AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

Varicella-zoster virus (VZV) is the cause of chickenpox and herpes zoster (also called shingles). Chickenpox follows initial exposure to the virus and is typically a relatively mild, self-limited childhood illness with a characteristic exanthem.

Approximately 1 per 4000 children develops VZV encephalitis, an acute neurologic disorder with potentially severe complications. In addition, immunocompromised children (eg, those receiving chemotherapy for leukemia or those with advanced HIV infection) can develop disseminated VZV infection, a potentially fatal complication.

After primary infection, VZV remains dormant in sensory nerve roots for life. Upon reactivation, the virus migrates down the sensory nerve to the skin, causing the characteristic painful dermatomal rash. After resolution, many individuals continue to experience pain in the distribution of the rash (postherpetic neuralgia). In addition, reactivation of VZV infection can cause a spectrum of atypical presentations, ranging from self-limited radicular pain without rash to spinal cord disease with weakness.

Pathophysiology

The host immunologic mechanisms suppress replication of the virus. Reactivation can occur if host immune mechanisms are compromised. This may be caused by medications, illness, malnutrition, or by the natural decline in immune function with aging. Upon reactivation, the virus migrates along sensory nerves and produces sensory loss, pain, and other neurologic complications. If motor nerve roots are also involved, weakness can develop in addition to sensory changes. Leptomeningeal involvement is rare but may develop when the ophthalmic branch of the trigeminal nerve is involved.

Frequency

United States

The rate of occurrence is about 5 persons per 1000 population. Immunosuppression increases this risk. The risk of postherpetic neuralgia increases with age. Approximately 50% of patients older than 60 years may have temporary or prolonged pain syndrome.

The frequency of VZV infection may decrease as the immunized children become adults.

International

VZV infection occurs with the same frequency in the United States and internationally.

Mortality/Morbidity

• Severe pain and insomnia are most bothersome to patients. About 95% of patients with zoster experience severe pain during the illness.
• Other presentations of zoster, including ocular (keratitis) and spinal cord (myelitis) presentations, may result in additional morbidity.
• Bacterial superinfection (impetiginization) of vesicular skin lesions can occur.

Race

The vesicular eruption of VZV infection may be more difficult to diagnose in patients with darker skin.

Sex

VZV infection occurs with equal frequency in males and females.

Age

• After primary infection, zoster can occur at any age. However, the risk of zoster increases with age.
• The risk of postherpetic neuralgia also increases with advancing age.

CLINICAL

Section 3 of 10  

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

History

• Pain and paresthesia are typically the first symptoms. Until the characteristic vesicular rash erupts, diagnosis may be difficult.
• A prodromal period during which symptoms may vary is common. Pain occurs in 41% of patients, itching in 27%, and paresthesias in 12%.
• During the acute illness, 90% of patients experience pain, 20% describe helplessness and depression, and 12% experience flulike symptoms.

Physical

• Herpes zoster (shingles)
• • The most common presentation is the shingles vesicular rash, which most commonly affects a thoracic dermatome.
  • After a prodromal illness of pain and paresthesias, erythematous macules and papules develop and progress to vesicles within 24 hours. The vesicles eventually crust and resolve.
  • Pain and sensory loss are the usual symptoms, but motor weakness also occurs and is frequently missed on examination. Motor weakness results when the viral activity extends beyond the sensory root to involve the motor root. Cases of actual monoplegia due to varicella-zoster virus (VZV) brachial plexus neuritis have been reported.
• Zoster multiplex
• • Shingles may appear in multiple dermatomes, both contiguous and noncontiguous, on either side of the body.
  • They are more common in individuals who are immunocompromised.
  • Terminology depends on the number of involved dermatomes and on whether the condition is unilateral or bilateral. For example, zoster duplex unilateralis refers to the involvement of 2 unilateral dermatomes. Cases of zoster simultaneously occurring in 7 noncontiguous dermatomes have been reported.
• Zoster sine herpete
• • VZV infection may reactivate without causing cutaneous vesicles. These patients have severe dermatomal pain, possible motor weakness and possible hypesthesia, but no visible rash or vesicles.
  • Studies show that VZV infection may present as acute peripheral facial palsy in 8-25% of patients who have no cutaneous vesicles. This is more common in immunosuppressed patients who use acyclovir (or other agents) as zoster prophylaxis.¹
• Myelitis
• • VZV infection may also cause central nervous system deficits.
  • Although deficits are more common in immunocompromised individuals, such presentations do occur in the general population.
  • In one report, the condition began as a typical shingles rash, but spinal cord involvement became apparent 3 weeks after the onset of the initial rash.
  • The manifestations are usually bilateral. The physical findings may progress.
  • The underlying pathology typically progresses for 3 or more weeks. Progression for 6 months in immunocompromised individuals has been reported.
  • With intravenous acyclovir treatment, most cases fully resolve. Recurrence is rare but has been reported.
  • Zoster encephalitis is also rare but is reported in otherwise healthy individuals.
• Ramsay-Hunt syndrome
• • This syndrome occurs when the geniculate ganglion is involved.
  • The clinical presentation includes a peripheral facial palsy, pain in the ear and face, and vesicles in the external ear canal.
  • Additional auditory and vestibular symptoms may be present. The vesicles are not present in all cases.
• Keratitis (herpes ophthalmicus)
• • This is caused by reactivation of VZV infection in the ophthalmic division of the trigeminal nerve.
  • The presentation may include conjunctivitis or corneal ulcers. Complications include blindness.
  • The vesicles do not have to be present.
  • Rarely, in cases of herpes ophthalmicus, the virus migrates along the intracranial branches of the trigeminal nerve, causing thrombotic cerebrovasculopathy with severe headache and hemiplegia.

Causes

Immunosuppression increases the risk of both typical shingles and atypical presentations, such as myelitis, encephalitis, disseminated disease, and visceral involvement.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Lumbar muscle strain
Sciatica
Cervical spinal cord transection

WORKUP

Section 5 of 10  

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

Lab Studies

• When the presentation includes the typical dermatomal rash, additional studies are not required.
• If the diagnosis is in doubt, a Tzanck smear can be performed and has a sensitivity of about 60%. To obtain a Tzanck smear, remove the crust from a vesicle and scrape the underlying moist skin with a No. 15 surgical blade. Smear the cells from the vesicle base onto a slide, fix for 1 minute with absolute alcohol, and stain with Wright stain (other staining methods can also be used).
• The diagnosis can also be confirmed with a culture of vesicular fluid that is positive for varicella-zoster virus (VZV).
• In cases of zoster sine herpete, DNA analysis via polymerase chain reaction (PCR) can be used for early diagnosis if laboratory turnaround time is reasonably short. If not, the decision of whether to start empiric acyclovir must be based on clinical grounds alone.

Imaging Studies

• MRI may be useful if myelitis or encephalitis is suspected.

Procedures

• Lumbar puncture may be helpful if signs suggest myelitis or encephalitis. The cerebrospinal fluid (CSF) shows increased levels of protein and pleocytosis because the inflammatory response involves the leptomeninges. CSF PCR can be used to detect VZV DNA.
• Although seldom necessary, biopsy results provide a definitive diagnosis.

Histologic Findings

• The varicella zoster virus is a DNA virus with a genome that encodes 70 proteins.
• The Tzanck preparation shows characteristic findings of giant cells with 2-15 nuclei. Recently infected epithelial cells contain a single enlarged nucleus with a thick nuclear membrane.
• After reactivation, meningeal biopsy samples show a local inflammatory response, consisting of plasma cells and lymphocytes, that encompasses the leptomeninges.
• Evidence has shown that motor neuron involvement is demyelinating rather than axonal.

TREATMENT

Section 6 of 10  

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

Medical Care

• Treatment options are based on the patient's age, immune state, duration of symptoms, and presentation.
• Several studies indicate that antiviral medications decrease the duration of symptoms and the likelihood of postherpetic neuralgia, especially when initiated within 2 days of the onset of rash. In typical cases that involve individuals who are otherwise healthy, oral acyclovir may be prescribed. An important study by Kubeyinje (1997) suggested that the use of acyclovir in healthy young adults with zoster is not clearly justified, especially in situations of limited economic resources.²
• Acyclovir has 2 limitations—bioavailability and the existence of some resistant strains of varicella-zoster virus (VZV).
• Other medications, including valacyclovir, penciclovir, and famciclovir, are also available. They may have an increasing role in the treatment of typical zoster. Studies suggest that, when compared with oral acyclovir, the new medications may decrease the duration of the patient's pain.

Surgical Care

Surgical care may be required for complications of zoster, such as necrotizing fasciitis.

Consultations

• Consultation with a neurologist is indicated in cases of myelitis or encephalitis.
• Consultation with an infectious disease specialist may be helpful if bacterial superinfection or viral resistance to acyclovir is evident.
• Consultation with an ophthalmologist is indicated upon optic involvement.
• Consultation with a dermatologist may be helpful when the rash is atypical.

MEDICATION

Section 7 of 10  

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

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Current research is considering whether the varicella vaccine may also prove efficacious as treatment for active varicella-zoster virus (VZV) infection.

Drug Category: Antiviral agents

Three medications may help reduce pain and symptoms and the incidence of postherpetic neuralgia. All need to be used with caution in patients with renal compromise. Hemolytic uremic syndrome is rare but has been reported. All 3 agents may be used for 7-10 d, depending on response. Only acyclovir is available in an intravenous form.

Drug Name	Valacyclovir (Valtrex)
Description	Prodrug rapidly converted to the active drug acyclovir. More expensive but has a more convenient dosing regimen than acyclovir.
Adult Dose	1000 mg PO tid for 7-10 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid, zidovudine, or cimetidine coadministration prolongs half-life and increases CNS toxicity of valacyclovir
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in renal failure and coadministration of nephrotoxic drugs; associated with onset of hemolytic uremic syndrome

Drug Name	Famciclovir (Famvir)
Description	Prodrug that, when biotransformed into active metabolite penciclovir, may inhibit viral DNA synthesis/replication.
Adult Dose	500 mg PO tid for 7-10 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration of probenecid or cimetidine may increase toxicity; coadministration increases bioavailability of digoxin
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 coadministration of nephrotoxic drugs

Drug Category: Vaccine, Live Virus

These agents are used to induce active immunity.

Drug Name	Varicella zoster vaccine (Zostavax)
Description	Lyophilized preparation of Oka/Merck strain of live, attenuated varicella-zoster virus (VZV). Shown to boost immunity against herpes zoster virus (shingles) in older patients. Reduces occurrence of shingles in individuals >60 y by about 50%. For individuals aged 60-69 y, it reduces occurrence by 64%. Also slightly reduces pain compared with no vaccination in those who develop shingles. Indicated for prevention of herpes zoster.
Adult Dose	<60 years: Not established >60 years: Following reconstitution with entire vial of diluent supplied, use separate sterile needle and syringe to withdraw entire contents of reconstituted vial and administer SC; administer in upper arm
Pediatric Dose	Not indicated
Contraindications	Documented hypersensitivity to vaccine or components (eg, gelatin, neomycin); history of primary or acquired immunodeficiency states (eg, leukemia, lymphomas, malignant neoplasms affecting bone marrow or lymphatic system, AIDS); immunosuppressive therapy including high-dose corticosteroids; active untreated tuberculosis
Interactions	None reported
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	Common adverse effects include erythema, pain, tenderness, itching, and inflammation at injection site; may also cause headache; may cause extensive vaccine-associated rash or disseminated disease in individuals on immunosuppressive therapy (see Contraindications); defer vaccination if fever or acute illness is present; do not inject intravascularly; administer within 30 min of reconstitution; not a substitute for varicella virus vaccine (Varivax) for children

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Patients with ocular involvement may be treated in the hospital.
• Inpatient treatment may be appropriate for people who develop complications.
• The main patient complaint is pain.
• Inpatient treatment is appropriate for immunocompromised people or those with atypical presentations, including myelitis.

Further Outpatient Care

• Typical cases of zoster may be treated in the outpatient setting.
• Initial evaluation should address the possibility of atypical manifestations.

Deterrence/Prevention

• In May 1995, the American Academy of Pediatrics reviewed the literature on the safety and effectiveness of varicella vaccine and recommended that all susceptible children and adolescents without a contraindication receive routine varicella vaccination. They reaffirmed this recommendation in January 2000. However, many logistic and financial barriers have prevented the widespread adoption of this recommendation.
• Both clinical varicella and zoster may occur despite vaccination. However, in 3 large studies, vaccination was 100% effective in preventing severe disease.

Complications

• In cases of typical zoster, both streptococcal and staphylococcal superinfections are common potential complications.
• • With ocular, spinal cord, or other involvement, permanent injury is a risk. With ocular involvement, the patient may require long-term antiviral treatment.
  • One study suggests that trigeminal distribution and advanced age increase risk of complications.³
• Other complications include the following:
• • Necrotizing fasciitis
  • Gastrointestinal complications
  • Fatal hemorrhagic encephalitis
  • Motor weakness
  • Postherpetic neuralgia (most common) (The underlying pathophysiology of the condition may involve peripheral nerve injury or continued viral activation without rash, similar to zoster sin herpete.)
  • Vasculopathy

Prognosis

• Postherpetic neuralgia remains the most common complication of varicella-zoster virus (VZV) infection reactivation, affecting up to 50% of the patients older than 60 years. Most cases are temporary, but many cases persist chronically, impairing productivity and quality of life.
• A landmark study by Rowbotham and Fields (1996) shows no clear relationship between loss of peripheral nerve function and postherpetic neuralgia pain.⁴ Although many mechanisms may cause the pain, this study helps explain the efficacy of topical agents such as capsaicin or lidocaine patches.
• As evidence of the complexity of the issue, Oaklander and colleagues (1998) examined patients with postherpetic neuralgia and found bilateral damage in patients with unilateral shingles. Neurite loss was noted in the contralateral homologous region in test subjects who experienced no pain and had no history of shingles.⁵
• Many treatment options are available for postherpetic neuralgia.
• • Oral medications
  • Topical preparations
  • Gamma knife procedures
  • Jaipur blocks

Patient Education

• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Shingles and Chickenpox.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Failure to diagnose zoster may lead to a delay in treatment, which may increase the likelihood of postherpetic neuralgia.
• Alleviation of pain is important. Emerging evidence suggests that adequate pain control may reduce the incidence of postherpetic neuralgia.
• Failure to treat zoster with antiviral medication may increase the likelihood of postherpetic neuralgia. However, one study suggests this is not the case in young, otherwise healthy individuals.
• Failure to recognize keratitis, myelitis, and encephalitis may lead to morbidity and, rarely, mortality.
• Immunocompromised patients often take acyclovir prophylactically. Because of this, zoster may have an atypical presentation without a rash (zoster sine herpete).
• Zoster sine herpete is a difficult diagnosis and requires high clinical suspicion.

REFERENCES

Section 10 of 10

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

1. Furuta Y, Fukuda S, Suzuki S, et al. Detection of varicella-zoster virus DNA in patients with acute peripheral facial palsy by the polymerase chain reaction, and its use for early diagnosis of zoster sine herpete. J Med Virol. Jul 1997;52(3):316-9. [Medline].
2. Kubeyinje EP. Cost-benefit of oral acyclovir in the treatment of herpes zoster. Int J Dermatol. Jun 1997;36(6):457-9. [Medline].
3. Galil K, Choo PW, Donahue JG, Platt R. The sequelae of herpes zoster. Arch Intern Med. Jun 9 1997;157(11):1209-13. [Medline].
4. Rowbotham MC, Fields HL. The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain. Apr 1996;119 ( Pt 2):347-54. [Medline].
5. Oaklander AL, Romans K, Horasek S, et al. Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Ann Neurol. Nov 1998;44(5):789-95. [Medline].
6. Baik JS, Kim WC, Heo JH, Zheng HY. Recurrent herpes zoster myelitis. J Korean Med Sci. Aug 1997;12(4):360-3. [Medline].
7. Carreau JP, Gola R, Cheynet F, Guyot L. [Zona of the cranial nerves. Current aspects]. Rev Stomatol Chir Maxillofac. Oct 1998;99(3):155-64. [Medline].
8. Cohen JI. Varicella-zoster virus. The virus. Infect Dis Clin North Am. Sep 1996;10(3):457-68. [Medline].
9. Cohen JI, Brunell PA, Straus SE, Krause PR. Recent advances in varicella-zoster virus infection. Ann Intern Med. Jun 1 1999;130(11):922-32. [Medline].
10. Devinsky O, Cho ES, Petito CK, Price RW. Herpes zoster myelitis. Brain. Jun 1991;114 (Pt 3):1181-96. [Medline].
11. Fabian VA, Wood B, Crowley P, Kakulas BA. Herpes zoster brachial plexus neuritis. Clin Neuropathol. Mar-Apr 1997;16(2):61-4. [Medline].
12. Feder HM Jr, LaRussa P, Steinberg S, Gershon AA. Clinical varicella following varicella vaccination: don't be fooled. Pediatrics. Jun 1997;99(6):897-9. [Medline].
13. Gilden DH, Cohrs RJ, Mahalingam R. VZV vasculopathy and postherpetic neuralgia: progress and perspective on antiviral therapy. Neurology. Jan 11 2005;64(1):21-5. [Medline].
14. Goh CL, Khoo L. A retrospective study of the clinical presentation and outcome of herpes zoster in a tertiary dermatology outpatient referral clinic. Int J Dermatol. Sep 1997;36(9):667-72. [Medline].
15. Goldman GS. Universal varicella vaccination: efficacy trends and effect on herpes zoster. Int J Toxicol. Jul-Aug 2005;24(4):205-13. [Medline].
16. Hong JJ, Elgart ML. Gastrointestinal complications of dermatomal herpes zoster successfully treated with famciclovir and lactulose. J Am Acad Dermatol. Feb 1998;38(2 Pt 1):279-80. [Medline].
17. Hovens MM, Vaessen N, Sijpkens YW, de Fijter JW. Unusual presentation of central nervous system manifestations of Varicella zoster virus vasculopathy in renal transplant recipients. Transpl Infect Dis. Sep 2007;9(3):237-40. [Medline].
18. 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].
19. Mainka C, Fuss B, Geiger H, et al. Characterization of viremia at different stages of varicella-zoster virus infection. J Med Virol. Sep 1998;56(1):91-8. [Medline].
20. Morgan R, King D. Characteristics of patients with shingles admitted to a district general hospital. Postgrad Med J. Feb 1998;74(868):101-3. [Medline].
21. Nagel MA, Gilden DH. The protean neurologic manifestations of varicella-zoster virus infection. Cleve Clin J Med. Jul 2007;74(7):489-94, 496, 498-9 passim. [Medline].
22. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. Apr 1996;65(1):39-44. [Medline].
23. Sparks L, Russell C. The new varicella vaccine: efficacy, safety, and administration. J Pediatr Nurs. Apr 1998;13(2):85-94. [Medline].
24. Stein GE. Pharmacology of new antiherpes agents: famciclovir and valacyclovir. J Am Pharm Assoc (Wash). Mar-Apr 1997;NS37(2):157-63. [Medline].
25. Sugisaki K, Yoshida H. Varicella zoster virus meningoencephalitis accompanied by sporadic skin lesions in an older immunocompetent adult. J Infect Chemother. Aug 2007;13(4):270-2. [Medline].
26. Svozilkova P, Rihova E, Diblik P. Varicella zoster virus acute retinal necrosis following eye contusion: casereport. Virol J. Aug 31 2005;2:77. [Medline].
27. Vu AQ, Radonich MA, Heald PW. Herpes zoster in seven disparate dermatomes (zoster multiplex): report of a case and review of the literature. J Am Acad Dermatol. May 1999;40(5 Pt 2):868-9. [Medline].
28. Westenend PJ, Hoppenbrouwers WJ. [Fatal varicella-zoster encephalitis; a rare complication of herpes zoster]. Ned Tijdschr Geneeskd. Mar 21 1998;142(12):654-7. [Medline].

Article Last Updated: Sep 14, 2007