. Ensure that the patient is taking the maximum oral antiviral therapy with good compliance. If uveitis appears, there can be a rapid development of inflammation that requires aggressive treatment. A loading dose of topical Pred Forte (prednisolone acetate 1%, Allergan) given every 15 minutes for a few hours, followed by a week of hourly dosing, is a reasonable start. Cycloplegia with a long-acting agent, such as homatropine 5%, is necessary. As with potential corneal scarring, seek subspecialty consultation if herpes associated uveitis is slow to resolve.

fig6


Herpes and Bell’s Palsy

Bell’s facial nerve palsy has been shown to have herpes simplex or herpes zoster as causative factors in some cases.16,17 Although controversial, many clinicians use oral antivirals, such as acyclovir, in addition to the standard oral prednisone treatment.18 As facial nerve palsy patients often present to optometric practices, it is worth while to consult with the treating physician regarding the possibility of initiating antiviral therapy.

Dry eye due to exposure with poor lid function is your main concern in these patients. Assurance of proper systemic therapy takes the patient’s care to a higher level.

Proper, effective care of patients suffering from the herpes viruses can be quite rewarding. When complications lead to referral for specialty care, you remain a vital part of the health care team. Thorough knowledge of treatment options and keen observation will help your patients get through these difficult episodes.

Dr. Potter is chief of optometry and contact lens services at Millennium Eye Care, in Freehold, N.J.

References

  1. Levine MM, Liu MA, Rappuoli R, Good MF, Eds. New Generation Vaccines, 3rd ed. New York: Marcel Dekker, Inc.; 2004:661-2.
  2. Frank GM, Hendricks RL. Recent Developments in Herpes Stromal Keratitis. In: Pleyer U, Foster CS, Eds. Uveitis and Immunological Disorders. New York: Springer-Verlag Berlin Heidelberg; 2007: 91-93.
  3. Mott KR, Chentoufi AA, Carpenter D, et al. The role of a glyco-protein K (gK) CD8+ T-cell epitope of herpes simplex virus on virus replication and pathogenicity, Invest Ophthalmol Vis Sci. 2009 Jun;50(6):2903-12.
  4. Facts About The Cornea and Corneal Disease. National Eye Institute website, March 2010. Available at: http://nationaleyeinstitute. net/health/cornealdisease/ (accessed March 19, 2010).
  5. Collum LM, McGettrick P, Akhtar J, et al. Oral acyclovir (Zovirax) in herpes simplex dendritic corneal ulceration. Br J Ophthalmol. 1986 Jun;70(6):435-8.
  6. Pavan-Langston D. Viral Disease of the Ocular Anterior Segment: Basic Science and Clinical Disease. In: Foster CS, Azar DT, Dohlman CH, Eds. Smolin and Thoft’s The Cornea: Scientific Foundations and Clinical Practice, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:310.
  7. Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology. 1994 Dec;101(12):1871-82.
  8. The Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. The Epithelial Keratitis Trial. Arch Ophthalmol. 1997 Jun;115(6):703-12.
  9. Sheppard JD, Wertheimer ML, Scoper SV. Modalities to decrease stromal herpes simplex keratitis reactivation rates. Arch Ophthalmol. 2009 Jul;127(7):852-6.
  10. von Bókay J. Über den ätiologischen Zusammenhang der Vari-zellen mit gewissen Fällen von Herpes Zoster. Wien klin Wchnschr. 1909; 22:1323-26.
  11. Holdeman NR. Herpes Zoster Ophthalmicus. In: Onofrey B, Skorin L, Holdeman NR, Eds. Ocular Therapeutics Handbook: A Clinical Manual, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2005:215.
  12. Foster CS. Uveitis. Lecture presented at annual meeting of American Academy of Ophthalmology, 2002; New Orleans, LA.
  13. Wood MJ, Shukla S, Fiddian AP, Crooks RJ. Treatment of acute herpes zoster: effect of early (< 48 h) versus late (48-72 h) therapy with acyclovir and valaciclovir on prolonged pain. J Infect Dis. 1998 Nov;178 Suppl 1:S81-4.
  14. Vaccines and Preventable Diseases: Herpes Zoster Vaccine Q&A (Shingles). May 2009. Centers for Disease Control and Prevention website. Available at: www.cdc.gov/vaccines/vpd-vac/shingles/vac-faqs.htm (accessed January 2010).
  15. Miserocchi E, Waheed NK, Dios E, et al. Visual outcome in her-pes simplex virus and varicella zoster virus uveitis: a clinical evaluation and comparison. Ophthalmology. 2002 Aug;109(8):1532-7.
  16. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle. Ann Intern Med. 1996 Jan 1;124(1 Pt 1):27-30.
  17. Furuta Y, Ohtani F, Chida E, et al. Herpes simplex virus type 1 reactivation and antiviral therapy in patients with acute peripheral facial palsy. Auris Nasus Larynx. 2001 May;28 Suppl:S13-7.
  18. Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med. 2007 Oct 18;357(16):1598-607.

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