eMedicine Specialties > Emergency Medicine > Infectious Diseases
Herpes Zoster Ophthalmicus
Updated: Sep 18, 2008
Introduction
Background
Varicella-zoster virus (VZV) causes 2 distinct syndromes. The primary infection (chickenpox) is a contagious and usually benign febrile illness. Following this infection, virus particles remain in the dorsal root or other sensory ganglion where they may lay dormant for years to decades. As a result of aging, immunosuppressive illness, new stress, or medical treatments, the virus-specific cell-mediated immune responses may decline. 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.1 The reported annual incidence of HZ varies from 1.5-3.4 cases per 1000 individuals.2 The key risk factor for the development of HZ is waning of the cell-mediated immune system associated with the normal aging process. However, the incidence of shingles among individuals older than 75 years exceeds 10 cases per 1000 individual-years. This may be due to the fact that immunity wanes as adults age. The lifetime risk of HZ is currently estimated to be 10-20%.2,3
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). 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. 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
One of the most common complications of herpes zoster in any location is postherpetic neuralgia; neuropathic pain which can persist along the affected dermatome for weeks or even years after the resolution of the rash. Specific complications of herpes zoster ophthalmicus 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
One study has shown a higher prevalence in women than in men.4
Age
The incidence of HZ increases dramatically with age.4
Clinical
History
- The prodromal phase of herpes zoster ophthalmicus 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 the Hutchinson sign, the appearance of typical HZ lesions at the tip, side, or root of the nose. This is the area of skin innervated by the anterior ethmoidal branch of the nasociliary nerve. 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 one study.5
- 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 H2 O).
Causes
See Pathophysiology.
Differential Diagnoses
| Conjunctivitis | Scleritis |
| Corneal Abrasion | Stroke, Hemorrhagic |
| Corneal Ulceration and Ulcerative
Keratitis | Stroke, Ischemic |
| Glaucoma, Acute Angle-Closure | Subarachnoid Hemorrhage |
| Headache, Cluster | Toxoplasmosis |
| Headache, Migraine | Trigeminal Neuralgia |
| Iritis and Uveitis | |
| Meningitis | |
| Neoplasms, Brain |
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
Laboratory Studies
- The herpes zoster (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 aid in the diagnosis of HZO.
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
Emergency Department Care
Emergency department care of herpes zoster ophthalmicus (HZO) 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.
- Oral acyclovir has been shown to shorten the duration of signs and symptoms, as well as to reduce the incidence and severity of HZO complications. While it has effect in reducing the pain during the acute phase, it has no demonstrated effect on reducing the incidence or severity of postherpetic neuralgia.6 Acyclovir appears to benefit patients the most whose therapy is initiated within 72 hours of onset of the skin lesions, with higher complication rates occurring among patients whose treatment was delayed.6,7
- Both famciclovir and valacyclovir (500 mg tid) have been shown to be as effective as acyclovir (800 mg 5 times a day) in the treatment of herpes zoster and reduction in complications.8,9 These medications have simpler dosing regimens than acyclovir, which may increase patient compliance.
- 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 immunocompromised and 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.
- The use of oral corticosteroids has been shown to reduce the duration of pain during the acute phase of the disease and to increase the rate of cutaneous healing; however, it has not been shown to decrease the incidence of postherpetic neuralgia.10,11 While steroids do improve quality of life, they are not appropriate for all patients and should be reserved for those patients who are relatively healthy and in whom there is no contraindication.
- 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 ocular steroid 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.
- 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 HZO12 :
- 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.
- An anesthesia consultation may be helpful in treating patients with refractory pain.
- Occasionally, a surgical consultation is required for debridement of involved forehead skin epithelium.
Medication
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.13 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.
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.
Acyclovir (Zovirax)
Reduces duration of cutaneous lesions and herpetic pain. Indicated for patients presenting within 48 h of rash onset.
Dosing
Adult
800 mg PO q4h or 5 times/d for 7-10 d
Renal dose if creatinine clearance (mL/min/1.73 m2) is:
>25, No adjustment necessary
10-25: 800 mg q8h
0-10: 800 mg q12h
Pediatric
Not established; suggested dose is 10-20 mg/kg (up to 800 mg) PO q4h or 5 times/d for 5 d
Interactions
Antifungals and interferons may have synergistic or additive effect; probenecid prolongs half-life (drugs eliminated by renal excretion); zidovudine may increase CNS toxicity
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use renal dose in renal failure or when using with nephrotoxic drugs
Famciclovir (Famvir)
Prodrug of penciclovir, reduces duration of viral shedding, thereby limiting duration of new lesion formation, accelerating healing.
Dosing
Adult
500 mg PO 3 times/d for 7 d
Pediatric
Not established
Interactions
Probenecid or other drugs eliminated by renal excretion prolongs half-life and may increase toxicity; drugs metabolized by aldehyde oxidase
Contraindications
Documented hypersensitivity
Precautions
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
Valacyclovir (Valtrex)
Prodrug of acyclovir, produces serum acyclovir levels that are 3-5 times as high as those achieved with oral acyclovir therapy.
Dosing
Adult
1000 mg PO 3 times/d for 7 d
Pediatric
Not established
Interactions
Probenecid, cimetidine prolongs half-life (increases peak plasma concentrations)
Contraindications
Documented hypersensitivity
Precautions
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
Analgesics
Acute herpetic pain control and postherpetic neuralgia pose quite a challenge for physicians. Following are some options for pharmacological analgesia.
Oxycodone (OxyContin, Roxicodone, OxyIR)
Indicated for relief of moderately severe to severe pain.
Dosing
Adult
5 mg PO q6h for total dose of 80 mg/d (or higher in tolerant individuals)
Pediatric
0.05-0.15 mg/kg/dose PO q6h, not to exceed 5 mg/dose
Interactions
Phenothiazines may decrease analgesic effects; CNS depressants or tricyclic antidepressants increase toxicity
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause more sedation and respiratory depression in acute alcoholism, adrenocortical insufficiency (eg, Addison disease), debilitated patients, hypothyroidism, severe impairment of hepatic, pulmonary or renal function, and toxic psychosis
Topical analgesics
These agents are indicated for application to normal, intact skin, to provide topical anesthesia.
Capsaicin (Dolorac, Zostrix)
Natural substance derived from plants of Solanaceae family. Useful for acute pain relief; may titrate up to higher concentration (1%).
Dosing
Adult
Apply topically 0.025-0.075% cream tid/qid to affected area
Pediatric
Apply as in adults
Interactions
None reported
Contraindications
Documented hypersensitivity; broken or irritated skin
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Discontinue use if condition worsens or if symptoms persist for 14-28 d
Lidocaine 5% Patch (Lidoderm)
Useful as topical for pain relief, especially indicated for postherpetic neuralgia
Dosing
Adult
Up to 3 patches at a time to painful area (maximum of 12 h)
Pediatric
Not established
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
Contraindications
Documented hypersensitivity
Precautions
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
Tricyclic antidepressants
These agents are used for pain relief in postherpetic neuralgia.
Nortriptyline (Pamelor)
Useful as analgesic for certain chronic and neuropathic pain syndromes.
Dosing
Adult
10-25 mg PO at bedtime; begin at low dose and titrate upwards (to 75-150 mg/d)
Pediatric
Not recommended for children
Interactions
Reserpine, alcohol may have additive or synergistic effects; increased side effects such as sedation and confusion with other anticholinergic drugs and sympathomimetic drugs; cimetidine increases the plasma concentrations; CYP2D6 enzyme system inhibitors thus may increase levels of other drugs metabolized by this system
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Use of MAOIs in past 14 d; recent MI; history of seizures, cardiac arrhythmias, glaucoma, or urinary retention
Anticonvulsants
Only one drug in this class, gabapentin, has been proven to be useful for the management of postherpetic neuralgia in adults.
Gabapentin (Neurontin)
Only anticonvulsant to be evaluated for management of post-herpetic neuralgia; proven to be effective in randomized placebo-controlled trial.
Dosing
Adult
300 mg PO qd (single dose); titration of dose as necessary over 4 wk period, to total daily dose of 3600 mg (divided into 2-3 doses as dosage increases)
Pediatric
Not established
Interactions
Not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs; absorption and concentration may increase with cimetidine, morphine, and naproxen; decreases concentration of hydrocodone; Maalox may decrease gabapentin's bioavailability
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in severe renal disease
Follow-up
Further Inpatient Care
- For patients with herpes zoster ophthalmicus, 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.14 Therefore, changes to the current vaccination policy may be anticipated.
- Based on the results of the Shingles Prevention Study, in 2006, the FDA has approved the Zostavax vaccine for the prevention of herpes zoster in people aged 60 years and older. More than 38,000 adults older than 60 years were enrolled in a randomized, double-blind, placebo-controlled trial of the vaccine. The vaccine reduced the incidence of herpes zoster by 61.1% (p<0.001) and the incidence of postherpetic neuralgia by 66.5% (p<0.001).15
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
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Keywords
herpes zoster ophthalmicus, eye infection, herpes zoster, varicella-zoster virus, varicella zoster virus, VZV, HZO, herpes virus, chickenpox, shingles, human herpesvirus type 3
Contributor Information and Disclosures
Author
Maria M Diaz, MD, Staff Physician, Department of Emergency Medicine, State University of New York Downstate Medical Center
Maria M Diaz, MD is a member of the following medical societies: Phi Beta Kappa
Disclosure: Nothing to disclose.
Coauthor(s)
Mark A Silverberg, MD, FACEP, MMB, Assistant Professor, Assistant Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate at Brooklyn
Mark A Silverberg, MD, FACEP, MMB is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Medical Editor
Robin R Hemphill, MD, MPH, Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University
Robin R Hemphill, MD, MPH is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
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Douglas Lavenburg, MD, Clinical Professor, Department of Emergency Medicine, Christiana Care Health Systems
Douglas Lavenburg, MD is a member of the following medical societies: American Society of Cataract and Refractive Surgery
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CME Editor
John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
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Chief Editor
Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
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