The management of ocular herpesvirus infections

SURVEY OF OPHTHALMOLOGY

VOLUME 21

The Management Herpesvirus H. B. OSTLER,

l

NUMBER 2*SEPTEMBER-OCTOBER

1976

of Ocular

Infections

M.D.

The Francis I. Proctor Foundation for Research in Ophthalmology and the Department of Ophthalmology, University of California, San Francisco, California

Abstract. The many treatment methods in current use for every known complaint only seem to aggravate the difficulty of treating ocular herpes simplex virus (HSV) infections, which are generally self-limited in the immunocompetent host. The cornea is already a somewhat immune-deficient tissue since its lack of blood vessels separates it partially from the host, and treatment with glucocorticoids, which are immunosuppressive, increases the risk of damaging complications such as scarring, prolonged morbidity, bacterial or fungal superinfection, and the occasional cornea1 perforation. -Accepted methods of treatment of specific lesions, are discussed, as are some methods that are not yet accepted, but which seem promising. Herpes zoster may result in scarring and significant loss of vision even without the use of glucocorticoids, the disease often manifesting itself in the already compromised host. The major complication is postherpetic neuralgia. None of the available treatment methods has been fully satisfactory, and every effort should be made to prevent eye lesions in patients with early infection of the ophthalmic branch of the trigeminal nerve. Stimulation of cellular immunity by various means appears to offer some new promise for control of the disease. Management of varicella, cytomegalovirus, and infectious mono-

nucleosis are also discussed. (SW Ophthalmol 21:136-147, 1976) Key words. chorioretinitis conjunctivitis cytomegalovirus disciform keratitis herpes simplex herpes zoster infectious mononucleosis keratitis meningoencephalitis l

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he management of ocular herpesvirus disease will be covered in three parts: I. Herpes Simplex Infections; II. Herpes Zoster Infections; and III. Other Entities. I. HERPES SIMPLEX INFECTIONS

General Considerations Until the advent of the glucocorticoids, herpes simplex virus (HSV) keratitis was selflimited. Except in very rare instances, it cleared in three to five months at the longest, and cornea1 perforations due to HSV alone were almost unheard of.6’ It is a tragic fact, 136

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varicella

however, that HSV keratitis (or keratoiritis) is now a major cause of prolonged morbidity, blindness or seriously reduced vision, and corneal perforation. Since the use of the glucocorticoids, moreover, HSV keratitis is frequently complicated by superinfections of the cornea with opportunistic pathogens, both bacteria and fungi. The major theme in management should be, DO NO HARM. One should bear always in mind that untreated HSV ocular infections, except in the rarest of cases, are selflimited, and most of the problems encountered are iatrogenically induced. If one

MANAGEMENT

OF OCULAR HERPESVIRUS INFECTIONS

137

suspects HSV ocular infection, both topical “rebound” inflammation must be promptly and systemic glucocorticoids should be detected by constant monitoring of the avoided, and if they are being used for any patient. reason at the time of the onset of the disease, Principles of Treatment of Ocular or are being used to treat the disease when the HSV Infections patient is first seen, they should be tapered off The treatment of HSV infections of the eye and eventually stopped to allow the patient’s own immune mechanisms to bring the infec- should be directed toward the following: 1. Destruction or neutralization of the tion under control. virus outside the cell; The glucocorticoids in pharmacologic 2. Prevention of cell-wall adsorption and doses can inhibit the immune process in all of intracellular penetration by the virus; its stages.s1 But as with other viral infections, 3. Elimination of the infected cells; cellular immunity must ultimately come into 4. Interference with replication of the virus play to control HSV infections, and this and intracellular destruction of the virus; makes the suppression of cellular immunity 5. Immunopotentiation or improvement of by systemic or topical glucocorticoids patently undesirable. Furthermore, the gluco- cellular immunity, which in turn either inacticorticoids apparently potentiate the action of vates or destroys the virus; 6. Prevention of recurrences; and collagenase by four to fifteen times, depending upon the type of the glucocorticoid 7. Supportive, nonspecific therapy. preparation.’ As a result, collagenase proDESTRUCTION OR NEUTRALIZATION OF duced by the epithelium or by polymorphoTHE VIRUS OUTSIDE THE CELL nuclear cells may “melt” the stroma. The glucocorticoids also predispose to the superHSV can readily be destroyed by iodine infection of herpetic lesions with opportunisand such organic solvents as ether, quatertic bacteria and fungi, and the geographic nary ammonium cationic detergents, proteocornea1 ulcers seen in HSV patients who are lytic enzymes, phosphatases, and bile.68 Of using glucocorticoids tend to be notably these agents, iodine and ether are the two that larger than in patients not using glucocortihave been most widely used in the treatment coids.5S In HSV infections of the skin, the of dendritic keratitis. virus is lytic, and its spread is greatly faciliUnfortunately, all of the agents have some tated by the use of glucocorticoids. For all of destructive effect on the epithelium or underthese very good reasons, the glucocorticoids lying stroma. Ether’s toxicity for the cornea1 are contraindicated in HSV infections of the epithelium only makes it theoretically useful eye and in acute HSV infections of the skin.34 for the destruction of any HSV that might be When glucocorticoids have been used attached to the surface while destroying the previously and must be continued, at least epithelium itself. In practice, however, the use temporarily, I prefer to use as weak a solu- of ether seems to offer no real advantage over tion as possible as infrequently as possible. the simple removal of epithelial cells. Prior to For example, I often begin with Dexamethathe removal of the diseased cornea1 sone 0.1% diluted with sterile normal saline epithelium, the application of a 2% solution solution to a concentration of 0.05% or of tincture of iodine, or cauterization with 0.005%. I use this from one to three times a carbolic acid, followed after one minute by day, gradually increasing the frequency or neutralization with 4% cocaine, has been strength until the patient responds, and then recommended for healing cornea1 epithelium either maintaining the dosage at that level or rapidly without producing an underlying gradually reducing it until the patient’s reac- opacity.” In my opinion, however, all of the tion increases, or until I have weaned him cauterizing agents, including iodine and caraway from the glucocorticoids altogether. bolic acid, damage the underlying stroma and The tissues of a patient on glucocorticoid are to be avoided. therapy frequently become so habituated that Humoral immunity, produced by circulattoo rapid reduction or abrupt termination of ing antibodies, can make viruses noninthe drug may result in excessive inflam- fectious. Gamma globulin is useful only in mation, followed by scarring and loss of vi- patients with agammaglobulinemia, howsion. For this reason the glucocorticoids must ever, and in other patients it probably has no usually be gradually tapered off, and any value in the treatment of HSV infections.

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Surv Ophtholmol 21 (2) September-October

1976

OSTLER

Gamma globulin has been used in severe primary HSV infections, but evidence of benefit from its use is equivocal.” It may have some value in preventing herpes simplex of the newborn if given in high doses to a gravid woman with primary HSV vulvovaginitis, but it would, of course, be useful only prior to the performance of a Caesarean section in a patient with intact membranes.4B Vaccines prepared with HSV have been advocated, but their potential use in ocular HSV infections has not been fully evaluated.’ It is quite unlikely that killed vaccine would have more than temporary value, however, and the use of live HSV in an attempt to raise the level of antibodies would have no value and would produce new lesions at the site of inoculation. ” The possibility that type 2 HSV is carcinogenic must also be kept in mind.

ness of the underlying superficial stroma and Bowman’s membrane seems to be potentiated by both cauterizing agents and IDU. Cryotherapy (freezing) of the cornea1 epithelium is another form of epithelial debridement. It is statistically more effective for reducing time required for healing and recurrence of the ulcers22~43than either IDU therapy or carbolization and removal of the cornea1 epithelium. A cryoapplicator that reaches temperatures of -70” to -80°C is used. Multiple contiguous applications of six to eight seconds’ duration are made to the anesthetized cornea1 lesion until the entire epithelial defect has been treated.2a After the procedure, a cycloplegic is instilled and a pressure dressing applied, and the patient is asked to return after 48 to 72 hours. If necessary, the cryoapplications can be repeated after a few days.

PREVENTION

INTERFERENCE

OF CELLULAR

AND

INTRACELLULAR

THE

VIRUS

ADSORPTION

PENETRATION

OF

REPLICATION

OF THE

IDU (IUDR, idoxuridine, S-iodo-2’deoxyuridine)

Specific antibodies to HSV can prevent adsorption of the virus on epithelial cells, but as stated above, in practice, the use of gamma globulin is decidedly limited. Chymotrypsin can destroy the receptor sites on the cells,28 but, unfortunately, it is toxic for the stroma. ELIMINATION

WITH

VIRUS

OF THE INFECTED

CELLS

The removal of all loose (infected) epithelium reduces the amount of agent in the eye. This is as effective as the use of antiviral drugs, and the cornea1 epithelium heals just as rapidly. 55~75My practice is to instill 4% cocaine into the conjunctival sac to act as an anesthetic and to help loosen the epithelium. After wiping away all loose epithelium with a sterile cotton-tipped applicator, I even up the edges with a knife blade or platinum spatula. A cycloplegic drug is instilled into the eye, a pressure dressing is applied, and the patient is asked to return after 48 to 72 hours. The cycloplegic and pressure dressing (with examination and reapplication every 48 hours) is continued until the cornea is healed. If the defect has an angulated appearance at any of the examinations, or if it has the branching appearance of a dendritic or geographic ulcer, I again remove the epithelium and continue the patching. I do not use iodine or any cauterizing agent prior to removal of the epithelium, nor do I use idoxuridine (IDU) during the healing phase, since hazi-

IDU inhibits replication of HSV both in vitro and in viva,” but ID&resistant strains are known to exist.” IDU’s primary mechanism of action is not clearly understood, but we know that it inhibits a number of enzymes involved in the synthesis of DNA, and that it is incorporated into DNA.Eo IDU is extremely insoluble and thus has little effect on cornea1 stromal disease, on iritis, or on skin lesions when it is used topically. (Some encouraging results have been achieved with a 5% solution of IDU in undiluted dimethyl sulphoxide (DMSO), applied three or four times a day to skin lesions,” but this preparation is not available in the United States at this time.) Systemically administered IDU in massive doses may be of value in HSV encephalitis,” but we know that IDU suppresses bone marrow production, is immunosuppressive and hepatotoxic,B2 and can be both carcinogenic and teratogenic. 72 To be effective topically, the drug (0.5%) must be used five times daily in ointment form, or every hour during the waking hours and every two hours during the hours of sleep in drop form (0.1%). (The two methods can be combined: drops every hour through the day, and one application of ointment at night.) When IDU is used, there should be a marked improvement in the epithelial lesion within seven or eight days, and if not, the therapy should be changed.

MANAGEMENT

OF OCULAR HERPESVIRUS

Adenine Arabinoside ( ARA-A) and Hypoxanthine Arabinoside (ARA-hypoxanthine)

Hypoxanthine arabinoside is the highly soluble natural metabolite of adenine arabinoside; it has been claimed to be capable of intraocular penetration without being toxic 56-58In practice, however, the drug has about the same effect as IDU; i.e., it is useful in HSV epithelial keratitis, but it has no effect on either stromal or iris lesions.1*s2 ARA-hypoxanthine is not as antiviral as ARA-A, moreover.” ARA-A also has about the same effect on epithelial keratitis as IDU. It is less toxic, however, and so may sometimes be helpful if IDU is ineffective or cannot be used because of its toxicity. Like ARA-hypoxanthine, ARA-A has no effect on stromal keratitis32 or iritis,’ although it has been reported to be of value in HSV keratouveitis’ when systemically administered. Cytosine Arabinoside

139

INFECTIONS

(ARA-C)

Cytosine arabinoside (ARA-C) inhibits nucleoside reductase and DNA polymerase, but it is not incorporated into DNA.‘O When applied topically, it is toxic for the cornea, producing fine cornea1 opacities in the basement membrane of the epithelium and epithelial breakdown.38 It therefore has no role in the treatment of ocular HSV infections. Trifluorothymidine (F,TD)

Trifluorothymidine is more effective than IDU on epithelial keratitis, but it has little if any effect on HSV stromal keratitis or iritis.32,71In any case, it is not yet available for general use. Phosphonoacetic Acid (PAA)

Phosphonoacetic acid (PAA) acts to inhibit virus DNA synthesis.63 Topically, the drug appears to be as effective as IDU against HSV epithelial keratitis, but an unequivocal evaluation of its usefulness in man has not been made. Interferon and Interferon Inducers

Interferon, a species-specific protein38 produced naturally by humans and animals in reaction to disease, appears to act against a broad spectrum of viruses, including HSV. At present, the major source of interferon is a leukocyte extract from volunteer blood donors. The agent is very well tolerated by

almost all patients.s1 In man, topical interferon therapy has effected more rapid healing of HSV epithelial lesions than iodine cauterization,6B but it has apparently had very little effect on HSV keratitis in rabbits.’ It seems also to be helpful in preventing both primary herpetic infections9 and recurrences.54 Poly I: Poly c (Poly 1:C)

This double-stranded synthetic RNA molecule is so arranged that when presented to the cell, it is probably interpreted by the cell as foreign and stimulates the cell to produce interferon. It is an efficient inducer of interferon in vitro.‘* In the rabbit, an injection of poly 1:C induces interferon that can be detected for some six or eight weeks,**‘Obut in man it is apparently less efficient and induces interferon that can only be detected for one or two weeks.8*s8Given systemically, the drug is somewhat toxic for the rabbit eye,54 and given topically, it seems to have about the same effect as IDU,25 or to be even less effective than IDU.8 INTRACELLULAR VIRUS:

DESTRUCTION

PHOTODYNAMIC

OF THE

INACTIVATION

Sensitization of HSV with a substance like neutral red or proflavine makes the virus more susceptible to artificial light, and the combined effect is antiviral. Enveloped viruses are photosensitive, and the dye seems to greatly increase their photosensitivity.71 The dye has an affinity for the guanine base of the viral DNA, and upon exposure to light the guanine molecule is disrupted. This produces critical changes in the base sequence of the organization of the virus and destroys the virus.lg The possibility that photodynamic inactivation of HSV can be carcinogenic has been suggested by some,6’ but doubted by others. High concentrations of the dye are somewhat toxic for the cornea,” making its use in HSV ocular infections limited. Furthermore, if the infection was well established when such treatment was tried, no significant improvement in the clinical course of the disease, in virus recovery, or in the histopathological findings was noted.” It is possibly important, however, that the recurrence rate of cutaneous herpes at the same site appears to be much lower in photodynamically treated patients than in controls.16

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IMMUNOPOTENTIATION

Nonspecific immunopotentiation by means of BCG, staphage lysate, vitamin A, or levamisole is, at least theoretically, useful in the treatment of ocular HSV infections. Since cellular immunity must come into play to control HSV infection, immunopotentiation should be valuable, and in practice the use of levamisole has been followed by diminished clinical activity in epithelial and stromal infections and in severe iritis. Repeated vaccinations with smallpox vaccine should have a nonspecific immunopotentiating effect, but the actual usefulness of this method is equivoca1.42 Specific immunopotentiation with transfer factor (a relatively stable, dialysable protein and polynucleotide compound with a molecular weight of less than 10,000) can confer delayed hypersensitivity for specific antigens such as HSV, but its value has yet to be fully studied in man. We have seen one patient with combined Wiskott-Aldrich syndrome and ocular HSV infection in whom the use of transfer factor appeared to be beneficial. PREVENTION

OF RECURRENCES

There is a very delicate balance between HSV and HSV immunity, and little is required to weight the balance either on the side of the immune mechanisms (which are then able to keep the virus in check) or on the side of the virus (which then overcomes the immune mechanisms). Over 50% of patients with herpes keratitis will have recurrences within five years.*s Even with the use of the antiviral medications, recurrences are common and do not seem to have been reduced by any therapeutic means, except perhaps by the use of photodynamic inactivation when the lesions were cutaneous.lB To date, the best way to prevent recurrences is to identify each patient’s trigger mechanism and then have the patient avoid the trigger whenever possible. Unfortunately, some triggers escape detection. The triggers we have been able to identify are fever (e.g., in upper respiratory disease), exposure to extremes of temperature, ultraviolet light (sunlight), emotional stress, the onset of menstruation, and trauma. In most cases aspirin or another antipyretic can be taken at the onset of an upper respiratory or other infection, and can be continued as necessary to keep the fever down. The patient should be advised to avoid extremes of temperature, to wear dark glasses in bright

OSTLER

sunlight, and to avoid sunburn by the use of sunscreens or the limitation of exposure to the sun. Emotional stress, especially when expressed as anger or fear, releases adrenalin, and the patient should be counselled to avoid as much as possible the situations likely to provoke such reactions. In my experience, tranquilizers have had little effect on these emotional triggers. Many women find that they are more likely to develop fever blisters or reactivations of their ocular HSV at the onset of menstruation. The use of aspirin at the onset and throughout the first day of the menstrual period can often prevent HSV attacks in such cases. When trauma appears to be the trigger, patients should be cautioned about their special risks from ocular foreign bodies or exposure to dust and irritating fumes. SUPPORTIVE,

NONSPECIFIC

THERAPY

Alcohol-ether, Cetaphil,@etc The various medications used for lesions of the skin are helpful by virtue of their soothing and drying effects, but they should not be used on the lid margins or in the conjunctival sac. Cycloplegics The use of cycloplegics to dilate the pupil should be considered in any case in which there is an iritis. In HSV keratitis, unless it is accompanied by the very mild, reactive type of iritis, cycloplegics need not be used. Aspirin Both its antipyretic effect (which may help avoid triggering an herpetic recurrence) and its antiprostaglandin effect make aspirin a very useful drug in the management of HSV infection. I frequently recommend it in doses of two or four tablets daily for herpetic iritis. Patching of the Eye A pressure dressing is often of great value in promoting healing. A properly placed patch prevents the constant movement of the lid over the cornea and raises the temperature of the cornea1 epithelium to approach the temperature of the body. Both of these consequences of patching, and the proximate relationship of the moist conjunctiva and cornea, promote epithelial proliferation. It is not known, however, what effect the increase in temperature may have upon the proliferation of HSV itself, and one must be mindful of the potentiating effect patching can have on a

141

MANAGEMENT OF OCULAR HERPESVIRUSINFECTIONS

bacterial blepharitis and conjunctivitis.

A soft contact lens placed over the cornea serves the same purpose as a pressure dressing, allowing the epithelium to proliferate without being disturbed by the movement of the eyelids. In some cases of trophic ulcer, a soft contact lens can be very helpful.

lotions.” Menthol (12.5-25.096) can be added for its cooling effect. ” Lid margin lesions are best handled by careful cleansing of the area, cold packs, and other supportive therapy as necessary. (Topical IDU preparations have little or no effect on skin lesions.) Young children should be supplied with shields or arm restraints to prevent them from spreading the lesions by scratching.

Surgical Procedures

CONJUNCTIVITIS

Soft Contact Lens

Intermarginal lid adhesions. These have somewhat the same effect as a pressure dressing. They sometimes give gratifying results and can be removed after the cornea has healed and the disease is inactive, leaving only a minimal cosmetic defect. Conjunctivalflap. A thin conjunctival flap, performed as described by Gundersen,2s is often of great benefit in cases in which there is (1) marked thinning of the cornea1 stroma, (2) bacterial blepharitis, or (3) exceptionally, a trophic ulcer that remains unepithelialized even after a long time. The cornea can perforate underneath the flap, however, and we have seen five such cases in the past seven years. Lamellar graft. A lamellar graft, or a patch graft, may be useful when the cornea has perforated or when there is marked thinning of the stroma. This can be done without eliciting the severe reaction that often follows penetrating keratoplasty performed in active herpetic disease. Penetrating graft. A penetrating graft is difficult to perform in an active herpetic keratitis because of the marked stromal edema; the results are often poor because of the severe iritis that usually follows the procedure. Grafts can be successful, but large doses of glucocorticoids must often be used to control the inflammation, and one must be prepared to accept the consequences of their use. Moreover, even when penetrating grafts have been successful, and even when they have been performed in quiet eyes, recurrences within the graft occur in from 33 to 50% of cases.

The Treatment of Specific HSV Ocular Lesions LID LESIONS

AND SKIN LESIONS

Most skin lesions other than those on the lid margins can be treated with equal parts of alcohol and ether, or with CetaphiP lotion, calamine lotion, Unibase,@ or other drying

The conjunctivitis associated with primary HSV infection may be either follicular or pseudomembranous. It is self-limited, clearing within two or three weeks. In the pseudomembranous type, frequent irrigation of the conjunctival sac is helpful to remove the accumulated exudate, but fine linear or superficial flat scars may occur. IDU may be used, either in ointment form five times a day, or in drop form every hour during the day and every two hours during the night; however the end result differs very little from the result of using supportive care alone. IDU, in and of itself, may cause a follicular conjunctivitis often associated with a tender preauricular node.B8 In fact, in most cases of recurrent herpetic ocular infection in which a conjunctivitis develops, the conjunctivitis is iatrogenic and will gradually improve when the IDU is discontinued. EPITHELIAL MINIMAL

CORNEAL

LESIONS

OR NO STROMAL

WITH

DISEASE

The herpetic cornea1 ulcer with branching or angulated edges (i.e., the dendrite or geographic ulcer) suggests viral activity. A scraping from the margin of the ulcer often contains multinucleated giant cells, and HSV can usually be readily recovered in viral cultures from such a cornea. Treatment by removal of the infected (loose) cornea1 epithelium followed by patching of the eye for 72 hours, or by application of IDU ointment five times daily or IDU drops every hour during the day and every two hours at night, are about equally eflicacious.75 I prefer to remove the cornea1 epithelium and patch the eye. I do not apply iodine or ether, preferring to use only 4% cocaine to anesthetize and to help loosen the epithelium. In children, I often use IDU to avoid the need for an anesthetic, except when the lesion is near the visual axis. When this is the case, I merely remove the epithelium and patch. (IDU predisposes to the appearance of a ghost image under the dendritic lesion when

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Surv Ophthalmol 21 (2) September-October

Bowman’s membrane is exposed; or if there is already a ghost image, IDU increases its size. Therefore, I do nof use IDU after removing epithelium because of the drug’s apparent toxicity for exposed Bowman’s membrane.) EPITHELIAL STROMAL

KERATITIS

WITH

UNDERLYING

DISEASE

When there is underlying stromal disease, the removal of infected cornea1 epithelium is often followed by a long-standing cornea1 edema. This is probably the result of an added decompensation from the imbibition of fluids from the precorneal tear film when the epithelium is missing. In such cases, I either apply a pressure dressing, without further removal of epithelium, for 72 hours at a time, or instill IDU drops or ointment. When I need material for laboratory study, I merely scrape the edge of the epithelial lesion gently, or roll a dry, cotton-tipped applicator over the area to collect cells for viral culture. CHRONIC

INDOLENT

ULCERS

In 1936, these lesions were called “metaherpetic” by Gundersen,2E but in view of widespread confusion about the meaning of this term, which has also been applied to disciform lesions, we prefer not to use it. The “chronic indolent ulcer” is a shallow oval ulcer, actually a trophic ulcer, that fails to heal or heals very slowly. Its smooth, round appearance suggests that it has become noninfectious. Giant cells are not seen in scrapings, and cultures of scrapings are negative. Since removal of the epithelium in such cases may further delay healing, I prefer to use a pressure dressing for 48 to 72 hours at a time, and in rare cases, I have resorted to a conjunctival flap or lid adhesions. DISCIFORM

OSTLER

1976

KERATITIS

A disc-shaped lesion located in the stroma, and usually following a typical dendritic lesion, is called “disciform keratitis.” Such lesions are self-limited and clear within three to five months if not treated. Disciform keratitis clears very rapidly with the use of topical however, this adds the glucocorticoids; hazards of glucocorticoid therapy to the problem, and in the long run may convert a selflimited lesion with minimal residua to a lesion complicated by scarring and reduced vision. I explain these hazards to the patient and treat the eye with an occasional cycloplegic drop or a pressure dressing.

STROMAL

NECROSIS

EPITHELIAL

WITH

OR WITHOUT

DEFECTS

Stromal necrosis appears clinically as a dense white or yellow opacity with indistinct borders. Stromal vascularization may be present and may be actively progressing toward the lesion. If the patient is being treated with glucocorticoids, they should be tapered off as rapidly as possible, and to encourage healing, a pressure dressing or intermarginal lid adhesions (placed so that the lesion can still be seen) should be considered. Cycloplegics can also be used. IRITIS

Iritis due to HSV infection usually occurs in association with cornea1 lesions, but it can recur without clinical evidence of herpetic keratitis. As a rule, the iritis associated with HSV infection is a reactive iritis in which there are 1+ or 2+ cells and flare, a few white medium-sized keratic precipitates on the endothelium just behind the cornea1 lesion, and minimal iris infiltration. Occasionally, however, it may be severe, with 3+ or 4+ cells and flare, a hyphema or hypopyon, and marked iris infiltration with engorgement of the vessels near the pupil. In such lesions, the virus may be present within the iris.” The iritis of HSV infection responds poorly to the glucocorticoids; if one feels compelled to use them, the dose should be minimal. I do not use them unless the patient has already been using them and has a “rebound” inflammatory reaction when they are stopped. Dilatation of the pupil with strong cycloplegics is indicated. (The cycloplegics themselves may have an anti-inflammatory effect.) Carbonic anhydrase inhibitors should be given systemically if the pressure is elevated. CHORIORETINITIS

The chorioretinitis seen in infants neonatally infected with HSV is not amenable to therapy. It often occurs in association with HSV meningoencephalitis and the prognosis is grave. GENERALIZED

PRIMARY

MENINGOENCEPHALITIS, INFECTION

INFECTIONS, AND HSV

IN THE IMMUNOSUPPRESSED

HOST

In these conditions the use of systemic or cytozine arabinoside (Ara-C)6,33 should be considered, although the results in IDU3,%‘4

MANAGEMENT

animals have been erratic?“ In weanling mice, adenine arabinoside (Ara-A) was found to be superior to Ara-C in experimentally induced HSV encephalitis.24

INFECTIONS General Considerations

II. HERPES

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OF OCULAR HERPESVIRUS INFECTIONS

ZOSTER

Herpes zoster is an opportunistic infection caused by varicella-zoster (V-Z) virus.. Like recurrent herpes simplex, herpes zoster is usually the result of reactivation of a latent infection (harbored in a ganglion) in a host whose cellular immunity has been depressed by one means or another. Unlike HSV corneal infections, herpes zoster keratouveitis is not always self-limited and can cause a reduction in vision or even phthisis bulbi. In the majority of cases, however, it is benign, and the uveitis usually heals within a year. The severity of the infection itself, and of the keratouveitis in particular, as well as the duration of the disease, seem to be related to the age and physical condition of the patient. As a rule the disease is worse and lasts longer in the aged and physically debilitated.B6 The ophthalmic branch of the trigeminal nerve is affected in from 10 to 15% of the cases of herpes zoster,21 and patients with trigeminal zoster are more likely to develop neuralgia.

Ocular Lesions and Their Treatment SKIN LESIONS

In most cases the skin lesions of herpes zoster are self-limited and benign. Therapy should be supportive only. Drying lotions are believed to increase scarring and should not be used. In proven secondary infections (usually with Staphylococcus aureurj, topical antibiotics may be indicated. In the child, or in the occasional adult in whom the lesions itch or are irritating, systemic cyproheptadine (Periactinm) may be of value to prevent scratching, which predisposes to secondary infection and scarring. The small child should be restrained from scratching the area by the use of arm splints. Aspirin or other analgesics, including codeine and occasionally meperidine hydrochloride (Demerolm), may be necessary. Topical IDU ointment (40% in DMSO), applied continuously for four days, has been used in Great Britain with good results;ss however, the preparation is not available in

the United States. Intravenous cytosine arabinoside (Ara-C) has no value and may actually prolong disseminated zoster in severely compromised hosts.s1 CONJUNCTIVITIS

Herpes zoster conjunctivitis is rare and usually self-limited. The conjunctiva is hyperemit and may show a few follicles. Occasionally vesicles appear and quickly ulcerate. Treatment is nonspecific and directed toward removal of the secretions and supportive care. Secondary infection should be treated according to its nature. KERATOUVEITIS

When the tip or side of the nose has a vesiculobullous eruption in a case of zoster, there is often an associated keratouveitis. In the normal or partially immunosuppressed host, the keratouveitis is often transitory and does not require therapy. But in the markedly immunosuppressed host, including the aged, the keratouveitis tends to be more severe and can result in reduced vision. It can be suppressed with topical glucocorticoids, but they usually greatly prolong the disease,e4 and for this reason I prefer not to use them. If they have been used prior to my seeing the patient, however, and if the keratitis is severe or involves the visual axis, I may use a weak solution such as Dexamethasone O.l%, diluted 1: 5 or 1: 10, once or twice daily. The striking amelioration of the inflammatory signs and symptoms that can sometimes be achieved with an extremely weak glucocorticoid preparation is surprising. SECONDARY

GLAUCOMA

Unlike the secondary glaucoma of HSV infections, the secondary glaucoma of V-Z infection may be difficult to treat. I prefer to use potent topical cycloplegics and systemic carbonic anhydrase inhibitors. In rare instances, I have been unable to control the intraocular pressure in this way and have been compelled to use a topical glucocorticoid. When applying a glucocorticoid, I use a weak solution, however (see paragraph on keratouveitis, above), and taper it off as rapidly as possible. SCLERITIS

The scleritis of herpes zoster is rare and usually occurs late in the disease, often two or

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SurvOphthalmol 21 (2) September-October

three months after the onset of the skin eruption. The scleritis often runs a prolonged course, resulting eventually in thinning of the sclera, which is detected by a bluish discoloration of the area. Response to the glucocorticoids is less than dramatic, and although I have used them topically in every case of zoster scleritis I have seen, I am not convinced that they were beneficial. OPTIC NEURITIS AND CRANIAL NERVE PALSIES

Treatment with systemic Ara-A or Ara-C has been recommended for zoster that produces motor disturbances, for generalized zoster, and for zoster encephalitis.g4 Since these drugs are both toxic and immunosuppressive, however, their potential value must be weighed against their potential danger. POSTHERPETIC

NEURALGIA

The most frequent and most troublesome complication of herpes zoster is postherpetic neuralgia. It is more likely to develop in patients over age 50 than in younger patients, especially if they have trigeminal herpes zoster; among patients 70 years old or older, it afflicts about 50%~‘~Systemic glucocorticoids (60 mg daily for the first week, tapered rapidly during the second and third weeks) have apparently reduced both the average duration of pain during the acute disease and the overall prevalence of postherpetic neuralgia.12 But the distinct possibility that the infection may become generalized as a result of systemic glucocorticoid therapy must be kept in mind. Mild analgesic drugs (the mildest possible) may be sufficient to relieve postherpetic neuralgia. Recently we have used chlorprothixene (Taractanm) 50 mg q.i.d. for five days, in 13 patients with postherpetic neuralgia. In 11 of the 13, the drug either greatly relieved the pain or abolished it altogether. Favorable results with the use of Taractan@ were first reported by Farber” in 1974. When Taractan@ fails to aive relief, carbamazepine (Tegretola) is wal worth trying. PREVENTION

OF OPHTHALMIC

OSTLER

1976

ZOSTER

In most instances, there is a lag period of one or two days between the onset of the skin lesions of zoster and the involvement of the eye. According to Gundersen,24 if a patient with early herpes zoster has a vesiculobullous

eruption on the tip or side of the nose, further spread of the lesions, especially to the eye, can be prevented by the use of varicella-zoster hyperimmune globulin. III. OTHER

ENTITIES

Varicella Infections Most of the lesions of varicella are selflimited and recover completely. Supportive care is indicated, including treatment of any secondary infection. SKIN LESIONS

Since itching may be a prominent feature of varicella skin lesions, systemic Periactin@ may be advisable. To prevent secondary infection and scarring in young patients, arm splints should be considered if there is a tendency for the child to scratch the lesions. Seccondary infection with Staphylococcus aureus is uncommon but should be treated specifically when it occurs. If a patient develops severe or hemorrhagic varicella (as may occur if there is concomitant leukemia or Hodgkin’s disease, or if the patient is on high doses of immunosuppressive drugs), systemic ARA-A may be indicated.ss OTHER

OCULAR

LESIONS

The ocular lesions due to varicella, other than the skin lesions on the eyelids, are so rare, and the results of treating them so poorly documented, that they cannot be properly evaluated. At this time it seems appropriate to recommend supportive care only. PREVENTION

OF VARICELLA

In patients exposed to varicella or zoster who are at special risk, such as those with leukemia or other malignant diseases, the use of varicella-zoster hyperimmune globulin, given within 72 hours after exposure, has been found to prevent or significantly modify the disease.20*20

Cytomegalovirus Disease Although intravenous Ara-A has reduced viral excretion of cytomegalovirus (CMV) in several oatients.* there is no generally accepted: satisfactory treatment For cytomegalovirus disease. The results with both Ara-Cs5 and IDU” in newborn infants have been erratic, and floxuridine (FUDR) used in one infant had no effect.16 The neurological

MANAGEMENT

damage present at birth in congenital infection is probably irreversible, but the extent to which Ara-A may curtail further damage remains to be seen.’ Probably the greatest chance of success with Ara-A will be in the immunocompetent host.2

infectious Mononucleosis Infectious mononucleosis was thought to be favorably influenced by glucocorticoids,20 but the disease is self-limited and the improvement that followed treatment was probably consistent with the natural course of the infection.12 Supportive care, including bed rest, appears to be all that is needed.

References 1. Abel R, Kaufman HE, Sugar J: The effect of intravenous adenine arabinoside in herpes simplex heratouveitis in humans, in Pavan-Langston D, Buchanan RA, Alford CA Jr (eds): Adenine Arabinoside: an Antiviral Agent. New

York, Raven Press, 1975, pp 393-399 2. Baublis JV, Whitley RJ, Lawrence TC, Alford CA Jr: Treatment of cytomegalovirus infection in infants and adults, in Pavan-Langston D, Buchanan RA, Alford CA Jr (eds): Adenine Arabinoside: an Antiviral Agent. New York, Raven Press, 1975, pp 247-260 3. Breeden CJ, Hall TC, Tyler HR: Herpes simplex encephalitis treated with systemic 5-iodo-2’deoxyuridine. Ann Intern Med 65:1050-1056, 1966 4. Brown SI, Weller CA, Vidrick AM: Effect of corticosteroids on cornea1 collagenase of rabbits. Am J Opbtbalmol 70:744-747, 1970 5. Brunnell PA, Ross A, Miller LH, Kuo B: Prevention of varicella by zoster immune globulin. N Engl J Med 280:1191-l 194, 1969 6. Buckley TF, MacCallum FO: Herpes simplex virus encephalitis treated with idoxuridine. Br Med J 2:419-420, 1967 I. Cantell K, Tommila V: Effect of interferon on experimental vaccinia and herpes simplex virus infection in rabbit eyes. Lancet 2:683-684,

1970

8. Centifanto YM, Goorha RM, Kaufman HE: Interferon induction in rabbit and human tears. Am J Opbtbalmol 70:1006-1009, 1970 9. Chowchuvech E, Sawicki L, Weissenbacher M, Galin MA: Clinical evaluation of early polyinosinic-polycytidylic acid therapy in experimental herpes simplex keratoconjunctivitis. Ann Opbtbalmol 6:127-138, 1974 10. Chu MY, Fisher GA: Comparative studies of leukemic cells sensitive and resistant to cytosine arabinoside. Biocbem Pbarmacol 14:333-341,

11. Conchie

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OF OCULAR HERPESVIRUS INFECTIONS

1965

AF,

Barton

BW,

Tobin

JO:

Congenital cytomegalovirus treated with idoxuridine. Br Med J 4:162-163, 1968 12. Eaton OM, Stevens H, Silver HM: Respiratory failure in polyradiculoneuritis associated with infectious mononucleosis. JAMA 194:609-611, 1965 13. Elliott FA: Treatment of herpes zoster with high doses of prednisone. Lancet 2:610-611, 1964 14. Evans AD, Gray OP, Miller MH, et al: Herpes simplex encephalitis treated with intravenous idoxuridine. Br Med J 2:407-410,1967 15. Farber GA, Burks JW: Chlorprothixene therapy for herpes zoster neuralgia. South Med J 67:808-8 12, 1974 16. Felberg TD, Smith EB, Knox JM, et al: Photodynamic inactivation of herpes simplex. JAMA 223~289-292, 1973 17. Feigen RD, Schockelford PG, DeVivo DG, Haymond MW: Floxuridine treatment of congenital cytomegalic inclusion disease. Pediatrics 48:3 18-32 I, 197 1 18. Field AK, Tytell AA, Lampson GP, Hilleman MR: Inducers of interferon and host resistance. V. In Vitro Studies. Proc Nat1 Acad Sci USA 61:340-346, 1968 19. Freifelder D, Uretz RB: Mechanism of photoinactivation of coliphage T7 sensitized by acridine orange. Virology 30:97-103, 1966 20. Frenkel EP, Shiver CB Jr, Berg P, Caris TN: Meningoencephalitis in infectious mononucleosis. JAMA 162:885-886, 1956 21. Fulginiti VA: Herpes zoster, in Demis DJ, Crounse, RG, Dobson RL, McGuire J (eds): Clinical Dermatology, Vol 3. Hagerstown, Md, Harper & Row, 1975, Unit 14-7, pp l-8 22. Fulhorst HW, Richards AB, Bowbyes J, Jones BR: Cryotherapy of epithelial herpes simplex keratitis. Am J Opbtbalmol 73:45-51, 1972 23. Gershon AA, Steinberg S, Brunell PA: Zoster immune globulin, a further assessment. N Engl J Med 290~243-245, 1974 24. Griffith JF, Fitzwilliam JF, Casagrande S, Butler SR: Experimental herpes simplex virus encephalitis. Comparative effects of treatment with cytosine arabinoside and adenine arabinoside. J Infect Dis 132:506-510, 1975 25. Guerra R, Frezzotti R, Dianzani F, Rita G: A preliminary study of treatment of human herpes simplex keratitis with an interferon inducer. Article 1. Ann NY Acad Sci 173:823-830,

1970

26. Gundersen T: Herpes corneae, with special reference to its treatment with strong solutions of iodine. Arch Opbtbalmol 15:225-249, 1936

27. Gundersen T: Convalescent blood for treatment of herpes zoster ophthalmicus. Trans Am Opbtbalmol Sot 38: 124- 137, 1940

28. Hughes . WF: Treatment of herpes simplex keratltls. A Keview. Am J Opbtbalmol 67:313-328,

1969

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Surv Ophtholmol 21 (2) September-October

1976

29. Hussey HH:. Varicella-zoster infections, zoster immune globulin. JAMA 228:876, 1974 30. Jawetz E, Coleman VR, Dawson CR, Thygeson P: The dynamics of IUDR action in herpetic keratitis and the emergence of IUDR resistance in vivo. Ann NY Acad Sci 123:282-291, 1970 31. Jones BR: Prospects in treating viral disease of the eye. Trans Ophthalmol Sot UK 87:537-579, 1967 32. Jones BR, McGill JI, McKinnon JR, et al: Preliminary experiences with adenine arabinoside in comparison with idoxuridine and trifluorothymidine in the management of herpetic keratitis, in Pavan-Langston D, Buchanan RA, Alford CA Jr (eds): Adenine Arabinoside: An Antiviral Agent, New York, Raven Press, 1975, pp 411-416 33. Juel-Jensen BE: Severe generalized primary herpes treated with cytarabine. Br Med J 2:154-155, 1970 34. Juel-Jensen BE, MacCallum FO: Herpes Simplex, Varicella and Zoster. Philadelphia, Lippincott, 1972, p 50 35. Ibid, pp 163-166 36. Ibid, pp 161 and 172 37. Ibid, pp 170-174 38. Kaufman HE, Capella JA, Maloney ED, et al: Cornea1 toxicity of cytosine arabinoside. Arch Ophthalmol 72:535-540, 1964 39. Kaufman HE, Ellison BS, Centifanto YM: Difference in interferon response and protection from ocular virus infection in rabbits and monkeys. Am J Opbthalmol 74:89-92, 1972 40. Kaufman HE, Ellison ED, Waltman SR: Double-stranded RNA, an interferon inducer in herpes simplex keratitis. Am J Ophthalmol 68:486-49 1, 1969 41. Kaufman HE, Martola EL, Dohlman C: Use of 5-iodo-2’deoxyuridine (IDU) in treatment of herpes simplex keratitis. Arch Ophthalmol 68:235-239, 1962 42. Kern AB, Schiff BL: Smallpox vaccinations in the management of recurrent herpes simplex, a controlled evaluation. J Invest Dermatol 33:99-102, 1959 43. Krawawicz T: Cryogenic treatment of herpes simplex keratitis. Br J Ophthalmol 49:37-39, 1965 44. Lahav M, Ducker D, Bhatt PN, Albert DM: Photodynamic inactivation in experimental keratitis. Ophthalmol herpetic Arch 93:207-218, 1975 45. Lepine, P, deRudder J, Maurin J, Honcoq E: Essai de therapeutique de l’herpbs rtcidivant par un vaccin prepare en culture cellulaire et inactive par les rayons ultra-violets. I: Preparation du vaccin et essais d’immunisation sur l’animal. Sem HBp Paris 40:1471, 1964 46. MacCallum FO, Juel-Jensen BE: Herpes

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simplex virus skin infection in man treated with idoxuridine in dimethyl sulphoxide. Results of a double-blind controlled trial. Br Med J 2:805-807, 1966 Melnick JL, Rawls WE: Photoinactivation of herpes simplex virus continues to look promising. Letters to the editor. JAMA 226:79-80, 1973 Nahmias AJ, Josey WE, Naib ZM: Neonatal herpes simplex infection. JAMA 199:164-168, 1967 Norn MS: Dendritic (herpetic) keratitis. I: recurrence Incidence, seasonal variations, therapy. Acta rate, visual impairment, Ophthalmol 48:91-107, 1970 O’Day DM, Jones BR, Poiver R: Photodynamic inactivation of ocular herpes. Abstracted Symp Assoc Res Vis and Ophthalmol p 5 1, 1973 Ostler HB: The limited role of glucocorticoids in the management of herpes simplex keratitis and keratoiritis. Sure Ophthalmol (In press) Ostler HB, Oh JO, Dawson CR, Burt WL: Toxicity of Poly I-Poly C for rabbit eyes. Nature 228:362-364, 1970 Overby LR, Robishaw EE, Schleicher JB, et al: Inhibition of herpes simplex virus replication by phosphonoacetic acid. Antimicrob Agents Chemother 6:36&365, 1974 Park JH, Galin MA, Billace A, Baron J: Prophylaxis of herpetic keratoconjunctivitis with interferon inducers. Preliminary observation. Arch Ophthalmol 81:840-842, 1969 Patterson A, Jones BR: The management of ocular herpes. Trans Ophthalmol Sot UK 87:59-84, 1967 Pavan-Langston D, Dohlman CH, Geary PA, Sulzewski D: Intraocular penetration of ARA-A and IDU. Therapeutic implications in clinical herpetic uveitis. Trans Am Acad Ophthalmol Otolaryngol 77:455-466, 1973 Pavan-Langston D, Langston RHS, Geary PA: Idoxuridine, adenine arabinoside, and hypoxanthine arabinoside in the prophylaxis and therapy of experimental ocular herpes simplex, in Pavan-Langston D, Buchanan RA, Alford CA Jr (eds): Adenine Arabinoside: an Antiviral Agent. New York, Raven Press, 1975, pp 337-344 Pavan-Langston D, Langston RHS, Geary PA: Prophylaxis and therapy of experimental ocular herpes simplex. Arch Ophthalmol 92:417-421, 1974 Plotkin SA, Stetler H: Treatment of congenital cytomegalic inclusion disease with antiviral agents. Antimicrob Agents Chemother pp 372-379, 1969 Prusoff WH: Recent advances in chemotherapy of viral diseases. Pharmacol Rev 19:209-250, 1967

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61. Rapp F, Li JH, Jerkofsky M: Transformation of mammalian cells by DNA containing viruses following photodynamic inactivation. Virology 55:339-346,

1973

62. Silk BR, Roome APCH: Herpes encephalitis treated with intravenous idoxuridine. Lancet 1:41 I-412, 1970 63. Steele RW, Chapa IA, Vincent MM, et al:

Effects of adenine arabinoside on cellular immune mechanisms in man, in Pavan-Langston D, Buchanan RA, Alford CA Jr (eds): Adenine Arabinoside: an Antiviral Agent. New York, Raven Press, 1975, pp 275-280 64. Stevens DA, Jordan GW, Waddell TF, Merigan TC: Adverse effect of cytosine arabinoside in disseminated zoster in a controlled trial. N Engl J Med 289:873-878, 1973 65. Thygeson P: The changing characteristics of herpes zoster keratouveitis. Trans Pat Coast Oto-Opbtbalmol Sot 55: 129-l 36, 1974 66. Thygeson P, Sexton RR, Corwin ME: Obser-

vations of the IUDR therapy of herpetic keratitis. Trans Pat Coast Oto-Opbthalmol Sot 44:8 l-94, 1963 67. Thygeson P, Spencer WH: Changing charac-

ter of infectious cornea1 diseases. Emerging opportunistic microbiologic forms 1928-1973. Trans Am Ophthalmol Sot 71:246-253,

1973

with interferon. Acta Ophthalmol41:478-482, 1963 70. Tomlinson AHI MacCallum

FO: The effect of iodo-deoxyurrdme on herpes simplex virus encephalitis in animals and man. Ann NY

Acad Sci 173:20-28, 1970 71. Wallis C, Trulock S, Melnick JL: Inherent

photosensitivity of herpes virus and other enveloped viruses. J Gen Virol 5:53-61, 1969 72. Welch AD: Some mechanisms involved in selective chemotherapy. Ann NY Acad Sci 123:19-41, 1965 73. Wellings PC, Awdry PN, Bors FH, et al:

Clinical evaluation of trifluorothymidine in the treatment of herpes simplex cornea1 ulcers. Am J Ophthalmol 73:932-942, 1972 74. Wheeler CE Jr: Herpes Simplex, in Demis DJ,

Crounse RG, Dobson RL, McGuire J (eds): Clinical Dermatology, Vol 3. Hagerstown, Md, Harper & Row, 1975, Unit 14-2, pp l-l 1 75. Whitcher J, Dawson CR, Hoshiwara I, et al: Herpes simplex keratitis in a developing country. Natural history and treatment of dendritic and geographic ulcers in Tunisia. Arch Opbthalmol 94(4):587-592, 1976 76. Witmer R, Iwamoto T: Electron microscopic

observation of herpes-like particles in the iris. Arch Ophthalmol 79:331-337,

1968

68. Tokumaru

T, Scott TF: The herpes virus group, in Lennette EH, Schmidt NJ (eds): Diagnostic Proceedings for Viral and Rickettsial Diseases. New York, American Public

Health Association, 1969, pp 331-433 69. Tommila V: Treatment of dendritic keratitis

Reprint requests should be addressed to: Dr. H.B. Ostler, Francis I. Proctor Foundation, University of California, San Francisco, California 94143