A young immunocompetent patient with bilateral immune stromal keratitis due to varicella zoster and herpes simplex Clin Exp Optom 2014

Julie M Albietz* † PhD BAppSci(Hons) GradCertOcTher Lee M Lenton* FRANZCO FRACS MBBS * Vision Eye Institute, Brisbane, Australia † Queensland University of Technology, Brisbane, Australia E-mail: [email protected]

Submitted: 3 January 2014 Revised: 26 February 2014 Accepted for publication: 6 March 2014 This report describes the diagnostic features, clinical management and the issues associated with management of a young immunocompetent man, who presented with a presumed left herpes simplex immune stromal keratitis and 10 months later, a right immune stromal keratitis associated with herpes zoster ophthalmicus.

CASE HISTORY A 35-year-old Caucasian man presented to Vision Eye Institute with a history of left epiphora, photophobia and blur. Symptoms had been present for approximately two weeks. His past ocular history was significant for a right corneal alkali-based chemical burn due to hair dye, sustained nine years previously, which had required hospitalbased intensive topical therapeutic management for one week. Following this incident, the vision in the right eye had been somewhat impaired. He had no significant general health problems. There was no previous history of herpetic corneal disease. Visual acuity (VA) was R 6/12 and L 6/9. Slitlamp examination revealed a band of right inferior vascularisation from five o’clock to nine o’clock and a clear central cornea (Figure 1). A left diffuse, vascularised, anterior stromal keratitis was evident (Figures 2A and 2B). There was no associated anterior uveitis. Both corneas


were negative for vital staining with sodium fluorescein and rose Bengal. Of clinical significance was the reduction in left central corneal sensation relative to the right eye as measured with a 0.12 mm nylon monofilament (Cochet-Bonnet aesthesiometer, Luneau Ophthalmlogie, Chartres, France): R 6 cm and L 4.5 cm (normal value 5.5 ± 0.8 cm).1 Applanation intraocular pressure (IOP) was R 10 mmHg and L 9 mmHg. There was a moderate bilateral anterior staphylococcal blepharitis. A fluidfilled vesicle was present on the left upper mucocutaneous junction of the lip. A polymerase chain reaction (PCR) swab of the left conjunctival fornix was negative for herpes viruses, adenovirus and Chlamydia. A left forniceal bacterial swab was also negative. PCR of the facial vesicle was positive for herpes simplex virus-1 (HSV-1). Left immune stromal keratitis (ISK) presumed due to HSV-1 was diagnosed and the patient was prescribed a slowly tapering course of prednisolone acetate one per cent (Prednefrin forte, Allergan, Irvine, CA, USA) commencing at two hourly and topical acyclovir three per cent ointment (Zovirax ophthamic ointment, GlaxoSmithKline, Middlesex, UK) commencing at thrice daily. Concomitant use of eyelid hygiene procedures twice daily and preservative-free artificial tears (Blink Intensive, Abbott, Abbot Park, IL, USA) four times daily was prescribed. The outdoors wearing of 100 per cent UV protection sunglasses and a hat were advised. Symptoms and signs in the left eye gradually improved over three months with VA of 6/6 achieved. The topical steroid and antiviral therapies were discontinued and the patient was advised to continue UV protective measures, lid hygiene procedures and non-preserved artificial tears. Three months following cessation of the topical steroid and antiviral, left VA was 6/6 and a mild residual anterior stromal scar with

© 2014 The Authors Clinical and Experimental Optometry © 2014 Optometrists Association Australia

diminished filling of the corneal vessels was evident. At 10 months after the initial presentation, the patient presented via referral from a general medical practitioner with presumed right herpes zoster ophthalmicus (HZO) following a three day prodromal of right-sided scalp, forehead and periocular pain followed by the eruption of a painful right-sided oedematous, vesicular rash. A PCR swab of a forehead vesicle was positive for varicella-zoster virus (VZV). The rash had started on the scalp and migrated down the forehead to the periocular area and had been present for one week (Figure 3A). Oral valacyclovir 1000 mg (Valtrex, GlaxoSmithKline, Middlesex, UK) thrice daily had been commenced approximately 48 hours after the rash appeared. VA was R 6/15 and L 6/6. A right diffuse patchy anterior immune stromal keratitis was present (Figures 3B and 3C). The left corneal appearance was unchanged (Figure 2C). There was no associated anterior uveitis. Both corneas were negative for vital staining with sodium fluorescein and rose Bengal. IOP was 14 mmHg R and L. The patient was advised to continue his seven-day course of oral valacyclovir and was commenced on prednisolone acetate one per cent four times daily in the right eye. He was advised to continue bilateral lid hygiene procedures and non-preserved artificial tears. Pregabalin (Lyria, Pfizer, New York, USA) 150 mg per day for two months was prescribed by his general practitioner for zoster-related neuropathic pain. The right stromal haze gradually resolved over the following three months and the prednisolone acetate was gradually tapered and withdrawn. VA was R 6/12 and L 6/6. Corneal aesthesiometry was R 3.0 cm L 3.5 cm. Artificial tears and lid hygiene were continued. Following discussion with the patient’s general practitioner and given the recent Clinical and Experimental Optometry 2014


Bilateral herpetic immune stromal keratitis Albietz and Lenton

Figure 1. Right inferior vascularisation due to past chemical burn. The central cornea is clear. history of bilateral herpetic corneal disease, the patient was commenced on a prophylactic 12-month course of oral valacyclovir 500 mg daily. DISCUSSION The presentation of a bilateral consecutive immune stromal keratitis without epithelial involvement due to herpes simplex in one eye and then herpes zoster ophthalmicus in the other eye in an immunocompetent 35-year-old is atypical and an extensive review of the literature revealed that a similar case has not been reported. Herpetic corneal disease typically manifests as a dendritic epithelial ulcerative keratitis in herpes simplex2 and a punctate epitheliopathy or infiltrative dendritic epithelial keratitis in herpes zoster ophthalmicus.3,4 The incidence of new and recurrent epithelial keratitis in the USA has been estimated at 15.6 per 100,000 person years, and for stromal keratitis this incidence is considerably lower at 2.6 per 100,000 person years.2 The incidence of herpes zoster keratitis is 8.8 per 100,000 person years.5 Epithelial keratitis has been reported in 51 to 60 per cent of individuals with herpes zoster ophthalmicus and stromal keratitis occurs somewhat less frequently in 40 to 54 per cent.3,4 While herpes simplex keratitis can occur at any age, herpes zoster ophthalmicus occurs more frequently in the elderly and in the immunocompromised. A recent review of confirmed cases of herpes zoster ophthalmicus determined only 13 per cent (8/134) occurred in the 25 to 44 year age group.5 Clinical and Experimental Optometry 2014


Immune stromal keratitis, also known as interstitial keratitis, is a non-ulcerative inflammatory reaction of the corneal stroma occurring as a result of a CD4+ immunemediated host response.6,7 It may present as small, white stromal opacities (as per this patient’s right eye presentation) or as a dense white cellular infiltrate (as per the left eye). An accompanying immune ring may be present. The chronic and recurrent nature of this response can lead within days or weeks to corneal stromal oedema, neovascularisation, thinning and scarring (as per the left eye). The inflammation can occur at any level or location on the cornea.7 Fortunately, in our patient the involvement was restricted to the anterior stroma and was not accompanied by endotheliitis, trabeculitis or iridocyclitis,8 nor was the patient a steroid responder and hence the complications of elevated IOP associated with the steroidbased management of immune stromal keratitis were not encountered. In a case series review of the aetiology of ISK, herpes simplex virus accounted for the majority (71.4 per cent) of unilateral active cases of ISK and VZV for 8.6 per cent.7 In the same immune stromal keratitis case series, 14.3 per cent of cases were classified as idiopathic following medical work-up and laboratory assessments. While PCR assessment of the tear fluid in clinically active HSV is positive in approximately 81 per cent of active epithelial keratitis cases, it is only positive in approximately 59 per cent of active stromal keratitis cases.9 It remains possible, although not probable, that the left stromal keratitis, presumed herpetic due to reduced corneal

sensation and PCR HSV-1 concurrent positive facial lesion but not confirmed by PCR of tear fluid in the conjunctival sac, was indeed a stromal staphylococcal hypersensitivity reaction associated with the co-existent staphylococcal blepharitis. Stromal keratitis associated with herpes simplex and herpes zoster is a leading cause of corneal opacification and corneal blindness in the developed world and an important indication for penetrating keratoplasty.2,7,10 Hence, issues surrounding timely diagnosis, ongoing therapeutic management, regular review and implementing strategies aimed at preventing and/or managing recurrences are of importance to maintaining life-long vision. HSV-1 keratitis is usually diagnosed by a recurrent characteristic clinical course involving dendritic epithelial lesions and possible associated facial blisters; however, HSV-1 can infect the underlying corneal stroma and cause herpetic stromal keratitis.11 Stromal keratitis may involve active viral replication within the stroma with an overlying epithelial defect and high risk of stromal melting and perforation (necrotising keratitis) but more commonly, as in this case, it occurs as a result of an immune-mediated host response.11 Neurotrophic keratitis and perforation can occur, particularly in chronic or recurrent cases.11 Herpes zoster ophthalmicus is typically diagnosed by a characteristic and usually painful zoster rash involving the forehead, periocular area and nose and in this case, was verified by PCR swab of a forehead blister. Herpes zoster is the second clinical manifestation of VZV and occurs only in individuals who have had primary varicella infection and with increasing frequency in the elderly as a result of waning of cell-mediated immunity.8 In immunocompetent individuals, psychological stress and trauma have been identified as additional risk factors.12 Our relatively young patient denied experiencing any recent trauma or any atypical psychological stress. The most serious complications of herpes zoster ophthalmicus develop from involvement of the nasociliary branch of the trigeminal nerve, which innervates the globe.12 If the eye becomes involved, the ocular sequelae can include blepharoconjunctivitis, episcleritis, scleritis, punctate epithelial keratitis, dendritic keratitis, anterior stromal keratitis, neurotrophic keratopathy, uveitis with varying different degrees of associated ocular damage and visual impairment. In addition to the © 2014 The Authors

Clinical and Experimental Optometry © 2014 Optometrists Association Australia

Bilateral herpetic immune stromal keratitis Albietz and Lenton

Figure 2. Left vascularised immune stromal keratitis associated with herpes simplex virus-1 under low (2A) and high (2B) magnification at initial presentation and at 10 months after the initial presentation (2C).

Figure 3. Right herpes zoster ophthalmicus rash eruption (3A) and associated immune stromal keratitis under low (3B) and high magnification (3C).

vision-threatening complications of herpes zoster ophthalmicus, the most common complication of herpes zoster is postherpetic neuralgia (PHN), which can cause chronic and debilitating pain and suffering for years and is often refractory to treatment.8,12 Current management strategies for acute herpetic stromal keratitis based on the results of the herpes Eye Disease Studies (HEDS) were employed to manage this patient’s herpetic corneal disease. These strategies are aimed at inhibiting viral replication with oral or topical antiviral medications and broadly inhibiting the damaging immune response with topical corticosteroids.11,13,14 The current standard of care for both necrotising and non-necrotising HSV stromal keratitis includes topical corticosteroids and topical antivirals.11 In HSV stromal disease, a 10-week tapering course of topical corticosteroid (prednisolone) combined with topical antiviral cover reduced the persistence and progression of the disease and shortened the duration of stromal inflammation.13 Furthermore, no additional benefit was observed upon

administration of oral acyclovir, compared to placebo, in conjunction with topical corticosteroids and topical antivirals.14 The topical antiviral used in the HEDS study, trifluridine ophthalmic solution one per cent, is unavailable through the Australian Pharmaceutical Benefits Scheme (PBS) and an alternative PBS listed antiviral, topical acyclovir ointment three per cent, was used. In rare cases of topical acyclovir resistance, trifluridine ophthalmic solution can be accessed through the Australian Therapeutic Goods Administration’s Special Access Scheme. Simultaneous use of the topical acyclovir antiviral ointment and topical prednisolone acetate suspension could potentially retard the absorption of the steroid suspension. Hence, separation of the timing of the instillation of antiviral ointment and topical steroid warrants consideration and increased dosing of the topical steroid may be required, if the stromal inflammation fails to respond to treatment. With protracted use of the topical antiviral over 10 to 14 days, a toxic epitheliopathy typically arises, which can aid penetration of the topical steroid into the stroma, as the epithelium is the greatest barrier to steroid pen-

© 2014 The Authors Clinical and Experimental Optometry © 2014 Optometrists Association Australia

etration. Changing the route of administration from topical to oral acyclovir may be considered, if the toxic epitheliopathy is severe and non-preserved unit dose artificial tears can be prescribed to improve epithelial health and comfort. HEDS also demonstrated that antiviral therapy with oral acyclovir 400 mg twice daily significantly reduced the recurrence of stromal HSV keratitis.15 Many clinicians now use valacyclovir, 500 mg once daily for prophylaxis due to its equivalent efficacy, greater bioavailability and simpler dosing regimen.16 This prophylactic course of oral antiviral for herpetic corneal disease is not covered by the PBS and hence the affordability of ongoing antiviral prophylaxis is an issue for patients. Longer-term follow-up data from the HEDS study, suggest that when the UV index was higher (that is, four or more), spending eight or more hours per week outdoors was associated with increased risk of ocular HSV recurrence.17 With the average UV index in Brisbane being four or more all year round, wearing close-fitting wraparound sunglasses and a hat has been advised for all outdoor activities. Clinical and Experimental Optometry 2014


Bilateral herpetic immune stromal keratitis Albietz and Lenton

In the case of herpes zoster ophthalmicus, the HEDS studies have demonstrated that oral antivirals, administered ideally within the first 24 to 72 hours of onset of the zoster rash for seven days decrease pain, shorten the duration of viral shedding, promote healing of skin lesions and decrease the incidence of ocular complications.18 While our patient was administrated the oral antivirals at 48 hours, antivirals given after three days may still be effective in treating herpes zoster.19 There are several antivirals available for herpes zoster infection, including acyclovir (800 mg, five times daily), valacyclovir (1000 mg, three times daily) or famciclovir (500 mg three times daily), which when used for seven days proved to be therapeutically equivalent in regards to resolution of zosterassociated pain, PHN, cutaneous healing and treatment safety. Valacyclovir was prescribed in this instance due to its higher bioavailability and less rigorous dosing schedule.19 Unfortunately, oral antivirals do not reliably prevent PHN.18,19 The goal of treating PHN is to manage the neuropathic pain, which may require several therapies. Management should be guided by the patient’s age, co-morbidities, preferences and costs and involve the patient’s general medical practitioner. First-line therapies, all assessed with randomised clinical trials, include GABA analogues (gabapentin and pregabalin), lidocaine patch and tricyclic antidepressants. A recent expert opinion recommended GABA analogues and topical lidocaine five per cent patches as first-line treatments for PHN, because both demonstrated efficacy in treatment and are relatively safe.19 The risk with PHN is that the severity of pain increases with age and not all sufferers respond to pharmacological interventions.19 Our relatively young patient experienced moderate but short-term PHN, which was adequately controlled with pregabalin, which is PBS listed for neuropathic pain not satisfactorily controlled using other drugs. Of the available choices and in line with current practice patterns,20 the topical steroid prednisolone acetate one per cent was prescribed for the right immune stromal keratitis with a slow taper over three months due to the chronic/recurrent nature of the disease. While herpes zoster ophthalmicusassociated immune stromal keratitis and iritis have commonly been described as immunologically mediated diseases, there is growing evidence that these complications Clinical and Experimental Optometry 2014


may also be mediated by chronic or recurrent zoster infection and a belief among the majority of recently surveyed corneal specialists that prolonged antiviral therapy could reduce recurrences of herpes zoster ophthalmicus while it is being administered. Currently there is an absence of studies and hence treatment guidelines for recurrent or chronic herpes zoster ophthalmicus regarding the efficacy of prolonged antiviral therapy or the adult zoster vaccine to reduce chronic or recurrent corneal disease associated with herpes zoster ophthalmicus.20 CONCLUSIONS This unusual manifestation of bilateral herpetic immune stromal keratitis in a young immunocompetent patient will require ongoing management and review. An important contributor to visual loss from corneal herpetic disease is its chronic and /or recurrent and neurotrophic nature, and hence routine ocular surface management strategies have been prescribed. Our patient has been advised of his diminished bilateral corneal sensitivity and encouraged to present promptly should he notice any change in vision or symptoms that might suggest reactivations, recurrences or secondary complications. This will afford him the best opportunity for early intervention and minimise further loss of vision. REFERENCES 1. Golebiowski B, Papas E, Stapleton F. Assessing the sensory function of the ocular surface: implications of use of a non-contact air jet aesthesiometer versus the Cochet-Bonnet aesthesiometer. Exp Eye Res 2011; 92: 408–413. 2. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol 2012; 57: 448–462. 3. Liesegang TJ. Corneal complications from herpes zoster ophthalmicus. Ophthalmology 1985; 92: 316– 324. 4. Cobo M, Foulks GN, Liesegang T, Lass J, Sutphin J, Wilhelmus K, Jones DB. Observations on the natural history of herpes zoster ophthalmicus. Curr Eye Res 1987; 6: 195–199. 5. Borkar DS, Tham VM, Esterberg E, Ray KJ, Vinoya AC, Parker JV, Uchida A et al. Incidence of herpes zoster ophthalmicus: results from the Pacific Ocular Inflammation Study. Ophthalmology 2013; 120: 451–456. 6. Hayashi K, Hooper LC, Shimomura Y. Who pays the toll for solving the enigma of corneal herpes? Cornea 2013; 32 (Suppl 1): S3–S12. 7. Schwartz GS, Harrison AR, Holland EJ. Etiology of immune stromal (interstitial) keratitis. Cornea 1998; 17: 278–281. 8. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology 2008; 115 (Suppl 2): S3–S12.

9. Fukuda M, Deai T, Higaki S, Hayashi K, Shimomura Y. Presence of a large amount of herpes simplex virus genome in tear fluid of herpetic stromal keratitis and persistent epithelial defect patients. Semin Ophthalmol 2008; 23: 217– 220. 10. Yawn BP, Wollan PC, St Sauver JL, Butterfield L. Herpes zoster eye complications: rates and trends. Mayo Clin Proc 2013; 88: 562–570. 11. Knickelbein JE, Hendricks RL, Charukamnoetkanok P. Management of herpes simplex virus stromal keratitis: an evidence-based review. Surv Ophthalmol 2009; 54: 2262–34. 12. Weinberg JM. Herpes zoster: epidemiology, natural history and common complications. J Am Acad Dermatol 2007; 57 (Suppl 6): S130–S135. 13. Wilhelmus KR, Gee L, Hauck WW, Kurinij N, Dawson CR, Jones DB, Barron BA et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 1994; 101: 1883–1895. 14. Barron BA, Gee L, Hauck WW, Kurinij N, Dawson CR, Jones DB, Wilhelmus KR et al. Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology 1994; 101: 1871–1882. 15. Wilhelmus KR, Beck RW. Moke PS, Dawson CR, Barron BA, Jones DJ, Kaufman HE et al. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 1998; 339: 300–306. 16. Miserocchi E, Modorati G, Galli L, Rama P. Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study. Am J Ophthalmol 2007; 144: 547–551. 17. Ludema C, Cole SR, Poole C, Smith JS, Schoenbach VJ, Wilhelmus KR. Association between unprotected ultraviolet radiation exposure and recurrence of ocular herpes simplex virus. Am J Epidemiol 2014; 179: 208–215. 18. Cobo LM, Foulks GN, Liesegang T, Lass J, Sutphin JE, Wilhelmus K, Jones DB et al. Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology 1986; 93: 763–770. 19. Kim SR, Khan F, Tyring SK. Varicella zoster: an update on current treatment options and future perspectives. Expert Opin Pharmacother 2014; 15: 61–71. 20. Sy A, McLeod SD, Cohen EJ, Margolis TP, Mannis MJ, Lietman TM, Acharya NR. Practice patterns and opinions in the management of recurrent or chronic herpes zoster ophthalmicus. Cornea 2012; 31: 786–790.

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A young immunocompetent patient with bilateral immune stromal keratitis due to varicella zoster and herpes simplex.

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