Eye (1988) 2, Suppl S56-S69

Herpes Simplex Virus Ophthalmia

MARJORIE A MONNICKENDAM

London

Herpes simplex virus ophthalmia (HSVO) is uninteresting drudge", but all those who have caused by herpes simplex virus (HSV). HSV is followed in the Prince's footsteps have helped to a common cause of keratoconjunctivitis and it is create the fascinating but as yet incomplete the major infectious cause of corneal blindness picture of HSVO which is presented here. in industrialised countries. HSVO has been intensively studied at the Institute of Ophthal­ The Pathogen mology, and these studies have led to major Herpessimplex virus is an enveloped DNA virus. advances in the recognition of the range of eye It can be divided into two types, HSV type 1 diseases caused by HSV, methods of diagnosis (HSV-l) which is associated with infections of and treatment, and in our understanding of the the eye, nose and lip, and HSV type 2 (HSV-2) pathogenesis of HSVo. Professor Barrie Jones which is associated with genital infections. initiated these studies and many people have Recurrent disease is a characteristic of HSV been involved. Their names are not mentioned infections. This results from the ability of HSV here, but they appear on the many papers which to infect sensory nerves and remain dormant in have been published. I felt that it would be the sensory nerve ganglia, protected from the appropriate to mark the fortieth anniversary of host's defence mechanisms. From time to time, the Institute of Ophthalmology by reviewing HSV spreads from its ganglion along the nerves these papers, and also the papers written by to the skin or mucous membranes, causing those people who began their studies of HVSO recurrent disease. HSV can also persist in the at the Institute of Ophthalmology, and who have cornea in the absence of active HSVo. In a continued their studies at other institutions. recent study, HSV was isolated from 10 out of 34 Two papers published in the late 1950s serve (29 %) corneal buttons obtained from patients as reference points.1,2 They make interesting with a definitive history of ulcerative herpetic reading for anyone concerned about infections of keratitis who were undergoing penetrating the outer eye, and they serve to remind us of the keratoplasty.3 HSV may also be able to persist difficulties our predecessors faced in the elsewhere. diagnosis and management of patients with It has often been assumed that there is little or HSVo. The opening paragraph of the first of no difference between different strains of HSV-l. these papers reads as follows: However, studies in animal models (which are "Conjunctivitis is rather an ophthalmic described later) indicate that a strain of HSV-l Cinderella for she appeared to be an uninterest­ isolated from a particular clinical form of HSVO ing drudge to whom few people paid any real produces the same form of HSVO in experimen­ attention. However, if we follow in the Prince's tally infected animals. These observations footsteps and really look at her we find that she indicate that different strains differ in their is actually fascinating and attractive, full of pathogenicity in the eye. Although the biological diverse possibilities and eager to reward our basis for this difference is not yet clear, some interest." 1 preliminary studies indicate that strains of Some ophthalmologists may still consider HSV-l isolated from patients with chronic conjunctivitis and keratoconjunctivitis to be "an stromal disease excrete larger amounts of

Correspondence to: Marjorie A Monnickendam, Section of Virology, Institute of Ophthalmology, Judd Street, London WC1H 9QS. HERPES SIMPLEX VIRUS OPHTHALMIA S57

'soluble' precursor glycoprotein D than strains skin. It could be isolated from eye-washings on isolated from patients with recurrent dendritic day four, and corneal disease was first seen on ulcers or keratoconjunctivitis.4 day six. Spread of HSV to eye-washings and the development of corneal disease could be Epidemiology prevented by removing a section of the sensory Source of infection nerves which supply the snout. This indicates There are several ways in which HSV-l can reach that spread to the eye from the snout requires an the eye. It can be transferred mechanically from intact nervous supply. 7 herpetic lesions elsewhere on the same indivi­ At present we do not know how HSV-1 reaches dual or from herpetic lesions on another the eye in the majority of patients. We need to individual. Barrie Jones considered that herpetic know in order to develop effective methods of lesions on other individuals were the source of preventing HSVo. infection, and he divided his patients into two groups: "the first consisting of children who Prevalence have been kissed by their blistered parents, and In 1957, there were 23 cases of HSVO in a series the second consisting of young adults who have of 124 patients (19 %) with acute conjunctivitis been kissed by their blistered lovers. To the eye, attending Moorfields Eye Hospital and the the menace of the virus-laden kiss is heightened London Hospital. HSV was the most common by the tendency of the labial herpetic to avoid lip cause of acute conjunctivitis in these patients. 1 contact and prefer instead cheek or brow."2 It could be predicted that there should have Laboratory animals develop HSVO following been an apparent rise in the prevalence of HSVO inoculation of HSV-1 into the eye, and these in the past 30 years. Recognition of the range of findings support the hypothesis that HSVO can eye diseases caused by HSV-l and improved result from direct infection of the eye. How methods of laboratory investigations should have many patients acquire HSVO by direct infection? increased the frequency with which an accurate In a study in London of patients experiencing diagnosis of HSVO is made, but this does not their first attack of HSVO, nine patients (8 %) appear to have happened. had been in contact with individuals who had Some recent studies give widely differing active herpetic skin lesions, and 17 patients estimates of the prevalence of HSVo. In a study (16 %) had herpetic lesions on their own lips, of patients with acute conjunctivitis attending an nose or face.5 However, 82 patients (76 %) had ophthalmic casualty clinic at Moorfields Eye no history of contact with herpetic lesions. Hospital, nine out of 140 patients (6 %) had How do the majority of patients acquire their clinical features typical of HSVo. 8 HSV was infections? There are several possibilities. They isolated from four of these patients and from a could acquire it through the transfer of HSV to further four patients who lacked typical lid the eye from the discharges of individuals who and/or corneal lesions. This gives a prevalence shed HSV-1 in their discharges but who are rate of 9 %. In addition, serological results asymptomatic. This hypothesis is supported by indicated that a further 16 had recent or current the observation that HSV was isolated from tears HSV-l infection. If it is assumed that all of these and saliva of four out of 11 individuals (36 %), 16 patients had HSVO rather than cold sores or none of whom had a history of herpes infec­ genital infection, then this gives a prevalence tion.6 Thus apparently normal individuals can rate of 21 %. This figure is similar to that be sources of infection. Infection of the eye reported earlier. 1 In a survey of 4,132 unselected could be followed immediately by the develop­ specimens from patients with conjunctivitis or ment of HSVO. Alternatively, it could remain keratoconjunctivitis, HSV was isolated from 94 , asymptomatic and therefore undiagnosed, but which gives an isolation rate of 2.3 %.9 This later recur, producing typical HSVO. Another figure is much lower than that reported earlier, 1 possibility is that HSV infection may occur first but is an underestimate of prevalence. Specimens at another site (eg skin or mouth), and later for viral isolation are often not taken from spread to the eye through the nerves producing patients who have typical clinical features of HSVo. This hypothesis is supported by studies HSVO, while other patients have serological in mice. HSV-1 was inoculated into the snout findings which suggest current or recent S58 MARJORIE A. MONNICKENDAM exposure to HSV-l, but HSV cannot be isolated Age from them. In a study of patients with acute or Barrie Jones divided his first group of 17 patients chronic conjunctivitis attending an eye casualty with what he described as "primary" HSVO into clinic at St. Thomas' Hospital, 14 out of 248 two groupS.2 The first group consisted of eight patients (6 % ) had dendritic ulcer, but HSV could patients (47 %) who were 10 years old or less. not be isolated from any of them. Serological The second group of nine patients (53 %) were studies indicated that four of these 14 had current between 15 and 30 years old. However, this or recent exposure to HSV-l as did a further 24 bimodal age distribution has not been observed patients. If it is assumed that these 24 patients all subsequently. It is not known whether this is a had HSVO, then the prevalence rate is 14 % .1 0 phenomenon which has since disappeared, or This figure is also lower than that reported whether it occurred by chance. earlier. 1 A continuous age distribution has been These three studies have produced widely observed in all subsequent studies. In a study of varying estimates of the prevalence of HSVO, patients with herpetic corneal ulceration, the one of which is a little higher than the figure mean age was 49 years and the age range was obtained in 1957, and the other two are eight to 80 years. The mean age was rather high substantially lower. During this time, it has been because these patients took part in a treatment recognized that HSV-l causes a range of eye trial from which women of child-bearing age diseases and several new and improved were excluded.14 Patients with bilateral herpetic laboratory tests have been developed for the ulceration had a mean age of 28 years and a diagnosis of HSVO, but there has not been any range of five to 60 years. 15 Patients experiencing substantial increase in the prevalence of HSVo. their first attack of HSVO also had a continuous This suggests that the current prevalence of age distribution, ranging from nine months to 66 HSVO is probably lower than the prevalence in years, with a mean age of 25 years. Thirty-nine 1957. patients (36 %) were less than 15 years old and 69 There are very few studies of HSVO in patients (64 %) were aged 15 years or more.5 developing countries. A survey of corneal The ages of the patients who experienced ulceration in Tanzanian children showed that recurrent attacks of HSVO ranged from 18 HSV was the commonest cause of corneal months to 56 years and the mean age was 18 ulceration. It was associated with corneal years. Recurrent attacks of HSVO were ulceration in 47 out of 130 children (36 %). A significantly more common in patients under 20 total of 16 children (12 %) in the study became years than in older patients. 13 blind, but only one of these was a child with In the study of corneal ulceration in Ta nzanian HSVO, indicating that it is not a common cause children, 51 % of children were less than two of childhood blindness in Ta nzania.11 These years old, 21 % were aged two to four years old findings are in marked contrast to those obtained and 28 % were aged five to 10 years old.ll in a study of children in northern Nigeria, where corneal ulceration following measles is the Sex commonest cause of childhood blindness. HSV There has been a long-running debate as to was detected in ocular specimens from 16 out of whether sex has an effect on susceptibility to 34 children (47 %) and it was concluded that HSVo. Studies carried out at the Institute of HSVO secondary to measles keratitis was a Ophthalmology have produced a crop of con­ major cause of blindness. 12 flicting observations, which are listed in Ta ble I. It appears that men and women are equally Seasonal Variations susceptible to acute follicular conjunctivitis,16 a In 1957, HSVO was most common in the first attack of HSVO,5 and recurrent HSVO.13 Autumn.1 In more recent studies of patients Men appear to be at greater risk of developing with a first attack or recurrent attacks of HSVO, ulcerative herpetic keratitis,14 and are even more the highest number of cases occurred in June, likely to develop recurrent ulcerative herpetic but there was no clear seasonal pattern. 5,13 disease. Men are also more likely to develop Other studies have not included data on seasonal bilateral ulcerative herpetic disease. 15 However, variation. there was no preponderance of men among the HERPES SIMPLEX VIRUS OPHTHALMIA S59

Table I Sexual distribution of forms ofHSVO

Form ofHSVO Number Males (%) Females (%) Reference

Acute follicular conjunctivitis 25 12 (48) 13 (52) 16 First episode of HSVO 108 58 (54) 50 (46) 5 Recurrent episode of HSVO 35 16 (46) 19 (54) 13 Ulcerative herpetic keratitis 152 98 (65) 54 (36) 14 Recurrent ulcerative herpetic keratitis 61 49 (80) 12 (20) 14 Bilateral ulcerative herpetic keratitis 30 21 (70) 9 (30) 15 Keratouveitis 50 21 (42) 29 (58) 17 Severe disease requiring keratoplasty 20 7 (35) 13 (65) 18 Severe disease requiring keratoplasty 34 17 (50) 17 (50) 3

patients who developed complicated HSVo. In a ophthalmia and adult chlamydial ophthalmia. At group of 50 patients with HSV kerato-uveitis and Moorfields Eye Hospital, 25 such patients were raised intra-ocular pressure (lOP), there were seen in an 18-month period. They were fewer males than females. 17 In one study of diagnosed by the isolation of HSV (88 %) or a patients with severe HSVO who required four-fold or greater increase in complement­ keratoplasty, seven out of 20 patients (35 %) were fixing (CF) antibodies against HSV (12 %). men and 13 (65 %) were women.18 In another Although there were no herpetic lesions on the study, there were equal numbers of men and lids, face or cornea at presentation, five (20 %) women who required keratoplasty following subsequently developed herpetic lesions. All the severe HSVO. 3 cases had unilateral disease at presentation and The situation therefore remains confused and eight patients (32 %) subsequently developed further studies are needed. It would be bilateral disease. 16 interesting and helpful to determine if one sex is In a study of 108 patients with a first episode at greater risk of developing complicated HSVO of HSVO in London,5 the infection was than the other, since it would indicate that host unilateral in 88 patients (81 %), and bilateral in factors related to sex are important in the 20 patients (19 %). Twel ve out of these 20 development of complicated and potentially patients presented with bilateral HSVO, while blinding HSVo. eight had unilateral HSVO at presentation and developed bilateral disease within a week. Clinical features Common symptoms were redness, lacrimation, HSV causes a spectrum of ocular diseases, discharge, itching, irritation and swelling of lids. including follicular conjunctivitis with or All patients had conjunctivitis which was without lid lesions, corneal disease, uveitis, accompanied by lid vesicles and/or ulcers in 100 glaucoma and retinitis. HSVO is commonly patients (93 %), while eight patients (7 %) had divided into primary and recurrent disease. follicular conjunctivitis without typical lid or Primary HSVO is described as an acute, corneal lesions. Almost all patients had moderate to severe follicular conjunctivitis or moderate to severe papillary responses, particu­ keratoconjunctivitis, commonly associated with larly in the upper palpebral conjunctiva. Most typical periocular vesicles and/or ulcers. It was patients had follicles which were small and reported in 1957 that HSV caused nearly one­ discrete and were found mainly in the lower third of all cases of follicular conjunctivitis. I In palperbral conjunctiva. Epithelial and subepi­ 1959, the majority of patients (61%) had many thelial punctate keratitis were found in 36 typical HSV lesions on their eye lids, 26 % had patients (33 %). Sixteen patients (15 %) had a few lesions, and 13 % had no lesions. The dendritic ulcers, while two patients had disci­ cornea was involved in two-thirds of cases.2 form keratitis.5 Dendritic ulcers and disciform The absence of lid and corneal lesions in some keratitis are generally considered to be forms of cases of HSVO presents problems in the recurrent HSVO but these patients were differential diagnosis of HSVO, adenovirus experiencing their first attack of HSVO. S60 MARJORIE A. MONNICKENDAM

It is generally accepted that recurrent HSVO whether they are unique to London. These affects the cornea and uvea, causing dendritic, findings also indicate that the present termino­ geographic or amoeboid ulcers, stromal disease logy of primary and recurrent HSVO is con­ including diffuse stromal keratitis, interstitial fusing and potentially misleading since there keratitis and limbal vasculitis, and anterior appears to be no clear-cut distinction between uveitis. In 1959, Barrie Jones stated "recurrent the clinical features of primary and recurrent episodes in which the latent virus-host relation is HSVo. It has therefore been proposed that the upset by some non-specific trigger mechanism present terminology of primary HSVO and factor, tend to produce circumscribed lesions recurrent HSVO should be abandoned, and within the area initially infected. Typical HSVO should be described by its clinical vesicles and ulcers appear on the lids but the features, regardless of whether it is a first attack acute follicular conjunctivitis of the primary or recurrent attack.20 For example, HSVO can infection is not repeated".2 However this no be described as HSV conjunctivitis or blepharo­ longer appears to be true of patients seen in conjunctivitis (with lid vesicles or ulcers), HSV London.13 Patients who had a first attack of blepharokeratoconjunctivitis, or HSV keratitis HSVO were followed for two to 15 years. (dendritic ulcer, geographic ulcer or diffuse Recurrent HSVO occurred in 35 out of 108 keratitis) or HSV keratouveitis. The adoption of patients (32 %), and the clinical features were this nomenclature would help to provide a similar to those of the first attack. All clearer clinical picture of HSVO, and it would patients with recurrent HSVO had conjunctivitis not affect management and treatment. The terms with or without lid lesions. Only three (9 %) primary HSVO and recurrent HSVO should be had dendritic ulcer, which was associated reserved for those patients whose immunological with a disciform keratitis in only one case. status has been determined. Only those Patients who had severe conjunctivitis and experiencing a first attack of HSVO who sero­ lid lesions in their first attack were more likely convert during infection should be described as to develop recurrent HSVO than patients who having primary HSVO. had mild conjunctivitis and lid lesions. However Bilateral herpetic corneal ulcers are unusual, there was no relationship between corneal and a survey of patients at Moorfields Eye disease and recurrent HSVo. The recurrence Hospital showed that it occurred in approxi­ rate was higher in patients who were less mately 3 % of all patients with HSV corneal than 20 years old than in older patients, and disease. 15 Thirty patients were studied and tended to be higher in patients whose first bilateral corneal ulcers occurred simultaneously attack was bilateral compared with those in the first episode of HSVO in 17 of these 30 whose first attack was unilateral. The duration patients (57 %). Twenty patients (67 %) were and severity of HSVO was reduced in successive under 30 years old, and 12 (40%) were atopic. attacks. 13 Recurrent ulcers were common, and were The prognosis for patients with HSVO is followed by the development of stromal keratitis. generally considered to be poor. "The disease is These patients also had a high likelihood of especially serious in children because of the developing progressive corneal inflammation likelihood of multiple recurrences and progres­ and opacification.15 HSV keratouveitis can lead sive ocular damage throughout life". 19 However, to raised intraocular pressure (lOP) and studies at the Institute of Ophthalmology show glaucoma. Raised lOP was observed in 50 out of that the prognosis for the vision of a patient 183 patients (28 %) with HSV keratouveitis, and presenting with a first attack of HSVO appears to five (3 %) developed a glaucomatous visual field be much better than predicted. Only one-third of defect. Patients with raised lOP had all patients who had a first attack of HSVO had a developed corneal ulcers or stromal keratitis repeated attack. These repeated attacks during their first attack of HSVo. They had resembled the first attack but were less severe, suffered from recurrent HSVO for a few weeks while recurrent corneal disease affected only a to 30 years before the development of raised lOP. very small proportion of patients. Further However, none of these patients had active studies of patients with HSVO are needed to see corneal ulcers when they presented with raised if these findings can be confirmed elsewhere or lOP. 17 HERPES SIMPLEX VIRUS OPHTHALMIA S61

Diagnosis Ophthalmology, human embryonic kidney cells (1) Clinical diagnosis or HEp2 cells were used. The test took 21 days, Careful history-taking and clinical examination which was much too long, and more rapid are needed to establish a correct aetiological methods of growing HSV and identifying diagnosis. The presence of moderate to severe infected cells have been developed. It was found papillae and follicles with lid vesicles or ulcers, that high speed centrifugation (15,000xg at 35°C dendritic or geographic corneal ulcers, for one hour) significantly increased the rate of disciform or diffuse stromal keratitis can all HSV isolation from clinical ocular and genital indicate HSVo. However, HSVO can present as specimens and also from laboratory isolates. conjunctivitis without lid lesions or corneal Centrifugation did not affect the time taken for ulcers, and in such cases, a correct aetiological the appearance of cytopathic effect. This diagnosis can only be made from the results of suggests that centrifugation does not affect laboratory tests. In a study of patients with acute growth of HSV agent in cells, but it increases the conjunctivitis at Moorfields Eye Hospital, four efficiency with which cells are infected.22 out of 140 patients (3 %) had HSVO without Centrifugation can be combined with an typical lesions.8 A correct aetiological diagnosis immunofluorescent method of staining infected is essential for the provision of effective treat­ cells after 48 hours of incubation. This rapid ment of HSVO; an incorrect diagnosis may be method detected 21 % more infected specimens followed by treatment which is ineffective or than the conventional method.23 which exacerbates the disease and leads to sight­ threatening complications. Serological diagnosis A presumptive diagnosis of HSVO can be made (2) Laboratory diagnosis by detecting specific antibodies in blood or tears. "The specific viral nature of the cutaneous The universally accepted criteria for serological vesicles or ulcers is readily proved by the diagnosis are seroconversion or a four-fold or examination of scrapings, in which multinucleate greater rise in serum titre. However, two samples viral giant cells and others with acidophil of serum, collected during acute and convales­ intranuclear inclusions are found".2 cent stages at least two weeks apart, are The modern laboratory does not rely solely on required. This limits the usefulness of material from vesicles or ulcers, and nowadays, serological tests in diagnosing HSVo. Tests on a conjunctival scrapings and swabbings, tears and single specimen can be useful. It is generally blood are all used. Current laboratory methods accepted that IgM is the first antibody produced for the diagnosis of HSVO can be divided into during an immune response, and hence its three types: direct detection tests, culture tests presence is an indicator of active or very recent and serological tests. Modern tests are highly infection. High levels of IgG antibodies in blood specific and sensitive, but they all depend on the and the presence of antibodies in tears may ability of the clinician to take adequate speci­ suggest current or recent infection. Serological mens at the appropriate stage of the disease. tests for HSVO must also distinguish between antibodies to HSV-I which is associated with Direct detection tests HSVO and skin infections, and HSV-2 which is Tests for the direct detection of HSV have been associated with genital infections. developed using immunofluorescent staining Serological diagnosis of HSVO presents methods to detect infected cells. The use of these problems because many people have antibodies tests to diagnose HSVO using conjunctival and against HSV-l in their blood but no history of corneal specimens has begun, and they appear to infection with HSV. The prevalence of anti­ compare well with conventional culture tests.21 bodies to HSV varies widely and reflects standards of living. In the mid 1960s, it was Culture tests observed that 33 % of British-born clinical HSV can infect many cell types, and a conven­ students at Oxford had antibodies compared with tional method of growing HSV is to inoculate 62 % of students born in third-world countries.24 cells and look for the development of typical The prevalence of HSV antibodies is lower in cytopathic effect. At the Institute of people born after 1945 than in older people, S62 MARJORJE A. MONNICKENDAM which indicates that HSV infection is becoming and is then known as secretory IgA. It is found less common. Serological diagnosis of HSVO in discharges, but is not present in blood. based on seroconversion, four-fold rise in titre Secretory IgA antibodies against HSV in tears or the presence of IgM or high levels of IgG is may be a better indicator of HSVO than other therefore becoming far more useful. antibodies in tears because they are locally The CF test is the conventional test for the produced. Studies carried out in other serological diagnosis of HSV infection. laboratories have indicated that the presence in However, this test has several limitations. Blood tears of secretory IgA antibodies against HSV must be collected by venepuncture and serum may be helpful in diagnosing HSVo. A collected from the clotted blood, so the CF test comparison of antibodies in tears from patients is not rapid or convenient to perform. The with HSVO, patients with inflamed eyes due to volume of tears which can be collected is too other causes and controls with normal eyes was small for this test. A micro-IF test, using small carried out using radioimmunoassay. Significant volumes of blood or tears collected on cellulose amounts of secretory IgA antibodies against sponges and naked viral particles as antigen was HSV were found in tears from patients with therefore developed.25 This test was used to HSVO but not from other patients and controls study antibodies in sera from 68 patients with and were therefore good indicators of HSVo. In HSVO from whom HSV had been isolated. IgM contrast, IgG antibodies were found in tears antibodies against HSV-1 were found in sera from patients with HSVO and from other from 27 patients (40 %), and IgG antibodies were patients with inflamed eyes. IgG antibodies in found in sera from 63 patients (93 %). In tears indicate ocular inflammation and are contrast, no patients had IgM antibodies against therefore poor indicators of HSVo. 28 A recent HSV-2, and only 10 patients (15 %) had IgG anti­ study of HSVO using an enzyme immunoassay bodies against HSV-2, which were present at to measure HSV antibody levels produced much lower levels than IgG antibodies against similar results. The presence of secretory IgA HSV-1. Serological studies of patients with was found to be a good indicator of HSVO since typical dendritic corneal ulceration showed that it was present in 20 of 53 HSV patients (38 %), six out of 28 patients (21 %) seroconverted.26 but it was not found in control patients with These patients were therefore presumably inflamed eyes due to other causes. IgA and IgG experiencing their first exposure to HSV-1, and were present in tears from both groups of these findings support the observation that patients. They were present at lower levels in corneal ulcers can develop during a first attack tears than in sera. It was therefore concluded that of HSVo. IgA and IgG antibodies against HSV in tears HSV may cause acute retinal necrosis, and came from the blood and were transudated into serological studies support this hypothesis. tears in inflamed eyes. They were therefore not Three patients with acute retinal necrosis had reliable indicators of HSVo.29 Clearly, our IgG antibodies to HSV-1 in their intraocular present serological methods of diagnosing fluids, and two had IgG antibodies to HSV-1 in HSVO have their limitations and there is a need their sera. In contrast, antibodies were detected for tests which are more specific. in the intraocular fluids of only two out of 120 (2 %) control patients undergoing routine Treatment intraocular surgery, although 25 had antibodies "Herpes is an infectious disease caused by a in sera.27 While these observations do not prove virus against which we have no effective drug".2 that HSV-1 causes acute retinal necrosis, they Thirty years ago, there were no antiviral drugs. suggest that it may be involved. The presence of So what could the ophthalmologist do? Accord­ antibodies in intraocular fluids may be due to ing to Barrie Jones, there were six "potent local antibody production, sequestration of anti­ weapons" for treating HSVO, viz: bodies in the eye, or leakage from the blood. 1. debridement and disinfection of epithelial Similarly, antibodies against HSV-1 in the tears lesions; may be locally produced, or they may leak into 2. masterly inactivity; the tears from the blood. IgA acquires secretory 3. antibiotic therapy to reduce the danger of pieces during its passage through epithelial cells intercurrent bacterial or fungal infection; HERPES SIMPLEX VIRUS OPHTHALMIA S63

Table II Comparative clinical trials of antiviral agents and methods of tissue removal for the treatment ofHSVO

Treatment Form ofHSVO Reference

Iodoxuridine vs placebo Dendritic ulcer 30 Iodoxuridine vs cauterisation Dendritic ulcer, dendritic ulcer with stromal 38 keratitis, steroid-enhanced dendritic ulceration Cryotherapy vs carbolisation with Dendritic ulcer, steroid-enhanced ulcer 39 iodoxuridine vs placebo Trifluorothymidine vs iodoxuridine Dendritic ulcer, geographic ulcer 31 Trifluorothymidine with or without Dendritic ulcer, geographic ulcer 32 hydroxy propyl methyl cellulose Debridement with interferon vs placebo Dendritic ulcer 37 Trifluorothymidine vs adenine arabinoside Geographic ulcer 33 Acyclovir vs iodoxuridine Dendritic ulcer, geographic ulcer 34 Acyclovir vs adenine arabinoside Dendritic ulcer 36 Acyclovir and debridement vs acyclovir Dendritic ulcer 35

4, lamellar grafting to limit the extent and clinical trial of IDU conducted at the Institute of duration of stromal disease; Ophthalmology were published in 1963.30 In the 5. steroid therapy to minimise or abolish the past 25 years, comparative clinical trials of stromal reaction; several other antiviral drugs and mechanical 6. tarsorraphy to help indolent nonviral ulcers methods for removing infected tissue have been to heal. carried out (Table II). There are two questions Atropine, heat, dark glasses, bandages, tonics which these comparative clinical trials have and general supportive measures were also sought to answer; first, is the treatment effective considered to be important. In addition "the against various forms of HSVO and secondly, problem of preventing recurrences is by no does the treatment affect the rate of recurrence of means hopeless. To a recurrent herpetic patient HSVO? it is worth the time and trouble it takes to track In the first trial of IDU, several groups of down the individual trigger factor; to use aspirin patients with dendritic ulceration and, at most, in full doses for any febrile upset; to avoid minimal stromal keratitis, were treated in a excessive sun and use dark glasses; to have double-blind fashion. It was concluded that sedation for emotional upsets; or in troublesome "IDU was a highly effective therapeutic agent in cases to have a preventive lamellar keratoplasty. the treatment of simple dendritic ulceration . . . Above all it is important to explain the disease as maximal benefit was attained with five days' a whole to the sufferer and to his family, who, intensive treatment in conjunction with pad and together with the surgeon, become a team whose heat. With these measures a beneficial aim it is to prevent stromal and other therapeutic response was noted in 86 % of ulcers complications".2 whilst complete resolution was attained in 76 % Current methods of treatment of HSVO have of the cases".30 Other antiviral drugs which have two aims: firstly to reduce viral replication and been used in clinical trials are trifluorothymidine shedding of viral particles, and secondly to (F3T),31,32 adenine arabinoside (AA),33 and reduce tissue damage. Antiviral agents and acyclovir.34,35.36 The antiviral agent interferon mechanical removal of infective tissue reduce has also been testedY The first antiviral drugs viral replication and shedding of viral particles, had very limited solubility in water, making it and they are used to treat follicular unlikely that therapeutic levels could be attained conjunctivitis, keratoconjunctivitis and corneal in the deeper corneal tissues. In addition, they ulcers. Anti-inflammatory drugs prevent tissue evoked toxic or hypersensitivity responses in damage, and are used to treat stromal keratitis some patients, while other patients had ulcers and uveitis. which appeared to be resistant to treatment. At The first antiviral drug used to treat HSVO present, topical acyclovir is the treatment of was idoxuridine (lDU). The results of the first choice. S64 MARJORJE A. MONNICKENDAM

Methods of removing infected tissue include herpetic corneal ulcer before entering the trial cauterisation,38 cryotherapy and carbolisation,39 suffered from recurrence regardless of which proflavine photoinactivation,40 and mechanical treatment they received. There were early debridement. 41,35,37 It has been found that all indications that the rate of recurrence was lower these methods of treatment are useful and they in patients experiencing their first herpetic are usually followed by treatment with antiviral corneal ulcer who were treated with F3T agents. In a review of the advantages and compared with those treated with IDo. disadvantages of various methods for removing However, when the patients were at a later stage, infected tissue, it was concluded that mechanical it was found that the rate of recurrence within 12 debridement with a cotton-tipped applicator was months was 23 % in the group treated with IDU the most effective and safest, since diseased and 24 % in the group treated with F3T.43 epithelial cells brushed off very easily, leaving A five-year follow-up of patients with the normal cells behind.41 dendritic or geographical corneal ulcers who had The second aim of treatment is to prevent been treated with AA, F3T or mechanical recurrent HSVo. However, it soon became wiping debridement14 revealed that 32 out of apparent that antiviral measures had little effect 152 patients (21 %) developed recurrent ulcers on the rate of recurrent disease. Recurrent within six months and that 61 (40 %) had disease was observed within the first year in recurrent ulcers within five years. Recurrences patients who were treated with IDU or placebo were more common in patients whose ulcers drops in the first trial. 30 It was reported that five healed slowly than in those whose ulcers had years after this trial, the mean interval between healed quickly, and were more common in men attacks of HSVO in the group of patients whose than in women. Recurrent ulcers developed in 39 dendritic ulcers were cured with IDU was 3.6 out of 73 patients (53 %) who had a previous years. The mean interval was 3.1 years in the episode of herpetic ulceration before the trial group whose dendritic ulcers failed to respond to compared with 22 out of 79 patients (28 %) who placebo drops and who required cauterisation. did not have a previous episode.14 In a There was no significant difference in the mean comparative clinical trial of acyclovir and AA for interval between the two groupS.38 More the treatment of dendritic ulcers, patients in both detailed analysis of these patients was later groups developed recurrent ulcers and disciform carried out.42 There was no difference in the keratitis. In the group treated with acyclovir, rates of recurrent corneal ulceration and eight out of 28 patients (29 %) and in the group subsequent stromal disease in the two groups. treated with AA, nine out of 29 patients (31 %) They were 56 % and 26 % respectively in the were affected. 36 group treated with IDU, and 66 % and 24 % These results are disappointing to the clinician respectively in the group treated with placebo. treating patients with HSVO, because they show However, the rate of recurrence was much higher that at present there is no way of preventing in patients who had a previous episode of HSVO recurrent HSVo. However, the observation that before the trial compared with those who had not the rate of recurrence of corneal ulceration is experienced a previous episode (83 % and 43 % higher in people with a previous episode than in respectively). Patients with a previous episode those without a previous episode is interesting. It were also more likely to develop stromal disease suggests that the rate of recurrence depends on compared with those without a previous episode the strain of virus and/or on host responses (35 % and 17 % respectively). Comparison of the which can control recurrence. These are patients who took part in the trial of IDU and interesting avenues which require further cauterisation showed that the rate of recurrence exploration. of HSVO was the same in both groupS.42 Anti-inflammatory drugs are used in the treat­ A review of the patients who took part in the ment of HSVO, and the effects depend on the comparative clinical trial of F3T and IDU32 form of HSVo. Steroids are beneficial in treating showed that there was no significant difference stromal keratitis and uveitis, but have a in the rate of recurrence or the development of deleterious effect on those forms of HSVO which stromal keratitis in the two groups of patients. respond well to antiviral measures. Barrie Jones All the patients who had a previous history of reported the beneficial effects of cortisone on HERPES SIMPLEX VIRUS OPHTHALMIA S65 stromal disease.44 However, it was later with thinning and threatened perforation while observed that concomitant treatment with the other had a geographic ulcer and uveitis.46 antiviral drugs was needed to prevent recurrence There are indications that acyclovir treatment of corneal ulceration.3 8 When patients with may reduce the need for steroid therapy. In a stromal disease were entered in a double-blind comparative clinical trial of acyclovir and AA,36 trial of steroid drops with IDU or placebo, it was steroids were not required to treat any of the 15 observed that 10 out of 24 patients (42 %) treated patients with stromal infiltration who were with steroid and placebo developed dendritic treated with acyclovir, whereas four out of the 20 ulceration, compared with four out of 26 patients patients with stromal infiltration who were (1 5 %) treated with steroid and IDD.38 The treated with AA required steroids. These obser­ deleterious effects of steroid treatment on the vations may reflect the ability of acyclovir to forms of HSVO which respond well to antiviral reach the deeper layers of the cornea and prevent treatment have been reported in several clinical HSV replication. The rate of HSV isolation from trials. In one trial, the size of the dendritic corneal buttons of patients with quiescent HSVO lesions were measured before treatment undergoing keratoplasty was much lower in commenced. They were significantly larger in patients treated with acyclovir than in patients patients who had been treated with topical treated with other antiviral drugs.3 IDU, F3 T steroids by the referring practitioner compared and AA. with patients who had not received topical Corneal grafting can restore sight to the steroids. Extensive geographic ulcers were found patient who has major visual impairment due to in 22 out of 24 patients (92 %) who had been corneal opacification resulting from HSVO. In a treated with topical steroids compared with three review of corneal grafting in patients with severe out of 77 patients (4 %) who had not been treated HSV043, 132 grafts were performed on 91 with topical steroids. It was observed that patients. The two-year survival rate was 64 % treatment with IDU ointment was significantly and the five-year survival rate was 62 %. Graft better than cauterisation in patients who had rejection was related to the degree of vasculari­ previously been treated with steroids and that zation in the recipient's own cornea. The these patients also had a high incidence of severe rejection rate was 54 % in recipients whose own complications. 38 corneas were fully vascularized, and 16 % in In the comparative clinical trial of F3 T and recipients whose own corneas were avascular. IDU, all eight patients who had received steroids HSVO recurred in 32 % of patients who had before antiviral treatment suffered from received high doses of steroids for graft recurrent corneal ulcers. Four out of eight rejection, but only in 6 % of patients who had not patients (50 %) developed significant stromal rejected their grafts and had not received high disease compared with five out of 27 patients doses of steroids. (1 9 %) who had not initially received steroids.3 2 Although there have been major advances in Problems resulting from the use of steroid the treatment of HSVO in the past 30 years, it is drops to treat HSVO continue. A total of 130 clear that there is still a need for substantial patients with HSV corneal ulcers who had improvements in treatment to prevent recurrent received topical steroids before referral were disease and to limit the damage which can follow seen at Moorfields Eye Hospital in the lO-year the development of HSVo. These improvements period between 1967 and 1976. These patients may come from a better understanding of the tended to present later, have larger dendritic immunopathogenesis of HSVO, including, for ulcers, and were more likely to have geographic example, the roles of glycoproteins in different ulcers. Their ulcers took longer to heal, and forms of HSVo. recurrent disease and visual impairment were more common.45 More recently, it was reported Host responses that 54 out of 1800 patients (3 %) presenting in The observation that steroid treatment has a one month at the Casualty Department at Moor­ deleterious effect on some forms of HSVO and a fields Eye Hospital had received steroid eye beneficial effect on others indicates that host drops from their general practitioners. Two of responses have two major roles in HSVo. these had HSVO; one had a geographic ulcer Steroids have a deleterious effect on forms of S66 MARJORIE A. MONNICKENDAM

Table III ExperimentalHSVO in the rabbit eye Animal Models HSV is not highly host specific. It infects the Treatment Reference eyes of several species of laboratory animals and Amphotericin B methyl ester with 50 the rabbit has commonly been used because it iodoxuridine has large eyes. The rabbit cornea can be Interferon 51 trephined and infected in a reproducible manner Adenine arabinoside and analogues 52 at several sites using capillary tubes which have Acyclovir vs trifluorothymidine, 53 been dipped into preparations containing HSV, adenine arabinoside and analogues so that a small number of rabbit eyes can be used Acyclovir vs idoxuridine 54 to assay the effects of antiviral measures or Idoxuridine and adenine arabinoside 55 in non-immune and previously immunisation on the infectivity of HSV. This infected animals technique was first used to study the effects of Previous skin or eye infection 57 topically-applied anti-vaccinia virus serum on Previous skin infection and/or 58 vaccinia virus infection of the rabbit eye.49 It topical steroids has since been used to study the effects of Hyperimmune gammaglobulin 60 antiviral and anti-inflammatory drugs on, and Vaccination 59 immune responses to HSV infection of the rabbit eye (Table III). It was found that all the antiviral HSVO which respond to antiviral treatment, and drugs tested were active against HSV in the this suggests that they are important in control­ rabbit cornea. Amphotericin B methyl ester ling replication of HSV. On the other hand, (AME) inhibited the development of HSV steroids have a beneficial effect on herpetic ulcers, and when AME and IDU were used stromal disease and uveitis, suggesting that host together, their effects were additive, showing responses are involved in tissue damage. that they inhibited HSV replication in different Systemic host responses have been studied ways. However, AME had no effect on because this is easier than looking at responses established corneal ulcers. 50 Human interferon in the infected eye. Studies of systemic immune also inhibited the development of corneal responses in HSVO have shown that there are no lesions, and the degree of inhibition depended on major differences between patients with different the concentration of interferon in the first forms of HSVo. 48 Levels of CF antibodies were treatment given one hour after inoculation. 51 similar in patients with dendritic ulcers or active The effects of AA and various analogues were stromal disease, atopic patients with HSVO and also investigated. 52 Acyclovir was also tested controls. Cell-mediated immune responses to and found to be more effective than F3T, AA or HSV were assessed using lymphocyte transfor­ its analogues,53 and as effective as ID U. 54 mation and macrophage migration inhibition. It was observed that antiviral drugs were less There were no major differences in lymphocyte effective in previously infected animals than in transformation between serologically-positive non-immune animals.55,56 The effects of controls and the three groups of patients with previous HSV infection were analysed in more HSVO when purified lymphocytes were used, detail, and it was found that animals with although responses were markedly lower in previous infection of the skin or contralateral eye patients with stromal disease when a whole­ were equally resistant to ocular infection, and blood technique was used. Significant amounts that previously infected eyes were more of macrophage migration inhibiting factor were resistantY Steroid treatment produced a far produced by peripheral blood lymphocytes from larger exacerbation of corneal ulceration in all nine patients with stromal disease, six out of previously infected animals, compared with nine patients with dendritic ulcers and fiveout of animals infected for the first time, 58 supporting 12 controls. The amounts produced were highly the hypothesis that host responses play an variable.48 However, nothing is known about the important role in limiting the development of function of lymphocytes in the eyes of patients HSVo. Topical treatment with human hyper­ with HSVO, and it could be misleading to immune gamma globulin was very effective in extrapolate results of systemic responses in vitro the early stages of infection, but had little effect to local responses in vivo. on established disease, or on disease in pre- HERPES SIMPLEX VIRUS OPHTHALMIA S67 viously infected animals with or without steroid I would like to thank Professor Darougar and Dr. Ralph treatment. 59 It was found that vaccination with Woodland for their critical reading of this paper. I am also an inactivated subunit vaccine induced resistance grateful to the editor of "Eye" for marking the 40th Anniversary of the Institute of Ophthalmology, because to corneal infection and reduced the extent of this has given me the opportunity to read the many papers 60 corneal ulceration. of HSVO which have been written by colleagues and It has generally been assumed that there is friends in the past 30 years. very little difference in the pathogenicity of References different strains of HSV-I for the eye. However, I Jones BR, Andrews BE, Henderson WG, Schofield recent studies using guinea-pigs and rabbits have PB. The pattern of conjunctivitis at Moorfields shown that strains isolated from patients' with during 1956. Trans Ophthalmol Soc UK, 1957, conjunctivitis produced conjunctivitis, while 77: 291-302. strains isolated from patients with corneal ulcers 2 Jones B. The management of ocular herpes. Trans produced corneal ulcers. 61 Clearly, this is an Ophthalmol Soc UK, 1959, 79: 425-37. area which requires further research, which can 3 Easty DL, Shimeld C, Claoue CMP, Menage M. only be carried out in animals. Herpes simplex virus isolation in chronic stromal keratitis: human and laboratory studies. Cur Eye Res, 1987, 6: 69-74. 4 Tullo AB, Coupes D, Klapper P, Cleator G, Chitkara D. Analysis of glycoproteins expressed The Future? by isolates of herpes simplex virus causing In most people, the relationship between HSV diffe rent fo rms of keratitis in man. Cur Eye Res, and its human host is amicable and, as in all the 1987, 6: 33-8. best fairy-tales, "they lived happily ever after". 5 Darougar S, Wishart MS, Viswalingam ND. The problem is how to make this come true for Epidemiological and clinical fe atures of primary everyone infected with HSV-l. As this review has herpes simplex virus ocular infection. Br J 1985, 2-6. demonstrated, we understand far more about Ophthalmol, 69: 6 HSVO and methods of treatment have changed Kaufman HE, Brown DC, Ellison EM . Recurrent herpes in the rabbit and man. Science. 1967, 156: almost beyond recognition in the past 30 years. 1628-9. However, HSV-I can still cause damage to the 7 Shimeld C, Dyson H, Lewkowicz-Moss S, Hill TJ, eye. Antiviral treatment limits infection, but it Blyth WA , Easty DL. Spread of HSV-I to the does not prevent recurrent disease, and we do mouse eye after inoculation in the skin of the not know how HSV-I infection is transmitted. A snout requires an intact nerve supply to the sub-unit vaccine has produced promising results inoculation site. Cur Eye Res, 1987, 6: 9-12. in experimental infection HSVO in the rabbit.58 8 Wishart PK, James C, Wishart MS, Darougar S. Could this vaccine be used to prevent HSVO in Prevalence of acute conjunctivitis caused by humans? A prospective trial would involve the chlamydia, adenovirus, and herpes simplex virus vaccination of a large number of people, very in an ophthalmic casualty unit. Br J Ophthalmol, 1984, 68: 653-5. few of whom would be at risk of developing 9 Darougar S, Woodland RM , Walpita P. Value and HSVO and. might therefore be considered cost effectiveness of double culture tests fo r impractical. Alternatively a live vaccine could diagnosis of ocular viral and chlamydial infec­ be developed using a non-disease-producing tions. Br J OphthalmoJ, 1987, 71: 673-5. strain, provided it is possible to distinguish 10 Reacher M, Darougar S, Wishart M, Forsey T, between disease-producing and non-disease­ Eakin S and Falcon M. Chlamydia, adenovirus, producing strains, and if there is cross­ herpes simplex virus and bacteria as causes of protection between the two. But here again, the conjunctivitis in patients attending an eye clinic. number of people required for a prospective trial (paper in preparation). II would be very large and such a vaccine would Foster A and Sommer A. Corneal ulceration, measles, and childhood blindness in Tan zania. Br not help patients who already have HSVo. The J Ophthalmol. 1987, 71: 331-43. story therefore remains incomplete, the happy 12 Sandford-Smith JH and Whittle HC: Corneal ending remains elusive and there is still plenty of ulceration fo llowing measles III Nigerian scope for the ophthalmologist, virologist, children. Br J Ophthalmol, 1979, 63: 720-4. immunologist and biochemist to collaborate in 13 Wishart MS, Darougar S, Viswalingam ND. finding the solution. Recurrent herpes simplex virus ocular infection: S68 MARJORJE A. MONNICKENDAM

epidemiological and clinical fe atures. Br J herpes simplex virus in lacrimal fluid from Ophthalmol. 1987, 71: 669-72. patients with herpes keratitis - a possible 14 Wilhelmus KR. Coster DJ, Donovan HC. Falcon diagnostic parameter. Br J Ophthalmol. 1982, 66 : MG, Jones BR. Prognostic indicators of herpetic 648-53. keratitis. Analysis of a five-year observation 29 Fox PD, Khaw PT, McBride BW, McGill 11, Wa rd period after corneal ulceration. Arch KA. Tear and serum antibody levels in ocular Ophthalmol. 1981, 99: 1578-82. herpetic infection: diagnostic precision of 15 Wilhelmus KR, Falcon MG, Jones BR. Bilateral secretory IgA . Br J Ophthalmol. 1986, 70: 584-8. 1981, herpetic keratitis. Br J Ophthalmol. 65: 30 Patterson A, Fox AD, Davies G, Maguire C, et aI . 385-7. Controlled studies of IDU in the treatment of 16 Darougar S, Hunter PA , Viswalingam M, Gibson herpetic keratitis. Trans Ophthalmol Soc UK. JA , Jones BR. Acute fo llicular conjunctivitis and 1963, 83: 583-91. keratoconjunctivitis due to herpes simplex virus 31 We llings PC, Awdry PN, Bors FH, Jones BR, et al. 1978, 843-9. in London. Br J Ophthalmol. 62: Clinical evaluation of trifluorothymidine in the 17 Falcon MG and Williams HP. Herpes simplex treatment of herpes simplex corneal ulcers. Am J kerato-uveitis and glaucoma. Trans. Ophthalmol Ophthalmol. 1972, 73: 932-42. Soc UK, 1978, 98: 101-4. 32 McGill J, Holt-Wilson AD, McKinnon JR, 18 Falcon MG, Jones BR, Williams HP, Coster DJ. Williams HP, Jones BR. Some aspects of the Management of herpetic eye disease. Trans clinical use of trifluorothymidine in the treatment Ophthalmol Soc UK. 1977. 97: 345-9. of herpetic ulceration of the cornea. Trans 19 Notkins AL, Bankowski RA, Baron S, Graykowski Ophthalmol Soc UK. 1974, 94: 342-52. EA, et al . Wo rkshop on the treatment and 33 Coster DJ, Jones BR, McGill 11. Treatment of prevention of herpes simplex virus infections. J amoeboid herpetic ulcers with adenine Infect Dis, 1973, 127: 117-9. arabinoside or trifluorothymidine. Br J 20 Darougar S, Monnickendam MA, Wo odland RM . Ophthalmol. 1979, 63: 418-21. Management and prevention of ocular viral and 34 Coster DJ, Wilhelmus KR, Michaud R, Jones BR. chlamydial infection. CRC Critical Reviews in A comparison of acyclovir and idoxuridine as Microbiology. (in press). treatment fo r ulcerative herpetic keratitis. Br J 21 Schwab IR, Raju VK, McClung J. Indirect Ophthalmol. 1980, 64: 763-5. immunofluorescent antibody diagnosis of herpes 35 Wilhelmus KR, Coster DJ, Jones BR. Acyclovir simplex with upper tarsal and corneal scrapings. and debridement in the treatment of ulcerative Ophthalmology. 1986, 93: 752-6. herpetic keratitis. Am J Ophthalmol. 1981, 91: 22 Darougar S, Gibson JA , Thaker U. Effect of 323-7.

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