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Year : 1999  |  Volume : 47  |  Issue : 1  |  Page : 11-14

Clinical pattern of recurrent herpes simplex keratitis

Department of Ophthalmology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Jagjit S Saini
Cornea and External Diseases Section, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

PMID: 16130278

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Purpose: To document the clinical pattern in recurrent herpes simplex disease.
Methods: Eyes with clinically documented pattern of corneal manifestation on more than one occasion were analysed. For each eye recruited, the clinical pattern of the disease at each recurrence of herpes simplex corneal disease, age, disease-free intervals, triggering factors, laterality and steroid abuse were noted and evaluated.
Results: For an average follow up of 6.9 years, a recurrence rate of 0.6 episodes per year was observed. Disease-free intervals of 75.7 months for epithelial herpes simplex disease was considerably longer than the 21.3 months observed for stromal disease. Clinical pattern of recurrence was of the same type following first episode of disciform keratitis, epithelial keratitis and endothelitis in 84%, 72.7%, and 75% of the eyes respectively.
Conclusion: Herpes simplex disease often recurs in the same manifest clinical pattern as the first episode. This clinical evidence provides additional support for the potential role of herpes simplex biotypes in determining manifestation of clinical disease pattern.

Keywords: Ocular herpes simplex, keratitis, recurrent pattern

How to cite this article:
Saini JS, Agarwala R. Clinical pattern of recurrent herpes simplex keratitis. Indian J Ophthalmol 1999;47:11-4

How to cite this URL:
Saini JS, Agarwala R. Clinical pattern of recurrent herpes simplex keratitis. Indian J Ophthalmol [serial online] 1999 [cited 2023 Sep 25];47:11-4. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?1999/47/1/11/22905

Recurrent corneal infection by the herpes simplex virus (HSV) is a common cause of blindness in otherwise healthy individuals.[1][2][3] Various manifestations of this disease range from benign blepharitis, conjunctivitis, and epithelial keratitis to vision-threatening stromal disease and uveitis. Following primary infection with HSV, the virus is demonstrable in its latent form in the sensory nerve ganglion. Reactivation of this virus in the trigeminal ganglion and its neuronal spread into the cornea has been widely accepted as the mechanism for recurrent ocular herpetic infections.[4]

Studies in animal models have shown three factors that contribute to the severity of an ocular HSV infection. These are: genetic make up of the host, the host immune system, and the virulence of the infecting strain of HSV.[5] While it is not known clearly why some eyes demonstrate only epithelial involvement when others show stromal disease, it is speculated that different strains of HSV account for the varied disease pattern.[6] Certain HSV type I strains are shown to consistently cause severe epithelial disease, stromal involvement and iritis.[7][8][9] On the other hand, other strains of HSV type I either do not produce stromal disease (CGA3 strain) or cause only mild involvement (F strain). [9,10]

Conceivably this strain-specific HSV disease pattern as seen in animal models could probably also be true for human eyes. This study analyses recurrences of epithelial and disciform HSV keratitis to provide data on the possible pattern of the HSV ocular disease in recurrences.

  Materials and Methods Top

Data of 40 patients from the cornea and external disease service with a diagnosis of documented recurrent herpes simplex infection were analysed retrospectively. Only those patients with more than one recurrence after the initial presentation with us were included in this study. The mean follow up was 6.9 years (range 1-22 years).

A definite diagnosis of epithelial keratitis was made when dendritic (seen as branching linear epithelial ulcer) or geographic ulcer (seen as a broad area of epithelial involvement with irregular angulated borders) was seen.[3] Disciform keratitis was diagnosed in presence of central corneal stromal edema with or without keratic precipitates beneath the lesion. Stromal keratitis was diagnosed when deep layers of corneal stroma were diffusely infiltrated and in absence of other causes of keratitis, previous dendritic keratitis or loss of corneal sensation. Presence of mild stromal edema, medium-sized keratic precipitates, aqueous flare and cells, was clinically diagnosed as endothelitis. Keratouveitis was diagnosed when there was manifest significant corneal edema with or without vascularisation and marked signs of anterior uveitis. As it was difficult to clinically differentiate mild keratouveitis from endothelitis, for the purpose of analysis of pattern of recurrences, endothelitis cases were clubbed with keratouveitis cases. Diagnosis of neurotrophic ulcer was made when a persistent central epithelial defect with gray thickened border was observed following a previous diagnosis of HSV corneal disease.[3] The number of eyes diagnosed with stromal keratitis at initial presentation in our clinic was too small for statistical analysis; these were not included in the analysis.

The data collected for all patients in the study, at each occurence of the disease was age, sex, duration of disease-free interval, clinical type of HSV corneal disease, triggering factors (such as fever, ocular surgical or non-surgical trauma, psychological stress, menstruation, exanthematous skin eruptions), laterality, and steroid exposure.

The uniform treatment policy for HSV corneal disease was: epithelial disease treated with topical 3% Acyclovir ointment and cycloplegics; disciform keratitis treated with 3% Acyclovir ointment, dexamethasone drops (when epithelium was intact), and 1% cyclopentolate/atropine eye drops.

Endothelitis was treated with topical Acyclovir ointment and corticosteroid drops. For secondary glaucoma, Timolol eye drops 0.5% were added. Only one case of steroid-dependent chronic disciform keratitis was treated effectively with oral Acyclovir. The life table method was used to access the cumulative incidence of recurrences.

  Results Top

Data of 40 patients (32 males and 8 females) with an average age of 43.9 years (range 11-72 years) were retrieved from our records. Age distribution is shown in [Figure - 1]; 52.5% of the patients belonged to age group 31-50 years. Onset of the disease was spontaneous in 62.5% and a trigger for recurrence was known in 37.5%. Major precipitating factors were: history of minor ocular trauma in 20%; fever in 15%; and exanthematous skin eruptions in 2.5% cases. Bilateral herpetic keratitis was seen in 15% of patients. The average age of the bilateral cases was 40 years. None of the cases showed simultaneous onset. The clinical manifestations were similar in all those with bilateral disease.

Disciform keratitis was seen in 25 eyes (62.5%) of our patients and epithelial disease in 11 eyes (27.5%) [Figure - 2] at initial presentation. Clinically it was difficult to differentiate endothelitis from mild keratouveitis. Hence these two entities were considered together, totalling 4 eyes (10%). Of the 25 cases of disciform edema 21 cases (84%) recurred as disciform edema only. One case (4%) recurred as purely dendritic ulcer and one case (4%) demonstrated geographical ulcer along with stromal edema. Two cases (8%) with history of self-administration of steroids presented as neurotrophic ulcers [Figure - 3].

Of those with epithelial disease, the recurrence was in the form of epithelial disease every time in 8 eyes (72.7%); 3 eyes (27.3%) demonstrated stromal disease [Figure - 4]. Of the 4 cases of endothelitis, 3 were seen to recur purely as endothelitis. The fourth case demonstrated purely an epithelial pattern while on topical steroid therapy.

Eyes recruited in this study demonstrated 2-7 recurrences during the follow-up period. Eleven eyes recorded more than 2 recurrences. Overall a recurrence rate of 0.6 per patient per year was seen in our patients. Patients with recurring disciform keratitis were seen to have an average time interval of 21.3 months between attacks. Epithelial recurrences were found to have a longer disease-free interval of 75.7 months between episodes. This time difference in disease-free intervals was seen to be statistically significant (p<0.005). Recurrence rates were not significantly different in males and females.

The likelihood of a recurrence of ocular herpetic infection is shown in [Figure - 5]. At one year after the initial episode there is a 37.5% incidence of a recurrence and at 2 years, it is 50%. By 10 years the cumulative incidence of recurrence is 95%. Among the individuals with a first episode of recurrence the cumulative incidence for a second was 36.6% by 1 year, 63.6% by 2 years and 100% by 5 years. The recurrence rate is seen to rise with the number of episodes. The trend was towards shorter intervals between episodes with an increasing number of recurrences.

  Discussion Top

Herpes simplex virus infection of the eye is an important cause of corneal blindness.[1][2][3] It is the recurrence of the disease which results in ocular morbidity because of HSV antigen retention, recruitment of immune cells into a normally avascular structure, and consequent anatomic and physiologic disruption of the cornea through an immune inflammatory reaction.[11] In adults, the recurrence rates of HSV are about 25% within a year and 33% within 2 years.[12] Various nonspecific factors such as trauma, fever, psychological stress and climatic changes are implicated as precipitating factors.

In our study the average age of patients was 43.9 years with 67.5% of patients in the age group of 31-60 years. This was comparable with other studies which show a higher incidence of herpetic keratitis at 40-60 years.[13] Men were found to have the disease 4 times more often than women. Epidemiological surveys have also demonstrated an increased proportion of men developing the disease.[14] Bilateral disease was seen in 15% of the cases. Other series had reported between 3% and 19%,[15][16][17] incidence of bilateral HSV corneal disease. Average age of patients developing bilateral disease was 40 years and none of them showed simultaneous involvement of the eyes. The disease was of spontaneous onset in 62.5% of the cases. A definite history of trauma could be elicited in 20% of the cases; 15% had fever as a precipitating factor.

Among the recruited cases, 25 eyes (62.5%) demonstrated disciform stromal disease, 11 eyes (27.5%) epithelial disease and 4 eyes (10%) keratouveitis or endothelitis as the main clinical feature. In epidemiological studies stromal disease accounts for only 12%, and iritis for 9%, of HSV ocular disease.[18] The inherent bias in referral hospital patients may have accounted for the higher proportion of stromal disease in this study.[19]

Our observations document that recurrences following disciform keratitis continue to manifest as disciform keratitis in a majority (84%) and only 8% demonstrate epithelial involvement in subsequent attacks. In most instances (72.7%) the epithelial disease recurred clinically as epithelial disease with the remaining 27.3% showing subsequent stromal involvement. All our cases of endothelitis recurred as endothelitis primarily with one case demonstrating epithelial disease while on topical steroid therapy. The average duration of disease-free interval between attacks was longer for epithelial recurrences (75.7 months) than stromal disease (21.3 months).

Little is conclusively known about the genesis of ocular herpes simplex virus infection and recurrences. Varied manifestations could be attributed to virulence of virus strains and altered immune response to the virus.[20] Earlier observations had documented that HSV epithelial disease tends to recur more often as epithelial disease.[13],[18] Earlier studies had also documented low recurrences of epithelial disease in eyes manifesting HSV stromal disease or iritis.[21] Recurrent HSV corneal disease pattern is also independent of the known prognostic factors[13] and the histocompatibility antigens in the host.[22] Recurrence rates in epithelial and disciform stromal HSV corneal disease are demonstrated to be distinctly different in this study. These and our observations of relative occurrence of ocular HSV clinical manifestations in recurrences lend credence to the concept that the viral strain determines the clinical pattern of the disease[23][24][25].

  References Top

Liesegang TJ. A community study of ocular herpes simplex. Cur Eye Res 1991;10:111-15.  Back to cited text no. 1
Wilhelmus KR, Gee L, Hauck WW, Kurinij N, Dawson CR, Jones DB, et al. (for the Herpetic Eye Disease Study Group). Herpetic Eye Disease Study - A controlled trial of corticosteroids for herpes simplex keratitis. Ophthalmology 1994;101:1883-96.  Back to cited text no. 2
Agarwal V, Biswas J, Madhavan HN, Mangat G, Reddy MK, Saini JS, et al. Current perspectives in infectious keratitis. Ind J Ophthalmol 1994;42:171-91.  Back to cited text no. 3
Liesegang TJ. Biology and molecular aspects of herpes simplex and varicella zoster virus infections. Ophthalmology 1992;99:781-99.  Back to cited text no. 4
Brandt CR, Grau DR. Mixed infection with Herpes Simplex Virus Type 1 generates recombinants with increased ocular and neurovirulence. Invest Ophthalmol Vis Sci 1990;31:2214-23.  Back to cited text no. 5
Centifanto-Fitzgerald YM, Fenger T, Kaufman HE. Virus proteins in herpetic keratitis. Exp Eye Res 1982;35:425-41.  Back to cited text no. 6
Irvine AR, Kimura SJ. Experimental stromal herpes simplex keratitis in rabbits. Arch Ophthalmol 1967;78:654-63.  Back to cited text no. 7
Metcalf JF, McNeill JI, Kaufman HE. Experimental disciform edema and necrotizing keratitis in the rabbit. Invest Ophthalmol 1976;15:979-85.  Back to cited text no. 8
Wander AH, Centifanto YM, Kaufman HE. Strain specificity of clinical isolates of Herpes Simplex Virus. Arch Ophthalmol 1980;98:1458-61.  Back to cited text no. 9
Sery TW, Nagy RM, Nazario R. Experimental disciform keratitis: II. Local cornea hypersensitivity to a highly virulent strain of herpes simplex. Ophthalmic Res 1972/1973;4:99-109.  Back to cited text no. 10
Klein RJ. Pathogenetic mechanisms of recurrent herpes simplex virus infection. Arch Virol 1976;51:1-3.  Back to cited text no. 11
Shuster JJ, Kaufman HE, Nesburn AB. Statistical analysis of rate of recurrence of herpes virus ocular epithelial disease. Am J Ophthalmol 1981;91:328-31.  Back to cited text no. 12
Wilhelmus KR, Coster DJ, Donovan HC, Jones BR, Falcon MG. Prognostic indicators of herpetic keratitis. Analysis of five-year observation period after corneal ulceration. Arch Ophthalmol 1981;99:1578-82.  Back to cited text no. 13
Leopold IH, Sery TW. Epidemiology of herpes simplex keratitis. Invest Ophthalmol Vis Sci 1963;2:498-503.  Back to cited text no. 14
Darougar S, Wishart MS, Viswalingam ND. Epidemiological and clinical features of primary herpes simplex virus ocular infection. Br J Ophthalmol 1985;69:2-6.  Back to cited text no. 15
Wilhelmus KR, Falcon MG, Jones BR. Bilateral herpetic keratitis. Br J Ophthalmol 1981;65:385-87.  Back to cited text no. 16
Thygeson P, Kimura SJ, Hogan MJ. Observations on herpetic keratitis and keratoconjunctivitis. Arch Ophthalmol 1956;64:375-88.  Back to cited text no. 17
Liesegang TJ. Epidemiology of ocular herpes simplex. Natural history in Rochester, Minn., 1950 through 1982. Arch Ophthalmol 1989;107:1160-65.  Back to cited text no. 18
Uchio E, Matano H, Mitsui K, Sugita M, Okada K, Goto K, et al. A retrospective study of herpes simplex keratitis over the last 30 years. Jpn J Ophthalmol 1994;38:196-201.  Back to cited text no. 19
Saini JS, Datta U, Pradhan D. Cell mediated immunity in herpes simplex keratitis in man. Acta Ophthalmologica 1990;68:519-24.  Back to cited text no. 20
Wilhelmus KR, Dawson CR, Barron BA, Bacchetti P, Gee L, Jones DB, et al, (for the Herpetic Disease Study Group). Risk factors for herpes simplex virus epithelial keratitis recurring during treatment of stromal keratitis or iridocyclitis. Br J Ophthalmol 1996;80:969-72.  Back to cited text no. 21
Meyers-Elliot RH, Elliot JH, Maxwell WA, Pettit TH, O'Day DM, Terasaki PI, et al. HLA antigens in recurrent herpes simplex virus keratitis. Am J Ophthalmol 1980;89:54-57.  Back to cited text no. 22
Buckmaster EA, Gompels U, Minson A. Characterization and physical mapping of an HSV-1 glycoprotein of approximately 115,000 molecular weight. Virology 1984;139:408-13.  Back to cited text no. 23
Norrild B. Humoral response to herpes simplex virus infections. In: Roizman B, Lopez C, editors. The Herpes-viruses. New York: Plenum Press; 1985. p 69-86.  Back to cited text no. 24
Mori Y, Inoue Y, Shimomura Y. Herpetic epithelial keratitis caused by acyclovir resistant strain. Jpn J Ophthalmol 1994;38:407-10.  Back to cited text no. 25


  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]


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