AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Varicella-zoster virus (VZV) causes 2 distinct syndromes. The primary infection is varicella (or chickenpox), a contagious and usually benign illness often occurring as epidemics in children. Following this infection, virus particles remain in the dorsal root or other sensory ganglion where they may lay dormant for years to decades. At some later point in life, the virus-specific cell-mediated immune responses may decline as a result of aging, immunosuppressive illness, new stress, or medical treatments. Such conditions allow a reactivation of latent VZV and result in a localized cutaneous rash erupting in a single dermatome called herpes zoster (HZ), or shingles. Patients with HZ involving the first division of the trigeminal nerve have a disease process termed herpes zoster ophthalmicus (HZO). HZO was described long ago by Hippocrates, but its relation to VZV was not elucidated until the advent of modern medical tools such as the immunohistochemical assays.

Pathophysiology

When liberated from the trigeminal ganglion, the reactivated VZV (human herpesvirus type 3) travels down the first division (ophthalmic) of the trigeminal nerve to the nasociliary nerve. This branch then divides to innervate the surface of the globe and the skin on the nose down to its tip. This process typically takes 3-4 days for the virus particles to reach the nerve endings. As the virus travels, it leads to perineural and intraneural inflammation, which may damage the eye itself and/or other surrounding structures.

Frequency

United States

More than 90% of adults in the United States have serologic evidence of VZV infection and therefore are at risk for HZ. The reported annual incidence of HZ varies from 1.5-3.4 cases per 1000 individuals. The key risk factor for the development of HZ is waning of the cell-mediated immune system associated with the normal aging process; the incidence of shingles among individuals older than 75 years exceeds 10 cases per 1000 individual-years. The lifetime risk of HZ is estimated to be 10-20%.

The other well-defined risk factor for HZ is acquired inhibition of the cell-mediated immune response, such as those patients on immunosuppressive drugs and those with the human immunodeficiency virus (HIV) and more specifically with AIDS. In fact, the relative risk of HZ is at least 15 times greater in those with HIV infections than in those without. The recurrence rate of HZ in AIDS patients has been reported to be as high as 25% compared to less than 4% in immunocompetent individuals. Interestingly, HIV-positive patients who develop HZ are more likely to progress on to AIDS than those who do not. These statistics also apply to children who are infected with HIV in utero.

HZO represents 10-25% of all cases of herpes zoster. The risk of ophthalmic complications in patients with HZ does not seem to correlate with age, gender, or severity of the skin rash.

Mortality/Morbidity

Complications of HZO are centered around the destruction of the ocular structures manifesting as various ocular diseases that can lead to permanent loss of sight. Commonly affected structures include the following:

• Eyelids, conjunctiva, episclera and sclera: Periorbital and conjunctival edema (1 wk); secondary Staphylococcus aureus infection (1-2 wk); focal scleral atrophy (late); scarring that leads to incomplete eyelid closure and thus corneal exposure and desiccation (latent)
• Cornea: Punctate epithelial keratitis (swollen epithelium, 1-2 d); dendritic keratitis (tree branchlike epithelial defects, 4-6 d); stromal keratitis (fine infiltrates beneath the surface, 1-2 wk); deep stromal keratitis (lipid infiltrates and corneal neovascularization, 1 month to years); neurotrophic keratopathy (erosions, persistent defects, corneal ulcers, months to years)
• Anterior chamber: Uveitis (inflammation and iris scarring leading to glaucoma and cataract, 2 weeks to years)

Race

No race suffers from HZO more than any other race.

Sex

This disease affects both genders equally.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• The prodromal phase of HZO usually includes an influenzalike illness with fatigue, malaise, and low-grade fever that may last up to 1 week prior to the development of unilateral rash over the forehead, upper eyelid, and nose (the first division of trigeminal nerve dermatome or V1).
• About 60% of patients have varying degrees of dermatomal pain prior to rash eruption. Subsequently, erythematous macules appear that progress to form clusters of papules and vesicles (clear vesicles on red base, 3-5 d). These lesions then evolve into pustules, which soon lyse and crust over (5-7 d).

Physical

• Ocular manifestations of HZ can vary in time of onset, and patients may have only ophthalmic symptoms without the typical skin rash. One prognostic indicator is Hutchinson sign, the appearance of typical HZ lesions at the tip, side, or root of the nose (nasociliary nerve dermatome). Because the nasociliary nerve also innervates the cornea such skin lesions may herald ocular involvement. The prognostic value of the Hutchinson sign has been validated in a recent study.¹
• Visual acuity can be considered to be a vital sign of the ophthalmologic examination, and the eye examination should begin here.
• • Systematically examine the most superficial/external structures first and look for eyelid, conjunctival, and scleral swelling.
  • Check for extraocular motor integrity and visual field deficits.
  • Perform a funduscopic examination (dilated if possible), and try to elicit photophobia to ascertain the possible presence of iritis. Decreased corneal sensitivity can be seen when testing with a cotton fiber.
  • Corneal epithelial lesions may be visible after fluorescein application.
  • A slit lamp examination should be used to look for cells/flares in the anterior chamber and the presence of stromal infiltrates.
  • After topical anesthesia of the eye, measure the intraocular pressures (normal pressure is below 12-15 cm H₂O).

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Bacterial keratoconjunctivitis
Adult inclusion (chlamydial) conjunctivitis
Allergic conjunctivitis
Recurrent corneal erosion
Toxic conjunctivitis
Fungal keratitis
Retinal necrosis
Connective tissue disease
Optic neuritis
Oculomotor palsy
Space-occupying lesion in the brain (tumors, toxoplasmosis, abscesses)
Multiple sclerosis

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• The HZ rash is distinctive enough that a clinical diagnosis is usually accurate. Nevertheless, the typical dermatomal rash may be absent or the location can be more diffuse, especially in the immunocompromised patients. Occasionally, only ocular signs and symptoms may be present, making the diagnosis difficult.
• Classically, a Tzanck smear and Wright stain can be performed to demonstrate herpes virus infections (cells are scraped from the base of cutaneous lesions and smeared on a glass slide for microscopy), but such tests do not distinguish VZV from other herpes viruses. Viral culture is also a possibility, yet the virus is relatively difficult to recover from the scrapes. A direct immunofluorescence assay can be used and is more sensitive than viral culture. Like culture, the direct immunofluorescence assay can differentiate herpes simplex virus infections from VZV infections. The assay also has a lower cost and a more rapid turnaround time. Polymerase chain reaction techniques can be useful in detecting the virus DNA from the lesions.

Imaging Studies

• No imaging studies are needed with this disease process.

Other Tests

• Because HZ may occur in HIV-infected individuals who are otherwise asymptomatic, serologic testing for the retrovirus may be appropriate in patients without apparent risk factors for HZ (nonimmunosuppressed individuals younger than 50 years).

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Emergency Department Care

Emergency department care includes local wound care, adequate analgesia, starting antiviral agents, and antibiotics for secondary bacterial infection. When the blinking reflex and eyelid function are compromised, an eye lubricant is needed to prevent corneal desiccation injury.

• A recent study in a community setting determined that antiviral agents decrease the frequency of complications and adverse outcomes due to HZO.² In particular, neurotrophic keratitis was less frequent among patients who received antiviral therapy. Among treated patients, development of serious inflammatory complication was associated with a delay in the initiation of antiviral therapy. Thus, according to this study, all patients with acute HZO should receive antiviral treatment. In order to be most effective, antiviral agents should begin within 72 hours of the onset of the rash. The effectiveness of therapy started more than 72 hours after symptom onset is not clearly established, yet there is no evidence against the benefits of antiviral agents even after 72 hours. Theoretically, the ongoing viral replication can be deterred at any time if the rash continues, especially if new lesions appear.
• The standard duration of antiviral therapy for HZ is 7-10 days. Nevertheless, the VZV DNA had been shown to persist in the cornea for up to 30 days. This is especially true in elderly individuals. This information implies that the antiviral regimens may have to be continued, particularly for the immunocompromised and the elderly patients, although no clinical trials have proven their efficacy in this particular patient population. More serious complications, such as retinal involvement, may require days of intravenous therapy and months of oral antiviral therapy.
• If a patient complains of severe pain at any point at or beyond the appearance of crusted vesicles, the clinician should strongly suspect that postherpetic neuralgia has developed. Treatment of postherpetic neuralgia is complex. A multifaceted, patient-specific approach is important. Clinical trials have shown that opioids, tricyclic antidepressants, and anticonvulsants (carbamazepine, gabapentin) may reduce the severity or duration of postherpetic neuralgia, either as single agents or in combination. Topical application of lidocaine patches or capsaicin cream may provide relief for some patients. Consultation with a pain therapist may be required.
• Anesthesia-based interventions such as local anesthetic blocking of sympathetic nerves or stellate ganglion blockade may produce transient relief, yet their effectiveness in reducing the protracted pain is still in question. Transcutaneous electric nerve stimulation, and if necessary, neurosurgery (eg, thermocoagulation of substantia gelatinosa Rolandi) has been found to be helpful in exceptional cases.
• In conjunction with the antiviral agents, corticosteroids are used to alleviate the pain and increase the rate of cutaneous healing. Steroid eye drops may be beneficial for HZO, yet it is only helpful in certain ocular diseases (see below), and can exacerbate others (ie, epithelial keratitis). Therefore, ophthalmologic consultation is mandatory prior to initiating steroid therapy. Although multiple reports have suggested that antiviral/steroid therapy decreases the duration of pain, the therapy does not seem to prevent postherpetic neuralgia.
• Each specific ophthalmic complication due to HZO has specific treatment modalities, and these should be initiated in consultation with an ophthalmologist. The following is the recommended treatment as shown in Shaikh and Ta's review of HZO³:
• • Blepharitis/conjunctivitis - Palliative, with cool compresses and topical lubrication; topical antibiotics for secondary infections
  • Stromal keratitis - Topical steroids
  • Neurotrophic keratitis - Topical lubrication; topical antibiotics for secondary infections; tissue adhesives and protective contact lenses to prevent corneal perforation
  • Uveitis - Topical steroids; oral steroids; oral acyclovir; cycloplegics
  • Scleritis/episcleritis - Topical nonsteroidal anti-inflammatory agents and/or steroids
  • Acute retinal necrosis/progressive outer retinal necrosis - Intravenous acyclovir (1500 mg per m² per day divided into 3 doses) for 7-10 days, followed by oral acyclovir (800 mg orally 5 times daily) for 14 weeks; laser/surgical intervention

Consultations

• An ophthalmologic consultation is crucial if the diagnosis of HZO is a possibility.
• Occasionally, a surgical consultation is required for debridement of involved forehead skin epithelium.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Antiviral agents, acyclovir, valacyclovir, and famciclovir, are approved in the United States for the management of HZ. Because of their superior pharmacokinetic profiles and simpler dosing regimens, valacyclovir and famciclovir may be preferred over acyclovir.

In an attempt to make the dosing regimen easier to ensure compliance, some researchers studied famciclovir to see if less frequent dosing would be as effective as current dosing recommendations.⁴ While the once-daily regimen of famciclovir 750 mg reduced the cutaneous symptoms and pain as effectively as the standard regimen, the effect on postherpetic neuralgia and ocular disease was not discussed.

The use of corticosteroids in HZO is only recommended in combination with antiviral agents. Corticosteroid therapy should not be used in patients at risk for corticosteroid-induced toxicity (eg, patients with diabetes mellitus or gastritis). Topical steroids alone do not reactivate the virus but may exacerbate spontaneous recurrences.

Drug Category: Antiviral agents

These agents interfere with DNA synthesis and inhibit viral replication. The current recommendation is to begin the antiviral therapy within 72 hours of symptom onset. An adjustment in the dose of the chosen antiviral agent is required in patients with renal insufficiency. Antiviral therapy reduces the frequency of late ocular complications from about 50% in untreated patients to about 20-30% in treated patients.

Drug Name	Famciclovir (Famvir)
Description	Prodrug of penciclovir, reduces duration of viral shedding, thereby limiting duration of new lesion formation, accelerating healing.
Adult Dose	500 mg PO 3 times/d for 7 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid or other drugs eliminated by renal excretion prolongs half-life and may increase toxicity; drugs metabolized by aldehyde oxidase
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in renal failure or when using with nephrotoxic drugs

Drug Name	Valacyclovir (Valtrex)
Description	Prodrug of acyclovir, produces serum acyclovir levels that are 3-5 times as high as those achieved with oral acyclovir therapy.
Adult Dose	1000 mg PO 3 times/d for 7 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid, cimetidine prolongs half-life (increases peak plasma concentrations)
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in renal failure or when using with nephrotoxic drugs

Drug Category: Analgesics

Acute herpetic pain control and postherpetic neuralgia pose quite a challenge for physicians. Following are some options for pharmacological analgesia.

Drug Category: Topical analgesics

These agents are indicated for application to normal, intact skin, to provide topical anesthesia.

Drug Name	Lidocaine 5% Patch (Lidoderm)
Description	Useful as topical for pain relief, especially indicated for postherpetic neuralgia
Adult Dose	Up to 3 patches at a time to painful area (maximum of 12 h)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	With Class I antiarrhythmic drugs (eg, tocainide, mexiletine) toxic effects can be synergistic or additive; when used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Localized skin irritation; systemic toxicity from cutaneous absorption of lidocaine very rare

Drug Category: Tricyclic antidepressants

These agents are used for pain relief in postherpetic neuralgia.

Drug Category: Anticonvulsants

Only one drug in this class, gabapentin, has been proven to be useful for the management of postherpetic neuralgia in adults.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Consider admission for the involvement of multiple dermatomes, immunocompromised conditions, and significant facial bacterial superinfection. IV antiviral medications should be administered as mentioned earlier.

Further Outpatient Care

• Patients should have adequate and timely outpatient follow-up for management of HZO. Reexamination after 1 week at the most should be scheduled in the initial stages. Antiviral medications should be administered and continued as mentioned above.

Transfer

• Transfer is rarely, if ever, indicated unless the patient develops systemic manifestations that require a higher level of care that the current hospital can provide.

Deterrence/Prevention

• Studies have shown that the varicella vaccine in children is highly effective in preventing chickenpox. Nevertheless, reports exist of outbreaks of varicella disease in highly immunized groups.⁵ Therefore, changes to the current vaccination policy may be anticipated. Whether vaccine-induced immune booster will reduce the incidence or severity of HZ in older adults is being tested in clinical trials.

Complications

• Other varied-onset ocular sequelae of HZ include problems with perfusion and virus-induced necrosis of the retina. Acute retinal necrosis is characterized by blurred vision, pain, coalescent patches of necrosis, inflammation of vitreous humor, occlusive vasculitis, and detachment of the retina. Progressive outer retinal necrosis syndromes that involve the macula occur in immunocompromised individuals and carry an extremely grave prognosis. Cranial nerve palsies (most commonly the oculomotor nerve) may be related to secondary vasculitis within the orbital apex and usually resolve spontaneously within 6 months. Cases of optic neuritis (swelling of the optic nerve head) have also been reported.
• Postherpetic neuralgia affects about 7% of patients with HZ, and individuals experience constant or intermittent pain in the distribution of the affected dermatome. It may last from months to years.

Prognosis

• The course of the disease can become chronic or relapsing since the eye has rendered itself vulnerable. Systemic antiviral therapy can lower the emergence of complications, yet no currently available regimen has been found to eliminate all of the complications.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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2. Severson EA, Baratz KH, Hodge DO, Burke JP. Herpes zoster ophthalmicus in olmsted county, Minnesota: have systemic antivirals made a difference?. Arch Ophthalmol. Mar 2003;121(3):386-90. [Medline].
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4. Shafran SD, Tyring SK, Ashton R, et al. Once, twice, or three times daily famciclovir compared with aciclovir for the oral treatment of herpes zoster in immunocompetent adults: a randomized, multicenter, double-blind clinical trial. J Clin Virol. Apr 2004;29(4):248-53. [Medline].
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8. Colin J, Prisant O, Cochener B, et al. Comparison of the efficacy and safety of valaciclovir and acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology. Aug 2000;107(8):1507-11. [Medline].
9. Gnann JW, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med. Aug 1 2002;347(5):340-6. [Medline].
10. Gross G, Schofer H, Wassilew S, et al. Herpes zoster guideline of the German Dermatology Society (DDG). J Clin Virol. Apr 2003;26(3):277-89; discussion 291-3. [Medline].
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12. Hutchinson J. Clinical report on herpes zoster frontalis ophthalmicus. Ophth Hosp Rep. 1864;3(72):865-6, 5:191.
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14. Liang MG, Heidelberg KA, Jacobson RM, McEvoy MT. Herpes zoster after varicella immunization. J Am Acad Dermatol. May 1998;38(5 Pt 1):761-3. [Medline].
15. Liesegang TJ. Herpes zoster virus infection. Curr Opin Ophthalmol. Dec 2004;15(6):531-6. [Medline].
16. Mosby's. Drug Consult (Online reference). 2005.
17. Opstelten W, van Wijck AJ, Stolker RJ. Interventions to prevent postherpetic neuralgia: cutaneous and percutaneous techniques. Pain. Feb 2004;107(3):202-6. [Medline].
18. Ragozzino MW, Melton LJ, Kurland LT, et al. Population-based study of herpes zoster and its sequelae. Medicine (Baltimore). Sep 1982;61(5):310-6. [Medline].
19. Vafai A, Berger M. Zoster in patients infected with HIV: a review. Am J Med Sci. Jun 2001;321(6):372-80. [Medline].
20. Whitley RJ, Weiss H, Gnann JW, et al. Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med. Sep 1 1996;125(5):376-83. [Medline].
21. Wood MJ, Johnson RW, McKendrick MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med. Mar 31 1994;330(13):896-900. [Medline].
22. Zaal MJ, Volker-Dieben HJ, Wienesen M, et al. Longitudinal analysis of varicella-zoster virus DNA on the ocular surface associated with herpes zoster ophthalmicus. Am J Ophthalmol. Jan 2001;131(1):25-9. [Medline].

Article Last Updated: Apr 4, 2006