AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

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

INTRODUCTION

Section 2 of 12  

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

Background

Varicella-zoster virus (VZV) is a member of the Herpesviridae family. It is the etiologic agent of varicella (chickenpox), the primary infection, and herpes zoster, the reactivation.^{1, 2}

Herpes zoster ophthalmicus involves the tissues innervated by the ophthalmic division of the trigeminal nerve and accounts for 10-25% of all cases of shingles. The sequelae of herpes zoster ophthalmicus can be devastating and include chronic ocular inflammation, visual loss, and debilitating pain.^{3, 4, 5, 6, 7}

Herpes zoster oticus involves the inner, middle, and external ear. Herpes zoster oticus presents as excruciating otalgia with an associated cutaneous vesicular eruption (external canal and pinna). When associated facial paralysis is present, the disease is called Ramsay Hunt syndrome.^{8, 9}

Pathophysiology

After primary infection, VZV enters the dorsal root ganglia (trigeminal = herpes zoster ophthalmicus, geniculate = herpes zoster oticus), where it remains latent for the lifetime of the individual.¹⁰

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

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 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. The patient has a long-lasting, enhanced, cell-mediated immunity response to VZV.^{11, 12, 13}

Frequency

United States

Regarding primary infection, more than 90% of the population is infected by adolescence, and approximately 100% are infected by 60 years of age.¹⁴

Herpes zoster affects about 10-20% of the population.¹⁵ The rate is approximately 131 per 100,000 person-years in white individuals.

According to Pavan-Langston's review, 1 million consultations for herpes zoster occur per year; approximately 250,000 of the patients thus examined develop herpes zoster ophthalmicus. A subset of 50% of these patients develops complications of herpes zoster ophthalmicus.

Ramsay Hunt syndrome is the cause of as many as 12% of all cases of facial paralysis.

Mortality/Morbidity

• 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 immunosuppressed individuals, including elderly persons, individuals who are immunosuppressed (eg, those with HIV infection or AIDS), persons receiving immunosuppressive therapy, and persons with primary infection in utero or in early infancy.
• • CNS complications: Meningoencephalitis, myelitis, cranial nerve palsies, and granulomatous angiitis may result in the development of a cerebrovascular accident.¹⁶
  • Disseminated zoster: Hematogenous spread may result in the involvement of multiple dermatomes and visceral involvement and may lead to death due to encephalitis, hepatitis, or pneumonitis.
• In herpes zoster ophthalmicus, complications may be associated with inflammatory changes (infiltrative, eg, keratitis, or vasculitic, eg, episcleritis/scleritis, iritis, ischemic papillitis, orbital vasculitis).^{17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31}  Other complications occur as a result of nerve damage (eg, neurotrophic keratitis, some ocular motor palsies, neuralgia) and tissue scarring (eg, lid deformities, neuralgia, lipid keratopathy).^{32, 33, 34, 35, 36, 37, 38, 39} Ramsay Hunt syndrome (zoster involving cranial nerves V, IX, and X) usually causes symptoms more severe than those of Bell palsy.^{8, 40} In numerous studies, only 10-22% of individuals with significant facial paralysis had complete recovery. However, in one report, 66% of patients with incomplete paralysis had complete recovery.
• Secondary bacterial infection, typically streptococcal or staphylococcal, may occur at the site of the rash.⁴¹ Secondary bacterial infections may lead to deep, unsightly scars. They may be avoided by maintaining good hygiene and by preventing scratching, which may lead to untimely scab removal and tissue repair disruption. 
• Postherpetic neuralgia (ie, pain that persists for more than 1 month after resolution of the vesicular rash) is a common and oftentimes excruciating complication of herpes zoster. This is more common in patients older than 50 years.^{42, 43, 34, 44, 45}

Race

In 1995, Schmader et al reported that the lifetime incidence of herpes zoster in whites is twice that of African Americans.

Sex

No known sex predilection exists.

Age

• Primary infection with VZV is a childhood disease.
• VZV reactivation or herpes zoster is primarily a disease that affects healthy older adults.
• Incidence increases with age, peaking in the seventh decade of life.

CLINICAL

Section 3 of 12  

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

History

Patients with herpes zoster often report a history of chickenpox. In some cases, a present state of immunocompromise may be noted.

Herpes zoster results in a prodrome (ie, fever, malaise, headache, dysesthesia) that occurs 1-4 days before the development of the cutaneous lesions (rashes). Prodromal pain is typically confined to the same dermatomal distribution. The rashes, which are initially vesicular, gradually become pustular and then crust over during a period of 7-10 days. Similar to chickenpox, once crusting occurs, the lesions cease to be infectious. 

Scarring and hypopigmentation or hyperpigmentation may persist for a long period. For infected and manipulated lesions, deep scars may form.⁴⁶

• Herpes zoster ophthalmicus
• • Acute orbital and globe lesions develop within 3 weeks of the rash. These lesions may resolve rapidly and completely, or they may lead to a chronic course and linger for years.
  • Recurrence is a characteristic feature of herpes zoster ophthalmicus. Relapse may occur as late as 10 years after onset.
  • Symptoms of herpes zoster ophthalmicus may include eye pain, red eye (usually unilateral), decreased vision, skin/eyelid rash and pain, fever, malaise, and tearing.
• Herpes zoster oticus
• • Usually, patients present with excruciating otalgia.
  • Symptoms include painful burning blisters (in and around the ear, on the face, in the mouth, and/or on the tongue), vertigo, hearing loss, and eye pain.
  • Onset of pain may precede the rash by several hours or days.

Physical

• Exanthem
• • Grouped vesicles, usually involving 1, but occasionally up to 3, adjacent dermatomes.^{47, 48}
  • Vesicles become pustular, and occasionally hemorrhagic, with evolution to crusts in 7-10 days.
• Herpes zoster ophthalmicus¹³
• • Vesicular rashes involving the ophthalmic division of the trigeminal nerve. Crusting begins on the fifth to sixth day.
  • In 1864, Hutchinson proposed that the cutaneous involvement in the distribution of the nasociliary nerve heralds ocular involvement. Time has proven him correct (Hutchinson sign). It is now accepted that severe ocular complications can occur with a vesicular rash anywhere on the forehead.⁴⁹
• Herpes zoster oticus
• • Examination reveals a vesicular exanthem involving the external auditory canal, concha, and pinna. Other possible areas of involvement can include postauricular skin, lateral nasal wall, soft palate, and anterolateral tongue.
  • Vertigo and sensorineural hearing loss and/or paralysis of the facial nerve may be noted.
  • Clinically, total loss of the ability to wrinkle the ipsilateral brow differentiates a peripheral seventh nerve lesion from a central seventh nerve lesion, which spares the forehead.
  • Other associated findings may include dysgeusia (alteration in taste) and inability to fully close the ipsilateral eye, which may lead to an occasional presenting complaint of eye dryness and irritation.

Causes

Known risk factors for developing herpes zoster relate to the status of cell-mediated immunity to VZV.

• Various factors can account for the increased incidence of herpes zoster:
• • VZV-specific immunity and cell-mediated immunity, which generally declines with age
  • Immunosuppression (eg, HIV infection, AIDS)^{50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62}
  • Immunosuppressive therapy⁶³
  • Primary infection in utero or in early infancy, when the normal immune response is decreased
• VZV virology
• • VZV is a double-stranded DNA virus with a diameter of 150-200 nm, a lipid envelope bearing the host cell membrane, and glycoprotein spikes. These envelope proteins are essential to understanding the VZV-specific immunity and the production of improved vaccines.
  • Intranuclear replication of VZV in the host cell occurs and produces an intranuclear inclusion body. Viral DNA transcription to messenger RNA leads to synthesis of viral proteins in the host cell cytoplasm. These newly synthesized viral proteins are transported to the host cell nucleus. Assembly with replicated viral DNA into nucleocapsids ensues. Finally, an outer envelope is acquired as the assembled virus passes through the cytoplasm prior to its release from the cell.

DIFFERENTIALS

Section 4 of 12  

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

Other Problems to be Considered

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

WORKUP

Section 5 of 12  

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

Lab Studies

• Herpes zoster 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.
• On rare occasion that a differential diagnosis of several skin lesions must be made, confirmatory laboratory examinations may be undertaken. These tests include morphologic, immunomorphologic, viral isolation, serologic, and cellular immunity tests.
• Morphologic tests may involve the Tzanck staining techniques (eg, Giemsa, Wright, and/or Papanicolaou staining and light and/or electron microscopy).
• • Tzanck smears are regarded as simple procedures for the rapid presumptive diagnosis of VZV.
  • Typical findings are multinucleated giant syncytial cells, homogenization of nuclear chromatin, and acidophilic intranuclear antibodies with faceted contours. These results may help in identifying the herpes virus, but they cannot be used to distinguish VZV.
• Scrapings for smears and cultures are usually negative, and biopsy is required for definitive diagnosis. Biopsy typically includes culture and histopathologic examination with special stains and/or polymerase chain reaction of extracted DNA.^{64, 65}
• Immunologic tests for viral antigen
• • Direct immunofluorescence or immunoperoxidase stains
  • Radioimmunoassay
  • Enzyme-linked immunosorbent assay
  • Agar gel immunodiffusion
  • Immunoelectrophoresis
• Molecular biology of VZV DNA^{66, 67, 68}
• • In situ hybridization
  • Polymerase chain reaction

Other Tests

• Cell-mediated immunity testing
• • VZV antigen skin test
  • VZV lymphocyte proliferation
• Serology for VZV antibodies
• • Neutralizing or complement-fixing antibody tests
  • Enzyme-linked immunosorbent assay
  • Radioimmunoassay
  • Membrane antigen immunofluorescence
  • Immune adherence hemagglutination

Procedures

• Biopsy for direct immunofluorescence testing (see Lab Studies)

Histologic Findings

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, and 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).

TREATMENT

Section 6 of 12  

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

Medical Care

Current therapeutic strategies for acute herpes zoster ophthalmicus include antiviral agents, systemic corticosteroids, antidepressants, and adequate pain control.^{69, 70, 20, 71, 72, 73, 74, 75, 76, 77, 24, 78}

• Treatment of acute herpes zoster ophthalmicus is optimal if started within 72 hours of rash onset. Pavan-Langston has outlined the following protocol for treatment⁷⁹:
• • Oral antiviral drugs (eg, famciclovir 500 mg 3 times/d [tid], valacyclovir 1 g tid, or acyclovir 800 mg 5 times/d for 7 d)
  • Tricyclic antidepressants nortriptyline, amitriptyline, or desipramine 25 mg, adjust up to 75 mg at bedtime (qhs) for several weeks if needed (to inhibit acute and prolonged postherpetic neuralgia [PHN]).
  • Additional topical corticosteroids, antibiotics, cycloplegics, antivirals, and glaucoma medications as necessary for keratitis, iritis, or glaucoma.
  • Treat late PHN with tricyclic antidepressants (as listed above) and/or capsaicin ointment daily (qd) or 4 times/day (qid) or lidocaine patches. Neurontin 30-600 mg by mouth (PO) tid and/or OxyContin SR 10-20 mg PO 2 times/day (bid) with topical medications similar to those used in acute disease.^{43, 80, 81}
• Virustatic agents that are dependent on viral thymidine kinase phosphorylation and targeted at viral polymerase include acyclovir, valacyclovir, penciclovir, famciclovir, sorivudine, and bromovinyldeoxyuridine.⁸²
• Virustatic agents that not dependent on viral thymidine kinase phosphorylase and targeted at viral polymerase include vidarabine, foscarnet, and cidofovir (hydroxyphosphonylmethoxypropyl).⁸²

Surgical Care

Some patients may require minor surgical procedures, such as a lateral tarsorrhaphy or lid traction sutures. In other patients with widespread corneal scarring, penetrating keratoplasty may be performed.^{83, 84, 85, 86}

Consultations

• Ophthalmic care is required if there is ocular involvement (eg, globe, lids) and/or if the tip of the nose is involved (herpes zoster ophthalmicus).
• Counseling with a psychiatrist may be necessary in patients with excruciating pain due to PHN.
• Additional consultations with an anesthesiologist in a pain clinic may be warranted in severe cases of PHN.
• Consider consulting an ear, nose, and throat (ENT) specialist if otalgia and/or eruptions are present around the external auditory canal and pinna.
• In rare cases, consultation with a surgeon is required for debridement of any involved epithelium.
• Consultation with an infectious disease specialist should be considered in cases of disseminated zoster or zoster with visceral involvement.

MEDICATION

Section 7 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Drug Category: Antivirals

Antivirals are indicated for the treatment of acute herpes zoster (shingles). It also is indicated for the treatment or suppression of genital herpes.

Drug Category: Interferons

These drugs are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, or intralesionally.

Drug Category: Blood and blood products

Blood and blood products are used to improve the clinical and immunologic aspects of a disease. They may decrease autoantibody production, and increase solubilization and removal of immune complexes.

Drug Category: Vaccines

Vaccines provide active immunity against viral infections.

Drug Category: Corticosteroids

These agents help to relieve acute pain, decrease vertigo, and limit the development of PHN.

Drug Category: Analgesics

Pain control is essential to providing quality patient care. Analgesics ensure patient comfort and have sedating properties that are beneficial for patients who have sustained trauma or have painful lesions. Various narcotic agents are available individually or in combination with acetaminophen, aspirin, or NSAIDs.

Drug Category: Tricyclic antidepressants

These drugs are used for pain relief, especially in cases of PHN.

Drug Category: Ocular lubricants

These drugs promote hydration of the cornea and conjunctiva.

FOLLOW-UP

Section 8 of 12  

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

Further Inpatient Care

• Hospital admission should be considered for any of the following situations: severe symptoms, immunosuppression, and more than 2 dermatomal involvements.
• Wet to dry dressings with sterile saline solution or Burow's 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 (ZnO) with about 0.5% iron(III) oxide (Fe₂O₃), 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 dry weeping or oozing blisters. There is no proof that calamine has any real therapeutic effect on rashes and itching.

Further Outpatient Care

• Follow-up care in a pain clinic may be advised.
• Continued counseling care with a psychiatrist may be warranted in some situations.

In/Out Patient Meds

• See Medication.

Deterrence/Prevention

• In 1995, the 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.⁸⁷
• Theoretically, a vaccine could be used (1) to provide immunity to varicella, and (2) to boost the immunity of patients with previous varicella to prevent herpes zoster.⁸⁸ 
• See related CME at Changing the Paradigm From Treatment to Prevention: Strategies for Reducing the Burden of Varicella, Herpes Zoster, and Herpes Simplex Infections.

Complications

• Pavan-Langston reviewed complications of untreated herpes zoster ophthalmicus and noted the following:
• • Severe acute pain (90%)
  • Infectious, scarring rash (85%)
  • Conjunctivitis, episcleritis, and scleritis (75%)
  • Lid distortion (70%)
  • Infectious and/or immune keratitis (55%)
  • Uveitis (45%)
  • PHN, 20-60% (age <40-60 y)
  • Glaucoma and/or cataract (10%)
  • Neuro-ophthalmic (8%)
• Liesegang presented a series of 86 consecutive patients with complications from herpes zoster ophthalmicus, which included the following:
• • Lid complications (ie, ptosis, hemorrhagic necrosis, ectropion, scarring)
  • Canalicular occlusion
  • Keratitis
  • Scleritis or episcleritis
  • Iridocyclitis
  • Glaucoma (ie, secondary)
  • Cataract
  • Neuro-ophthalmic
  • Postherpetic neuralgia
• Foster and Sainz de la Maza's review of 172 cases of scleritis included a case secondary to herpes zoster.²¹ Another case resulted in herpes zoster episcleritis. However, immune-mediated diseases are the main disorders associated with scleritis.
• Ramsay Hunt syndrome (geniculate zoster) occurs with herpetic infection of the geniculate ganglion. In addition to facial paresis, a herpetic eruption may be found either in the external auditory canal, the pinna, or the palate.
• Bell palsy is the most common lower motor neuron facial paresis. VZV has been implicated in its pathogenesis.
• Herpes zoster ophthalmicus with delayed contralateral hemiplegia has been reported.

Prognosis

• Of 1 million individuals examined each year for herpes zoster, 250,000 develop herpes zoster ophthalmicus.
• About 50% of patients with herpes zoster ophthalmicus develop complications.^{89, 90}

Patient Education

• Herpes zoster should be properly identified as early as possible. Patients should consult a physician immediately after the rash erupts.
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Chickenpox and Shingles.

MISCELLANEOUS

Section 9 of 12  

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

Medical/Legal Pitfalls

• The risk of herpes zoster is increased among persons infected with HIV.
• HIV infection should be considered in any patient with herpes zoster who is younger than 45 years or who is in a recognized risk group for AIDS.

Special Concerns

• Geriatric individuals: The natural declining immunity with age is believed to allow the reactivation of VZV in the sensory ganglia.
• Immunocompromised individuals
• • This population includes immunosuppressed organ-transplant recipients and immune-deficient patients with cancer, leukemia, and AIDS. These patients are at increased risk of acquiring the infection.
  • Herpes zoster is more likely to be severe and prolonged and to lead to dissemination (>20 vesicles outside the primary and immediately adjacent dermatome) in this population than in others.
  • 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.

ACKNOWLEDGMENTS

Section 10 of 12  

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

The authors and editors of eMedicine gratefully acknowledge the assistance of Ryan I Huffman, MD, with the literature review and referencing for this article.

MULTIMEDIA

Section 11 of 12  

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

Media file 1:  Dendritic keratitis. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School.
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Media file 2:  Dendritic keratitis. Image courtesy of Manolette Roque, MD, Ophthalmic Consultants Philippines Co, EYE REPUBLIC Ophthalmology Clinic.
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Media file 3:  Epithelial defect and melting secondary to varicella-zoster virus infection. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School.
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Media file 4:  Slit-beam study shows the excavation of a corneal ulcer secondary to herpes zoster. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School.
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Media file 5:  Corneal ulcer stained with fluorescein. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School.
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Media file 6:  Corneal ulcer. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School.
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Media file 7:  Corneal ulcer. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School.
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Media file 8:  Corneal scar from a previous episode of herpes zoster keratitis. Image courtesy of C. Stephen Foster, MD, Massachusetts Eye Research and Surgery Institute, Harvard Medical School.
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