Herpes Zoster Ophthalmicus 

Varicella-zoster virus (VZV) causes 2 distinct syndromes. The primary infection, chickenpox, is a contagious and usually benign febrile illness. After this infection resolves, 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; see images below). HZO was described long ago by Hippocrates, but its relation to VZV was not elucidated until the advent of modern medical tools such as immunohistochemical assays.

HZO accounts for 10-25% of all cases of shingles. The sequelae of HZO can be devastating; they include chronic ocular inflammation, visual loss, and debilitating pain.^{[1, 2, 3, 4, 5]}

For more information on herpes zoster, see Herpes Zoster, Pediatric Herpes Zoster, and Herpes Zoster Oticus.

Patient education

For patient education information, see the Bacterial and Viral Infections Center, as well as Chickenpox and Shingles.

After primary infection, varicella-zoster virus (VZV) enters the dorsal root ganglia, where it remains latent for the lifetime of the individual.^[6] When liberated from the trigeminal ganglion, the reactivated VZV travels down the first division (ophthalmic) of the trigeminal nerve to the nasociliary nerve. Branches of the nasociliary nerve innervate the surface of the globe and the skin on the nose down to its tip.

The viral particles typically take 3-4 days to reach the nerve endings. As the virus travels, it provokes perineural and intraneural inflammation, which may damage the eye itself and/or other surrounding structures.

The frequency of dermatologic involvement in herpes zoster is similar to the centripetal distribution of the initial varicella lesions. This pattern suggests that the latency may arise from contiguous spread of the virus during varicella from infected skin cells to sensory nerve endings with subsequent ascent to the ganglia. Alternatively, the ganglia may become infected hematogenously during the viremic phase of varicella, and the frequency of the dermatome involvement in herpes zoster may reflect the ganglia most often exposed to reactivating stimuli.

The appearance of the cutaneous rash due to herpes zoster coincides with a profound VZV-specific T-cell proliferation. Interferon-alpha production appears with the resolution of herpes zoster. In immunocompetent patients, specific antibodies (immunoglobulins G, M, and A) appear more rapidly and reach higher titers during reactivation (herpes zoster) than during the primary infection. The patient has a long-lasting, enhanced, cell-mediated immunity response to VZV.^{[7, 8, 9]}

Infection with varicella-zoster virus (VZV) places a person at risk for herpes zoster (HZ). In the United States, more than 90% of the population is infected with VZV by adolescence, and approximately 100% are infected by 60 years of age.^{[10, 11]} The reported annual incidence of HZ varies from 1.5-3.4 cases per 1000 individuals.^[12] Herpes zoster ophthalmicus (HZO) represents 10-25% of all cases of HZ. Approximately half of these patients develop complications of HZO. The risk of ophthalmic complications in patients with HZ does not seem to correlate with age, sex, or severity of the rash.

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 begins to rise strongly in the sixth decade of life; among individuals older than 75 years, the rate exceeds 10 cases per 1000 individual-years. The lifetime risk of HZ is currently estimated to be 10-20%.^{[12, 13, 14]}

The other well-defined risk factor for HZ is acquired inhibition of the cell-mediated immune response, such as from treatment with immunosuppressive drugs or infection with 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 with 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.

In the United States, as many as 10,000 hospitalizations and approximately 100 deaths occur per year as a result of complications from VZV infection. Morbidity and mortality affect mostly elderly persons, individuals with immunosuppressive disorders (eg, those with HIV infection or AIDS), persons receiving immunosuppressive therapy, and persons who incurred primary infection in utero or in early infancy.

Race, sex, and age demographics

Although HZ is generally considered not to have a racial predilection, in 1995, Schmader et al reported that the lifetime incidence of HZ zoster in whites is twice that of African Americans.^[15] Similarly, although HZ has generally not been considered to have a sex predilection, one study has shown a higher prevalence in women than in men.^[16]

Primary infection with VZV is a childhood disease, while VZV reactivation is primarily a disease that affects healthy older adults. The incidence of HZ increases dramatically with age, peaking in the seventh decade of life.^{[16, 10]}

Patient history

The prodromal phase of herpes zoster ophthalmicus (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; see image below). These lesions then evolve into pustules, which soon lyse and crust over (5-7 d). Lesions may resolve rapidly and completely, or they may lead to a chronic course and linger for years. As with chickenpox, once crusting occurs, the lesions cease to be infectious.

Scarring and hypopigmentation or hyperpigmentation may persist for a long period. With infected and manipulated lesions, deep scars may form.^[17]

Other symptoms of HZO include eye pain, conjunctivitis (usually unilateral), tearing, decreased vision, and skin/eyelid rash.

Physical examination

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, which is the appearance of typical HZ lesions at the tip, side, or root of the nose (see images below). This is the area of skin innervated by the infratrochlear and external nasal branches 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.^[18] However, severe ocular complications can occur with a vesicular rash anywhere on the forehead.^[18]

Ophthalmologic examination

Visual acuity can be considered to be a vital sign of the ophthalmologic examination. The eye examination should begin with this.

Systematically examine the most superficial/external structures first. Look for eyelid, conjunctival, and scleral swelling. Then check for extraocular motor integrity and visual field deficits.

Perform a funduscopic examination (dilated if possible). 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. An epithelial defect and a corneal ulcer are shown in the images below.

A slit-lamp examination (see image below) should be used to look for cells/flares in the anterior chamber and the presence of stromal infiltrates.

After applying topical anesthesia to the eye, measure the intraocular pressures (normal pressure is below 12-15 mm Hg).

Complications

One of the most common complications of HZ in any location is postherpetic neuralgia. This neuropathic and oftentimes excruciating pain can persist along the affected dermatome for weeks or even years after the resolution of the rash.^[10] Postherpetic neuralgia is more common in patients older than 50 years.^{[19, 20, 21, 22, 23]}

HZ may become disseminated. Dissemination implies a viremia, which may lead to visceral (eg, lungs, liver, brain) or neurologic (eg, motor neuropathies of the cranial and peripheral nervous system, encephalitis, meningoencephalitis, myelitis, Guillain-Barré syndrome) infection. The risk of dissemination is increased in immunosuppressed patients, including immunosuppressed organ-transplant recipients and immune-deficient patients with cancer, leukemia, and AIDS .

Specific complications of HZO center on the destruction of the ocular structures and manifest as various ocular diseases that can lead to permanent loss of sight.

Complications involving the eyelids, conjunctiva, episclera, and sclera include the following:

• Periorbital and conjunctival edema (1 wk)
• Secondary Staphylococcus aureus infection (1-2 wk)
• Focal scleral atrophy (late)

Secondary bacterial infections may lead to deep, unsightly scars. In addition, scarring can lead to incomplete eyelid closure and thus corneal exposure and desiccation. Patients can avoid scarring by maintaining good hygiene and by refraining from scratching, which may lead to untimely scab removal and tissue repair disruption.

Complications involving the cornea include the following (also see images below):

• Punctate epithelial keratitis (swollen epithelium, 1-2 d)
• Dendritic keratitis (tree branch–like 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)Sclerokeratouveitis secondary to infection with the varicella-zoster virus. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School. Dendritic keratitis. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School. Dendritic keratitis. Image courtesy of Manolette Roque, MD, Ophthalmic Consultants Philippines Co, EYE REPUBLIC Ophthalmology Clinic.

A complication involving the anterior chamber is uveitis, with inflammation and iris scarring leading to glaucoma and cataract. This occurs over 2 weeks to years.

Varicella-zoster virus (VZV; human herpesvirus type 3) is a member of the Herpesviridae family (human herpesvirus type 3). It is the etiologic agent of varicella (chickenpox), the primary infection, and herpes zoster, the reactivation.^{[24, 25]}

Known risk factors for developing herpes zoster relate to the status of cell-mediated immunity to VZV. The following are risk factors for VZV infection:

• VZV-specific immunity and cell-mediated immunity, which generally declines with age
• Immunosuppression (eg, HIV infection, AIDS)^{[26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38]}
• Immunosuppressive therapy^[39]
• Primary infection in utero or in early infancy, when the normal immune response is decreased

The differential diagnosis of HZO includes the following:

• Conjunctivitis
• Corneal Abrasion
• Corneal Ulceration and Ulcerative Keratitis
• Glaucoma, Acute Angle-Closure
• Iritis and Uveitis
• Keratitis, Herpes Simplex
• Ocular Manifestations of HIV
• Scleritis
• Toxoplasmosis
• Trigeminal Neuralgia

Other disorders to consider include the following:

• 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
• Traumatic abrasions
• Paralytic ptosis
• Cicatricial lid retraction or loss
• Iridocyclitis
• Cataract
• Postherpetic neuralgia
• Orbital apex syndrome
• Inflammatory syndromes
• Argyll Robertson pupil
• Retinitis
• Choroiditis
• Extraocular muscle palsies
• Cluster headache
• Tension headache
• Hemorrhagic stroke
• Ischemic stroke
• Isolated facial nerve trauma

Herpes zoster (HZ) is diagnosed mostly on the basis of the characteristic pain and appearance of the dermatomal rashes. More often than not, laboratory tests are unnecessary. Empiric treatment, when indicated, should not be delayed pending the results of diagnostic tests.

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.

On the rare occasion that a differential diagnosis of several skin lesions must be made, confirmatory laboratory examinations may be undertaken. Classically, a Tzanck smear and Wright stain can be performed to for the rapid presumptive diagnosis of varicella-zoster virus (VZV). Cells are scraped from the base of cutaneous lesions and smeared on a glass slide for microscopy; typical findings are multinucleated giant syncytial cells, homogenization of nuclear chromatin, and acidophilic intranuclear antibodies with faceted contours. However, 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 of a biopsy sample 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.^{[40, 41]}

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

Cell-mediated immunity testing includes the following:

• Varicella-zoster virus (VZV) antigen skin test
• VZV lymphocyte proliferation

Serology for VZV antibodies includes the following:

• Neutralizing or complement-fixing antibody tests
• Enzyme-linked immunosorbent assay
• Radioimmunoassay
• Membrane antigen immunofluorescence
• Immune adherence hemagglutination

Histopathologic findings result from viral replication, secondary inflammation, and vascular occlusion. The pathologic hallmark of reactivating herpes zoster is ganglionic inflammation and hemorrhagic necrosis of the ganglion and corresponding sensory nerve.

Characteristic findings in involved areas include the following:

• Multinucleated giant cells
• Intranuclear inclusion bodies
• Ballooning and reticular degeneration
• Acantholytic keratinocytes
• Perivascular infiltrate (polymorphonuclear neutrophils [PMNs] and mononuclear cells)

In chronic herpes zoster infections, a granulomatous reaction (epithelioid and multinucleated giant cells) may be found intraocularly (eg, ciliary body, choroid, retina).

Emergency department care

Emergency department care of herpes zoster ophthalmicus (HZO) includes local wound care, adequate analgesia, starting antiviral agents, and starting antibiotics if secondary bacterial infection is present. When the blinking reflex and eyelid function are compromised, an eye lubricant is needed to prevent corneal desiccation injury.

Antiviral treatment

Oral acyclovir (5 times/d) has been shown to shorten the duration of signs and symptoms, as well as to reduce the incidence and severity of HZO complications. While can reduce the pain during the acute phase, it has no demonstrated effect on reducing the incidence or severity of postherpetic neuralgia.^[42] Acyclovir appears to benefit patients the most when therapy is initiated within 72 hours of onset of the skin lesions, with higher complication rates occurring among patients whose treatment was delayed.^{[42, 43]}

Both famciclovir (500 mg tid) and valacyclovir (1 g 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.^{[44, 45]} Like acyclovir, these agents are approved in the United States for the management of HZ. These medications have simpler dosing regimens than acyclovir, which may increase patient compliance.

Shafran et al found that a once-daily regimen of famciclovir 750 mg reduced the cutaneous symptoms and pain of HZ as effectively as the standard regimen.^[46] Although this simpler regimen might enhance compliance, this study did not address the effect on ocular disease or postherpetic neuralgia.

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, VZV DNA has been shown to persist in the cornea for up to 30 days. This is especially true in elderly individuals. This finding 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.

Corticosteroid 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.^{[47, 48]} 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.

Corticosteroids are recommended for HZO only for use 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. In addition, while steroid eye drops may be beneficial for HZO, they are helpful only in certain ocular diseases (see below) and can exacerbate others (ie, epithelial keratitis). Therefore, ophthalmologic consultation is mandatory prior to initiating ocular steroid therapy.

Treatment of postherpetic neuralgia

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.

Pavan-Langston has outlined the following protocol for treatment of postherpetic neuralgia^[49] :

• Tricyclic antidepressants - nortriptyline, amitriptyline, or desipramine 25 mg; adjust up to 75 mg at bedtime (qhs); for several weeks if needed
• Topical treatment with capsaicin ointment daily (qd) or 4 times/day (qid) or lidocaine patches
• Gabapentin (Neurontin, 30-600 mg tid) and/or sustained-release oxycodone (OxyContin SR, 10-20 mg bid)^{[21, 50, 51]}

In a small study by Kanai et al, administration of lidocaine 4% ophthalmic eyedrops produced a significant reduction in eye and forehead pain. Analgesic onset was noted via a visual analog scale within 15 minutes after administration and persisted for a median of 36 hours (range, 8-96 h).^[52]

Although anesthesia-based interventions such as local anesthetic blocking of sympathetic nerves or stellate ganglion blockade may produce transient relief, 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) have been found to be helpful in exceptional cases.

Treatment of ophthalmic complications

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 in Shaikh and Ta's review of HZO^[53] :

• 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

Surgical treatment

Some patients may require minor surgical procedures to correct scarring, such as a lateral tarsorrhaphy or lid traction sutures. In other patients with widespread corneal scarring, penetrating keratoplasty may be performed.^{[54, 55, 56, 57]} (See images below.)

Consultations

The following consultations may be indicated:

• Ophthalmologic consultation is crucial if the diagnosis of HZO is a possibility
• Anesthesia consultation may be helpful for patients with refractory pain
• Surgical consultation is occasionally required for debridement of involved epithelium
• Psychiatric consultation may be necessary in patients with excruciating pain due to postherpetic neuralgia
• Infectious disease specialist should be considered in cases of disseminated zoster or zoster with visceral involvement

Inpatient Care

Hospital admission should be considered for patients with any of the following:

• Severe symptoms
• Immunosuppression
• Involvement of more than 2 dermatomes
• Significant facial bacterial superinfection

Antiviral medications should be administered intravenously.

Wet-to-dry dressings with sterile saline solution or Burow solution (pharmacological preparation made of 5% aluminum acetate dissolved in water) should be applied to the affected skin for 30-60 minutes 4-6 times per day.

Calamine lotion, a mixture of zinc oxide with about 0.5% iron(III) oxide, may be used as an antipruritic (anti-itching) agent. It is also used as a mild antiseptic to prevent infections that can be caused by scratching the affected area, as well as an astringent for weeping or oozing blisters. There is no proof that calamine lotion has any real therapeutic effect on rashes and itching.

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 continued. Follow-up care in a pain clinic may be advised.

Prevention

In 1995, the US Food and Drug Administration (FDA) licensed a live attenuated varicella vaccine for immunization of healthy infants, children, adolescents, and adults in the United States who have not had chickenpox and who are not pregnant.^[58] 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.^[59] Therefore, changes to the current vaccination policy may be anticipated.

Based on the results of the Shingles Prevention Study, in 2006, the FDA 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% and the incidence of postherpetic neuralgia by 66.5%.^[60]

In March 2011, the Food and Drug Administration (FDA) lowered the approved age for use of Zostavax to 50-59 years. Zostavax was already approved for use in individuals aged 60 years or older. Annually, in the United States, shingles affects approximately 200,000 healthy people aged 50-59 years. Approval was based on a multicenter study, the Zostavax Efficacy and Safety Trial (ZEST).^[61] The trial was conducted in the United States and 4 other countries in 22,439 people aged 50-59 years. Participants were randomized in a 1:1 ratio to receive either Zostavax or placebo. Participants were monitored for at least 1 year to see if shingles developed. Compared with placebo, Zostavax significantly reduced the risk of developing zoster by approximately 70%.

HZ immunization guidelines are available from the Advisory Committee on Immunization Practices.^[62]

Herpes zoster ophthalmicus (HZO) can become chronic or relapsing. Recurrence is a characteristic feature of HZO. Relapse may occur as late as 10 years after onset.

About 50% of patients with HZO develop complications.^{[63, 64]} Systemic antiviral therapy can lower the emergence of complications, yet no currently available regimen has been found to eliminate all of the complications.