Cso 23.12 coverHerpes Zoster Ophthalmicus: More than Meets the Eye
Guillermo Rocha, MD, FRCSC; Mercedes Muzychuk, OD
The varicella virus is common; in recent decades the In this paper, a review of the basics of the herpes
infection was found to affect 50% of Canadians by age 5 zoster virus will be covered. Aspects of ophthalmic
and 90% by age 12.6 Although the rate of infection with complications and postherpetic neuralgia will be
VZV is high, the reported incidence of herpes zoster discussed. Finally, the recent advent of the zoster
ranges from 2.2-3.4/1000 people per year.2 Incidence and vaccine will be discussed.
severity increase with age. Along with variation of incidence with age, there appears to be a disparity between males and females. In a The varicella zoster virus (VZV) causes two distinct study examining the epidemiology of shingles in Alberta clinical manifestations: varicella (chickenpox) and from 1986-2002, the rate of herpes zoster was found to be zoster (shingles).1 After primary infection with VZV increasing, with more females being affected than males (chickenpox), the virus becomes latent in the sensory at every age group, with the disparity between females ganglia.2 Herpes zoster occurs when the virus reactivates and males being highest in the 50 to 54 year age group.7 from the sensory ganglia and spreads to the corresponding The incidence of herpes zoster is also higher in dermatome,2 producing the characteristic zoster rash. It is thought that the likelihood of reactivation increases with compromised individuals present with distinct inflam- age because of an age-related decrease in cell mediated mation, hemorrhages, and necrosis that follows a multi- immunity to the VZV.3 Multiple subclinical reactivations dermatomal pattern.4 The rash can also be moderate can occur during a lifetime.4,5 If reactivation occurs, the with few symptoms.4 In addition, there is a higher re-exposure to VZV is thought to endogenously boost the incidence of disseminated zoster among immuno- immunity,5 decreasing the chance of further episodes. During reactivation, VZV replication causes vesicular eruptions and inflammation of the skin producing the HERPES ZOSTER OPHTHALMICUS
characteristic dermatomal zoster rash.4 Diagnosis of Herpes zoster ophthalmicus (HZO) is a manifestation VZV is supported by the presence of prodromal pain, an of the varicella zoster virus involving ocular structures.
asymmetric dermatomal rash respecting the midline, HZO results from reactivation of the VZV in the first and corresponding zoster-associated segmental pain.4 (ophthalmic) branch of the trigeminal nerve.8 Clinical While zoster can occur in any dermatome, it most manifestations (Table I) of HZO can be caused by direct commonly occurs in the thoracic dermatomes (50% to viral invasion, secondary inflammation and changes to the 56%) and in cranial nerves V, VII, and VIII (20%).4 autoimmune mechanisms, and neurotrophic disorders.8 The cervical, lumbar, and sacral segments are less If left untreated, 50% to 70% of HZO patients will frequently involved.4 In its disseminated form, VZV can develop ocular complications8 that can threaten the also involve internal organs.4 Table I Clinical manifestations of HZO.8
G. Rocha — Brandon Regional Health Centre, University of Manitoba,Brandon, MB; University of Ottawa Eye Institute, Ottawa, ON; M.
Direct viral invasion Superficial keratitis (punctate keratitis, Muzychuk — University of Waterloo School of Optometry, Waterloo, ON dendritic keratitis and conjunctivitis) Correspondence to: Guillermo Rocha, MD, FRCSC, GRMC Vision Centre, Secondary inflammation/ Stromal keratitis Medical Centre Building, Suite 20, 144-6th Street, Brandon, MB, Canada Alterations of autoimmune R7A 3N2; [email protected] Dr. Rocha has received consulting fees from Merck Frosst Canada.
Dr. Muzychuk has no financial interest in the above-named technology Neurotrophic changes Neurotrophic keratitis or its applications.
11 Clinical & Surgical Ophthalmology 28:3/4, 2010
Table II Ophthalmic manifestations of HZO.2
Swelling, vesicular rash Ptosis, eyelid retraction Episclera or sclera Focal sectoral atrophy Epithelial keratitis Neurotrophic or exposure keratopathy Stromal keratitis Corneal neovascularization, deposition Focal iris atrophySecondary glaucoma13 Ocular hypertension Usually self-limiting Rare complications Extraocular muscle palsies Self-limiting, may be related to orbitalapex syndrome14 Retinal vasculitis, retinitis *Unilateral anterior uveitis with sectoral iris atrophy without associated (previous) keratitis is a distinct entity among herpetic eye diseases.15 long-term integrity and visual function of the eye.9 HZO crusting occur. Although most patients present with the is present in 10% to 20% of all zoster cases.2 typical HZ rash, a small percentage of patients will Approximately 1/100 people will develop HZO in their present with ophthalmic manifestations alone.2 Hutchinson's sign, the presence of nasociliary skin Ophthalmic Manifestations
lesions, is a useful prognostic factor for ocular inflam- Table II describes the ophthalmic manifestations of HZO mation with herpes zoster.9 Attention should be focused in both the acute and late phase.2 on the tip of the nose, the inner corner of the eye, and theroot and side of the nose to help identify patients at risk of Eyelids and Ocular Adnexa
ocular involvement. The nasociliary nerve has two Although the varicella rash does not typically result in branches: the infratrochlear and external nasal branches, scarring, cicatricial skin changes often result from HZO.
which innervate the skin at the medial canthus of the This is more pronounced in the area of the forehead eye and at the root, and along the side of the nose. This and eyelids because the tissue is thin.10 If edema of the prognostic value of Hutchinson's sign is more significant eyelids is significant, ptosis may result.10 At the other end when both branches of the nasociliary nerve are involved, of the spectrum, cicatricial changes or orbicularis muscle and there is less likelihood of ocular involvement if palsy may result in lagophthalmos.10 The affected area lesions are restricted to a single branch.9 However, the may also become hypersensitive, making lid manipulation absence of Hutchinson's sign does not rule out nasociliary extremely painful (Fig. 1).10 nerve involvement. The frontal nerve, which innervatesthe scalp, forehead, and upper eyelid, is the most common site for the primary and most severe skin lesions in acute Many different forms of conjunctivitis can result from HZO.
ophthalmic zoster.9 In patients with acute ophthalmic These include pseudomembranous, membranous, and zoster, the major prognostic factors for ocular inflam- follicular responses.10 A mucopurulent discharge is common mation are severity and distribution of skin lesions as this during active disease. Vesicles may occur on the bulbar or is thought to represent the immune status of the host palpebral conjunctival surfaces. If these vesicles rupture, against the spreading virus.9 sequelae range from mild inflammation to infection, The prodromal phase begins up to a week before the ulceration, scarring, and symblepharon formation.10 onset of the skin rash and can involve pain, itching,malaise, photophobia, and low grade fever.2 The rash begins with progressive pain sensations and the formation It is hypothesized that early corneal lesions are due to of erythematous macules which then progress to clusters direct damage from viral invasion while later stages result of papules and clear vesicles. New skin lesions typically from vasculitis, immune reactions to viral antigens, appear for the next 3 to 5 days; then pustulation and delayed hypersensitivity, and/or damage to nerves and Herpes Zoster Ophthalmicus: More than Meets the Eye — Rocha, Muzychuk 12
Fig. 1 Herpes zoster ophthalmicus, V1. Courtesy Michele Mabon, MD, FRCSC.
Fig. 2 Corneal pseudodendrite. Courtesy Michele Mabon, MD, FRCSC.
Fig. 3 Nummular keratitis. Courtesy Michele Mabon, MD, FRCSC.
Fig. 4 Neurotrophic keratitis with melt. Courtesy Michele Mabon, MD, FRCSC.
tissues.10 Early corneal findings include punctate with ocular manifestations.6 It is not known why some epithelial keratitis, pseudodendrites (Fig. 2), and anterior develop no HZO complications, or minimal ones, stromal infiltrates (Fig. 3).10 Later findings include while others develop severe complications.14 This may mucous plaques, disciform keratitis, neurotrophic be related to virulence of the infection, host immune keratitis (Fig. 4), and exposure keratits.10 Corneal scarring status, or both.14 after infection is common and can range from faintstromal haze to an opaque region with associated Less commonly, corneal ulcers and Postherpetic neuralgia (PHN), the most common perforations can develop.10 complication of HZ, occurs when pain persists along the In one case report, a patient with post-zoster corneal course of the nerve after the acute segmental HZ rash has scarring was successfully treated with phototherapeutic healed.16 Incidence of PHN is highest at one month after keratectomy with mitomycin C followed by wavefront- rash resolution and in most patients this pain will improve guided photorefractive keratectomy 4 months later.11 In with time.16 Depending on the definition, PHN occurs in another case report involving a herpes zoster eye in which 9% to 34% of patients,16 and in at least one-third of these the patient developed an inflamed hypopyon ulcer which patients the pain cannot be adequately relieved.16 progressed to Descemetocele, a Boston keratoprosthesis The incidence and severity of PHN increases with was successfully used to replace the damaged cornea.12 age: at age 60, 50% of patients have pain that persists for In British Columbia from 2001 to 2003, 7.3% of longer than one month following the rash, increasing herpes zoster hospitalizations were due to herpes zoster to 75% at age 70.16 PHN is more commonly encountered 13 Clinical & Surgical Ophthalmology 28:3/4, 2010
preventing ocular complications.8 Similarly, another Table III Antiviral drugs that reduce the severity and duration of
multicenter, randomized, double-masked study found famciclovir (500 mg, 3x/day) to have similar efficacy toacyclovir (800 mg, 5x/day) for HZO.21 Acyclovir is available topically in ointment form and 800 mg, q4h, 5x/day may be considered in conjunction with an oral antiviral ifeye involvement is severe.2 Even though the ointment 1000 mg, q8h, 3x/day form creates a much higher concentration of drug inthe anterior segment, topical acyclovir is not sufficient 500 mg, q8h, 3x/day for monotherapy.2 Gabapentin can be used in conjunction with antivirals during the acute phase of HZ to help prevent development in the thoracic dermatomes, especially T5, and in the and minimize severity of postherpetic neuralgia.17 ophthalmic division of the trigeminal nerve.16 When pain was assessed after the use of both valacyclovir Considering that 30% to 50% of patients with (1000 mg TID) for 7 days with an increasing dose of severe PHN do not respond well (if at all) to treatment, gabapentin (maximum dose 1200 mg TID) for 6 months, it prevention either by vaccination or aggressive treatment was found that at 3 and 6 months post-zoster the of herpes zoster may be the best option.16 reported moderate and severe intensity pain was decreasedrelative to historic controls treated with acyclovir.17 Treatment with corticosteroids like prednisolone may Antiviral drugs (Table III) reduce the severity and be used in conjunction with antivirals to provide initial duration of herpes zoster but typically do not prevent relief from pain intensity.17 It has been demonstrated that the development of PHN.17 If initiated within 72 hours patients receiving prednisolone had improved cutaneous of HZ rash onset, oral antiviral therapy with acyclovir, healing and relief of acute pain.18 However, this benefit is valacyclovir, and famciclovir decreases the period of only experienced during the first few weeks of the disease acute pain, virus shedding, rash, and both acute and course and the associated adverse effects may not out- late-onset anterior segment complications.18 Valacyclovir weigh the benefits.17 Corticosteroids have not been found and famciclovir also decrease the incidence and severity to provide any further decrease in the incidence of PHN of PHN.18 In most studies, antiviral therapy is commenced when used together with antiviral medications.17 within 72 hours of rash onset but no data exists demon- Current treatment options for PHN include anti- strating that later antiviral therapy does not provide any convulsants (gabapentin, pregabalin), lidocaine patch 5%, therapeutic benefit.17 capsaicin cream, opioid analgesics, and tricyclic In has been demonstrated in clinical trials that antidepressants.17 In clinical trials, all of these agents are acyclovir decreases the pain duration and prevalence of found to alleviate the pain of PHN.17 Previously, tricyclic herpes zoster by approximately half.17 The two newer antidepressants had been used as the first-line treatment drugs, valacyclovir and famciclovir, have been shown to for PHN but gabapentin and the lidocaine patch 5% have have equivalent or superior efficacy in comparison to superior tolerability and are now both approved as acyclovir in the treatment of herpes zoster.17,19,20 In first-line treatments. Opioids can be used for cases that addition, these two drugs have significantly higher are unresponsive or difficult to manage.17 Combination bioavailability16 and simpler dosing regimens,17 and they therapy is standard in clinical practice.17 both decrease the incidence and severity of PHN.18 Antiviral therapy is necessary in patients with HZO IMPLICATIONS OF CHILDHOOD
in order to prevent or minimize ocular complications.
VARICELLA VIRUS VACCINATION
Acyclovir, valacyclovir and famcyclovir all have similar Before the varicella vaccination was approved for use in efficacy for the treatment of HZO. In a trial with immuno- the US in 1995, there was continuing controversy regarding competent patients with HZO, the incidence and severity the use of infant varicella vaccination.14 Considerations of common complications (dendriform keratopathy, included vaccination and revaccination costs, long-term stromal keratopathy, uveitis) were significantly decreased efficacy, whether or not adult varicella would increase as a with oral acyclovir treatment (600 mg, 5x/day for 10 result, and if this could cause an increase in the incidence of days) within 7 days of rash onset.17 In a multicenter, herpes zoster.14 Some countries have yet to begin vaccination randomized, double-masked study comparing the efficacy while others have abandoned varicella vaccination programs and safety of valacyclovir and acyclovir for the treatment as a result.14 A publicly funded varicella vaccination of HZO, it was found that valacyclovir (2x 500 mg tablets, program began in Alberta in 2001 (the vaccine was licensed 3x/day) is as effective as acyclovir (800 mg, 5x/day) in in Canada in 1998).7 Herpes Zoster Ophthalmicus: More than Meets the Eye — Rocha, Muzychuk 14
Before introduction of the varicella vaccination, almost would receive periodic re-exposure to wild-type virus to every child developed chickenpox.14 Since the introduction boost their immunity.14 of the childhood vaccine in the US in 1995, there has been The purpose of the Shingles Prevention Study was to an 88% decrease in hospitalizations due to chickenpox.
determine if vaccination with live attenuated VZV vaccine It is estimated that $84.9 million was spent in the US from would decrease the incidence and severity of herpes 1994 to 1995 for varicella hospitalizations and ambulatory zoster and post herpetic neuralgia in those older than 60.5 visits. In 2002, this decreased by 74% to $22.1 million.
This randomized, double-blind, placebo-controlled study While vaccination decreases the incidence of chickenpox, was conducted in adults age 60 and older. The Shingles mathematical models predict an increase in shingles Prevention Study found that the vaccine decreased the approximately 5 years after vaccine implementation7 due to incidence of both herpes zoster (51.3%) and postherpetic a decrease in cell mediated immunity. neuralgia (66.5%) in the vaccine group. In those who did To prevent herpes zoster, boosts in cell-mediated develop herpes zoster, the duration and associated pain of immunity (from either periodic exposure to persons with herpes zoster was decreased. The vaccine was not varicella or routine periodic release of VZV from the found to induce cases of herpes zoster5 and adverse events ganglia) are necessary.14 Studies have shown that before related to the vaccine were limited to the injection site the introduction of childhood varicella immunization, (erythema, pain, tenderness, swelling, or pruritus – all adults who lived or worked with children had lower generally mild).5 The duration of efficacy for the Zostavax vaccine in risk of developing herpes zoster than those adults with the past four years has not yet been determined and it is infrequent exposure to children.14 With fewer children not yet known whether revaccination will be required.23 being exposed to the wild-type varicella virus in the In summary, herpes zoster and its complications can future, this is expected to create an increased incidence of be a debilitating condition. Aggressive early management shingles in those under 50 (in this age group, the risk of with antiviral medications will decrease the incidence and developing zoster was previously low because of routine severity of postherpetic neuralgia. The advent of the boosts in cell-mediated immunity).14 Similarly, decreased zoster vaccine may help reduce the incidence of ocular exposure along with a decrease in cell-mediated immunity complications from HZO. ❏ is expected to increase the incidence of shingles in theelderly.14 Among the vaccinees, the incidence of zoster is expected to be lower because they may develop a lower The authors wish to express their appreciation to degree of ganglion population by the virus (skin lesions Michele Mabon, MD, FRCSC, from the University of develop only in a small number of vaccine recipients).14 Montreal, for providing the clinical photos. The gradual disappearance of wild-type varicella as more children receive vaccination means that adults will not be receiving routine boosts in cell-mediated immunity Brisson M, Edmunds WJ, Law B, et al. Epidemiology of from re-exposure to the virus from infected children.14 The varicella zoster virus infection in Canada and the UnitedKingdom. Epidemiol Infect 2001; 127: 305-314. zoster vaccine is meant to substitute for this boosting Opstelten W, Zaal MJW. Managing ophthalmic herpes effect that will not be provided by vaccinated children.14 zoster in primary care. BMJ 2005; 331: 147-151. Levin MJ, Smith JG, Kaufhold RM, et al. Decline in varicella-zoster virus (VZV)-specific cell-mediated A variety of drugs are available to reduce the severity immunity with increasing age and boosting with a high-dose VZV vaccine. JID 2003; 188: 1336-1344. and duration of herpes zoster and to attempt to manage Gross G, Schofer H, Wassilew S, et al. Herpes zoster guide- the associated pain of postherpetic neuralgia.22 However, line of the German Dermatology Society (DDG). J Clin no medications can prevent disease development or Virol 2003; 26: 277-289. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to Zostavax, a live attenuated virus vaccine for herpes prevent herpes zoster and postherpetic neuralgia in older zoster, was approved for the prevention of herpes zoster adults. N Engl J Med 2005; 352: 2271-2284. Edgar BL, Galanis E, Kay C, et al. The burden of varicella in the US in 2006 for individuals age 60 and older.23 and zoster in British Columbia 1994-2003: baseline assess- Cell-mediated immunity against the varicella zoster ment prior to universal vaccination. Canada Communicable virus progressively decreases with age and although the Disease Report 2007; 33: 1-15.
mechanism is still unclear, the VZV vaccine is thought to Russell ML, Schopflocher DP, Svenson L, Virani SN.
boost this immunity.3,5 The fact that the zoster vaccine is Secular trends in the epidemiology of shingles in Alberta.
approved only for adults age 60 and over may result Epidemiol Infect 2007; 135: 908-913. Colin J, Prisant O, Cochener B, et al. Comparison of the in an increase in the incidence of herpes zoster in those efficacy and safety of valacyclovir and acyclovir for the under 50 in the next several decades, who, before the treatment of herpes zoster ophthalmicus. Ophthalmology development of the childhood varicella vaccination, 2000; 107: 1507-1511. 15 Clinical & Surgical Ophthalmology 28:3/4, 2010
Zaal MJW, Völker-Dieben HJ, D'Amaro J. Prognostic 16. Watson CPN, Oaklander AL. Postherpetic neuralgia. Pain value of Hutchinson's sign in acute herpes zoster Practice 2002; 2: 295-307. ophthalmicus. Graefe's Arch Clin Exp Ophthalmol 2003; 17. Tyring SK. Management of herpes zoster and postherpetic neuralgia. J Am Acad Dermatol 2007; 57: S136-142. 10. Kaufman SC. Anterior segment complications of herpes 18. Pavan-Langston D. Herpes zoster - antivirals and pain man- agement. Ophthalmology 2008; 115: S13-S20. zoster ophthalmicus. Ophthalmology 2008; 115: S24-S32. 19. Beutner KR, Friedman DJ, Forszpaniak C, et al.
11. Kaufman SC. Use of photorefractive keratectomy in a Valacyclovir compared with acyclovir for improved patient with a corneal scar secondary to herpes zoster therapy for herpes-zoster in immunocompetent adults.
ophthalmicus. Ophthalmology 2008; 115: S33-S34. Antimicrobial Agents and Chemotherapy 1995; 39: 12. Pavan-Langston D, Dohman CH. Boston keratoprosthesis treatment of herpes zoster neutrophic keratopathy.
20. Shen M, Lin H, Lee SS, et al. Double-blind, randomized, Ophthalmology 2008; 115: S21-S23.
acyclovir-controlled, parallel-group trial comparing the 13. Thean JHJ, Hall AJH, Stawell RJ. Uveitis in herpes zoster safety and efficacy of famciclovir and acyclovir in patients ophthalmicus. Clinical and Experimental Ophthalmology with uncomplicated herpes zoster. J Microbiol Immunol 2001; 29: 406-410. Infect 2004; 37: 75-81. 21. Tyring S, Engst R, Corriveau C, et al. Famciclovir for 14. Liesegang TJ. Herpes zoster ophthalmicus - natural history, ophthalmic zoster: A randomized acyclovir controlled risk factors, clinical presentation, and morbidity.
study. Br J Ophthalmol 2001; 85: 576-581. Ophthalmology 2008; 115: S3-S12. 22. Betts RE. Vaccination strategies for the prevention of 15. Van der Lelij A, Ooijman FM, Kijlstra A, et al. Anterior herpes zoster and postherpetic neuralgia. J Am Acad uveitis with sectoral atrophy in the absence of keratitis - A Dermatol 2007; 57: S143-147. distinct clinical entity among herpetic eye diseases.
23. Merck & Co., ed. Highlights of prescribing information – Ophthalmology 2000; 107: 1164-1170. Zostavax Zoster Vaccine Live; 2006.
Herpes Zoster Ophthalmicus: More than Meets the Eye — Rocha, Muzychuk 16
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