Ocular Herpetic Disease

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ADVANCES IN THEMANAGEMENT OF

OcularHerpetic DiseaseRESEARCH PERSPECTIVE

DEBORAH PAVAN-lANgSTON, MD, FACS

CLINICAL PERSPECTIVE

TERRY KIM, MD, AND VICTOR CHANg, MD

HISTORICAL PERSPECTIVE

HERBERT E. KAuFMAN, MD

FACULTY ADVISOR MICHAEl B. RAIZMAN, MD

C A N D E OC/S C, ™

Keeping Medical Education in Sight sm

Course Director – Sonal Tuli, MD university of Florida, gainesville, Fl, uSA

A Continuing Medical Education ProgramJointly sponsored by the university of Florida College of Medicine and Candeo Clinical/Science Communications, llC Supported by an unrestricted educational grant from Bausch + lomb, Inc.©2011 Candeo Clinical/Science Communications, llC

CMECONTINUING MEDICAL EDUCATION

Find complete Continuing Medical Education information on page 2 and the Examination on page 20.

2

STATEMENT OF NEEDHerpes simplex keratitis remains a significant cause of blindness and a leading indication for corneal transplant.1 Even relatively moderate cases can prove extremely painful and lead to corneal scarring. In patients with latent herpes simplex type 1 (HSV1), a number of ophthal-mic procedures and medications are known to create a predisposition to ocular outbreaks. Moreover, each recurrence increases the risk of sight-threatening complications.2-4 At the same time, leading experts in herpes keratitis have noted a significant educational gap among ophthalmologists in terms of their ability to proactively identify patients with prior history of ocular herpes—yet this is a critical step toward maximizing prophylaxis prior to performing any of the invasive procedures or intense UV light exposures known to trigger recurrences.2,3

Another educational gap exists pertaining to the emerging standard of care that calls for lifelong prophylaxis for patients who experience two or more occurrences of herpes keratitis.5

Pertinent to this use, many patients may find a topical drop preferable to long-term systemic (oral) medication. In Europe and elsewhere out-side the United States, ophthalmologists have long used both oral and topical antiviral agents to help prevent herpes keratitis in their patients.6 By contrast, until recently, no topical ocular antiviral has been available in the United States with the exception of trifluridine, which many ophthalmologists avoid because of its toxicity to the ocular surface.

This has now changed with the recent introduc-tion of ganciclovir 0.15% gel, FDA approved for the treatment of herpes keratitis. The availability of this new agent opens up possibilities for US ophthalmologists wanting an effective, less toxic, and more comfortable topical antiviral for their patients. Moreover, recent clinical studies suggest that ganciclovir gel is effective in treat-ing adenovirus and varicella-zoster infections of the eye.7-9 These results and their relevance to clinical practice warrant exploration by US ophthalmologists.

The proposed enduring material will educate US ophthalmologists about perioperative and/or lifelong prophylaxis in patients with a history of herpes keratitis. It will likewise provide the most current information on the potential uses and ef-ficacy of ganciclovir 0.15% ophthalmic gel—not only in regards to prophylaxis of herpes keratitis, but also in the treatment of other viral eye infec-tions. It will draw on research and clinical experi-ence both within and outside the United States. Additionally, it will feature the perspectives of leading experts on the treatment and prevention of sight-threatening herpetic infections as well as other viral ocular infections against which topical ganciclovir has shown efficacy.

REFEREncES1. Liesegang TJ. Herpes simplex virus epidemi-

ology and ocular importance. Cornea. 2001 Jan;20(1):1-13.

2. Kurbanyan K, colby K. cataract and refractive surgery in herpetic eye disease. Int Ophthal-mol Clin. 2010;50(1):13-24.

3. Hassan M, Patel DK, Subrayan V. Primary herpes virus keratitis after penetrating kerato-plasty. Ann Ophthalmol. 2009;41(3-4):203-5.

4. Rao A, Tandon R, Sharma n, Sihota R, Gupta V, Dada T. Herpetic keratitis and keratouveitis after mitomycin-c use in glaucoma filtering surgery: a short case series. Eur J Ophthalmol. 2009;19(6):1088-90.

5. Lairson DR, Begley cE, Reynolds TF, Wilhelmus KR. Prevention of herpes simplex virus eye

disease: a cost-effectiveness analysis. Arch Ophthalmol. 2003;121(1):108-12.

6. colin J. Ganciclovir ophthalmic gel, 0.15%: a valuable tool for treating ocular herpes. Clinical Ophthalmol. 2007;1(4):441–53.

7. Kinchington PR, Romanowski EG, Jerold Gor-don Y, et al. Prospects for adenovirus antivi-rals. J Antimicrob Chemother. 2005;55:424–9.

8. Tabbara KF. Ganciclovir effects in adenoviral keratoconjunctivitis. Poster B253. Presented at ARVO 2001. Fort Lauderdale, Florida.

9. Kim SJ, Equi R, Belair ML, Fine HF, Dunn JP. Long-term preservation of vision in pro-gressive outer retinal necrosis treated with combination antiviral drugs and highly active antiretroviral therapy. Ocul Immunol Inflamm. 2007;15(6):425-7.

OFF-lAbEl USE STATEMENTThis work discusses off-label uses of antiinfective medications.

GENErAl INFOrMATIONThis cME program is sponsored by the Uni-versity of Florida college of Medicine and is supported by an unrestricted educational grant from Bausch + Lomb, Inc.

Directions: Select one answer to each question in the exam (questions 1-10) and in the evalua-tion (questions 11-16). The University of Florida college of Medicine designates this activity for a maximum of 2.0 AMA PRA Category 1 Credits™. There is no fee to participate in this activity. In order to receive cME credit, participants should read the report, and then take the posttest. A score of 80% is required to qualify for cME credit. Estimated time to complete the activity is 2 hours. On completion, tear out or photocopy the answer sheet and send it to:

University of Florida cME Office PO Box 100233 Gainesville, FL 32610-0233

Or you can take the test online at http://cme.ufl.edu/XXXXXXXX.

DATE OF OrIGINAl rElEASEJanuary 2011. Approved for a period of 12 months.

AccrEDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and Poli-cies of the Accreditation council for continuing Medical Education (AccME) through the joint sponsorship of the University of Florida col-lege of Medicine and candeo clinical/Science communications, LLc. The University of Florida college of Medicine is accredited by the AccME to provide continuing medical education for physicians.

crEDIT DESIGNATION STATEMENT The University of Florida college of Medicine des-ignates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

TArGET AUDIENcEThis educational activity is intended for ophthal-mologists and ophthalmologists in residency or fellowship training.

lEArNING ObJEcTIVESAs a result of participation in this activity, partici-pants will be able to:

1. List the agents currently available for the prevention of herpes keratitis outbreaks as-sociated with ocular surgery and state the

advantages and disadvantages of each.

2. compare and contrast oral vs topical admin-istration of antiviral medication for prevention of ocular HSV1 recurrences.

3. List the factors believed to trigger ocular HSV1 recurrences and state prophylactic options appropriate to each.

4. Discuss available options for the treatment of ocular infection with adenovirus and varicella-zoster virus.

FAcUlTY AND DISclOSUrE STATEMENTSVictor chang, MD, is a former chief resident at the cullen Eye Institute, of the Baylor college of Medicine, and is currently a clinical fellow of cornea, external disease, and refractive surgery at the Duke Eye center, in Durham, north carolina. He states that in the previous twelve months he has not had a financial relationship with any commercial organization that produces, markets, re-sells, or distributes health care goods or services consumed by, or used on patients.

Herbert E. Kaufman, MD, is the emeritus Boyd professor of ophthalmology, pharmacology, and experimental therapeutics at the Louisiana State University Eye center. He states that in the previ-ous twelve months he has worked as a consultant for ReSearch Pharmaceutical Services, Inc.

Terry Kim, MD, is a professor of ophthalmology at the Duke University School of Medicine and the associate director of corneal and refractive surgery services at the Duke Eye center, in Dur-ham, north carolina. He states that in the past twelve months he has been a consultant to Alcon, Allergan, Inspire, ISTA, OSI, Ocular Therapeutics, Pfizer, and PowerVision.

Deborah Pavan-langston, MD, FAcS, is professor of ophthalmology at Harvard Medical School, director of clinical virology at Harvard’s Massachusetts Eye and Ear Infirmary, and a clini-cal research consultant at the affiliated Schepens Eye Research Institute. She states that in the pre-vious twelve months she has not had a financial relationship with any commercial organization that produces, markets, re-sells, or distributes health care goods or services consumed by, or used on patients.

Michael b. raizman, MD (Faculty Advisor), is a cornea specialist at Ophthalmic consultants of Boston. He is co-director of the cornea and cataract service and director of the cornea fellowship and the uveitis and immunology service at the new England Eye center. He is also an associate professor of ophthalmology at Tufts University School of Medicine, Boston. He states that in the past twelve months he has received research support from Alcon and has been a consultant to Alcon and Bausch + Lomb.

DISclAIMErParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and professional development. The information presented in this activity is not meant to serve as a guideline for patient care. Procedures, medications, and other courses of diagnosis and treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, applicable manufacturer’s product information, and comparison with recommendations of other authorities.

cOMMErcIAl SUPPOrTErS This activity is supported by an educational grant from Bausch + Lomb, Inc.

Advances in the Management of Ocular Herpetic Disease

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Ongoing research is revealing the many factors that lead to the development and progression of herpetic ocular disease, the leading infec-tious cause of corneal blindness in the devel-oped world. These fi ndings, combined with the results of clinical trials of antiherpetic therapies, can guide the clinician in diagnosing, treating, and in some cases, preventing these sight-threat-ening infections.

Of the eight herpes viruses that infect humans, fi ve cause signifi cant ocular disease. They are herpes sim-plex types I and II (HSV-1 and HSV-2), varicella-zoster (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Typically, herpetic infection is lifelong, with the initial infection followed by periods of latency. To date, research has only partially revealed the complex fac-tors involved in the reactivation of latent herpes virus. Ocular disease—whether associated with primary infec-tion or secondary reactivation—can take the form of blepharitis, conjunctivitis, epithelial keratitis, stromal (or endothelial) keratitis, or uveitis.

HSV keratitis is the most familiar of the ocular herpetic diseases and the single most common in-fectious cause of corneal blindness in the developed world.1 However, herpes zoster ophthalmicus, or ocular shingles, appears to be increasing in incidence and per-haps morbidity, particularly in older patients. Indeed, herpes zoster can cause more damage to the cornea than does HSV.2,3

CMV is most associated with severe retinitis in immunocompromised individuals. But recent reports suggest it is a more common cause of corneal endotheli-itis and iritis in the immunocompetent population than previously realized.4,5 Finally, the Epstein-Barr virus is associated with a range of ocular complications, from relatively inconsequential conjunctivitis to keratitis, uveitis, or optic neuritis.6,7

Despite the prevalence of herpetic ocular disease and its ability to cause signifi cant morbidity, many clini-cians lack awareness of these infections and the latency and reactivation factors that can trigger recurrence and progression. A deeper understanding of this family of viruses can guide differential diagnosis, prevention, and management of both active infection and associ-

PART ONE: The Research Perspective

Advances in the Management of ocular herpetic disease

ated infl ammatory damage. It can also help the clini-cian protect the silently infected patient who may be at elevated risk of ocular disease triggered by a variety of stress-related factors and ophthalmic procedures.

HErPES SIMPlEX HSV is globally endemic. Historical references ex-

tend at least as far back as Hippocrates, whose descrip-tion of spreading skin lesions gave us the Latinized herpes from the Greek herpion, “to crawl.”8 Humans are the only natural reservoir of HSV. HSV-1 is most associated with lesions in the facial area; HSV-2 with genital outbreaks.

Initial infection typically results from direct or indirect contact with lesions or the salivary droplets (HSV-1) or genital secretions (HSV-2) of a virus-shedding carrier.9 Common iatrogenic sources include the physi-cian’s unwashed hands and contaminated tonometer heads. HSV remains viable for up to 2 hours on a dry tonometer head, up to 8 hours if the instrument is

Deborah Pavan-langston, MD, FAcS

FIguRE 1Herpes simplex type I and Herpes zoster both establish latency in the ganglion of the trigeminal nerve, which innervates the eye, periorbital area, forehead, and lips. (Image: Gray’s Anatomy.)

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moist. Dry wiping and ophthalmic solutions such as anesthetics have little antiviral effect, but swabbing with 70% isopropyl alcohol is fully viricidal.10

Following initial infection, HSV-1 establishes lifelong latency in the trigeminal ganglion near the ventral area of the brain stem (Figure 1).11 On reactiva-tion, virus travels back down the trigeminal nerve, most commonly to the site of original infection (typically the lips), but with diversions possible to other trigeminally innervated tissues, including the eye.12

cHANGING EPIDEMIOlOGY

HSV-1 was once almost universally acquired in infancy and still appears to be so in developing nations. But epidemiological studies suggest that primary acqui-sition of HSV-1 is becoming progressively delayed in industrialized countries. German researchers identify-ing HSV-1 in the trigeminal ganglia of cadavers found it in just 18% of those under 20 years of age, but more than 90% of those age 60 or older.13 Other studies have documented an epidemic increase in HSV-2, with ap-proximately one in four Americans over age 30 geni-tally infected and a corresponding rise in potentially blinding neonatal infections.14,15

Epidemiological studies in Minnesota suggest that approximately 500,000 Americans have developed ocular HSV disease, with about 20,000 new cases and 28,000 recurrences diagnosed each year.16 Breakdown of the Minnesota data suggests that approximately 72% of ocular simplex disease involves the corneal epithelium; 41%, the lid or conjunctiva; 12%, the corneal stroma; and 9%, the iris and associated uveal tract.

A recent retrospective study at the Cullen Eye Institute documented recurrence rates in children simi-lar to those in adults, though with higher risk of bilat-eral involvement (26%).17 The transmission of HSV by corneal transplant is a dreaded cause of primary graft failure.18,19

rEAcTIVATION AND OcUlAr INVOlVEMENTMost ocular herpetic infections stem from reacti-

vation of latent virus, with or without associated “cold sores” around the mouth or nose. Though latent in-fection is near ubiquitous in the adult population, less than a third of immunocompetent adults experience clinical disease, and a still smaller subset is prone to frequent recurrence. HSV-1 strains clearly vary in their predisposition to breaking latency.20 Studies have like-wise revealed human gene variations that predispose individuals to recurrences.21,22

In addition, research has identified a variety of reactivation triggers including hormonal fluctuations, immune suppression, systemic illness, stress, lack of sleep, shoulder stiffness, physical fatigue, and local tis-sue damage, including subclinical cell damage caused by exposure to ultraviolet light.23,24 As noted in a study

by Shimomura, many patients report that psychologi-cal stress is a significant predictor of recurrence.24 The Herpes Eye Disease Study (HEDS) failed to corroborate this association and attributed it to recall bias.25

Of particular importance to ophthalmology is the realization that intense light exposure can trigger herpetic ocular disease and may partially explain its postoperative incidence after LASIK and PRK proce-dures.23,26,27 The local trauma of invasive procedures such as cataract removal and lamellar keratoplasty likewise carry the risk of this complication.23,28 Risk ap-pears to be highest for patients who have previously experienced ocular herpes. However, patients without such a history can also present with this complication following ophthalmic surgery, and a patient history of frequent labial or nasal herpes may indicate a general predisposition to reactivation.

Ocular steroids themselves do not appear to trig-ger reactivation of the herpes virus, but if reactivation

CORE CONCEPTS Most adults harbor latent herpes simplex and

zoster in the trigeminal ganglia. Reactivated viruses can follow innervation paths to cause sight-threatening ocular disease.

Patients vary in their predisposition to HSV reactivation. common triggers include systemic illness, local trauma (eg, ocular surgery), and UV light, including strong sunlight and laser procedures.

Initial HSV ocular disease tends to be limited to superficial dendritic keratitis, while subsequent recurrences can trigger sight-threatening stromal inflammation.

Research confirms a role for topical antiherpetic drugs for treating HSV epithelial keratitis. Oral antiherpetics are used for both the treatment of stromal disease and the prevention of recurrent ocular disease.

The incidence of herpes zoster disease is increasing in the adult population; individual susceptibility increases with age due to waning cellular immunity.

The eye is the second most common site of zoster disease, which may be even more sight-threatening than HSV infection.

Though rare, cMV anterior segment disease in the immunocompetent is more common than previously thought.

Symptomatic EBV infection (mononucleosis) can include a range of ocular manifestations, from conjunctivitis to keratitis.

AdvAnces in the MAnAgeMent of oculAr herpetic diseAse — pArt one: the reseArch perspective

5

occurs in the presence of steroids, an unusually aggres-sive disease can result.29,30

PrIMArY VS rEcUrrENT DISEASE HSV can cause a wide array of ocular disease (Table

1). As mentioned, most ocular disease involves reacti-vation of latent HSV. But primary ocular infections are not uncommon. Typically they involve rapidly spread-ing viral dendrites or geographic ulcers in the corneal epithelium because there is no antibody in the tear film to contain the virus. More distinctively, there is no associated immune reaction to cloud the stroma or deeper ocular tissues.

By contrast, recurrent infection can unfold against the background of a hypersensitive immune response. In many cases, the secondary disease remains confined to the epithelium in the form of infectious dendrites or geographic ulcers. In other cases, however, the im-mune reaction causes stromal edema, with invasion by lymphocytes, macrophages, and other white cells. This stromal immune reaction and its frequently associated corneal scarring pose the greatest lasting threat to vision.

Studies suggest that 10% of patients with epi-thelial keratitis will go on to experience stromal dis-ease within a year, and patients with a history of mul-tiple recurrences remain at increased risk for future recurrences.1,31

TrEATMENT ADVANcEMENTSBy the 1980s, trifluridine had become the pre-

ferred topical treatment of infectious epithelial HSV keratitis in the United States, surpassing older antivirals such as idoxuridine and vidarabine.32,33 The mecha-nism of action of all three drugs was a mild to moder-ately toxic, non-specific targeting of viral and cellular enzymes and DNA in infected and non-infected cells alike, with clinician and patient preference favoring trifluridine for its drop formulation and equal to supe-rior therapeutic effectiveness.33-35

That widespread preference has changed with the FDA approval of topical ganciclovir ophthalmic gel 0.15%, owing to ganciclovir’s therapeutic efficacy and low toxicity, which relate to its specific targeting of viral DNA in infected cells.36 In Europe, acyclovir 3% ointment is an additional option, with studies showing equal efficacy to ganciclovir gel but lower patient toler-ance—owing largely to ointment-associated blurring.37

By the late 1980s, research had demonstrated the superiority and ease of oral antiviral drugs for the treatment of infectious herpetic keratitis and the inhi-bition of recurrent HSV infectious disease. This proved particularly important when topical steroids were being used to treat stromal disease, scleritis, episcleritis, and iritis. Today, available oral antiherpetic drugs include acyclovir, valacyclovir, and famciclovir, all of which demonstrate low toxicity to uninfected cells as they

Table 1 Classification of ocular HSV diseaseI. Primary Infection A. neonatal B. Primary (children, adults)

II. Recurrent Infection A. Blepharitis B. conjunctivitis, scleritis c. Dendritic or geographic epithelial keratitis D. Sterile corneal neurotrophic ulceration E. Stromal keratitis (primarily immune) F. Endotheliitis/trabeculitis (primarily immune) G. Iridocyclitis (primarily immune)

are specifically activated by HSV- and HZV-induced en-zymes such as thymidine kinase and DNA polymerase.38

The first and most extensively studied oral anti-viral is acyclovir.39-41 No large controlled studies have compared acyclovir with newer drug analogs such as valacyclovir or famciclovir, but these newer drugs offer clear advantages for case management. Studies show, for example, that valacyclovir has five times acyclovir’s bioavailability and that famciclovir has a longer intra-cellular half-life than acyclovir.42,43 (See also, Table 2: FDA-approved antiviral agents for ocular disease.)

HEDS confirmed the value of combining oral antiherpetic therapy with topical corticosteroids in treating HSV stromal disease and iritis.44 The study employed a 10-week, tapered regimen of topical corti-costeroid. Compared to placebo, treatment produced more rapid resolution and a lower likelihood of disease progression. More recent research suggests that cyclo-sporine may be useful in controlling herpetic inflam-mation without the steroid-associated risk of elevating intraocular pressure.45

PrEVENTIONWhen it comes to preventing the recurrence of

ocular herpetic disease, our best guidance comes from ongoing HEDS trials and the recent Minnesota study on incidence, recurrence, and outcome of HSV eye disease.16,44 Some of the most recent HEDS findings include the ability of oral acyclovir to reduce the re-currence rate of all types of ocular HSV (19% recur-rence over 1 year with acyclovir vs 32% with placebo). Importantly, acyclovir maintenance therapy halved the annual recurrence rate of vision-threatening stromal disease (14% with acyclovir vs 28% with placebo).46 When used for long-term antiviral prophylaxis, both acyclovir and valacyclovir have been shown to decrease the risk of recurrent conjunctivitis, epithelial keratitis, stromal keratitis, and blepharitis, and to significantly in-hibit recurrent HSV in post-operative, HSV-penetrating keratoplasty.16,32,47-49


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In addition, a number of animal studies and uncontrolled patient series suggest that perioperative prophylaxis with oral acyclovir or valacyclovir can sig-nificantly reduce the incidence of laser-induced HSV reactivation.26,50,51

There is great interest in developing a vaccine able to prevent either primary infection or recurrent disease. But to date, neither passive nor active immu-nization has produced significant protection in animal models.14,52,53

HErPES ZOSTEr OPHTHAlMIcUS (HZO)Herpes zoster, or shingles, is caused by reactiva-

tion of the varicella virus that causes chickenpox. When this reactivation involves latent virus in the trigeminal ganglion, the result can be herpes zoster ophthalmicus (HZO). Approximately 20% of the world’s population suffers from herpes zoster at least once in a lifetime, and 10% to 20% of these people experience ophthal-mic involvement.54 Indeed, the eye is the second most common disease site, second only to the torso. Adding to the insult, cadaver studies show that trigeminal co-in-fection with herpes simplex and varicella is common.55

Two factors are expected to significantly increase

Table 2 FDA-approved antiviral agents for ocular disease

The ideal antiherpetic agent interrupts viral replication at a critical step without affecting the host’s cellular metabolism. These targeted steps include viral adsorption, penetration, uncoating, viral genome transcription, synthesis of viral proteins, and viral release. cell attachment and penetration require interaction between viral structures and cellular membranes. Uncoating is typically accomplished by cellular enzymes and influenced by viral proteins. Viral transcription likewise is performed by the cell but under the influence of virus-specific proteins. Key proteins include virus-specific thymidine kinase and DnA polymerase. Herpes viruses acquire host-derived nuclear membranes before migration to the cell surface for release. current antiherpetic therapy and research focuses on these functions, targeting components such as enzymes that are more specific to the herpes virus than to the infected cell.

Antiherpetic agents Mechanisms of action Target viruses

Trifluridine(pyrimidine nucleoside)

non-specifically inhibits viral and cellular thymidylate synthetase blocking DnA thymidine uptake

HSV-1, HSV-2

Acyclovir(acyclic pyrimidine nucleoside)

Preferential substrate for viral thymidine kinase → other enzymes → AcV-tri-PO4 → viral DnA chain termination. Poor GI uptake

HSV-1, HSV-2, VZV, EBV ± cMV

Valacyclovir(1-valine ester of acyclovir) Same as acyclovir. Enhanced GI uptake HSV-2, HSV-1 VZV, EBV HHV 6–8, cMV

Famciclovir(acyclic guanine derivative) Same as acyclovir HSV-1, HSV-2, VZV, EBV

Ganciclovir(acyclic purine nucleoside)

competes with deoxyguanosine for incorporation into viral DnA and DnA chain growth

cMV, HSV-1, HSV-2, VZV, EBV

Abbreviations: cMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; HSV, herpes simplex virus; VZV, varicella-zoster virus. (Adapted from Pavan-Langston D, John T. Ocular Antivirals. In: Albert D, Miller J, eds. Principles and Practice of Ophthalmology, 3rd ed., Philadelphia: Saunders;2008:215-22.)

zoster’s incidence in the coming years. The first is the demographic aging of the U.S. population—varicella activation being strongly associated with the waning of cell-mediated immunity in old age.54

The second is the introduction of the chickenpox vaccine to the early childhood immunization schedule. While of huge benefit to our children and future genera-tions, this has removed the immunological “booster” that exposure to actively infected children historically provided parents and other adults. A recent Australian study found herpes zoster rates in adults age 40 and older have been increasing 2% to 6% a year since the 2005 introduction of childhood varicella immuniza-tion in that country.56

The good news is that an effective zoster vaccine is now available for adults.57 It has been shown to decrease both the incidence of zoster and the severity of post-her-petic pain by 50% to 60%.58 However, the vaccine’s FDA-approval (and associated insurance coverage) remains limited to persons age 60 and older. This is unfortunate, as those in their 40s and 50s are likewise at elevated risk. Indeed, herpes zoster can manifest at any age, though in-cidence rises dramatically after age 60. Beyond age, risk factors include Caucasian ethnicity, female gender, ge-


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netic susceptibility, immune suppression, local trauma, and possibly psychological stress and depression.59,60

OcUlAr MOrbIDITYHZO’s high ocular complication rate may render

it even more vision threatening than HSV (Table 3). Its potential complications include dermatomal vesicular rash and severe pain, viral shedding, acute dendritiform or geographic corneal ulcers, anesthetic neurotrophic ulcers (which may perforate), corneal stromal immune keratitis, scleritis, episcleritis, iritis, and recurrent ocu-lar inflammatory disease, such as episcleritis, scleritis, iritis, or corneal ulceration.32,61 On occasion a patient may have dermatomal pain and/or iritis associated with “zoster sine herpete,” or reactivated VZV without the classic rash or keratitis.62

In particular, research suggests more corneal nerve

damage with zoster disease than with simplex, result-ing in a greater frequency of anesthetic corneas and ex-tensive scarring.61 Chief among zoster’s other sequelae is post-herpetic neuralgia emanating from local and central nervous system damage. It can range in sever-ity from mild and transient to enduring and intractable pain in the area of the affected dermatome.54,63 Recent research suggests that post-herpetic neuralgia affects 10% to 20% of herpes zoster patients over age 50 and up to 30% of those over age 80.64

Research has demonstrated that prompt, high-dose treatment with oral antivirals can significantly

reduce the incidence, severity, and sequelae of HZO.32,58

Unfortunately, ineffective and inadequate treatment is common given the tendency of nonspecialists to mis-take zoster’s pseudodendritic presentation for the less treatment-resistant herpes simplex. (See “The Clinical Perspective” for differential diagnosis and treatment.)

Zoster’s high complication rate has inspired a number of studies comparing the efficacy of treatment with high-dose acyclovir, valacyclovir, or famciclovir. Though a number of early studies showed equiva-lence, several recent clinical trials have demonstrated the superiority of valacyclovir and famciclovir in re-ducing the incidence of post-herpetic neuralgia.63-66 Valacyclovir and famciclovir also lend themselves to greater patient compliance at the high dosages needed to manage zoster. Topical ophthalmic antivirals such as ganciclovir gel may be a helpful adjunct to treatment when dendritic outbreaks prove resistant to oral drugs.

Studies show topical corticosteroids to be use-ful in managing associated stromal immune disease and endotheliitis—suppression of which is crucial for preserving corneal clarity. Importantly, steroids do not appear to exacerbate HZO.32

cYTOMEGAlOVIrUS CMV silently infects an estimated 50% to 80%

of adults in the United States.67 Initial infection typi-cally goes unnoticed, although the virus can produce a glandular-fever syndrome. Unlike herpes simplex and zoster, cytomegalovirus does not persist in neurogan-glia, but establishes latency in white blood cells such as T lymphocytes and monocytes.

CMV’s most common ocular manifestation is chorioretinitis in the immunocompromised patient.68 Prior to antiretroviral therapy, up to 45% of AIDS pa-tients developed blinding CMV infections. Intravenous ganciclovir often proved effective, though efficacy plummeted in severely immunocompromised patients. Fortunately, effective antiretroviral therapy (HAART) has dramatically reduced the toll of AIDS, including this ocular complication.69

Recently, it has become clear that corneal and iris CMV infection is more common in immunocompetent patients than previously thought. These infections can mimic herpes simplex or zoster stromal disease.68,70 The key difference is that CMV keratitis involves the deepest layers of the cornea (endotheliitis), while ocular sim-plex and zoster tend to involve superficial and middle stroma.70 Holland and others have reported transmis-sion of CMV by corneal transplantation.71

Diagnosis of this endotheliitis requires tapping the anterior chamber for evidence of cytomegalovi-rus DNA—a procedure currently restricted to major medical centers. CMV does not respond to acyclovir but is responsive to topical and systemic ganciclovir. Observation periods are long, ranging up to 14 months.


Table 3 Herpes zoster: incidence of corneal complications*

Finding Incidence

Punctate epithelial keratitis 51%

Pseudodendrites (acute) 50%

Anterior stromal infiltrates 41%

Keratouveitis, endotheliitis 34%

neurotrophic keratitis 25%

Delayed mucous plaques (pseudodendrites) 13%

Exposure keratitis 11%

Disciform keratitis 10%

Serpiginous ulceration 7%

Scleral keratitis 1%

Delayed limbal vasculitis <1%

*Adapted from Leisegang T. corneal complications from herpes zoster ophthalmicus. Ophthalmology. 1985;92:316-24.

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EPSTEIN-bArr VIrUSThe Epstein-Barr virus (EBV) is likewise globally

endemic, infecting up to 95% of the world’s population. Like cytomegalovirus, EBV establishes lifelong latency in white blood cells.72

Infection in early childhood tends to be asymp-tomatic. In adolescence and adulthood, it can cause infectious mononucleosis. The ocular manifestations of overt mononucleosis can include conjunctivitis, scleritis, and dendritic epithelial keratitis, stromal ker-atitis, and iritis.73,74 In the absence of mononucleosis,

Epstein-Barr ocular disease is rare and associated with relatively low-grade inflammation and minor scarring of the anterior cornea.

Deborah Pavan-Langston, MD, FACS, is professor of ophthal-mology at Harvard Medical School, director of clinical virology at Harvard’s Massachusetts Eye and Ear Infirmary, and a clini-cal research consultant at the affiliated Schepens Eye Research Institute. She states that in the previous twelve months she has not had a financial relationship with any commercial organiza-tion that produces, markets, re-sells, or distributes health care goods or services consumed by, or used on patients.

REFERENCES 1. Liesegang TJ. Herpes simplex virus epidemiology and ocular im-

portance. Cornea. 2001 Jan;20(1):1-13. 2. Starr CE, Pavan-Langston D. Varicella-zoster virus: mechanisms

of pathogenicity and corneal disease. Ophthalmol Clin North Am. 2002 Mar;15(1):7-15.

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12. Mott KR, Bresee CJ, Allen SJ, et al. Level of herpes simplex virus type 1 latency correlates with severity of corneal scarring and ex-haustion of CD8+ T cells in trigeminal ganglia of latently infected mice. J Virol. 2009 Mar;83(5):2246-54.

13. Liedtke W, Opalka B, Zimmermann CW, et al. Age distribution of latent herpes simplex virus 1 and varicella-zoster virus genome in human nervous tissue. J Neurol Sci. 1993;116:6-11.

14. Pepose JS, Keadle TL, Morrison LA. Ocular herpes simplex: changing epidemiology, emerging disease patterns, and the po-tential of vaccine prevention and therapy. Am J Ophthalmol. 2006;141:547-57.

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16. Young RC, Hodge, DO, Liesegang, TS et al. Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: The effect of oral antiviral pro-phylaxis. Arch Ophthalmol. 2010;128(9):1178-83.

17. Chong EM, Wilhelmus KR, Matoba AY. Herpes simplex virus kera-titis in children. Am J Ophthalmol. 2004;138:474-5.

18. Robert PY, Adenis JP, Denis F, et al. Transmission of viruses through corneal transplantation. Clin Lab. 2005;51(7-8):419-23.

19. Remeijer L, Duan R, van Dun JM, et al. Prevalence and clinical consequences of herpes simplex virus type 1 DNA in human cor-nea tissues. J Infect Dis. 2009;200(1):1-4.

20. Li S, Carpenter D, Hsiang C, et al. Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes

neurite sprouting in neuroblastoma cells following serum star-vation by maintaining protein kinase B (AKT) levels. J Gen Virol. 2010 Apr;91:858-66.

21. Koelle DM, Magaret A, Warren T, et al. APOE genotype is associated with oral herpetic lesions but not genital or oral herpes simplex virus shedding. Sex Transm Infect. 2010 Jun;86(3):202-6.

22. Bhattacharjee PS, Neumann DM, Hill JM. A human apolipopro-tein E mimetic peptide effectively inhibits HSV-1 TK-positive and TK-negative acute epithelial keratitis in rabbits. Curr Eye Res. 2009 Feb;34(2):99-102.

23. Toma HS, Murina AT, Areaux RG Jr, et al. Ocular HSV-1 latency, reactivation and recurrent disease. Semin Ophthalmol. 2008 Jul-Aug;23(4):249-73.

24. Shimomura Y. Herpes simplex virus latency, reactivation, and a new antiviral therapy for herpetic keratitis. Nippon Ganka Gakkai Zasshi. 2008 Mar;112(3):247-64.

25. Herpetic Eye Disease Study Group. Psychological stress and other potential triggers for recurrences of herpes simplex virus eye in-fections. Arch Ophthalmol. 2000 Dec;118(12):1617-25.

26. Asbell PA. Valacyclovir for the prevention of recurrent herpes simplex virus eye disease after excimer laser photokeratectomy. Tr Am Ophth Soc. 2000;98:285-303.

27. Levy J, Lapid-Gortzak R, Klemperer I, et al. Herpes simplex vi-rus keratitis after laser in situ keratomileusis. J Refract Surg. 2005 Jul-Aug;21(4):400-2.

28. Patel, N, Teng, C, Sperber, L, et al. New-onset Herpes simplex virus keratitis after cataract surgery. Cornea, 2009;28:108-10.

29. Kibrick S, Takahashi G, Liebowitz H, et al. Local corticosteroid therapy and reactivation of herpetic keratitis. Arch Ophthalmol. 1971;86:694-9.

30. Beyer CF, Arens MQ, Hill JM, et al. Penetrating keratoplasty in rabbits induces latent HSV-1 reactivation when corticosteroids are used. Curr Eye Res. 1989;8:1323-9.

31. 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. Arch Ophthalmol. 1997;115:703-12.

32. Pavan-Langston D. Viral disease in the cornea and external eye. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. 3rd ed. Philadelphia: WB Saunders;2008:633-700.

33. Pavan-Langston D, Foster CS. Trifluorothymidine and idoxuridine therapy of ocular herpes. Am J Ophthalmol. 1977; 84:818-25.

34. Pavan-Langston D, Buchanan RA. Vidarabine therapy of simple and IDU-complicated herpetic keratitis. Trans Am Acad Ophth Otol. 1976;81:813-25.

35. Guess, S, Stone, D, Chodosh, J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. 2007:5(3):240-50.

36. Kaufman, HE. Ganciclovir: a promising topical antiviral gel for herpetic keratitis. Expert Rev Ophthalmol. 2009;4(4):367-75.

37. Colin J. Ganciclovir ophthalmic gel 0.15%: a valuable tool for treating ocular herpes. Clinical Ophthalmol. 2007;1(4):441-53.

38. Pavan-Langston D, John T. Ocular Antivirals. In: Albert D, Miller J, eds. Principles and Practice of Ophthalmology, 3rd ed. Philadelphia: WB Saunders;2008:215-22.

39. Elion G. Mechanism of action and selectivity of acyclovir. Am J


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Med. 1982;73(1A):7-13. 40. Schwab, IR. Oral acyclovir in the management of herpes simplex

ocular infections, Ophthalmology. 1988;95:423-30. 41. Pavan-Langston DR. Viral Disease of the Ocular Anterior

Segment: Basic Science and Clinical Disease. In: Foster S, Azar D, Dohlman C, eds. The Cornea. Philadelphia: Lippincott Williams & Wilkins;2005:297-397.

42. Weller S, Blum M, Smiley M. Phase I pharmacokinetics of the acyclovir prodrug, valacyclovir. Antivir Res. 1993;20(suppl 1):144.

43. Perry CM, Wagstaff AJ. Famciclovir. A review of its pharmacologi-cal properties and therapeutic efficacy in herpesvirus infections. Drugs. 1995;50:396-415.

44. Wilhelmus KR, Gee L, Hauck WW. Herpetic Eye Disease Study: A controlled trial of topical corticosteroids for herpes simplex stro-mal keratitis. Ophthalmology. 1994;101:1883-96.

45. Knickelbein JE, Hendricks RL, Charukamnoetkanok P. Management of herpes simplex virus stromal keratitis: an evidence-based review. Surv Ophthalmol. 2009 Mar-Apr;54(2):226-34.

46. The Herpetic Eye Disease Study Group. Acyclovir for the preven-tion of recurrent herpes simplex virus eye disease. N Engl J Med. 1998;339:300-6.

47. Miserocchi E, Giulio G, Galli L, et al. Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus. Am J Ophthalmol. 2007;144:547-51.

48. Garcia D, Farjo Q, Musch D, et al. Effect of prophylactic oral acy-clovir after penetrating keratoplasty for herpes simplex keratitis. Cornea. 2007;26(8): 930-94.

49. Legmann-Simon A, Pavan-Langston D. Long-term oral acyclovir: Effect on recurrent infectious herpes simplex keratitis in grafted and non-grafted patients. Ophthalmology. 1996;103:1399-1405.

50. de Rojas Silva MV, Diez-Feijoo E, Javaloy J, et al. Prophylactic perioperative antiviral therapy for LASIK in patients with inac-tive herpetic keratitis. J Refract Surg. 2006 Apr;22(4):404-6.

51. Dhaliwal DK, Romanowski EG, Yates KA, et al. Valacyclovir inhi-bition of recovery of ocular herpes simplex virus type 1 after ex-perimental reactivation by laser in situ keratomileusis. J Cataract Refract Surg. 2001 Aug;27(8):1288-93.

52. Koelle DM, Ghiasi H. Prospects for developing an effective vac-cine against ocular herpes simplex virus infection. Curr Eye Res. 2005;30:929-42.

53. Dasgupta G, Chentoufi AA, Nesburn AB, et al. New concepts in herpes simplex virus vaccine development: notes from the battle-field. Expert Rev Vaccines. 2009 Aug;8(8):1023-35.

54. Pavan-Langston DR, Herpes Zoster: Antivirals and pain manage-ment. Ophthalmology 2008;115:S13-20.

55. Inoue H, Motani-Saitoh H, Sakurada K, et al. Detection of varicella-zoster virus DNA in 414 human trigeminal ganglia from cadavers by the polymerase chain reaction: a comparison of the detection rate of varicella-zoster virus and herpes simplex virus type 1. J Med Virol. 2010 Feb;82(2):345-9.

56. Jardine A,Conaty SJ,Vally H. Herpes zoster in Australia: evidence of increase in incidence in adults attributable to varicella immu-nization? Epidemiol Infect. 2010 Aug;23:1-8.

57. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults, N Engl J Med. 2005;352:2271-84.

58. Levin MJ, Gershon AA, Dworkin RH, et al. Prevention strategies for herpes zoster and post-herpetic neuralgia. J Clin Virol. 2010 May;48(Suppl 1):S14-9.

59. Schmader K, George LK, Burchett BM, et al. Racial and psychoso-cial risk factors for herpes zoster in the elderly. J Infect Dis. 1998 Nov;178(Suppl 1):S67-70.

60. Gershon AA, Gershon MD, Breuer J, et al. Advances in the under-standing of the pathogenesis and epidemiology of herpes zoster. J Clin Virol. 2010;48(Suppl 1):S2-7.

61. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk fac-tors, clinical presentation, and morbidity. Ophthalmology. 2008 Feb;115(Suppl 2):S3-12.

62. Gilden D, Wright R, Schneck S, et al. Zoster sine herpete: a clini-cal variant. Ann Neurol. 1994;35:530-3.

63. Tyring SK, Belanger R, Bezwoda W, et al. A randomized, double-blind trial of famciclovir versus acyclovir for the treatment of localized dermatomal herpes zoster in immunocompromised patients. Cancer Invest. 2001;19:13-22.

64. Gauthier A, Breuer J, Carrington D, Martin M, Remy V. Epidemiology and cost of herpes zoster and post-herpetic neu-ralgia in the United Kingdom. Epidemiol Infect. 2009;137:38-47.

65. Tyring SK, Engst R, Corriveau C, et al. Famciclovir for ophthalmic zoster: a randomised aciclovir controlled study. Br J Ophthalmol. 2001;85:576-81.

66. Tyring SK, Beutner KR, Tucker BA, et al. Antiviral therapy for her-pes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med. 2000;9:863-9.

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10

The human herpes viruses include several that can produce severe ocular disease, herpes simplex and varicella-zoster being chief among them. recent therapeutic advances have enhanced our ability to treat and prevent herpetic ocular disease. but optimal use of these agents still depends on the clinician’s ability to distinguish both the type of herpes virus involved and the nature of the ocular manifestation.

As corneal specialists we see an average of fi ve to ten cases of ocular herpetic disease each month, and ophthalmologists with more diversifi ed practices likely see fewer cases. Nonetheless, ocular herpes—par-ticularly disease due to herpes simplex virus (HSV)—is rightly infamous as the leading cause of infectious corneal blindness in the developed world, and many of the cases we see involve scarring extensive enough to warrant corneal transplantation.

Prompt diagnosis and appropriate treatment are vital to preventing such outcomes. The good news is that treatment options have expanded and improved in recent years. The Herpetic Eye Disease Study (HEDS) demonstrated that oral acyclovir can reduce the recur-rence of ocular herpes simplex, and last year brought the US introduction of ganciclovir gel, our fi rst new topical drug for herpetic eye disease since the advent of trifl uridine in the 1970s. Ganciclovir gel is a particu-larly welcome addition, as it requires less frequent dos-ing and lacks trifl uridine’s potential for ocular toxicity.

PART TWO: The Clinical Perspective


Terry Kim, MD, and Victor chang, MD

But diagnosis and differentiation of herpetic infections remain challenging. The pseudodendrites of herpes zoster, for example, can resemble the den-drites of herpes simplex on cursory examination. And a patient presenting with diffuse or multifocal stromal infl ammation may be actively infected with HSV, vari-cella-zoster virus, or rarely cytomegalovirus (CMV) or Epstein-Barr virus (EBV) (Table 1). As treatment regi-mens differ for these herpes viruses, proper diagnosis is crucial. In the following pages, we will review ad-vances in the diagnosis and treatment of herpetic eye infections and the damaging stromal infl ammation they can leave behind.

HErPES SIMPlEX Primary HSV infection begins with the virus enter-

ing compromised skin or mucous membrane. Many pri-mary infections remain subclinical. Others cause local-ized vesicular eruption, with or without accompanying fever. After initial infection of trigeminally innervated tissues, HSV type 1 migrates up the trigeminal nerve to establish latency in its ganglion. (HSV-2 generally establishes latency in the ganglion of the sacral nerve.)

Following reactivation, HSV travels back down the axon to cause an eruption of new lesions. Most often, the reactivated disease involves the original in-fection site. But HSV-1 can travel down any of the tri-geminal nerve’s facial pathways, including those leading to the eye. Around 90% of patients who develop HSV

Table 1 The human herpes viruses and ocular disease

Name Ocular disease Other manifestations

Herpes simplex virus-1 Blepharitis, conjunctivitis, keratitis, anterior uveitis, retinal necrosis Oral (fever blisters), encephalitis

Herpes simplex virus-2 Blepharitis, conjunctivitis, keratitis, anterior uveitis, retinal necrosis

Genital/anal lesions, severe neonatal infections, meningitis

Varicella-zoster virus Blepharitis, conjunctivitis, keratitis, anterior uveitis, retinal necrosis

chickenpox (primary infection), shingles (reactivation)

Epstein-Barr virus Epithelial and stromal keratitis Infectious mononucleosis (primary infection), lymphoma, nasopharyngeal carcinoma

cytomegalovirus Epithelial and stromal keratitis, retinitis Disseminated infections in the immunocompromised patient

11

keratitis recover with 20/40 acuity or better. But 3% to 5% are left with 20/100 or worse.1

In recent decades, an epidemic increase in genital herpetic infections has made HSV-2 a major cause of neonatal ocular herpes. Moreover, this strain appears to be more associated with acute retinal necrosis syn-drome than is HSV-1.1

PresentationThe great majority (~90%) of ocular herpes simplex

infections present unilaterally. Indeed, bilateral presen-tation suggests an immunocompromised state. We can classify herpes infections by their presentation (Figure 1):

Eyelid/ConjunctivaHSV dermatoblepharitis can result from either

primary infection or reactivation of latent virus. The skin lesions appear as vesicular eruptions of the eyelid or lid margin, occasionally accompanied by lymphatic swelling and pain (Figure 2). The lesions typically heal without scarring, but in some cases dermatoblepharitis can progress to conjunctivitis and keratitis.

CORE CONCEPTS Herpetic eye disease remains the leading cause

of infectious corneal blindness in the developed world.

Five types of herpes viruses can cause ocular disease, and differentiating between them can be key to appropriate treatment.

The HEDS trials settled many of the controversies surrounding the treatment of ocular herpes simplex.

Since the HEDS trials, treatment advances for ocular HSV have included more effective oral antiviral medications (valacyclovir and famciclovir) and a less toxic, more patient-friendly topical drug (ganciclovir ophthalmic gel).

FIguRE 2HSV dermatoblepharitis. (courtesy Wills Eye Hospital.)

HSV conjunctivitis can produce a follicular re-action indistinguishable from mild forms of adenovi-rus conjunctivitis. However, unlike adenovirus, HSV conjunctivitis rarely forms pseudomembranes. The presence of dendrites on the conjunctiva can help confi rm this diagnosis. With recurrence, conjunctivi-tis may occur without eyelid or corneal involvement; therefore HSV should be included in the differential diagnosis when patients present with follicular con-junctivitis alone.

Epithelial KeratitisHSV epithelial keratitis may initially manifest as

corneal vesicles. These small, raised, clear vesicles rep-resent the corollary to the vesicular lesions that can develop on skin and mucous membranes. Fluorescein aids visualization by pooling around the raised epi-thelial vesicles.

As the vesicular lesions of HSV progress, they co-alesce to form the classic herpes dendritic ulcer with its branching shape and terminal bulbs. The raised edges of the dendritic lesion are comprised of swollen epithe-lial cells containing live virus (Figure 3). In differentiat-ing herpes simplex from varicella-zoster keratitis, keep in mind that zoster lesions appear as tapering lines of heaped up epithelium without central ulceration (Figure 4). Fluorescein and vital dyes (eg, rose bengal

PRIMARY INFECTION

DERMATOBLEPHARITIS

STROMALKERATITIS:

Immune Stromal

Necrotizing

ENDOTHELIITIS:

Disciform

Diffuse

Linear

EPITHELIALKERATITIS:

Vesicular

Dendritic

Geographic

Marginal

IRIDOCYCLITISPOSTERIOR

UVEITISCONJUNCTIVITIS

LATENCY

FIguRE 1clinical forms of ocular herpes.

AdvAnces in the MAnAgeMent of oculAr herpetic diseAse — pArt two: the clinicAl perspective

12

Findings range from mild epithelial irregularity to mac-roulceration. The latter may be confused with an HSV geographic ulcer; but unlike the amoeboid shape of a geographic ulcer, neurotrophic ulcers appear oval or round. These ulcers may be associated with stromal thin-ning and scarring. Since the findings of neurotrophic keratopathy may be mistaken for active viral activity, the clinician may inadvertently prolong the course of topical antiviral agents, resulting in delayed healing if the antiviral agent has associated epithelial toxicity.

Stromal KeratitisAlthough HSV epithelial and endothelial disease

may result in stromal inflammation, primary HSV stro-mal keratitis can be divided into immune stromal (or interstitial) and necrotizing types. Immune stromal keratitis results from an antigen-antibody response and appears as unifocal or multifocal stromal haze with or without neovascularization. After the inflammation

subsides, stromal scarring may be severe enough to necessitate corneal transplantation. Non-HSV causes for immune stromal keratitis include varicella-zoster, EBV, syphilis, Acanthamoeba, mumps, Lyme disease, sarcoidosis, and Cogan syndrome.

Necrotizing stromal keratitis is a rare manifesta-tion of HSV that appears as a dense area of suppura-tive stromal inflammation and is associated with an epithelial defect. This entity is difficult to distinguish from bacterial or fungal keratitis and hence poses a therapeutic challenge that may require Gram staining and cultures for definitive diagnosis. Fortified antimi-crobial agents may be warranted until Gram stain and cultures prove negative.

EndotheliitisHSV endotheliitis is thought to be an immuno-

logically mediated manifestation of ocular herpes. This entity presents as keratic precipitates associated with varying degrees of stromal edema and uveitis. Based

or lissamine green) can be useful in distinguishing HSV dendrites. Since the HSV ulcers represent true epithe-lial defects, fluorescein stains the base of each lesion, and vital dyes will stain the epithelial cells comprising the raised edge. Clinicians should be mindful that rose bengal inhibits viral replication and, so, can decrease the yield of virus culture and possibly inhibit detec-tion by PCR.2,3

An HSV geographic ulcer can develop when the ulcerated base of a dendritic lesion widens, as com-monly occurs under the influence of topical cortico-steroids. The geographic lesion takes on an amoeboid shape with raised edges, which likewise stain with vital dyes (Figure 5).

HSV epithelial disease can also present as a mar-ginal ulcer. This type of epithelial defect is often as-sociated with stromal infiltration by white blood cells supplied by limbal blood vessels. Typically, there is no intervening zone of clear cornea between the infiltrate and limbus, as may be seen with staphylococcal mar-ginal keratitis.

HSV epithelial disease may lead to permanently de-creased corneal sensation and neurotrophic keratopathy.

FIguRE 5HSV geographic epithelial keratitis. (courtesy Wills Eye Hospital.)

FIguRE 4HZO’s pseudodendrites appear as lines of heaped epithelium without central ulceration. (courtesy Joseph Halabis, OD.)

FIguRE 3HSV dendritic epithelial keratitis. (courtesy Joseph Halabis, OD.)


13

on the distribution of keratic precipitates and overly-ing stromal edema, HSV endotheliitis can be divided into three clinical forms—disciform, diffuse, and linear. Disciform endotheliitis is associated with stromal edema in a round configuration (Figure 6). Diffuse endotheliitis manifests as scattered keratic precipitates with diffuse stromal edema. With linear endotheliitis, the keratic precipitates are arranged in a straight or wavy line with overlying stromal edema.

IridocyclitisHSV iridocyclitis may occur alone or secondary

to corneal disease. Findings include anterior cham-ber inflammation with fine keratic precipitates. Often, the uveitis is accompanied by trabeculiitis and ocular hypertension.

TreatmentIn the mid-1990s, treatment of ocular herpes sim-

plex advanced significantly with the results from HEDS, a series of prospective, randomized, double-masked and placebo-controlled multi-center trials. Indeed, HEDS helped resolve many of the controversies that had clouded the treatment of ocular HSV disease (Table 2).4-7

While HEDS addressed the use of oral acyclovir and topical trifluridine, our treatment options have since ex-panded with the introduction of additional oral therapies (valacyclovir and famciclovir) and a new topical medi-cation (ganciclovir ophthalmic gel 0.15%). Valacyclovir has five times acyclovir’s bioavailability, and famciclo-vir has a longer intracellular half-life than acyclovir.8,9

The recent FDA-approval of ganciclovir ophthal-mic gel provides us a new topical antiherpetic agent with several attractive attributes compared to older topi-cal antiviral formulations such as trifluridine. Before the introduction of topical ganciclovir, trifluridine’s ocular surface toxicity had already prompted many ophthal-mologists to switch to oral antiherpetic medications to treat epithelial keratitis. Since ganciclovir mainly tar-gets viral DNA (trifluridine, vidarabine, and idoxuridine target both cellular and viral DNA), we should expect selective killing of viral-infected cells and sparing of nor-

mal, non-infected cells with this newer agent, thereby lessening treatment-associated toxicity to the epithe-lium. We anticipate that the availability of ganciclovir gel will see many clinicians switching back to topical treatment from oral medications to avoid unnecessary systemic drug exposure and the potential for side effects such as the renal toxicities that, on rare occasion, have been associated with oral antiherpetic agents.

In our clinical experience, patients find ganciclo-vir’s ophthalmic gel preparation particularly comfort-able on the eye and convenient in its dosing. Application compliance is improved with ganciclovir’s less-frequent dosing (5 times daily vs 9 times daily with trifluridine). In addition, patients can store ganciclovir gel at room temperature versus the refrigeration that was recom-mended with trifluridine. An additional advantage in-cludes the use of a low concentration of benzalkonium chloride 0.075%, as opposed to the outdated and more toxic thimerosal 0.001%, which preserves trifluridine.

The gel formulation also extends contact time with the ocular surface, which should enhance pen-etration and bioavailability as well as prove beneficial for patients who tend to dilute topical ophthalmic medications with excess tearing or crying, as often seen with children.

Incorporating all these advances, we have devel-oped a set treatment plan based on the clinical presenta-tion of ocular HSV. (See box “Treatment of Ocular HSV.”)

Table 2Treatment guidance from the Herpetic (Herpes Simplex) Eye Disease Study (HEDS)

1

Topical corticosteroids are safe and effective in the treatment of stromal keratitis when used concomitantly with prophylactic oral acyclovir or topical trifluridine.

2 Prophylaxis with oral acyclovir reduces the recurrence of ocular HSV

3

The addition of oral acyclovir to treatment with topical trifluridine and corticosteroid may improve treatment of HSV iridocyclitis (nonstatistically significant trend).

4

The addition of oral acyclovir to topical trifluridine and corticosteroid treatment shows no benefit in treating HSV immune stromal keratitis.

5

The addition of oral acyclovir to topical trifluridine and corticosteroid treatment of HSV epithelial disease fails to reduce the likelihood of subsequent stromal keratitis or iridocyclitis.

nOTE: The HEDS trials employed acyclovir as the oral antiherpetic medication and trifluridine as the topical antiherpetic agent. newer options include valacyclovir and famciclovir as oral antiviral agents and ganciclovir ophthalmic gel for topical application.

FIguRE 6HSV disciform endotheliitis. (courtesy Wills Eye Hospital.)


14

ProphylaxisWe recommend long-term, possibly lifelong, pro-

phylaxis for patients with a history of severe stromal keratitis as well as those who experience more than one episode of epithelial keratitis per year. Lifelong prophylaxis is likewise warranted for patients receiving corneal transplants for vision loss related to herpetic scarring. Either oral acyclovir (400 mg twice daily) or valacyclovir (500 mg once daily) are suitable options so long as the patient maintains good renal function.

We recommend against elective laser procedures in patients who have a history of ocular herpetic disease, particularly if there is evidence of corneal scarring. This recommendation stems from clear evidence that stressors such as ocular trauma and exposure to strong UV light can trigger HSV reactivation.10-12 For the patient with a history of recurrent “fever blisters” or other forms of facial herpes, we recommend 1 week of prophylaxis with oral acyclovir or valacyclovir prior to refractive procedures.

When patients with a history of ocular herpes require glaucoma laser surgery, cataract removal, or other invasive ocular procedures, we recommend pro-phylaxis with oral acyclovir or valacyclovir for at least 1 week prior to surgery and for 1 to 6 months postop-eratively, depending on the frequency and severity of past herpes outbreaks.

HErPES ZOSTEr OPHTHAlMIcUS (HZO)The varicella-zoster virus that causes chickenpox

can, like HSV, establish lifelong latency in the trigeminal ganglion. When this virus reactivates in later life, it is referred to as herpes zoster, or “shingles.” Shingles can affect any area of the body, and the eye is second only to the trunk as the most common site of involvement.

PresentationHZO is frequently misdiagnosed as the more

treatable HSV. The distinguishing characteristics of herpes zoster epithelial keratitis include an elevated ridge of epithelium that is neither as coarse nor as thick as that associated with HSV. HZO keratitis also lacks HSV’s characteristic terminal bulbs. Instead HZO’s pseudodendrites have tapered ends and tend to be more infiltrative and branching in a Medusa-like pattern. In addition, the base of the HZO pseudodendrite is not ul-cerated and so does not stain with fluorescein (Figure 4).

Like herpes simplex, zoster tends to present uni-laterally. However, the zoster virus often affects an entire sensory dermatome, respecting the midline of the face (Figure 7). In addition, look for a recent his-tory of flu-like symptoms. Low grade fever and malaise are often present up to a week before vesicle eruption. Like herpes simplex, HZO can manifest as blepharo-conjunctivitis, epithelial keratitis, stromal keratitis, endotheliitis, or iritis.

Treatment and ProphylaxisIdeally, treatment with oral antiviral agents

should be initiated within 72 hours of the first ap-pearance of skin lesions. Moreover, HZO demands sig-nificantly higher dosages (800 mg of acyclovir 5 times daily for 7 to 10 days or 1 gm of valacyclovir 3 times daily for the same duration).

The discomfort of HZO blepharoconjunctivitis can be eased with cool compresses and lubrication (refrigerated artificial tears). An antibiotic ointment can be added to help prevent bacterial superinfection.

Antiviral agents are not typically needed for HZO epithelial keratitis due to the fleeting duration of the re-activated virus. Post-infection inflammation can produce stromal keratitis, keratouveitis, and iritis, which warrant treatment with topical steroids. Typically we treat with prednisolone acetate or difluprednate (the latter at half the dosing frequency of prednisolone acetate). Initial

FIguRE 7Zoster eruptions often involve an entire sensory dermatome of the face, producing a line of multiple vesicles that usually respects the midline. (courtesy Wills Eye Hospital.)

TREATMENT OF OCulAR HSV HSV dermatoblepharitis: Oral acyclovir

(400mg 5 times daily for 5 days) or valacyclovir (500 mg 3 times daily for 5 days).

Epithelial keratitis: Ganciclovir ophthalmic gel 0.15% (1 drop 5 times daily until the herpetic ulcer heals, which is typically within 1 week, followed by 1 drop 3 times daily for another 7 days) and/or oral acyclovir or valacyclovir (at above dosages).

Stromal keratitis: Topical prednisolone acetate 1% administered 8 times daily or topical difluprednate 0.05% administered 4 times daily, gradually tapering to 1 drop daily over 2 to 3 months, depending on clinical response—while continuing either oral or topical antiviral coverage.

Endotheliitis and Iridocyclitis: Topical steroids based on the severity of inflammation, along with oral antiviral coverage as above. Add topical intraocular pressure-lowering medications as needed.


15

application can be as frequent as eight times daily with prednisolone acetate or four times daily with diflupred-nate, with gradual tapering based on the persistence and severity of inflammation. Continued prophylaxis with oral or topical antiherpetic medication is not necessary.

As mentioned, the incidence of herpes zoster ap-pears to be rising in the general population, particularly among those over 40 years of age.13 Fortunately, we now have a zoster vaccine available, though its current FDA approval covers only those age 60 or older. Given HZO’s high morbidity, it behooves us as ophthalmologists to both encourage our older patients to avail themselves of this vaccine and work with primary care physicians to increase the awareness of its importance.

cYTOMEGAlOVIrUS AND EPSTEIN–bArr VIrUSEven as corneal specialists, we rarely see com-

plications related to infection with CMV or EBV, two other ubiquitous members of the herpes virus family. Childhood infection with either virus typically goes unnoticed, but can cause the flu-like malaise syndrome known as mononucleosis—seen most frequently in teenagers and young adults.

During such a period of active infection, Epstein-Barr can produce a wide range of anterior segment and neuroophthalmic findings. The former can include fol-licular conjunctivitis, scleritis, subconjunctival hemor-rhage, iridocyclitis, dendritic epithelial keratitis, and stromal keratitis. On rare occasions conjunctival biopsy reveals malignant lymphoma. Neuroophthalmic disease can include papilledema, optic neuritis, and cranial nerve palsies. We generally treat EBV anterior segment disease with topical steroids, sometimes coupled with systemic immunosuppressants. Malignant disease should be treated with surgical removal and chemotherapy.

Immune suppression can reactivate latent CMV

infection and produce ocular manifestations such as cho-rioretinitis. Before the advent of antiretroviral therapy, ophthalmologists saw many AIDS patients develop this potentially blinding complication. More recently, studies have revealed that ocular CMV disease, though rare in the immunocompetent population, is more common than previously thought.14 The ophthalmologist should remain aware that active CMV infection can mimic HSV or zoster disease, but can be distinguished by its associa-tion with inflammation that progresses to the deepest layers of the cornea (versus the surface). Diagnosis may require vitreous tapping for evidence of cytomegalovirus DNA. Active CMV chorioretinitis warrants treatment with intravenous ganciclovir (2-5 mg/kg IV every 8 hours for two weeks if tolerated without hemosuppression), followed by weekly intravitreal injections (400 μg.)15

cONclUSIONAs described in this article, the family of human

herpes viruses incorporates a diverse group of viruses that can produce a variety of ocular manifestations. Obtaining a good clinical history and knowing the distinguish-ing signs are crucial in identifying the exact entity and initiating the appropriate therapy for optimal results.

Terry Kim, MD, is a professor of ophthalmology at the Duke University School of Medicine, and the associate director of corneal and refractive surgery services at the Duke Eye Center, likewise in Durham, North Carolina. He states that in the past twelve months he has been a consultant to Alcon, Allergan, Inspire, ISTA, OSI, Ocular Therapeutics, Pfizer, and PowerVision. Victor Chang, MD, is a former chief resident at the Cullen Eye Institute, of the Baylor College of Medicine, and is currently a clinical fellow of cornea, external disease, and refractive surgery at the Duke Eye Center, in Durham, North Carolina. He states that in the previous twelve months he has not had a financial relationship with any commercial organization that produces, markets, re-sells, or distributes health care goods or services con-sumed by, or used on patients.

REFERENCES 1. Liesegang TJ. A community study of ocular herpes simplex. Curr

Eye Res. 1991;10(Suppl):111-5. 2. Chodosh J, Banks MC, Stroop WG. Rose bengal inhibits herpes

simplex virus replication in vero and human corneal epithelial cells in vitro. Invest Ophthalmol Vis Sci. 1992;33(8):2520-7.

3. Seitzman GD, Cevallos V, Margolis TP. Rose bengal and lissamine green inhibit detection of herpes simplex virus by PCR. Am J Ophthalmol. 2006;141(4):756-8.

4. Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994;101(12):1883-95;discussion 1895-6.

5. Oral acyclovir for herpes simplex virus eye disease: effect on pre-vention of epithelial keratitis and stromal keratitis. Herpetic Eye Disease Study Group. Arch Ophthalmol. 2000;118(8):1030-6.

6. 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. The Herpetic Eye Disease Study Group. Arch Ophthalmol. 1997;115(6):703-12.

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;101(12):1871-82.

8. Weller S, Blum M, Smiley M. Phase I pharmacokinetics of the

acyclovir prodrug, valacyclovir. Antivir Res. 1993;20(suppl 1):144. 9. Perry CM, Wagstaff AJ. Famciclovir. A review of its pharmacologi-

cal properties and therapeutic efficacy in herpes virus infections. Drugs. 1995;50:396-415.

10. Asbell PA. Valacyclovir for the prevention of recurrent herpes simplex virus eye disease after excimer laser photokeratectomy. Tr Am Ophth Soc. 2000;98:285-303.

11. Levy J, Lapid-Gortzak R, Klemperer I, et al. Herpes simplex vi-rus keratitis after laser in situ keratomileusis. J Refract Surg. 2005 Jul-Aug;21(4):400-2.

12. Beyer CF, Arens MQ, Hill JM, et al. Penetrating keratoplasty in rabbits induces latent HSV-1 reactivation when corticosteroids are used. Curr Eye Res. 1989;8:1323-9.

13. Jardine A, Conaty SJ, Vally H. Herpes zoster in Australia: evidence of increase in incidence in adults attributable to varicella immu-nization? Epidemiol Infect. 2010 Aug;23:1-8.

14. Van Boxtel LA, van der Lelij A, van der Meer J, Los LI. Cytomegalovirus as a cause of anterior uveitis in immunocom-petent patients. Ophthalmology. 2007 Jul;114(7):1358-62.

15. Hodge WG, Lalonde RG, Sampalis J, et al. Once-weekly intra-ocular injections of ganciclovir for maintenance therapy of cy-tomegalovirus retinitis: clinical and ocular outcome. J Infect Dis. 1996;174(2):393-6.


16

The ophthalmologist who developed the world’s fi rst effective antivirals refl ects on a half century of advances in the treatment and prevention of herpetic ocular infections.

When I was a first-year resident at the Massachusetts Eye and Ear Infi rmary in the 1950s, there were no treatments for viral diseases, unless you counted chicken soup. We managed ocular herpes by simply scraping off eroded surface tissue and applying iodine—a painful and diffi cult procedure that was far from effective. In some of the most severe cases, we would cover the entire ocular surface with periocular tissue, a procedure that relieved the excruciating pain but left the patient blind.

I will always remember one patient in particu-lar—a lovely woman with two children. I watched her go blind because we had nothing to stop her ocular herpes. In a sense, it drove me crazy. At least it drove me into the laboratory before and after my resident rounds each day.

Hundreds of laboratories were working on anti-viral therapies at the time. But I believed that virtually all of them were on the wrong path. They were trying to starve the herpes virus by blocking production of the nucleic acids that it needed to reproduce. But I believed that the virus would simply rob cells of the nucleic acids it needed to replicate—given the extremely high affi n-ity that viral DNA polymerase had for these building blocks. The end result would be dead cells, not less virus.

I believed that the only way to stop a herpes virus was to block its DNA polymerase. The fi rst drug I used was iododeoxyuridine, or IDU (Figure 1).1 This nucleic acid analog had been developed as a potential cancer drug. It did not prove terribly successful in treating can-cer, but it showed high affi nity for DNA polymerase. In effect, it tricked the herpes virus into taking it up and, so, committing suicide.

It was the fi rst effective antiviral and revolution-ized the fi eld. First, it demonstrated that one could treat viral disease—a huge question at the time, seeing that viruses essentially made themselves part of the cell. Second, it showed that a specifi c class of drugs, the substituted nucleotides, offered a way to block viral DNA polymerase.

PART THREE: The Historical Perspective


Herbert E. Kaufman, MD

Limiting IDU’s effectiveness against ocular herpes was the drug’s lack of solubility. It had to be adminis-tered every 2 hours around the clock. At least we had something; but I believed we could do better. I began working with trifl uridine (Figure 2).

THE TrIFlUrIDINE STOrYLike IDU before it, trifl uridine was an anticancer

drug. The connection is a logical one because viruses, like cancer cells, depend on the mass assembly of nucleic acids to fuel their rapid reproduction.

Trifl uridine proved to be a tremendously effec-tive ocular antiviral. In controlled studies, 97% of all herpetic keratitis infections treated with trifl uridine healed within 2 weeks.2 Without treatment, less than half of infections resolved this quickly.

Nonetheless I got laughed out of the park when it came to the price tag—over $600 a gram. Fortunately, a German company learned how to make trifl uridine for just $25 a gram. By the early 1970s, trifl uridine was in wide use—the drug of choice for the treatment of ocular herpes until the introduction of ganciclovir ophthalmic gel.

The problem with trifl uridine was that its action was not selective. It inhibits not only virus reproduc-tion, but also cellular DNA synthesis. As such, it can interfere with wound healing. Associated complications are rare, but can be serious when infection produces large corneal ulcers that require signifi cant cell division to heal. Other rare but serious side effects include al-lergic reaction and the occlusion of lacrimal drainage.

16

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17

cOrTIcOSTErOID cONTrOVErSY Another huge but controversial advance came

with corticosteroids. Blocking virus multiplication stopped the development of herpetic ulcers on the cor-neal surface. But it became clear that topical antivirals did little if anything to stop damage deeper within the eye. This deeper damage, we realized, did not stem di-rectly from viral activity, but from the immune system’s hypersensitive reaction to viral antigens. Moreover, it was the enduring damage from this inflammation that most threatened a patient’s sight.

Immune suppression would seem to be the answer. But it had long been known that corticoste-roids fueled active herpetic infec-tions. So one can imagine the re-action I received when I proposed that we could use corticosteroids to limit stromal damage if we simulta-neously used an antiviral to prevent the associated flare ups. I had good results with this approach in rabbit studies.1 But it took a lot of cour-age to try it in patients—courage inspired by a terrible disease that caused horrific pain and blindness.

The simultaneous suppres-sion of both infection and inflam-mation is now standard in the treat-ment of many viral and bacterial diseases that trigger destructive im-mune reactions. But at the time it was a radical idea—and one being proposed by a mere resident! Clinical studies would prove us right.3 But it would take the results of the first Herpes Eye Disease Study (HEDS) to lay doubts to rest. 4

THE ADVENT OF AcYclOVIrGertrude Elion gave us the next great advance in

herpetic therapy with her development of acyclovir. Like IDU and trifluridine, acyclovir must be activated by thymidine kinase before it can stop DNA synthe-sis. Both cells and viruses make this enzyme—each in a slightly different version. Elion’s breakthrough came with a slight alteration in the sugar groups on her sub-stituted nucleoside that rendered it selective. Viral DNA polymerase readily activated acyclovir, but the pickier cellular enzyme ignored it.

This difference in selectivity makes perfect sense when one considers that if our cells make errors in DNA metabolism, the result can be disastrous. But with a vi-rus, the goal is to multiply as fast as possible, mistakes be damned. Elion took advantage of this discrimina-tion to target the virus without harming the patient. In doing so, she gave us the first systemic antiviral.5

Still, doubts persisted about the ability of a sys-

temic drug to treat corneal herpes. As for topical use, acyclovir’s poor solubility meant that ophthalmic prepa-rations had to be in the form of a thick ointment that interfered with vision. This lack of patient friendliness may explain why acyclovir ointment was never brought to the U.S. market.

Meanwhile, we were keenly interested in whether long-term use of oral acyclovir could prevent the re-currence of ocular herpes. Answering this question was one of the goals of the HEDS study.6 Oral acyclovir (400

mg two times a day) reduced the risk of recurrence by about 40%. For the first time, we knew we had a way to reduce the reactivation of a viral disease. Additionally we found that when one stopped oral acyclovir, there was no rebound ef-fect. The overall risk of recurrence returns to what it was before treat-ment (around 25% over two years).

We had hoped that acyclo-vir would reduce the tendency of ocular herpes simplex to progress from surface infection to deeper stromal disease with each occur-rence. But HEDS showed no benefit in this regard.

More recent work in rab-bits, by Jim Hill and my group at Louisiana State University, suggests that at much higher doses, the re-

lated drug valacyclovir may in fact reduce both the re-currence and the severity of stromal disease and iritis.7 Valacyclovir has the advantage of being much more bioavailable than acyclovir, which is poorly absorbed through the gut. By contrast, valacyclovir passes read-ily into the bloodstream, where it is metabolized into acyclovir.

GANcIclOVIrThe recent US introduction of ganciclovir oph-

thalmic gel generated great excitement. But in intra-venous or ocular implant form, this member of the acyclovir family had already carved out a distinguished place in ophthalmology. Indeed, it is effective against some viruses that do not respond to acyclovir—includ-ing cytomegalovirus, which can cause vision-destroying infections in the immunocompromised.

Ganciclovir’s systemic toxicity contraindicates long-term oral or intravenous use. But its greater solu-bility lent itself to the patient-friendly ophthalmic gel formulation that has been widely used in Europe for over 15 years. European studies have demonstrated it to be as effective as acyclovir ointment in treating den-dritic herpes keratitis, with significantly higher patient tolerability.8,9 It has never gone head to head with tri-

17

In 1963, Herbert Kaufman’s antiherpetic breakthroughs put him on the cover of Medical World News.

AdvAnces in the MAnAgeMent of oculAr herpetic diseAse — pArt three: the historicAl perspective

18

fluridine, but appears to be at least as effective.In addition, I find it exciting that while acyclo-

vir ointment has never demonstrated efficacy against adenovirus conjunctivitis, there is early evidence that ganciclovir gel can reduce the duration of these com-mon infections and perhaps even mitigate potentially serious sequelae.10

Given its relative lack of toxicity, ganciclovir ophthalmic gel should now be the standard of care in the topical treatment of herpes keratitis. Yet there may still be a place for trifluridine. In our laboratory, we have found that ganciclovir and trifluridine can act synergistically against the herpes simplex virus.11 We do not yet know how important this synergy will prove in treating herpetic infections, but we are eager to explore the potential.

FUTUrE DIrEcTIONSAs a professor emeritus, I am eager to see oth-

ers build upon my work. In particular, we need ways to truly treat herpetic stromal disease and iritis. Yes, corticosteroids can suppress the inflammation while a

18

concurrent antiviral prevents complications. But often these treatments must be maintained for months and even then cannot be said to cure the disease so much as contain the body’s hypersensitivity reaction to the virus while the infection runs its course. The key to ef-fective treatment, I believe, will come from drugs that inhibit virus multiplication more powerfully.

In addition, we need ways to not just reduce the frequency of herpetic recurrences but stop them. This may come with greater understanding of how and why the latent herpes virus reactivates. We likewise need more effective treatments against other herpes viruses such as zoster, which can cause such terrible ocular damage. Clearly, we are only beginning to understand these often devastating viral infections. Much work remains to be done.

Herbert Kaufman, MD, is the emeritus Boyd professor of oph-thalmology, pharmacology, and experimental therapeutics at the Louisiana State University Eye Center. He states that in the previ-ous twelve months he has worked as a consultant for ReSearch Pharmaceutical Services, Inc.

REFERENCES 1. Kaufman HE, Maloney ED. IDU and hydrocortisone in experimen-

tal herpes simplex keratitis. Arch Ophthalmol. 1962 Sep;68:396-8. 2. Wellings PC, Awdry PN, Bors FH, et al. Clinical evaluation of

trifluorothymidine in the treatment of herpes simplex corneal ulcers. Am J Ophthalmol. 1972 Jun;73(6):932-42.

3. Kaufman HE, Martola El, Dohlman CH. Herpes simplex treat-ment with IDU and corticosteroids. Arch Ophthalmol. 1963 Apr;69:468-72.

4. Wilhelmus KR, Gee L, Hauck WW, Herpetic Eye Disease Study: A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994;101:1883-96.

5. Elion GB. Mechanism of action and selectivity of acyclovir. Am J Med. 1982;73:7-13.

6. Herpetic Eye Disease Study Group. Oral acyclovir for herpes sim-plex virus eye disease: effect on prevention of epithelial keratitis

and stromal keratitis. Arch Ophthalmol. 2000 Aug;118(8):1030-6. 7. Kumar M, Kaufman HE, Clement C, et al. Effect of high versus

low oral doses of valacyclovir on herpes simplex virus-1 DNA shedding into tears of latently infected rabbits. Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4703-6.

8. Hoh HB, Hurley C, Claoue C, et al. Randomised trial of ganci-clovir and acyclovir in the treatment of herpes simplex dendritic keratitis: a multicentre study. Br J Ophthalmol. 1996;80:140-3.

9. Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel (Virgan 0.15%) in the treatment of herpes simplex keratitis. Cornea. 1997;16:393–9.

10. Tabbara KF. Ganciclovir effects in adenoviral keratoconjunctivitis. Poster B253. Presented at ARVO 2001. Fort Lauderdale, Florida.

11. Hobden JA, Kumar M, Kaufman HE, et al. In vitro synergism of tri-fluorothymidine and ganciclovir against HSV- 1. Invest Ophthalmol Vis Sci. 2010 Sep 22. [Epub ahead of print]

AdvAnces in the MAnAgeMent of oculAr herpetic diseAse — pArt three: the historicAl perspective

19

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This CME program is sponsored by the University of Florida College of Medicine and supported by an unrestricted educational grant from Bausch + Lomb, Inc. Directions: Select the one best answer to each question in the Exam (Questions 1-10) and in the Evaluation (Questions 11-16) below by circling one letter for each answer. Participants must score at least 80% on the questions and complete the entire Evaluation section on the form below. The University of Florida College of Medicine designates this activity for a maximum of 2.0 AMA PRA Category 1 Credits™. There is no fee to participate in this activity. You can take the test online at http://cme.ufl.edu/XXXXXXXXXXX.

eXamination answer sheet advances in the management of ocular herpetic Disease

1. HSV remains viable on a moist tonometer head for:A. Up to 2 hours.B. Up to 8 hours.C. Up to 24 hours.D. Up to 48 hours.

2. Breakdown of Liesegang’s Minnesota data suggests that approximately what percentage of ocular simplex disease involves the corneal stroma?A. 75%B. 41%C. 12%D. 1%

3. Of the approximately 20% of the world’s population who develop herpes zoster, what percentage experience ocular involvement?A. 2% to 5%B. 10% to 20% C. 45% to 50%D. 70% to 80%

4. How is ocular CMV disease generally treated?A. Intravenous ganciclovir.B. Topical ganciclovir.C. Topical corticosteroids.D. All of the above.

5. Which of the following is/are known triggers for ocular herpetic disease?A. Local trauma and systemic

disease.B. Systemic and local immune

suppression.C. Laser refractive procedures and

cataract surgery.D. All of the above.

6. CMV and EBV are estimated to infect what percentages of American adults, respectively?A. up to 2% and 5%B. up to 22% and 55%C. up to 80% and 95%D. up to 98% and 100%

7. How does treatment of herpes zoster ophthalmicus differ from that of ocular herpes simplex? A. Zoster warrants higher doses of

oral antiherpetic agents.B. Zoster responds to lower doses of

oral antiherpetic agents.C. Topical corticosteroids should be

avoided with zoster.D. Zoster warrants aggressive

debridement.

8. Approximately what percentage of patients recover from HSV keratitis with 20/100 visual acuity or worse?A. 90%B. 30% to 40%C. 3% to 5%D. 1%

9. Approximately what percentage of ocular herpes simplex infections present unilaterally?A. 100%B. 90%C. 70%D. Less than 50%

10. Which of the following is diagnostic of herpes zoster keratitis but not simplex keratitis?A. A branching ulcer.B. Unilateral presentation.C. Ulcerated base that stains with

fluorescein.D. Non-ulcerated base that does not

stain with fluorescein.

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eXamination answer sheet advances in the management of ocular herpetic Disease

Ocular Herpetic Disease

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