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Varicella-Zoster Virus

Author: Wayne E Anderson, DO, Assistant Professor of Internal Medicine/Neurology, Western University of Health Sciences; Assistant Professor of Family Medicine, Touro University College of Osteopathic Medicine; Consulting Staff in Pain Management, Department of Neurology, California Pacific Medical Center; Consulting Staff in Neurology, Department of Neurology, California Pacific Medical Center

Updated: Nov 23, 2009

Introduction

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

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.

      Typical zoster in the vicinity of right popliteal...

      Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution

      Typical zoster in the vicinity of right popliteal fossa in a vertebral nerve L4 distribution.

    • 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.

Differential Diagnoses

Acute Nerve Injury( Tổn thương thần k inh cấp) Meningitis( Viêm màng não)
Cauda Equina ( Bệnh lý đuôi ngựa) Meningococcal Infections
Chronic Fatigue Syndrome( Hội chứng mệt mỏi mạn tính) Meningococcemia ( viêm não huyết cầu)
Electrical Injuries( các tổn thương do điện) Poxviruses
Eosinophilic Fasciitis ( viêm mạc acid) Spinal Cord Abscess( áp xe tủy sống)
Fibromyalgia Spinal Hematoma
Herpangina( viêm họng mụn nước) Spinal Stenosis
Herpes Simplex Streptococcus Group A Infections
Impetigo( chốc lở)
Lumbar Disc Disease
Lumbar Spondylosis( thoái hóa CS thắt lưng)

Other Problems to Be Considered

Lumbar muscle strain
Sciatica
Cervical spinal cord transection

Workup

Laboratory 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

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.
  • Dworkin et al (2009) conducted a randomized, placebo-controlled trial of oral oxycodone and oral gabapentin as potential treatments for acute pain in patients with herpes zoster. They found that controlled-release oxycodone was superior to placebo in the early period of pain (1-14 d). Gabapentin was not shown to yield a significantly greater relief of pain than placebo, although it conferred modest pain relief during the first week.3

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

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.

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.

Acyclovir (Zovirax)

Patients experience less pain and faster resolution of cutaneous lesions when used within 48 h from rash onset. May prevent recurrent outbreaks.

– Adult

800 mg PO 5 times/d for 7-10 d; difficult to verify patient compliance because of dosage frequency
10 mg/kg IV q8h for complications or atypical presentations or in cases of immunosuppression

– Pediatric

Not established; IV dose is based on body weight

=>Interactions:

Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir

=>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 nephrotoxic drugs

Topical Analgesics

Topical analgesics that contain capsaicin are effective in decreasing neuropathic pain caused by postherpetic neuralgia.

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