The enigma of herpes stromal diseaseIn herpes zoster stromal disease cases 78% had epithelial involvement, 54 of 57 responded to topical antivirals alone without the use of steroids,

British Journal of Ophthalmology, 1987, 71, 118-125

The enigma of herpes stromal diseaseJAMES McGILL

From Southampton Eye Hospital, Wilton Avenue, Southampton S09 4XW

SUMMARY Herpes stromal disease is due to direct damage as a result of viral replication, virallyinduced immune mechanisms, or a combination of the two. Viral replication may have a majorinitiating role in the production of herpes simplex and herpes zoster induced stromal disease, andsteroids may initially be harmful in their treatment. On topical antiviral drugs alone, in patientswho never previously had had topical steroids, 14 of 15 cases of herpes simplex induced disciformkeratitis responded favourably in an average of 44 days of treatment. This compared with one outof 14 responding if steroids had previously been used, 13 of 14 requiring topical steroids and anaverage 112 days' treatment. In herpes zoster stromal disease cases 78% had epithelialinvolvement, 54 of 57 responded to topical antivirals alone without the use of steroids, 2%recurred, and treatment averaged a total of 62 days. If steroids were used alone or in combinationwith antivirals, there was a 50% recurrence rate and 200 day total treatment duration.

Two sorts of herpetic infections affect the cornealstroma, namely those due to herpes simplex andthose due to herpes zoster infection. Both conditionspresent peculiar and testing diagnostic or therapeuticproblems in many cases, and both conditions areoften difficult to treat, prone to recurrences leadingto corneal scarring, progression of disease to otherparts of the eye not initially affected, and much visualloss. It is uncertain whether stromal disease is causedby viral replication alone (leading to cytolysis), byvirally induced immunological mechanisms, or acombination of both, and this uncertainty is reflectedin the inadequacy of treatment of these conditions.

Traditionally both conditions have been treatedwith steroids, but treatment has been prolonged,with frequent recurrences, and it is sometimes diffi-cult to wean a patient completely off low dosemaintenance topical steroids. Often despite treat-ment the disease spreads to parts of the eye notinitially affected.' Furthermore steroids, apart frombeing associated with local side effects, can lead to acontinuation of the disease process by enhancingviral replication and suppressing local immune anddefence mechanisms, and this could explain thechronicity of the disease.The aim of this paper will be to present evidence

that viral replication plays a major part in the diseaseprocess, and that early antiviral drug treatment ofthese two conditions has many advantages and ispossible without the concomitant use of steroids.Correspondence to J McGill, FRCS.

Herpes simplex stromal disease

Herpes simplex virus infection is common through-out the world and in the United Kingdom representsthe commonest infectious cause of blindness, with2-3% of all cases being notified to the centralregister.2 Stromal disease occurs in 25% of patientsafter their first herpes simplex epithelial ulcer,34 with75% occurring within the first year. If topical steroidsare used in the initial ulcerative attack, there is ahigher incidence of stromal disease.35 There are twosorts of stromal response, that underlying an activeepithelial ulcer, 4nd that occurring some time afterthe epithelial lesion has healed, or indeed occurringwithout a preceding epithelial lesion. In the lattercase the typical stromal lesion of disciform keratitis isa centrally localised infiltration with oedema andswelling of the corneal stroma, folds in Descemet'smembrane, and sometimes secondary glaucoma,uveitis, or occasionally an overlying dendritic ulcer.Alternatively the lesion may be eccentric or occupythe entire cornea. The exact classification, though, ofthe herpes simplex induced stromal diseases mustawait the determination of the exact and relative roleof virus replication and immune mechanisms.

Herpes zoster stromal disease

Herpes zoster infections occur in 0-2% of the popula-tion, with the trigeminal nerve the most commonlyinvolved. Of these cases ocular involvement occurs in

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The enigma ofherpes stromal disease

Table 1 Herpes zoster keratouveitis: a retrospectiveanalysis of112 patients, ofwhom 82 had epithelial lesions,showing the incidence ofstromal lesions and uveitissubsequently developing

Disciform Localised Uveitiskeratitis infiltrate

No. % No. % No. %

23 20-5 31 27-6 81 72.3With preceeding

epithelial lesion (82) 18 78.3 24 77-4 77 95No preceeding

epithelial lesion (0) 5 21-7 7 22-6 4 5

over 50%. In the acute phase 50-73% will developepithelial involvement, either a punctate kerato-pathy or pseudodendritic formation.67 In a recentretrospective analysis of 112 patients 42 (37-5%)developed stromal disease after previous epithelialinvolvement as opposed to only 12 patients (10.7%)developing stromal disease with no precedingepithelial involvement. In other words, if there hadbeen previous epithelial involvement, over 50% (42out of 82) developed stromal disease (Table 1).

In the same analysis it was found that anteriorstromal nummular infiltrates or passages were geo-graphically related to previous epithelial disease in92% of patients, occurring soon after the onset ofepithelial disease itself. Disciform keratitis occurredin 20% of patients, and characteristically after adelayed interval-after more than 21 days-78%having had previous epithelial disease. Uveitisoccurred in 72% of all patients, only 5% ofwhom hadnot had preceding epithelial disease. Late epithelialdisease, including delayed mucous plaques associ-ated with corneal anaesthesia and previous epithelialdisease, and neuroparalytic and exposure keratitis,represents epithelial disturbance rather than activeviral invasion, for no herpes zoster virus has beenisolated from these lesions.

Corneal response to viral infection

When viral infection takes place, tear immunopro-teins such as IgA and IgG act to neutralise the virusand prevent it colonising the epithelial cells. Oncethis has occurred, though, viral replication takesplace within the cells, which are destroyed, an ulcerresults, and free virus is released. Either viruspenetrates the stroma, enters the keratocytes, repli-cates, and leads to cytolysis, which in itself leads toan acute inflammation, or soluble viral antigenpermeates from the surface and becomes attached tothe stromal keratocyte membranes, altering theirmembrane antigenicity and setting up an immune

reaction. Finally, incomplete viral particles can enterthe stroma, setting up an immune reaction. In herpessimplex stromal disease the local cellular or immunereaction is mainly T cell mediated, with sensitisedlymphocytes producing cytotoxicity by way of a localcell mediated hypersensitivity. Natural killer T cells,whose action is not dependent on previous sensitisa-tion, may also play a part, for they have been shownin graft rejection to destroy donor endothelial cells.8Thus the stromal response is due to soluble sensitisedimmunoprotein, such as IgG, acting together with asensitised cell mediated system, with activation ofcomplement. The HLA antigen system is expressedin the normal corneal stroma with both class I HLAantigens, the major histocompatability complexantigen acting as an effective agent for both cellularand humoral immune systems, and class II HLAsystems present.9 After herpes simplex infectionHLA class II (HLA D) antigens are expressed onstromal cells (Ward K A, et al., in preparation). Suchabnormal expression of class II antigens is observedin a variety of autoimmune diseases and wouldexplain how the HSV virus can initiate a cellmediated response.Such humoral and cellular mediated responses

would block viral replication, causing an abortivereaction, but as the virus has already entered thekeratocyte its surface antigenicity would have beenaltered, so that the corneal defence mechanismwould recognise it as 'non-self', producing a cellmediated response. It is a feature of both herpessimplex and zoster disciform keratitis that the diseaseprocess is chronic. If the reaction was simply due to acell mediated hypersensitivity reaction, it would beexpected to be self limiting, but with topical steroidtreatment, either after or during withdrawal,rebound recurrences are frequent, suggesting con-tinued antigenic stimulus. Nowadays, very few casesof herpes simplex stromal disease are left untreatedwith steroids, and much of the severity of these caseshas been attributed to the advent of steroids,'0 whichlead to local immunosuppression but allow viralreplication to proceed with continued antigenicstimulation.But what is the evidence that viral replication plays

a part in the stromal response? In herpes simplexkeratitis, tear herpes simplex virus (HSV) specificsecretary IgA (sIgA) has been found after acuteepithelial disease," and there is a marked localproduction of virus specific IgG subclass in responseto epithelial and stromal inlection.9 Antibody in thissubclass may be poorly neutralising, as it fails to fixcomplement and only weakly promotes an antibody-dependent cell mediated cytotoxic reaction. More-over IgG4 antibody production may result in anatopic reaction, as it combines with mast cells and

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causes degranulation when cross-linked by antigens,and this would account for some of the stromaldestruction and response seen in stromal disease.

It was Barrie Jones who with Alan Patterson"showed that, if disciform keratitis was treated alonewith steroids, a herpes simplex ulcer would appear onthe epithelium in a high percentage of such cases.Herpes simplex particles have been demonstrated inthe corneal stroma"'7 and HSV isolated from organcultured corneal discs in patients with disciformkeratitis. 118 Herpes simplex viral particles have beenseen in necrotising stromal keratitis."'9 Someworkers have attributed disciform keratitis to a directviral invasion of the endothelium on the basis ofherpes simplex virus isolation from the aqueous,'and herpes simplex viral has been cultured from theaqueous in cases of focal iritis and persistent endo-theliitis with a secondary glaucoma.20 Incompletevirus, virions, or empty capsids have been found inthe stroma of a patient with disciform keratitis, withHSV antigen localised either near herpes virions inkeratocyte cell nuclei or in the stroma in areas ofdegenerating keratocytes'1'8 and on keratocytenuclear membranes. 16

The sources of such virus include the stroma itself,the ocular adnexa and tears, and the trigeminalganglion known to be colonised after infection21reaching the stroma by way of the corneal branches-the so-called back door approach22. Such continuedantigenic stimulation would suggest initiation byresidual virus or viral remnants. The clinical appear-ance of disciform keratitis can be produced in therabbit eye by herpes antigen injection,124 antigenbeing found on the stromal keratocytes with lympho-cytes in close proximity, suggesting a cell mediatedresponse. The direct injection of herpes virus intothe rabbit stroma produces infiltrates, though itssimilarity to the clinical picture of disciform keratitisis uncertain, and such an animal model is probablymore akin to the infiltrate beneath an ulcer in man.Antiviral treatment of these infiltrates with eithertriflurothymidine& or bromovinyldeoxyuridine26improved the stromal response.

In rabbits different herpes simplex strains producedifferent responses. Strains producing a stromalresponse have an increased glycoprotein contentcompared with those producing only epithelialresponses,27 and there is evidence that genetics playsa part, for the viral genome determines the extent ofocular herpes infection, its severity, its tendencytowards recurrent disease, and the tissue response tosteroids, independently of any host immunity orresistance.8 If the appropriate HSV strain is inocu-lated into the rabbit cornea, stromal involvement isseen beneath the ulcer, and a disciform keratitislesion is seen after the seventh day.281 But poly-

morphonuclear cells are important in the develop-ment of the lesion, for if the rabbits are treated withserum acting against the polymorphonuclear cells thereaction is much less.0

In herpes zoster infection the exact mechanism andpathogenesis of the ocular signs is not known, partlybecause of the paucity of pathology of the stromallesions and partly owing to the lack of a suitableanimal model. Herpes zoster virus has been culturedfrom the acute epithelial lesions of both punctatekeratopathy and pseudodendrites," from whichmultinuclear giant cells and intranuclear occlusionhave been found32 and which are the most commonmanifestation of ocular involvement. A high propor-tion (92%) of the anterior stromal deposits whichresolve into nummular scars occur in areas underly-ing a previous punctate keratopathy or pseudo-dendritic ulcer6 (Table 1). These lesions could be dueto direct viral invasion, or the diffusion of solubleviral antigen into the stroma, or damage to theterminal corneal nerves from virus travelling downthe trigeminal branch. Similarly keratouveitis fre-quently occurs after epithelial involvement-in 95%of patients6 (Table 1). It is uncertain whether theocular abnormalities are due to vasculitis causingischaemia or chronic inflammation. Histologicalexamination of early cases has shown that only theepithelium tends to be affected, with the deepcorneal layers clear, but in chronically affected casesgranulomatous reactions to Descemet's membranehave been seen,3" and viral particles have been foundin the endothelium'4 3 and retina.?6 Disciformkeratitis also occurs after epithelial disease but not inthe same area, and, as lymphocytes are found in theaffected region, it is thought to be due to a hyper-sensitivity reaction to viral antigen.6Thus the available evidence points to direct viral

involvement of the stromal lesions in both herpessimplex and zoster disease, either by setting up acytotoxic reaction after cellular invasion, or byinitiating immunological mechanisms which areresponsible for the clinical signs that are so familiar inthese cases. If it could be shown that those antiviralagents which enter the stroma in therapeutic concen-trations do control the disease process, this would beevidence that viral replication at least plays a part-an initiating role-in such disease processes.

Clinical results

TOPICAL ANTIVIRAL CHEMOTHERAPYHerpes simplex disease

INTRODUCTIONTopically applied chemotherapeutic drugs have adefinite role in the treatment of epithelial disease,

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121The enigma ofherpes stromal disease

Table 2 Outcome ofcomparative trial oftopical acyclovir(ACV) and adenine arabinoside (Ara A) on the stromalresponse beneath herpes simplex epithelial lesion. Treatmentwasfive times a day until the signs resolved, then it wasweaned offover two weeks

Number Healed Days to Steroidsheal required

ACV 20 20 12-3 0ARA-A 17 12 8-0 5

From McGill, Tormey, Walker.37

known to be due to viral replication and virallyinduced cell destruction, but do not affect eitherlatency' (recurrences) or the incidence of subse-quent stromal disease. Idoxuridine, which is highlyinsoluble and does not penetrate into the cornealstroma, has no effect on stromal disease, but thequestion arises whether alternative antivirals that dopenetrate have such an effect.

CLINICALPatients were divided up into those who had astromal response beneath an active corneal ulcer,and those who had a typical lesion of herpes simplexdisciform keratitis following on a previous attack ofdendritic ulceration but with no concurrent epithelialdisease present. In a double blind trial topicalacyclovir and adenine arabinoside were compared inthe treatment of the herpes simplex stromal responsebeneath the ulcer. Acyclovir was superior to Ara-A37(Table 2).

In disciform keratitis acyclovir alone was of effectonly in those patients who had never previously hadtopical steroids. Fourteen of 15 such patients re-sponded satisfactorily, but if topical steroids hadbeen used in a previous attack (with topical anti-virals) then only one of 13 responded satisfactorily.The duration of treatment of acyclovir treatedpatients was shorter and rebound recurrences fewerthan for those patients treated with a combination ofacyclovir and steroids. In other words, once steroids

were added to the regimen, all the familiar problemsof steroid treatment, namely prolonged treatmenttherapy and frequent recurrences, were seen (Table3). The degree of visual loss resulting from theresidual stromal scarring was the same in the twogroups, showing that withholding steroids did notlead to increased stromal scarring.

CONCLUSIONFor those patients with their first attack of disciformkeratitis and who have never been treated withsteroids, topical antivirals that penetrate to thecorneal stroma have in a comparatively short treat-ment course been successful in a high percentage ofcases, without any significant sight impairing residualstromal scarring. The reason why prior steroidtherapy makes the patient steroid dependent forsubsequent attacks is unknown.Adenine arabinoside is known not to penetrate the

corneal stroma in therapeutic amounts. This explainswhy topical acyclovir was superior in treating herpessimplex induced infiltrative stromal disease beneathan ulcer. That topical acyclovir alone was able tocontrol the stromal disease suggests that viral replica-tion plays at least a part in the disease process.Collum and his colleagues' found that, in a compari-son of acyclovir with or without topical steroids inthe treatment of disciform keratitis, 40% of thosepatients treated with acyclovir alone healed within 50days, but it is uncertain how many had had steroidspreviously, so that these results may have beenimproved if these patients had been excluded.Similarly Sanitato et al.'9 and Kaufman39 found thatacyclovir alone had a beneficial effect in five of 12patients with disciform keratitis, but it was not clearfrom their results how many of these patients had hadprior attacks treated with steroids. Acyclovir has alsobeen successfully used in the treatment of presumedherpetic iridoxcyclitis when given either topically(personal observation) or systemically.4'

It is suggested that for the first attack of herpessimplex induced stromal disease acyclovir or trifluoro-

Table 3 Response of topical acyclovir (ACV) or triflurothymidine (F3T) on herpes simplex disciform keratitis in patientswho either had never had topical steroids or had had a previous attack ofstromal disease treated with steroids and antivirals

No. Healed Signs Treatment Recurrences Average Change in visionresolved duration follow-up

(days) (months) Percent Loss I line Loss >1 linesame Snellen Snellen

No priorsteroidsACV 15 14 16-5 44-3 1 43-2 67% 33%F3T 1 1 21 40 0 8

PriorsteroidsACV 13 1 16-7 112 7 48-6 53-8% 23-1% 23-1%



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thymidine five times a day for two weeks should beinitiated. If after this time there is no regression of theclinical signs, topical steroids should be added and,once the signs have regressed, the patient cautiouslyand slowly weaned off. As viral resistance toacyclovir has been seen both experimentally andclinically,4'42 administration of the drug should belimited to as short a treatment period as clinicallynecessary.

HERPES ZOSTER INFECTIONIf a drug has an effect on the skin rash which is knownto be due to direct viral invasion, then, if zosterkeratouveitis in its many forms is due at least in partto viral invasion and virally induced tissue damage, itwould be expected that that drug would control someof the corneal disease.The earlier available antivirals had no effect on the

acute stages of the rash, or the incidence of post-herpetic neuralgia, when given either systemically as

adenine arabinoside43 and cytosine arabinoside43 or

topically as idoxuridine, which initially, when com-bined with dimethyl sulphoxide (DMSO) for skinpenetration, was thought to be of benefit45 but laterfound to have no benefit over DMSO alone.,%Systemic steroids used to lessen postherpeticneuralgia resulting from viral induced tissue damagecarried the risk of virol dissemination.47 Acyclovir hasbeen shown in vitro to have antiviral activity againstthe varicella zoster virus,48 and initial clinical trialssuggested a beneficial clinical effect on the skinrash.49 Placebo controlled double blind trials ofintravenous acyclovir have shown that acyclovirtreated patients fared significantly better in terms ofduration of new lesion formation and the time of lossof vesicles and the time to full crusting.052

Intravenous therapy is not an ideal mode oftherapy for most patients, and so an oral form of thedrug has been developed. In a multicentred con-

trolled clinical trial oral acyclovir at 800 mg five timesdaily for seven days has been found to be superior toplacebo in significantly reducing the skin rashduration and associated pain (McKendrick et al.,in press), whilst Cobo et al."3 have shown thatoral acyclovir at 600 mg five times a day for 10 days,when compared with placebo in herpes zosterophthalmicus, significantly reduced skin involvementand viral shedding, and ocular disease signs were

lessened.The question arises whether a drug effective

against the skin rash is effective also against cornealdisease.

CLINICALAn open study of acyclovir ointment in acute herpeszoster keratouveitis showed that most patients had a

quick resolution of their symptoms without anyrecurrence of the disease process.54 This was in sharpcontrast to the common clinical finding that patientstreated with topical steroids required a prolongedcourse and suffered frequent recurrences. For thisreason a double blind trial was set up to comparetopical steroid and acyclovir ophthalmic ointment inthe treatment of acute herpes zoster keratouveitis"5(Table 4). The total treatment duration in theacyclovir treated group was considerably less than forthe steroid treated group. In a short follow-up of lessthan one year, while 12 of the 19 steroid treatedpatients had a recurrence of their keratouveitis oncetreatment was either being tapered off or stopped,none of the acyclovir treated patients had a recur-rence. Corneal epithelial disease resolved signifi-cantly faster than in the acyclovir group, but therewas no significant difference in the resolution ofstromal disease, uveitis, or scleritis in the two groups.

In an attempt to gain a broader impression ofthe usefulness of acyclovir in acute herpes zosterkeratouveitis, a retrospective analysis was carried outof all patients with this disease presenting at theSouthampton Eye Hospital over a two-year periodand treated by a number of doctors.'5 Retrospectiveanalyses are not ideal, and exact differences betweengroups for particular signs resolving may not be clear,but, when the clinical outcome of these patientstreated with either topical acyclovir or steroids or acombination of both was reviewed, a definite patternemerged. Topical acyclovir alone controlled thedisease process in 51 out of 56 patients. Those treatedwith acyclovir fared significantly better, with aquicker resolution of their keratouveitis, as therewere no recurrences of the disease process in the firstyear after treatment had been stopped comparedwith a 50% incidence of those treated with topicalsteroids, many ofwhom are still on treatment, so thatthe total treatment duration of the steroid treatedpatients was much longer.-" With a longer follow-uptwo out of 56 of the patients treated with acyclovirhad a recurrence of their keratouveitis, one ofwhomhad had topical steroids for his lid involvement.6 Inan up-to-date retrospective analysis of all patientstreated with topical acyclovir the time taken forresolution was the same for the different types ofstromal disease (Table 5). But acyclovir, whencombined with steroids, showed no benefit comparedwith the steroids alone. In other words the addition ofsteroids produces all the problems of prolongedtreatment and frequent recurrences.These trials, however, may have merely been

showing the deleterious effect of steroids and not abeneficial one of acyclovir, as it was ethically imposs-ible to use placebo controls in patients who hadestablished keratouveitis causing a painful inflamed

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Table 4 Outcome oftreatment with eithertopical acyloviror topical steroids (Betnesol)five times a day on acute herpeszoster ocular involvement

Group Number Numberhealed initial treatment Numberdisease Totaltreatmentduration (median days) reappeared duration (median

days)

Acyclovir 17 16 75 0 75 (range 17-144)Steroids 19 18 68 12* (63%) 280t (range 34-440)

*p<O-00l (Fisher's exact test, 2-tailed).tp=0.002 (Mann-Whitney U test, 2-tailed).From McGill and Chapman.55

Table 5 Herpes zosterkeratouveitis: retrospectiveanalysis ofpatients treated with topicalacyclovircompared with thosetreated with steroids or a combination ofboth

Number Acyclovir (112) Steroids (74) Acyclovir + steroids (14)

No. Heated Days to heal No. Healed Days to heal No. Healed Days to heal

Epithelial 82 82 6-06 20 20 10 4 4 12Disciformkeratitis, 25 25 16 6 16 16 38 2 2 48Nummular keratitis 32 29 15-4 19 19 27-7 3 3 61Uveitis 89 83 21-7 56 56 53 7 7 92Average treatment duration 62-3 200 197Total recurrence rate 2% 50% 57%

eye. If in very early cases it could be shown thatacyclovir stopped the disease from developing (com-pared with placebo), this would support the conceptof an active role for this drug. In an attempt to settlethis problem a prophylactic double blind placebocontrolled trial was carried out on patients whoseskin rash had resolved and whose eye showedminimal involvement of conjunctival injection or

Table 6 Outcome ofa randomised double blind trialoftopical acyclovir compared withplacebo in the treatment ofherpes zoster keratouveitis. The ocularsigns at the onset wereminimal, either being conjunctival injection oran earlypunctate keratopathy (early corneal involvement). Theocular disease process was halted in the acyclovir treatedpatients butprogressed in 8-10 placebo treated patients,showing that acyclovir actively protects the eyefrom damageiftreatment is started early enough

Treatment No. ofpatients Halted Progressed

Acyclovir 10 10 0Placebo 10 2 8

Table 7 Herpes zoster keratouveitis: In ninepatients,showing the cause offailure to respond to topical acyclovir(severalpatients hadmore than one sign)

No.

Scleritis 3Nummular infiltrate (2 had marginal infiltrate) 3Uveitis 6

simply an acute punctate keratopathy (Table 6). Ofthe 20 patients treated 10 had topical acyclovir, 10topical placebo. All patients treated with topicalacyclovir fared well, with a quick resolution and nodisease progression or stromal involvement. Eightout of 10 of the patients treated with placebo had aprogression of their disease, with stromal involve-ment, and acyclovir had to be added before thedisease resolved.

In reviewing all 112 acyclovir treated patients, allbut one of whom presented within three weeks of theonset of their disease, we noted nine not respondingto acyclovir alone (Table 7). It is suggested that ifscleritis or uveitis persists, especially if synechiaehave formed, steroids should not be withheld.

CONCLUSIONMost cases of herpes zoster stromal disease followepithelial involvement, with nummular opacitiesoccurring sooner than disciform keratitis, suggestinga different mechanism. As epithelial lesions areknown to be associated with herpes zoster virus, andas stromal disease can be prevented if epithelialdisease is treated with antiviral chemotherapy, andestablished stromal lesions can be similarly treated,this evidence suggests that viral replication has amajor role in the development of these lesions.

Previously topical steroids were the only availabletreatment of herpes zoster keratouveitis, and theyhad to be continued for up to 18 months or more, withmuch disease progression, ocular damage and visualloss. With topical acyclovir there is a shorter treat-

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ment duration, less recurrence, and less diseasespread, but it must be emphasised that this compari-son may be showing up the deleterious effects ofsteroids on viral induced stromal disease, and furtherprophylactic oral and topically based clinical trialsare required to determine the relative effective roleof antivirals in this condition, particularly as the exactmechanism of the production of the different signs isnot yet known. For instance, nummular opacities,which develop earlier than disciform keratitis and indirect relation to epithelial ulcers, may be due to adifferent immune mechanism than the cell mediateddelayed immune mechanism of disciform keratitis.

General conclusion

In both herpes simplex and zoster ocular infections,stromal lesions usually follow after epithelial disease.The exact mechanism of these disease processes isnot yet fully understood, partly owing to the lack ofany suitable animal model. But the fact that stromaldisease occurs after epithelial disease, and the effectshown here of antivirals on stromal disease, suggestthat viral replication has a major role in the produc-tion of the stromal lesions. Antiviral treatment alonewithout the use of steroids offers considerable advan-tages, but the exact role of antivirals in the diseaseprocess must await further laboratory work andcoded clinical trials. Prophylactic placebo controlledtrials are required to determine whether topicalantivirals are superior to placebo in all aspects ofstromal disease, and whether any significant visionthreatening stromal scarring results from the with-holding of steroids.

Grateful thanks to my colleagues M J Absolon, FRCS, I HChisholm, FRCS, A R Elkington, FRCS, and C B Walker, FRCS,for referring patients to me and for allowing me. to review thepatients' case notes, and to Wendy Gilbert for typing themanuscript.

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