Herpes Zoster Ophthalmicus

Case scenario

Mrs AW, 64, presents at eye casualty with increasingly blurry vision associated with redness and irritation in the right eye commencing a week ago. On arrival, her vision in the right eye was poor, with an intraocular pressure (IOP) of 3 mm/Hg as measured by a tonometer. Left eye vision was unaffected at 6/6 with IOP of 9 mm/Hg. The patient does not wear corrective lenses and denied trauma, chemical exposure, discharge, foreign body sensation, sick contacts, or history of similar problems. Slit lamp examination revealed moderate right eye conjunctival irritation but no exudates nor obvious corneal scarring. Anterior chamber slit lamp exam showed a small size stromal infiltrate, but no hypopyon.

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Introduction

Herpes zoster ophthalmicus is an infection caused by the reactivation of dormant varicella zoster virus in the dorsal root or cranial nerve ganglia, extant from a prior infection.^1,2 The virus belongs to the family Herpesviridae, which also includes Epstein-Barr virus, cytomegalovirus and herpes simplex. 

Herpes zoster – also commonly known as shingles – has a higher incidence in patients over the age of 50 and affects approximately a third of the population at some point during their lifetime.^2,3

Early symptoms include localised tingling, pain and itchiness, followed by a characteristic maculopapular rash that develops into vesicular clusters that ulcerate and crust over 1–2 weeks.⁴

The rash is usually unilateral in nature, affecting a single dermatome, but may also affect adjacent dermatomes such as ophthalmic, cervical or thoracic areas.²

Risk factors for reactivation of the virus include female sex, increased age, immunosuppression (e.g. HIV, immunosuppressant medication use), poor nutrition, physical and/or emotional stress, and fatigue.^3,5 See Table 1.

As per Therapeutic Guidelines, all immunocompetent adult and adolescent patients should be prescribed antiviral medicine within the first 72 hours of rash presentation.⁴

Antiviral treatment should be prescribed for all immunocompromised patients, irrespective of rash duration. Antiviral treatment reduces pain severity, duration of viral shedding, and new lesion formation.⁴

The reduction in viral shedding reduces the risk of community transmission (i.e. to chicken pox-naive patients) and ocular complications. Healing usually occurs within 4 weeks, and once crusting of the pustular rash has occurred, the individual is no longer considered to be contagious.⁵

Approximately 10–25% of herpes zoster cases involve the ophthalmic branch (CN V1) of the trigeminal nerve. This manifestation of shingles is termed herpes zoster ophthalmicus (HZO). The infection causes inflammation of sensory nerves that can result in damage to the eye and surrounding tissues.³ Without appropriate treatment, HZO has high complication rates and is associated with disabling vision loss and significant healthcare costs.²

HZO can present with or without ocular involvement. Ocular involvement may include keratitis (approximately 66% of cases), iritis, uveitis, conjunctivitis, vitritis and retinitis.¹ However, ocular involvement is not always present and, in some cases, only skin of the V1 dermatomal region is affected.1 Postherpetic neuralgia (PHN) is another possible complication of HZO associated with significant morbidity.¹

Approximately 10% of patients with HZO may develop moderate or severe vision loss – predominately the result of corneal scarring. Older age, immunosuppressed status, poor initial visual acuity, and a history of symptomatic uveitis are all associated with higher incidence of vision loss.⁷

Table 1 – Risk factors for HZO and PHN

Diagnosis

In the absence of cutaneous symptoms, early stages of HZO can be characterised by a variability of clinical signs, thereby imposing a diagnostic uncertainty. A comprehensive examination by an optometrist or ophthalmologist, involving history and physical findings, is required for diagnosis. This includes IOP assessment and performing dilated pupil fundus exam, which allows evaluation of internal ocular health, and assessing atrophy of the iris.⁷

An early warning sign and predictor of ocular involvement is the Hutchinson’s sign (vesicles appearing on the nose). Laboratory tests such as viral polymerase chain reaction (PCR) involving swabbing a ruptured vesicle are reserved for atypical cases in which the diagnosis is unclear.^2,8

Antiviral medication management plans

When initiated early, antiviral therapy has been shown to reduce pain, speed rash-healing time, and reduce ocular complications.^2,5 Patients with an active HZO infection can be prescribed PBS antiviral agents irrespective of time frame since rash presentation.⁸

Therapeutic Guidelines recommends 7 days’ treatment duration with oral antivirals. However, usual practice is to continue high-dose antiviral therapy until disease resolution, which can extend for 14–21 days.⁴ This is especially true if used in conjunction with topical steroids which are known to dampen the host immune response.

The prophylactic use of antiviral therapies is common once HZO symptoms have resolved, despite the lack of randomised controlled data. It aims to minimise and prevent relapsing keratitis, which can lead to permanent ocular scarring and/or corneal perforation. Prophylactic use of antivirals in HZO is based on the clinical data from Herpetic Eye Disease Study (HEDS). As HZO shares a lot of similarity with the herpes simplex virus (HSV) eye disease, many clinicians use the result of HEDS and similar studies when prescribing long-term antiviral prophylaxis. Authors of the HEDS study evaluated the effects of low-dose oral antiviral prophylaxis (aciclovir 400 mg twice daily) versus placebo in preventing HSV recurrences in a patient cohort with past ocular HSV history.

Patients on long-term (1 year or longer) low-dose antiviral prophylaxis experienced significantly fewer recurrences of HSV stromal keratitis.⁹

The Zoster Eye Disease Study (ZEDS) is a randomised placebo-controlled clinical trial evaluating prophylactic use of valaciclovir for one year in HZO patients. The results are hoped to determine the standard of HZO care, which should help reduce complications and improve patient outcomes.¹⁰

Table 2 – Antiviral medication management for HZO treatment in adults^4,8

HZO ocular complications

Ocular manifestations can affect up to 66% of patients presenting with HZO and are responsible for significant morbidity, with 10% of patients developing permanent visual impairment.^1,7 The most common ocular manifestations are mucopurulent conjunctivitis, keratitis and uveitis.

Eyelid/conjunctiva

Conjunctivitis can occur within days of vesicular rash presentation, with the conjunctiva appearing oedematous and often with petechial haemorrhages. Symptoms usually resolve after one week; however, secondary bacterial infections, usually from Staphylococcus aureus, can develop and may require topical antibiotic (e.g. chloramphenicol 0.5% eye drops¹ four times daily for 7 days). Topical steroids may be useful in patients with significant inflammation. Preservative-free lubricating drops and ointments can be beneficial.^1,4

Blepharitis is common on the eyelids and patients can present with ptosis secondary to inflammation and oedema.³ For immunocompromised patients, prescribers may recommend application of chloramphenicol ointment applied three times daily to eyelids for prophylaxis of bacterial infection.

Episclera/sclera

Within one week, the sclera may present with localised or diffuse redness, swelling, and pain.² Patients can be prescribed topical corticosteroid eye drops such as dexamethasone (Maxidex) or prednisolone with phenylephrine (Prednefrin Forte) to control inflammation.¹¹ The use of topical corticosteroids in HZO is controversial, but usually necessary as a way of controlling inflammation. Once initiated, topical corticosteroids may require prolonged taper to prevent rebound inflammation. In some cases, treatment with low-dose topical steroids extends for prolonged periods of time as a way of preventing further morbidity with recurrent infections.

Cornea

Keratitis is the inflammation of the cornea and is marked by redness, lacrimation, blurred vision, photophobia and pain. HZO can cause a number of different complications involving the cornea, but epithelial and stromal keratitis seem to be responsible for the highest risk of visual loss.¹¹ Depending on the type and severity of keratitis, treatment options include oral antivirals and long-term use of topical steroids. Like above, the prolonged use of topical steroids requires slow taper in response to clinical progress.

Corneal inflammation can be responsible for IOP, which can be long- lasting and challenging to treat.¹² Prostaglandin analogues are usually first-line treatment in glaucoma but are best avoided in this cohort of patients due to their proinflammatory properties.

Uveitis

Uveitis can affect a large proportion of patients with HZO. It is an inflammation of uveal structures, but typically refers to the iris and ciliary body.

Prompt treatment is important in preventing long-term sequalae and minimising vision loss with use of topical steroids.¹²

Postherpetic neuralgia

The use of antiviral medications is important to reduce the pain, rash and ocular complications. It does not, however, reduce the incidence or severity of postherpetic neuralgia, which can persist for months or years.

According to the Australian and New Zealand College of Anaesthetists’ pain management guidelines, early and appropriate analgesia is an important part of herpes zoster treatment and may help reduce the incidence of postherpetic neuralgia. Paracetamol, and NSAIDs such as ibuprofen, are still considered first-line agents for mild presentations. More severe herpes zoster-related pain may benefit from multimodal analgesia with regular non-opioids, in addition to an opioid such as oxycodone or tramadol as required. Specialist advice is recommended for these cases.

Early utilisation of amitriptyline, at a dose of 25 mg daily for 90 days, has been found to significantly reduce incidence of postherpetic neuralgia in patients.

Once lesions have healed, 5% lignocaine patches can be applied to intact skin twice a day. It has been shown to reduce intensity of pain and is well tolerated. Topical capsaicin cream has been shown to reduce pain by attenuating cutaneous hypersensitivity via alternating neuronal pain pathway transmission. The use of capsaicin cream has been shown to be somewhat useful in pain management, but it requires frequent daily application (up to four times a day) and can cause significant burning, which can negatively impact patient compliance.¹³

Knowledge to practice

While the diagnosis of herpes zoster resides with the medical team, the pharmacist may be the first point of contact for patients seeking advice about initial symptoms. Assessment of the patient’s risk factor(s) will also help when evaluating the need for referral to a medical professional.

If a patient presents at a pharmacy with symptoms that may indicate herpes zoster infection, ask:

• When did the rash commence?
• Is the rash painful?
• Are you experiencing any visual disturbances?

In all suspected cases of herpes zoster, irrespective of ocular involvement, patients should be promptly referred for medical examination. Once diagnosed and a treatment plan prescribed, the pharmacist can help support with advice and review.

Conclusion

HZO still affects a large proportion of the population and is associated with significant morbidity and reduced quality of life. Prompt referral to a medical professional and appropriate treatment can reduce both the duration and severity of disease and minimise ocular complications. Pharmacists can recognise early signs of HZO, refer patients for urgent medical assessment and provide educational support to patients affected by HZO and their sometimes long- term journey to recovery. 

The lack of evidence-based treatment for chronic symptoms of HZO and the significant variability among ophthalmologists in their treatment approach highlight the need for large, randomised clinical trials to help standardise prevention and treatment management of herpes zoster. 

Evidence-based treatment guidelines will help improve patient outcomes and reduce HZO disease burden for patients and the healthcare system.

Key points

• Herpes zoster opthalmicus can present with or without ocular involvement and, in the absence of cutaneous symptoms, clinical signs can be variable so a comprehensive examination by an optometrist or ophthalmologist is required for diagnosis.
• The condition can have serious complications including vision loss and postherpetic neuralgia.
• When initiated early, antiviral therapy has been shown to reduce pain, rash healing time and ocular complications. Antiviral therapy has not been shown to reduce the incidence or severity of postherpetic neuralgia.

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References

1. Ting DSJ, Ghosh N, Ghosh S. Herpes zoster ophthalmicus. BMJ 2019;364:k5234.
2. Wehrhahn MC DD. Herpes zoster: epidemiology, clinical features, treatment and prevention. Australian Prescriber 2012;35:143–7.
3. Shaikh S, Ta CN. Evaluation and management of herpes zoster ophthalmicus. Am Fam Physician 2002;66(9):1723–30.
4. Antibiotic Expert Group. Antibiotic. Therapeutic Guidelines. Melbourne. 2022.
5. Le PR, M  BMJ Best Practice: Herpes Zoster Infection. 2022.
6. Kea L. Herpes Zoster Ophthalmicus. 2020: Comprehensive Ophthalmic Pearls:35–6.
7. Niederer RL, Meyer JJ, Liu K, et al. Herpes Zoster Ophthalmicus Clinical Presentation and Risk Factors for Loss of Vision. Am J Ophthalmol 2021;226:83–9.
8. Rossi S, ed. Australian medicines handbook. Adelaide: Australian Medicines Handbook; 2015.
9. de la Parra-Colin P, Garza-Leon M, Ortiz-Nieva, et.al. Oral antivirals for preventing recurrence of herpes simplex virus keratitis. Cochrane Database of Systematic Reviews 2017, Issue 4.
10. Mohammed TK, Cohen EJ, Jeng BH. A review of treatment for herpes zoster keratitis. Ophthalmology 2021;15(Corneal Disorders):43–5.
11. Herpes zoster ophthalmicus. Royal Victorian Eye and Ear Hospital. 2021. At: eyeandear.org.au/wp-content/uploads/2021/08/Herpes-Zoster-Ophthalmicus-Clinical-Practice-Guideline.pdf
12. Kalogeropoulos CD, Bassukas ID, Moschos MM, et.al, Eye and periocular skin involvement in herpes zoster infection. Med Hypothesis Discov Innov Ophthalmol 2015 Winter;4(4): 142–156.
13. Yong YL, Tan LT-H, Ming LC, et al. The effectiveness and safety of topical capsaicin in postherpetic neuralgia: a systematic review and meta-analysis. Front Pharmacol 2017;7:538.

LJUBICA BUKOROVIC BBioMedSc, BPharm, GradCertClinPharm is an Ophthalmology Clinical Pharmacist at Princess Alexandra Hospital, Brisbane, Queensland.

SCOTT MITCHELL BPharm BBioMedSc, GradCertClinPharm, AdvPP (II) is Assistant Deputy Director of Pharmacy (Clinical Support Services) at Princess Alexandra Hospital, Brisbane, Queensland.