Herpetic Corneal Infections

Home , Fungal keratitis, Herpes simplex keratitis, Neurotrophic keratitis, Retinitis

FocalPoints Clinical Modules for Ophthalmologists

VOLUME XXVI, NUMBER 8

SEPTEMBER 2008 (MODULE 2 OF 3)

Sonal S. Tuli, MD

Reviewers and Contributing Editors Consultants

George A. Stern, MD, Editor for Cornea & External Disease James Chodosh, MD, MPH Kristin M. Hammersmith, MD, Basic and Clinical Science Course Faculty, Section 8 Kirk R. Wilhelmus, MD, PhD Christie Morse, MD, Practicing Ophthalmologists Advisory Committee for Education Focal Points Editorial Review Board

George A. Stern, MD, Missoula, MT Claiming CME Credit Editor in Chief, Cornea & External Disease Thomas L. Beardsley, MD, Asheville, NC Academy members: To claim Focal Points CME cred- Cataract its, visit the Academy web site and access CME Central (http://www.aao.org/education/cme) to view and print William S. Clifford, MD, Garden City, KS Glaucoma Surgery; Liaison for Practicing Ophthalmologists Advisory your Academy transcript and report CME credit you Committee for Education have earned. You can claim up to two AMA PRA Cate- gory 1 Credits™ per module. This will give you a maxi- Bradley S. Foster, MD, Springfield, MA Retina & Vitreous mum of 24 credits for the 2008 subscription year. CME credit may be claimed for up to three (3) years from Anil D. Patel, MD, Oklahoma City, OK date of issue. Non-Academy members: For assistance Neuro-Ophthalmology please send an e-mail to [email protected] or a Eric P. Purdy, MD, Fort Wayne, IN fax to (415) 561-8575. Oculoplastic, Lacrimal, & Orbital Surgery Steven I. Rosenfeld, MD, FACS, Delray Beach, FL Refractive Surgery, Optics & Refraction C. Gail Summers, MD, Minneapolis, MN Focal Points (ISSN 0891-8260) is published quarterly by the American Academy of Ophthalmology at 655 Beach St., San Francisco, CA 94109-1336. Print Pediatric Ophthalmology & Strabismus and online 1 year subscription is $175 for Academy members (2 years, $315; Albert T. Vitale, MD, Salt Lake City, UT 3 years, $445) and $235 for nonmembers (2 years, $425; 3 years, $600). Online Ocular Inflammation & Tumors only 1-year subscription is $145 for members (2 years, $260; 3 years, $370) and $195 for nonmembers (2 years, $350; 3 years, $500). Periodicals post- age paid at San Francisco, CA, and additional mailing offices. POSTMASTER: Send address changes to Focal Points, P.O. Box 7424, San Francisco, CA Focal Points Staff 94120-7424. Susan R. Keller, Acquisitions Editor The American Academy of Ophthalmology is accredited by the Accredita- tion Council for Continuing Medical Education to provide continuing medical Kim Torgerson, Publications Editor education for physicians. The American Academy of Ophthalmology designates this educational activity for a maximum of two AMA PRA Category 1 Credits™. Physicians Clinical Education Secretaries and Staff should only claim credit commensurate with the extent of their participation in the activity. Gregory L. Skuta, MD, Senior Secretary for Clinical Education, Reporting your CME online is one benefit of Academy membership. Non- Oklahoma City, OK members may request a Focal Points CME Claim Form by contacting Focal Points, 655 Beach St., San Francisco, CA 94109-1336. Louis B. Cantor, MD, Secretary for Ophthalmic Knowledge, The Academy provides this material for educational purposes only. It is not Indianapolis, IN intended to represent the only or best method or procedure in every case, nor to replace a physician’s own judgment or give specific advice for case manage- Richard A. Zorab, Vice President, Ophthalmic Knowledge ment. Including all indications, contraindications, side effects, and alternative Hal Straus, Director of Print Publications agents for each drug or treatment is beyond the scope of this material. All information and recommendations should be verified, prior to use, with current information included in the manufacturers’ package inserts or other indepen- dent sources and considered in light of the patient’s condition and history. Ref- erence to certain drugs, instruments, and other products in this publication is made for illustrative purposes only and is not intended to constitute an endorse- ment of such. Some material may include information on applications that are not considered community standard, that reflect indications not included in approved FDA labeling, or that are approved for use only in restricted research settings. The FDA has stated that it is the responsibility of the physician to determine the FDA status of each drug or device he or she wishes to use, and to use them with appropriate informed patient consent in compliance with applicable law. The Academy specifically disclaims any and all liability for injury or other damages of any kind, from negligence or otherwise, for any and all claims that may arise out of the use of any recommendations or other information contained herein. The author(s) listed made a major contribu- tion to this module. Substantive editorial revisions may have been made based on reviewer recommendations. Subscribers requesting replacement copies 6 months and later from the cover date of the issue being requested will be charged the current module replacement rate.

ii FOCAL POINTS : MODULE 8, 2008 Learning Objectives

Upon completion of this module, Contents the reader should be able to: Introduction 1 • Describe the different clinical presentations of herpes simplex and herpes zoster corneal Herpes Simplex Keratitis 2 infections, including unusual presentations and • Life Cycle of Herpes Simplex Virus 2 complications of these diseases • Epithelial and Stromal Keratitis 3

• Discuss the Herpetic Eye Disease Study, its • Diagnosis 5 outcomes, and its limitations • Long-Term Complications 5

• Explain the current therapies available for herpetic • Treatment 5 eye disease, including surgery, understand the rationale for using these treatments, and outline Herpes Zoster Ophthalmicus 7 their complications • Diagnosis 8 • Acute Keratitis 8 • Chronic/Relapsing Keratitis 8 Financial Disclosures • Long-Term Complications 9 The authors, reviewers, and consultants disclose the following finan- • Treatment 9 cial relationships. James Chodosh, MD, MPH: (S) National Eye Institute. Kristin M. Hammersmith, MD: (L) Allergan. Steven I. Conclusion 11 Rosenfeld, MD, FACS: (L) Allergan. Albert T. Vitale, MD: (C) Bausch & Lomb. Clinicians’ Corner 13

The following contributors state that they have no significant financial interest or other relationship with the manufacturer of any commercial product discussed in their contributions to this module or with the manufacturer of any competing commercial product: Introduction Thomas L. Beardsley, MD; William S. Clifford, MD; Bradley S. Foster, MD; Christie Morse, MD; Anil D. Patel, MD; Eric P. Purdy, The word herpes is derived from the Greek word meaning MD; George A. Stern, MD; C. Gail Summers, MD; Sonal S. Tuli, MD; “to crawl,” because of the serpiginous nature of herpetic Kirk R. Wilhelmus, MD, PhD. lesions. Herpes viruses affecting humans include herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella- C = consultant fee, paid advisory boards, or fees for attending a zoster virus (VZV), cytomegalovirus, and Epstein- Barr meeting virus. These double- stranded DNA viruses have a viral- L = lecture fees (honoraria), travel fees, or reimbursements when derived capsid enclosed in a host cell–derived envelope speaking at the invitation of a commercial entity with viral- derived glycoprotein projections (Figure 1). S = grant support

Figure 1 Structure of herpes simplex virus.

FOCAL POINTS : MODULE 8, 2008 1 For the ophthalmologist, the three most important of these viruses are HSV-1, HSV-2, and VZV, all of which are neurotrophic. Once primary infection occurs, they enter the sensory nerve ganglia and reside there permanently. Periodic reactivations result in the morbidity seen with these viruses. In the United States, estimates note 60,000 new and recurrent cases of HSV keratitis and 50,000 to 100,000 cases of VZV keratitis, also called herpes zoster ophthalmicus (HZO), per year. Not only are these viruses a significant medical problem, but the economic implica- tions are staggering. Studies have estimated that treatment of each acute episode of HSV costs $200 to $300 and that systemic antiviral prophylaxis costs $8500 per event averted. In addition, there are intangible losses related to HSV infection, such as the loss of manpower.

Herpes Simplex Keratitis Keratitis caused by HSV, or herpes simplex keratitis (HSK), is the most common cause of corneal blindness in devel- oped nations. It was previously thought that HSV-1 had Figure 2 Life cycle of herpes simplex virus. TG = trigeminal a predilection for the trigeminal ganglion and HSV-2, for ganglion. the sacral ganglion. However, an increasing number of cases of ocular herpes are caused by HSV-2, and anec- dotal reports suggest that ocular HSV-2 infections may Primary HSV Infection. Primary HSV ocular infection be more severe and cause more scarring. is frequently missed and rarely affects the cornea. The most common pattern of infection is blepharoconjunc- Life Cycle of Herpes Simplex Virus tivitis that heals without scarring. The associated fol- Primary HSV infection occurs by direct contact with licular conjunctivitis is often mistaken for adenoviral infected secretions. On contact, the virus enters epithe- conjunctivitis. However, unilateral, nonepidemic follic- lial cells and starts replicating. Within hours, it enters ular conjunctivitis should always make one suspect HSV, the sensory nerve endings and travels to the sensory gan- as studies have shown at least 25% of such cases to be glion, where it may remain in a dormant form called culture-positive for HSV. latency (Figure 2). Alternatively, it may replicate and travel In rare instances, especially in patients with severe back down the nerve to cause a primary infection that is eczema or other immunocompromised states, this usu- clinically evident in 1% to 6% of infected patients. Once ally innocuous infection can become life- threatening. the primary infection resolves, the virus becomes latent Kaposi’s varicelliform eruption is characterized by exten- and remains in this state until certain triggers, such as sive vesicular eruptions over the entire body surface and fever, sunlight exposure, stress, and menses, cause it to can lead to multisystem failure. reactivate, multiply, and travel back down the nerve to cause recurrent infection. It is uncertain whether ocular Recurrent HSV Infection. Recurrent HSV infection most recurrences are caused by virus that initially infected frequently involves the cornea, although all other parts ocular tissues or by “back-door spread,” via the trigemi- of the eye can be affected concurrently or independently. nal ganglion, from an initial oral infection. HSV utilizes HSV can cause retinitis, trabeculitis, uveitis, and optic cellular enzymes for replication and the cell dies when it neuritis; discussion of these noncorneal infections is is released from the cell. The loss of ganglion cells with beyond the scope of this module. recurrent infections leads to decreased corneal sensation, one of the hallmarks of HSK.

2 FOCAL POINTS : MODULE 8, 2008 Epithelial and Stromal Keratitis

HSK can be subdivided into epithelial and stromal keratitis, although both are often present to some degree. Understanding the anatomic basis for this classification may give the ophthalmologist a clearer picture of the pathophysiology and treatment of the disease.

Epithelial Keratitis. These forms of keratitis are usually caused by actively replicating virus. Presentations of epithelial HSK include the following. Dendritic ulcer is the classic herpetic corneal lesion, caused by replicating virus. The lesion is linear and Figure 3 Herpetic epithelial disease showing a primar- dichotomously branching, with each branch terminat- ily dendritic ulcer with an early geographic component ing with a bulb (Figure 3). The borders of the lesion are superiorly. slightly raised and grayish and consist of HSV- infected cells that stain with rose bengal (RB) dye. In Figure 3, these HSV- infected cells have undergone balloon degen- eration. In contrast, the center of the lesion is devoid of cells and stains with fluorescein. The underlying stroma has minimal inflammation. After dendritic epithelial keratitis resolves, a dendritic scar, called a ghost dendrite, may remain in the superficial stroma. Geographic ulcer is similar to the dendritic ulcer, also caused by replicating virus, but has a much larger epithelial defect. As it progresses, the ulcer loses its dendritic shape and takes on a form that often resembles the shape of a country—hence the term geographic. This presentation usually occurs in persons with compro- mised immunity, especially patients taking topical cor- Figure 4 Geographic herpetic ulcer. Note several dendritic ticosteroids. It can also occur in individuals who have appendages extending from the body of the lesion. (Reprint- untreated, long- standing originally dendritic ulcers, in ed with permission from eMedicine.com, 2007. Available at: which case it can be hard to distinguish from a meta- www.emedicine.com/oph/topic100.htm) herpetic ulcer. The dichotomous branching and terminal bulbs of the geographic ulcer, which are seen peripher- differentiate from geographic ulcers, they can be distin- ally (Figure 4), however, often distinguish it from a meta- guished by their smooth, gray, elevated borders that do herpetic ulcer. not stain with RB. The RB dye stains the unhealthy epi- In marginal keratitis, lesions are located near the lim- thelial cells attempting to migrate across the base of the bus and can resemble staphylococcal catarrhal ulcers. ulcer, whereas fluorescein leaks through these poorly They tend to have more underlying stromal inflamma- adherent cells into the stroma and stains the periph- tion and tend to be more resistant to treatment. Also, ery—so-called reverse staining (Figure 5). they are more likely to become a trophic ulcer. Metaherpetic (trophic) ulcer is the only form of epi- Stromal Keratitis. These forms of keratitis are usually thelial ulceration that does not have any live virus. The an immune- mediated response to nonreplicating viral ulcer is called trophic if it arises de novo and metaherpetic particles, but more severe forms may be caused by live if it follows a dendritic or geographic ulcer, although the virus. The various forms of stromal keratitis cause a spec- terms are frequently used interchangeably. Metaherpetic trum of disease, but they can be subdivided clinically ulcers result from the inability of the epithelium to heal. based on the predominant site and type of involvement. The causes of poor epithelial healing are multifactorial Immune stromal keratitis is an inflammatory response and include toxicity from antiviral medications, loss of to viral antigen in the corneal stroma and can mani- innervation and neural- derived growth factors, poor tear fest as focal, multifocal, or diffuse stromal opacities. surfacing, and underlying, low- grade stromal inflam- It is often accompanied by stromal edema and a mild mation. Although metaherpetic ulcers are difficult to

FOCAL POINTS : MODULE 8, 2008 3 Figure 5 Metaherpetic or trophic ulceration. (Reprinted with Figure 6 Necrotizing keratitis. permission from eMedicine.com, 2007. Available at: www.emedicine.com/oph/topic100.htm)

anterior chamber reaction. Immune stromal keratitis may also occur as a partial or complete immune ring. If the inflammatory response is accompanied by corneal vascularization, it is called interstitial keratitis. These vessels can leak lipid, resulting in significant scarring. With quiescence, the vessels usually become ghost-like. One sensitive sign of recurrence is refilling of the vessels. HSV is now the most common cause of interstitial keratitis, especially unilateral, in the United States. The significantly greater inflammation in necrotizing keratitis (Figure 6) is thought to be a reaction to live viral Figure 7 Disciform keratitis. particles in the corneal stroma. This presentation is seen most commonly in patients with multiple recurrences of HSV infection, especially of HSV-2. Unless there is a high index of suspicion, necrotizing keratitis is difficult to distinguish from microbial forms of keratitis. It may cause corneal melting and perforation. There is frequently a significant associated uveitis, and/or trabeculitis leading to glaucoma. Localized endothelial dysfunction from an inflammatory response to viral antigen results in a disc-shaped area of corneal edema called disciform keratitis (Figure 7). There is minimal inflammation in the stroma, although focal keratic precipitates underlying the edema are characteristic. Pseudoguttae and Descemet’s folds in the edematous area may cause disciform keratitis to be Figure 8 Keratouveitis with mutton- fat keratic precipitates. confused with Fuchs dystrophy. However, in disciform keratitis, the contralateral cornea is normal, as HSV endotheliitis is almost always unilateral; Fuchs dystro- immune-mediated, but sectoral iritis, especially with phy is always bilateral. Diffuse endotheliitis is rare and is focal endotheliitis, is thought to be a marker of live virus usually accompanied by trabeculitis with elevated intra- released into the aqueous from the sympathetic nerves. ocular pressure. Keratouveitis can lead to significant morbidity from syn- In keratouveitis, uveitis predominates and is usually echiae, cataracts, and glaucoma. Unilateral uveitis asso- granulomatous, with large “mutton-fat” keratic pre- ciated with high intraocular pressure should raise a high cipitates on the endothelium (Figure 8). It is usually suspicion for HSV.

4 FOCAL POINTS : MODULE 8, 2008 Diagnosis decreased release of growth factors in response to injury, leading to persistent epithelial defects and neurotrophic Diagnosis of HSV epithelial keratitis is usually made ulcers that may melt and perforate. based on clinical findings, and laboratory tests are seldom needed. Laboratory tests are of no use in stromal Treatment keratitis. The following tests can be useful in challenging cases of epithelial keratitis. Treatment of HSV epithelial keratitis differs dramati- cally from that of HSV stromal keratitis, reflecting the Herpes Culture. Various viral transport media (eg, Rich- differing pathogeneses of these diseases. (See “Herpetic ards viral transport, HH medium) can be used. The virus, Eye Disease Study” for additional information.) once grown, can be typed to HSV-1 or HSV-2. A practical point is that RB is virucidal, and cultures done following Infectious Epithelial Keratitis. Epithelial keratitis often RB corneal staining may be falsely negative for HSV. resolves spontaneously; however, the aim of treatment is to minimize scarring and stromal inflammation. The Fluorescent Antibody (FAB) Testing. The corneal swab infected cells are poorly adherent, and gentle wiping can be smeared on a slide, or impression cytology using a debridement with a cotton- tipped applicator removes nitrocellulose membrane can be performed. Use of fluo- nearly all infected cells without damaging normal epi- rescein staining before FAB testing interferes with test thelium. Debridement results in much faster resolution results. and consequently less scarring. Debridement should be performed prior to initiating drug therapy. DNA Amplification. This test does not require a high The mainstay of treatment in the United States is topi- number of viral particles, but it is more expensive than cal trifluridine, which is very effective and should result the other tests mentioned here. in complete resolution. Topical acyclovir ointment, however, is the drug of choice in most other parts of the Tzanck Smear. Papanicolaou or Giemsa stains of corneal world because of low toxicity. It is not commercially smears are examined for the presence of multinucleated available in the United States but can be formulated at giant cells and intranuclear eosinophilic inclusion bodies compounding pharmacies. Topical acyclovir ointment (Cowdry type A). may be used in children, in whom frequent drops would be impractical, and in patients with trifluridine allergy. Serum Antibody Testing. This is of limited use. The pres- Oral acyclovir may be another option for both pediat- ence of anti-HSV IgM in a child may indicate active infec- ric and allergic patients. A good rule of thumb is that tion. However, false negatives are common and positive epithelial disease that is adequately treated but persists titers in adults merely indicate past infection, which is beyond 2 or 3 weeks is either metaherpetic (noninfec- nearly universal. tious), caused by virus that is resistant to the antiviral agent, or due to drug toxicity. If culture of persistent Long-Term Complications epithelial disease is negative, it should be treated as a metaherpetic ulcer. Unfortunately, resolution of HSK does not protect the eye from future complications. Stromal Keratitis. The mainstay of treatment is topical Recurrent disease is the major cause of the morbid- corticosteroids. Although HEDS did not show any statis- ity associated with HSK. Each recurrent episode causes tically significant difference in visual outcome with the increased inflammation and scarring and further use of corticosteroids, they do accelerate resolution of decreased corneal sensation. In addition, the risk of stro- HSV ocular infection. Simultaneous oral antiviral pro- mal disease increases with multiple recurrences of HSV phylaxis decreases the risk of HSV reactivation at the epithelial keratitis. ganglion level. Some authors advocate matching topi- Even when HSK is treated promptly, scarring is com- cal antivirals drop for drop with topical corticosteroids. mon and can cause significant morbidity. A recurrent Because doing so does not prevent reactivation at the episode usually occurs adjacent to the site of a previ- ganglion level and may increase toxicity, this author does ous episode—thus the visual axis is invariably involved not advise this, except in the treatment of necrotizing eventually. keratitis. In that case, aggressive antivirals—both topical Corneal hypesthesia is a sensitive sign of previous HSK. and systemic—and corticosteroid use are indicated. The lack of innervation causes poor tear production and

FOCAL POINTS : MODULE 8, 2008 5 Herpetic Eye Disease Study

The HEDS was a prospective, randomized, double- of stromal keratitis or iridocyclitis was quite low in the masked, placebo- controlled multicenter study to assess year after an episode of epithelial keratitis; this risk was the effect of adding topical corticosteroids and oral acy- lower than that previously suggested in the literature. clovir to conventional antiviral therapy (topical trifluridine, Acyclovir Prevention Trial (HEDS-APT). In patients Viroptic) for HSV keratitis and iridocyclitis. There were who had had an ocular HSV infection in the previous six parts to the study: three therapeutic, two preventive, year, use of oral acyclovir reduced by 41% the prob- and one cohort. The main findings are summarized here. ability that any form of HSK would return. The incidence Herpes Stromal Keratitis, Not on Steroid Trial of epithelial keratitis was reduced from 11% to 9% and (HEDS-SKN). Compared with the placebo group, the of stromal keratitis from 13% to 8%. Importantly, the patients who had received prednisolone phosphate rate of recurrent HSV stromal keratitis decreased 50%. drops had faster resolution of the stromal keratitis and Unfortunately, the effect did not persist once the acy- fewer treatment failures. However, delaying the initiation clovir was discontinued. More than one recurrence was of corticosteroid treatment did not affect the eventual reported in 4% of patients in the acyclovir group and in outcome of the disease, in that visual acuity was similar 9% of those in the placebo group. in the two groups at 26 weeks. Ocular HSV Recurrence Factor Study (HEDS- Herpes Stromal Keratitis, on Steroid Treatment RFS). No association was found between psychological (HEDS-SKS). There was no apparent benefit to adding or other forms of stress and ocular HSV recurrences. oral acyclovir to the treatment regimen of a topical corti- Also, previous episodes of HSV epithelial keratitis were costeroid and trifluridine. not a predictor of future occurrences, whereas previous, Herpes Simplex Virus Iridocyclitis, Receiving especially multiple, episodes of HSV stromal keratitis Topical Steroids (HEDS-IRT). The trial was stopped markedly increased the probability of subsequent stro- because of slow recruitment, but treatment failures mal keratitis. occurred at a higher rate in the placebo group than Limitations. Although HEDS was excellent in its in the acyclovir group, indicating a potential benefit to conception and plan, it had some limitations. First, adding oral acyclovir to the regimen of a topical steroid many of the trials had inadequate recruitment or a very and an antiviral. high dropout rate. Second, in the prevention trials, oral Herpes Simplex Virus Epithelial Keratitis Trial acyclovir was used for only 3 weeks. Third, the cortico- (HEDS-EKT). This trial assessed the effect of adding steroid regimen was standardized and not tailored to an oral acyclovir to topical antiviral therapy for acute HSV individual patient’s inflammation. Finally, trifluridine was epithelial keratitis. The addition of oral acyclovir provided used in both the study group and the placebo group in no benefit in preventing the development of stromal the trials evaluating acyclovir for the treatment of stro- keratitis or iritis. Incidentally, the study found that in the mal keratitis and iridocyclitis. control group (treatment with trifluridine alone), the risk

6 FOCAL POINTS : MODULE 8, 2008 Metaherpetic Keratitis. The basic principle of therapy clovir is the most specific for viral polymerase and thy- for this disease is to rapidly heal the epithelial defect. midine kinase and therefore causes the least cellular Methods to accomplish this include stopping use of toxic toxicity of these antivirals; however, it is the most likely medications, performing punctal occlusion, instilling to induce viral resistance. tear film supplements, fitting a bandage contact lens, Topical antivirals are the drugs of choice for acute amniotic membrane grafting, tarsorrhaphy, and, if there epithelial disease. Trifluridine is effective in the treat- is significant underlying inflammation, cautiously using ment of epithelial keratitis but can cause significant topical corticosteroids while watching carefully for cor- epithelial toxicity as mentioned above. It also contains neal melts. thimerosal as a preservative and has a highly acidic pH that adds to its toxicity. Trifluridine has a short half- life Prophylaxis and Medications. Oral antivirals are typi- and must be used every 2 hours. Systemic antivirals are cally used as systemic prophylaxis against reactivation of used primarily for prophylaxis of recurrent disease or as HSV at the ganglion level. Topical medications are toxic an antiviral cover during corticosteroid therapy for stro- with prolonged usage and are usually reserved for acute mal keratitis. The three main systemic antivirals for the epithelial disease. Prophylaxis is useful in patients who treatment of HSK are acyclovir, valacyclovir, and fam- have multiple recurrences (two or more in one year); ciclovir. They have a high therapeutic index but resis- those who have scarring close to the visual axis; those tance is an issue, especially in immunocompromised who are using topical corticosteroids for stromal disease; patients. Unfortunately there is cross- resistance among and those who are systemically immunocompromised. these three agents. For prophylaxis of HSV infection, acyclovir is most com- Topical corticosteroids used for the treatment of HSV monly used at a dosage of 400 mg twice daily. stromal keratitis and uveitis are always given under anti- All the current antivirals used in the treatment of viral cover. Typically, 1% prednisolone acetate or 0.1% ocular HSV (see Table 1) are nucleoside analogues that dexamethasone is used. The dosing frequency should be inhibit viral replication by competitively inhibiting viral based on the severity of the inflammation. On resolu- DNA polymerase. As they may also interfere with host tion of the inflammation, the steroids need to be tapered DNA synthesis, they can cause significant toxicity. Acy- gradually to prevent rebound inflammation.

Table 1. Antiviral Medications Used for the Treatment of Ocular Herpes Simplex Virus

ROUTE/DOSAGE DRUG (TRADE NAME) FORM DOSE FREQUENCY COMMENTS

Trifluridine (Viroptic) Topical drops 1% Every 2 hours Adverse effects include follicular conjunctivitis, redness, delayed epithelial healing.

Vidarabine (Ara-A) Topical ointment 3% 5 times a day Adverse effects same as for trifluridine. Can be obtained from compounding pharmacy.

Acyclovir (Zovirax) Topical ointment 3% 5 times a day Minimal adverse effects. Not commercially available in the US. Can be obtained from compounding pharmacy.

Oral 400 mg 5 times a day for treatment Adverse effects include headache, nausea, and twice a day for nephrotoxicity, neurotoxicity. prophylaxis

Valacyclovir (Valtrex) Oral 500 mg 3 times a day for treatment Adverse effects same as for acyclovir; and twice a day for thrombotic thrombocytopenic purpura prophylaxis and hemolytic uremic syndrome in immunosuppressed persons.

Famciclovir (Famvir) Oral 250 mg 3 times a day for treatment Adverse effects same as for acyclovir. and twice a day for prophylaxis

FOCAL POINTS : MODULE 8, 2008 7 son sign), there is almost always ocular involvement. Herpes Zoster Although the Hutchinson sign is a good rule of thumb, it is neither sensitive nor specific, and ocular involve- Ophthalmicus ment can occur in the absence of this sign. Ocular zoster can affect any part of the eye from the Varicella-zoster virus (VZV) is another neurotrophic virus conjunctiva to the optic nerve. It can cause keratitis, scle- that has a predilection for the trigeminal ganglion. The ritis, uveitis, trabeculitis, choroiditis, acute retinal necro- primary infection usually occurs in early childhood as sis, optic neuritis, nerve palsies, and cavernous sinus chickenpox, which got its name from the blisters on thrombosis. Discussion of these noncorneal infections is the skin that resemble chickpeas. Primary infection beyond the scope of this module. Keratitis can be classi- with VZV is nearly universal in childhood but can be so fied as acute or chronic/relapsing, both of which can lead mild that it is missed. However, if acquired in infancy or to long- term sequelae. adulthood or by immunocompromised persons, it can be fatal. Unlike HSV, VZV becomes latent in multiple ganglia simultaneously. It reactivates, usually in the elderly, Acute Keratitis as a vesicular rash commonly called shingles. The name Acute keratitis can occur up to 1 month following the derives from the Latin cingulum, which means girdle or onset of dermatitis. Some of the common manifestations belt, because of its distribution along a single derma- include the following. tome. The exact triggers for reactivation are unknown, Punctate keratitis and pseudodendrites consist of but decreased cellular immunity is common in those who swollen, poorly adherent epithelial cells and are usually have shingles. It is estimated that 95% of adults in the seen in the corneal periphery and appear “stuck on” (Fig- United States have antibodies to VZV and that 300,000 to ure 10). In contrast to HSV dendrites, these pseudoden- 500,000 individuals are affected by shingles each year. Of drites lack terminal bulbs and dichotomous branching these herpes zoster cases, approximately 25% are herpes and stain poorly with both fluorescein and RB. Although zoster ophthalmicus (HZO). VZV has been cultured out of these lesions, they do not respond to topical antivirals. Diagnosis Nummular keratitis is characterized by coin- shaped (nummular) lesions that appear in the superficial stroma. The brief prodrome of HZO consists of fever, malaise, and The lesions usually underlie areas of previous epithelial chills. The initial symptom is hyperesthesia or paresthe- keratitis. They probably represent an immune- mediated sia, which may be severe, along the affected dermatome. stromal reaction to viral antigens. This is followed by a maculopapular rash that becomes HZO-related keratouveitis and endotheliitis resemble vesicular and finally pustular before crusting (Figure 9). HSV keratouveitis and endotheliitis but are usually more One common feature of HZO is severe eyelid edema severe, even leading to the development of a hypopyon that accompanies the rash and that can be mistaken for or hyphema. Involvement of the trabecular meshwork preseptal cellulitis. If the tip of the nose is affected by reactivation along the nasociliary nerve (as manifested by the appearance of cutaneous vesicles—the Hutchin-

Figure 10 Herpes zoster pseudodendrites. Figure 9 Herpes zoster dermatitis.

8 FOCAL POINTS : MODULE 8, 2008 can lead to severe glaucoma that may be unresponsive to Herpes zoster can result in a persistent smoldering glaucoma medications but responds to steroids. keratitis that may only manifest as a corneal haze with Sclerokeratitis occurs as a crescent- shaped corneal overlying epithelial irregularity. This can lead to progres- infiltrate adjacent to an area of scleritis. It is clinically sive scarring and decrease in vision. identical to nonherpetic peripheral ulcerative keratitis, Neuralgia is almost always associated with acute HZO, and the etiology is thought to be limbal vasculitis and but pain that lasts longer than 1 month constitutes ischemia. postherpetic neuralgia (PHN), perhaps the most debilitating sequela of HZO. PHN occurs in 10% to 30% of Chronic/Relapsing Keratitis patients with HZO, and its risk factors include increasing age, prodromal pain, more severe rash, greater acute This form occurs up to several months following the ini- pain, and ophthalmic involvement. The pain is of vari- tial HZO infection. able quality and has been described by patients as burn- Mucous plaques can occur suddenly in an eye that has ing, shooting, sharp, throbbing, or tender. One classic been nearly quiescent. They appear as stuck- on, gray- feature of this pain is allodynia (pain following a stim- ish, branching lesions and have minimal underlying ulus that is normally non- noxious, such as wind). The inflammation (Figure 11). Mucous plaques stain with pain can be severe and unrelenting and can take over RB, and they can be easily wiped off the cornea, leav- the patient’s life, resulting in decreased functioning and ing an underlying epithelium that is intact but poorly increased risk of depression and suicide. adherent. Therefore, they are thought to be a variant of filamentary keratitis, although some investigators have Treatment found viral DNA in the lesions. Mucous plaques can be highly resistant to treatment, and multiple recurrences Topical antivirals have no role in the treatment of HZO. can lead to scarring. However, oral antivirals begun within 72 hours of onset Disciform keratitis is similar to the disciform keratitis of symptoms can reduce the severity of the disease and seen in HSK. of any long- term complications, including PHN. Recent Interstitial keratopathy: HZO keratitis can lead to vas- studies have indicated that in certain populations, such cularization, with a leash of vessels leading up to the as immunocompromised patients, this 72-hour window area of scarring. These vessels can exude large amounts can be extended. For every patient with HZO, oral acyclo- of lipid that can cause significant corneal opacification. vir can be used, 800 mg 5 times a day, for 7 to 14 days, regardless of the stage of the disease, because the risks Long-Term Complications associated with use of this drug are low. Valacyclovir and famciclovir can also be used but are more expensive. For As in HSV keratitis, neurotrophic ulcers can occur repeat- the treatment of HZO, a good rule of thumb is to double edly and cause problems long after the acute episode has the doses of the medications used for HSV keratitis. resolved. In contrast to HSV keratitis, however, profound The use of corticosteroids for the treatment of HZO is loss of corneal sensation can result from a single episode controversial. Systemic corticosteroids have been shown of HZO, and these ulcers are more likely to perforate. to reduce the dermatitis and acute pain of HZO, but they do not have any effect on PHN. Also, their use may increase the risk of ocular complications such as mucous plaques and keratitis. Topical corticosteroids may be necessary for treating uncontrolled inflammation. However, once they are initiated, it is difficult to wean patients from them. Sudden discontinuation of corticosteroids may allow the suppressed inflammation to rebound; thus, corticosteroids must be tapered gradually to a level that minimizes the risk of rebound inflammation, but keeps the keratitis in check. The ophthalmologist should discuss with the patient the possibility that use of a mild steroid (fluorometholone or loteprednol, two to three times per week) may be necessary indefinitely, because complete tapering of ophthalmic corticosteroids is not Figure 11 Mucous plaques. always attainable.

FOCAL POINTS : MODULE 8, 2008 9 As most long- term complications of HZO are related sant effect and an analgesic effect, and the antidepressant to the neurotrophic status and relative dryness of the activity appears to occur independently of the analge- affected eye, ocular surface support can decrease the risk sic activity. Therapy is started at a low dose and titrated of a poor outcome. Punctal occlusion, artificial tears, upward until pain relief occurs or adverse effects become bandage contact lenses, tarsorrhaphy, eyelid reconstruc- intolerable. Opioids are used as a last resort but can be tive surgery, and conjunctival flaps all have a role to useful in intractable cases. Oxycodone is most commonly play in the treatment of the various HZO complications. used. Capsaicin cream depletes substance P and is some- Tarsorrhaphy is especially useful in recalcitrant cases of what effective but causes significant burning. Topical neurotrophic keratitis. lidocaine patches are now FDA- approved for PHN. As the treatment of PHN is challenging and often frus- trating for both the clinician and the patient, it is impor- Vaccines. Both the chickenpox and shingles vaccines tant to give the patient the following information: (1) in have been used in the treatment of HZO. A live, atten- most cases, the pain associated with PHN resolves sponta- uated chickenpox vaccine using the Oka strain of VZV neously (70% of those with pain at 1 month will be pain was approved in the United States in 1995 (Varivax, free at 1 year); and (2) treatment is able to “take the edge Merck) and has been shown to decrease the incidence off” the pain, but unable to eliminate pain completely. of varicella- related hospitalizations and deaths by 75%. Table 2 summarizes the major types of drug therapy Unfortunately, the protective effect declines over time, for PHN. Neurontin (gabapentin) has been shown to be and breakthrough varicella is seen in children 3 years effective in treating the pain as well as the sleep distur- after vaccination or in infants vaccinated before the age bance associated with PHN and was approved by the of 1. There are some early indications that the vaccine FDA for this indication. Recently, Lyrica (pregabalin) was may reduce the occurrence of shingles later in life. approved by the FDA for the pain associated with PHN. With shingles vaccine, the challenge is preventing Amitriptyline and nortriptyline have both an antidepres- herpes zoster in patients who were already exposed to

Table 2. Drugs Used for the Treatment of Postherpetic Neuralgia

DRUG MAXIMUM DRUG CLASS (TRADE NAME) INITIAL DOSE DOSE COMMENTS

Anticonvulsants Gabapentin 100 mg qhs or tid 600–1200 mg Neurontin is FDA- approved for pain and sleep (Neurontin) tid disturbance associated with PHN. Adverse effects include somnolence, gait disturbances, memory disturbances, electrolyte abnormalities, liver toxicity. Carbamazepine 100 mg qhs 200 mg tid Adverse effects same as for gabapentin. (Tegretol) Pregabalin (Lyrica) 150 mg in divided 600 mg q day Lyrica is FDA- approved for pain associated doses with PHN. Adverse effects include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, difficulty concentrating.

Antidepressants Amitriptyline (Elavil) 25 mg qhs 150 mg q day Increase dose every 2 to 4 weeks. Adverse effects include sedation, dry mouth, blurred vision, postural hypotension, urinary retention. Nortriptyline 25 mg qhs 125 mg q day Adverse effects same as for amitriptyline. (Pamelor)

Opioids Oxycodone 10 mg q 12 hours 30 mg q 12 Adverse effects include constipation, nausea, hours sedation, pruritus, dependence.

Topical Capsaicin cream 0.025%–0.075% 3 to 5 times daily Intense burning with application; lessens over (Zostrix) time. Lidocaine patch 5% 3 patches a day for maximum FDA-approved for PHN. Adverse effects include (Lidoderm) of 12 hours local dermatitis, systemic absorption.

10 FOCAL POINTS : MODULE 8, 2008 and have latent VZV. A large clinical trial conducted by and are treated with measures to promote epithelial Merck and the Department of Veterans Affairs in col- healing. laboration with the National Institute of Allergy and The most important findings of HEDS were that use of Infectious Diseases at the National Institutes of Health topical corticosteroids shortened the course of HSV stro- found that a higher dose of the same attenuated virus mal keratitis, but did not alter the final outcome, and (Zostavax, Merck) reduced the incidence of herpes zoster prophylactic treatment with oral acyclovir decreased the by 51.3% and of PHN by 66.5% over 3 years. It is now rec- risk of recurrent HSV ocular infection by 41%. ommended for all individuals over the age of 60. It does VZV keratitis is usually a self- limited disease but can not treat zoster or PHN, and there is no information on persist for years. Topical antivirals are not useful for this whether this vaccine should be administered to patients condition. The use of systemic antiviral medications at who have already had zoster. a high dose within 72 hours of the onset of symptoms reduces the incidence of ocular morbidity, including PHN. PHN is a significant source of debilitating symptoms from VZV. The use of oral corticosteroids to reduce Conclusion the risk of PHN is controversial. Vaccines are available Primary HSV infection is usually unrecognized; clinical for chickenpox and shingles. disease is usually the result of reactivation of latent herpes simplex virus. Lack of corneal sensation is a sensitive sign of prior HSV corneal infection. Dendritic and Sonal S. Tuli, MD, is the director of Cornea and External geographic epithelial ulcers are caused by live virus and Diseases Service and assistant professor at the University are best treated with topical antiviral medications, such of Florida College of Medicine, Gainesville, Florida. as trifluridine. Stromal keratitis is an immune- mediated process and is best treated with topical corticosteroids, with oral antiviral prophylaxis. Neurotrophic (metaherpetic) ulcers are neither infectious nor immune-mediated

FOCAL POINTS : MODULE 8, 2008 11 Clinicians’Corner

Clinicians’ Corner provides additional viewpoints on 1. Are viral cultures ever necessary in the diagnosis of herpes simplex virus (HSV) keratitis? Is there any the subject covered in this issue of Focal Points. Con- value to typing the virus (HSV-1 versus HSV-2)? sultants have been invited by the Editorial Review Dr. Chodosh: Viral cultures are typically negative for, and therefore not usually helpful in, herpetic stromal Board to respond to questions posed by the Acade- keratitis. Viral cultures can occasionally be useful in atypical epithelial keratitis, if the diagnosis is uncertain. my’s Practicing Ophthalmologists Advisory Committee At the present time, available antiviral medications work equally well for HSV-1 and HSV-2, so outside of academic for Education. While the advisory committee reviews interest, there is little value to differentiating the two. Dr. Wilhelmus: For laboratory confirmation I prefer an the modules, consultants respond without reading the immunoassay, but I may submit a specimen for HSV isolation when faced with deciding between HSV and module or one another’s responses. – Ed. another diagnosis. Some examples of this dilemma are (1) atypical dendriform epitheliopathy associated with the use of a glaucoma medication, (2) persistent epithelial keratitis in an immunosuppressed person, (3) severe vesicular dermatoblepharitis, and (4) recurrent blepha- roconjunctivitis or follicular conjunctivitis. Neonatal HSV-2 is a concern for pediatric ophthalmologists, and viral typing might infer the route of transmission. Not normally establishing latency in the trigeminal ganglion, HSV-2 rarely causes corneal disease in adults. Oculogen- ital spread is feasible, but I seldom find patients with both ocular and genital herpes.

2. Does debridement of the cornea have a role in the management of HSV keratitis? Are medications necessary after debridement?

Dr. Chodosh: In immune- competent individuals, herpetic epithelial keratitis is a self- limited infection and resolves without treatment. Corneal epithelial debridement in herpetic epithelial keratitis has been shown to shorten the course of infection and may be more effective when antiviral medications are used concomitantly.

Dr. Wilhelmus: Minimal wiping debridement with a dry, sterile swab can speed healing of a dendrite and is part of

12 FOCAL POINTS : MODULE 8, 2008 my usual treatment plan. Since a dendrite reappears in lial keratitis. I almost always prefer a topical antiviral about half of debrided eyes, I almost always use adjunc- but will change to an oral agent for severe blepharocon- tive treatment with an antiviral agent over the week fol- junctivitis, epithelial keratitis in an immunosuppressed lowing debridement. or thimerosal-sensitive patient, or progressive stromal keratitis or uveitis. 3. Are stress and/or fever activators of HSV keratitis? 5. Is there a role for prophylaxis of HSV keratitis with Dr. Chodosh: The Herpetic Eye Disease Study (HEDS), oral antivirals? funded by the National Eye Institute, could not confirm the widely held belief that physical or emotional stress Dr. Chodosh: The HEDS treatment trials demonstrated triggers reactivation of HSV and causes recurrent her- a reduction in the probability of recurrent HSV kerati- petic eye disease. Detailed analysis of the HEDS data sug- tis by approximately one- half when patients took oral gests that the purported association between stress and acyclovir as compared to placebo, but did not examine HSV reactivation may be due to recall bias. who should receive antiviral prophylaxis. Subsequent cost- effectiveness studies have suggested that not every Dr. Wilhelmus: Stress rarely triggers ocular herpes, but patient with HSV ocular disease should be offered antivi- excess sunlight and corneal injury can lead to viral shed- ral prophylaxis. I recommend oral acyclovir prophylaxis ding. For this reason, I may prescribe a brief course of in any patient with multiple recurrences of HSV stromal twice-daily oral acyclovir, or its equivalent, for my HSV keratitis necessitating repeated or prolonged use of topi- patients when they go snow skiing, enter a golf tour- cal corticosteroids; recurrent stromal keratitis with scar- nament, undergo LASIK or cataract surgery, or have a ring and/or vascularization approaching the visual axis; loose corneal suture. Because prostaglandins might be or more than one episode of necrotizing HSV keratitis. involved in HSV reactivation, aspirin or a nonsteroidal I also use long- term oral antiviral prophylaxis in every anti-inflammatory drug might help prevent recurrent patient who is undergoing corneal transplant and has a herpes in a feverish patient. history of herpetic ocular disease.

4. Is there a role for combining topical and oral antivi- Dr. Wilhelmus: The HEDS trials showed that long- term rals in the management of HSV keratitis? Can den- suppression with an oral antiviral, such as acyclovir dritic HSV keratitis be treated with oral medications 400 mg twice daily, reduces the recurrence rate of HSV alone? keratitis. I advise prolonged oral antiviral prophylaxis for patients who have two or more recurrences annu- Dr. Chodosh: There is no Level 1 evidence to support the ally or whose last episode was stromal keratitis or led use of concomitant oral and topical antiviral therapy, to a complication. As shown by recent studies from the and HSV epithelial keratitis can be treated with oral anti- Cornea Service at Wills Eye Hospital, atopic patients virals alone. Many corneal specialists prefer to use oral are at increased risk for HSV infections that can be sup- antivirals because the potential ocular surface toxicity of pressed with oral antiviral prophylaxis. A small, 1-year topical antivirals can complicate later clinical decisions. trial in Italy concluded that oral valacyclovir once daily is Dr. Wilhelmus: Evidence- based ophthalmology is a goal of equivalent to acyclovir twice daily, but this convenience the Cochrane Eyes and Vision Group (www.cochraneeyes. is more expensive. org). The Cochrane systematic review on herpetic keratitis found two trials that looked at whether oral acyclovir 6. Discuss your management of necrotizing keratitis adds any benefit over topical treatment alone: a small caused by HSV. trial found an additive effect, but a larger trial showed Dr. Chodosh: Necrotizing HSV keratitis is relatively little added benefit. Thus, I rarely use both topical and uncommon and did not occur in sufficient numbers to oral antivirals together, except for chronic viral keratitis be studied as a separate entity in the HEDS treatment in people with AIDS and for severe keratouveitis. Also, trials. HSV necrotizing keratitis can be difficult to diag- based on a trial in Ireland 20 years ago, I believe oral and nose, as it can mimic bacterial or fungal keratitis and topical antivirals are nearly equivalent for HSV epithe-

FOCAL POINTS : MODULE 8, 2008 13 Clinicians’Corner

may have been treated with antibiotics and/or topical cor- sia prior to keratoplasty surgery may require permanent ticosteroids prior to presentation in the clinic. There is punctal occlusion and occasionally tarsorrhaphy to pre- some evidence from the laboratory that viral replication vent postoperative complications. within the corneal stroma may play a role in the intense Dr. Wilhelmus: I worry about undertaking corneal graft- immune and neovascular response characteristic of HSV ing in patients with herpetic keratitis because recur- necrotizing keratitis. I treat the keratitis with 7 to 10 days rent herpes, allograft rejection, and other complications of oral antiviral therapy at therapeutic doses, followed by increase the risk of graft failure. Therefore, unless per- a combination of prophylactic doses of oral antivirals and foration is about to happen, I consider surgery only cautious treatment with topical corticosteroids (bid or after the eye has been noninflamed for several months less). When treated in this fashion, patients typically heal and the patient has tapered corticosteroid treatment to within several days of starting topical corticosteroids. the desired level. Shortly before grafting, I may restart Dr. Wilhelmus: Management of herpetic necrotizing ker- the topical corticosteroid and oral antiviral, in hopes atitis begins with making the correct diagnosis. Many that graft inflammation, corneal neovascularization, patients with fungal keratitis or Acanthamoeba keratitis and viral reactivation will be less after surgery. I prefer are initially treated as if they have herpetic keratitis. interrupted sutures for these grafts and will use a topical I would consider the possibility of microbial keratitis, corticosteroid and oral antiviral for many months post- syphilis, or another disease before embarking on anti- operatively, often a year or more. viral and corticosteroid therapy. Another caveat: severe geographic epithelial keratitis may coexist with stromal 8. Is there a role for topical cyclosporine (Restasis) in inflammation, and antiviral therapy is needed for these the management of HSV keratitis? Should Resta- eyes before corticosteroids. For HSV necrotizing stromal sis be avoided in dry eye patients with a history of keratitis, I begin topical prednisolone phosphate 1% or HSV? prednisolone acetate 1%, at a dosing frequency of four Dr. Chodosh: Evidence exists to support both detriment to eight times per day, according to disease severity. I and benefit to cyclosporine in HSV infections. Systemic use a topical antiviral as prophylaxis against recurrent cyclosporine has been associated with severe recalci- epithelial keratitis. I may switch to an oral antiviral if trant HSV infections, and ocular topical cyclosporine there is an allergic or toxic reaction to trifluridine or if may delay resolution of HSV epithelial keratitis. Anec- stromal keratouveitis responds slowly to corticosteroids. dotal evidence also suggests a possible beneficial effect The topical corticosteroid is tapered over the next several of topical cyclosporine in HSV stromal keratitis. I see no weeks as corneal inflammation diminishes. specific role for topical cyclosporine in the management of HSV keratitis, except possibly in stromal disease in the 7. What are your “pearls” for managing penetrating setting of corticosteroid- induced ocular hypertension. I keratoplasty in patients with HSV? do not avoid topical cyclosporine in patients with dry eye Dr. Chodosh: First and foremost, I begin an oral antiviral and a history of HSV, but I would discontinue its use in at therapeutic doses several days prior to surgery. I taper any patient with HSV epithelial keratitis. the antiviral over the first year after keratoplasty, until Dr. Wilhelmus: While others have different experience, I reach prophylactic dose levels, and then maintain the I do not use cyclosporine for treating herpetic keratitis. medication indefinitely. Patients are instructed that they A history of herpetic keratitis is not a contraindication will need to take the oral antiviral for life. Otherwise, my for using Restasis, although I would stop it if a dendrite use of topical corticosteroids is the same as with other occurred. keratoplasty patients. I use interrupted corneal sutures so that individual sutures can be removed as necessary. Patients with significant postherpetic corneal hypesthe-

14 FOCAL POINTS : MODULE 8, 2008 9. What is your pharmacologic approach to the man- recent evidence suggests that chronic epithelial keratitis agement of postherpetic neuralgia in herpes zoster after HZO may reflect ongoing and persistent varicella- ophthalmicus (HZO)? zoster virus replication in the corneal epithelium, and may respond to antiviral therapy and reduction of topi- Dr. Chodosh: Historically speaking, postherpetic neural- cal steroids. The stromal keratitis of HZO is treated with gia was treated with topical capsaicin or low doses of topical corticosteroids. oral amitriptyline or carbamazepine. However, the field of pain management has exploded with new treatment Dr. Wilhelmus: Zoster corneal disease can be difficult modalities, including the new drug pregabalin, reported to control. Besides neurotrophic keratopathy, a par- to be a very effective medication for postherpetic pain. ticular problem is distinguishing smoldering chronic Furthermore, I find that patients with specific posther- zoster stromal keratitis from residual corneal opacifi- petic neuralgia are very individual and do not all respond cation. Drs. Seitzman, Strauss, and Margolis coined the to the same treatment. Therefore, today I typically refer term “steel wool keratopathy” to describe a degenerative such patients to a qualified pain specialist familiar with effect of chronic corneal inflammation. The stumbling the entire spectrum of available treatments. block is when to use corticosteroids. Dr. Dan Jones uses the term “steroid neglect” to describe slowly progressive Dr. Wilhelmus: I use oral valacyclovir or famciclovir, corneal disease that begs to be dampened by the timely three times daily for 1 week, to reduce the duration of use of a topical corticosteroid. Another challenge is how acute zoster- associated pain during shingles. The control to taper. I reduce a steroid’s concentration and frequency of postzoster neuralgia is more challenging. Tricyclic gradually for herpes zoster stromal keratitis and often antidepressants, opioids, and capsaicin cream can give continue a low dose for a very long time. No antiviral some relief, but I often consult with a neurologist for prophylaxis is needed. neuropathic pain management. We have used oral gabapentin (Neurontin), beginning at a low dose and titrating upward, or more recently pregabalin (Lyrica). James Chodosh, MD, MPH, is a professor of ophthal- 10. Discuss your management of chronic keratitis fol- mology at the Dean A. McGee Eye Institute, Univer- lowing HZO. sity of Oklahoma College of Medicine, Oklahoma City, Oklahoma. Dr. Chodosh: It is important to distinguish the sequelae of postherpetic corneal neuropathy from actual keratitis. Kirk R. Wilhelmus, MD, PhD, is a professor of ophthal- In the former, punctal occlusion and tarsorrhaphy may mology, Cullen Eye Institute, Baylor College of Medicine, be necessary to prevent corneal ulceration. In the latter, Houston, Texas.

FOCAL POINTS : MODULE 8, 2008 15 Suggested Reading Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001;20:1–13. Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Liesegang TJ. Varicella- zoster virus eye disease. Cornea. Study. A controlled trial of oral acyclovir for herpes simplex 1999;18:511–531. stromal keratitis. Ophthalmology. 1994;101:1871–1882. Liesegang TJ, Melton LJ III, Daly PJ, Ilstrup DM. Epidemiology Herpetic Eye Disease Study Group. Acyclovir for the preven- of ocular herpes simplex. Incidence in Rochester, Minn, 1950 tion of recurrent herpes simplex virus eye disease. N Engl through 1982. Arch Ophthalmol. 1989;107:1155–1159. J Med. 1998;339:300–306. Pavan-Langston D. Viral disease of the ocular anterior seg- Herpetic Eye Disease Study Group. A controlled trial of oral ment: basic science and clinical disease. In: Foster CS, Azar acyclovir for iridocyclitis caused by herpes simplex virus. Arch DT, Dohlman CH, eds. Smolin and Thoft’s The Cornea: Scientific Ophthalmol. 1996;114:1065–1072. Foundations and Clinical Practice. 4th ed. Philadelphia: Lippincott Herpetic Eye Disease Study Group. A controlled trial of oral Williams & Wilkins; 2005:297–397. acyclovir for the prevention of stromal keratitis or iritis in Wilhelmus KR, Dawson CR, Barron BA, et al. Risk factors for patients with herpes simplex virus epithelial keratitis. The herpes simplex virus epithelial keratitis recurring during Epithelial Keratitis Trial. Arch Ophthalmol. 1997;115:703–712. treatment of stromal keratitis or iridocyclitis. Herpetic Eye Erratum in: Arch Ophthalmol. 1997;115:1196. Comment in: Arch Disease Study Group. Br J Ophthalmol. 1996;80:969–972. Ophthalmol. 1998;116:259. Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Herpetic Eye Disease Study Group. Psychological stress and Study. A controlled trial of topical corticosteroids for herpes other potential triggers for recurrences of herpes simplex simplex stromal keratitis. Ophthalmology. 1994;101:1883–1895; virus eye infections. Arch Ophthalmol. 2000;118:1617–1625. discussion 1895–1896. Kertes PJ, Conway MD, eds. Clinical Trials in Ophthalmology: A Summary and Practice Guide. Philadelphia: Lippincott Williams & Wilkins; 1998. Related Academy Materials

Khan BF, Pavan- Langston D. Clinical manifestations and treat- External Disease and Cornea. Basic and Clinical Science Course, ment modalities in herpes simplex virus of the ocular anterior Section 8, 2007–2008. segment. Int Ophthalmol Clin. 2004;44:103–133.

16 FOCAL POINTS : MODULE 8, 2008

029030C