Harrison's Practice: Shingles and Postherpetic Neuralgia

Harrison's Practice

Shingles and Postherpetic Neuralgia

Definition

Herpes zoster (shingles)
- Acute dermatomal vesicular rash secondary to the reactivation of latent varicella-zoster virus (VZV), usually associated with severe pain and pruritus
- Any dermatome can be involved, but there are 3 classic clinical presentations, depending upon location of reactivation.
  - Dermatomal rash on trunk: involvement of a spinal root between T3 and L3
    - Most common presentation of zoster
  - Zoster ophthalmicus: involvement of the ophthalmic branch (V1) of the trigeminal nerve
    - Can lead to blindness if eye is involved and condition goes untreated
  - Ramsay Hunt syndrome: involvement of the facial nerve (cranial nerve VII)
    - Unilateral facial nerve palsy (resembling Bell’s palsy) associated with vesicular rash in the ipsilateral external auditory canal
Postherpetic neuralgia
- Severe pain and paresthesias in the zoster-affected dermatome that persists following resolution of the acute rash
  - Pain often described as burning or stabbing
  - Numbness and tingling also common
  - One of the most debilitating long-term complications of zoster

Epidemiology

Zoster
- Incidence/prevalence
  - ~400 cases per 100,000 persons annually
  - Lifetime incidence is estimated to be 10–20%; 25% in HIV-positive patients
- Sex
  - Affects men and women equally
- Age
  - Occurs at all ages
  - Incidence is highest among individuals > 50 years of age.

Postherpetic neuralgia
- Incidence (< 60 years old and > 60 years old, respectively)
  - 1 month post-zoster: 9%, 41%
  - 3 months post-zoster: 2%, 13%
  - 1 year post-zoster: 1%, 8%
- Age
  - Uncommon in young individuals
  - Incidence increases with age after 50.

Risk Factors

Zoster
- History of chickenpox
- Increasing age
- Immunosuppression (e.g., HIV infection, lymphoma, stem cell transplant recipients)
  - Among immunocompromised patients who get zoster, ~40% develop disseminated disease.
- Stress
- Trauma
Postherpetic neuralgia
- Increasing age
  - >40% of patients age 60 or older
- Location of rash
  - Highest risk: ophthalmic division (V1) of the trigeminal or brachial plexus root
  - Lowest risk: lumbar or sacral roots
- Severity of rash
- Severity of prodromal pain

Etiology

Zoster
- VZV
  - Member of the family Herpesviridae, also known as human herpesvirus-3
- During initial infection, VZV infects dorsal root ganglia (including the semilunar ganglion of the trigeminal nerve [cranial nerve V] and the geniculate ganglion of the facial nerve [cranial nerve VII]), where it remains latent until reactivated.
- Mechanism of reactivation is unknown.
- Patients with active herpes zoster lesions can transmit VZV to seronegative individuals, with consequent chickenpox.
Postherpetic neuralgia
- Long-term complication of zoster
- Reason why pain persists in some individuals and not in others is unknown.

Symptoms & Signs

Zoster
- Onset of disease is often heralded by pain within the dermatome that may precede eruption of the rash by 2–3 days.
- Prodrome can also include fever, malaise, and headache.
- General characteristics of the rash
  - Most commonly involves a single, unilateral nerve root
  - Erythematous maculopapular rash evolves rapidly into vesicular lesions.
  - Lesions may remain few in number.
  - New lesions may continue to form for 3–5 days.
  - Rash is typically very pruritic and painful.
  - Usually lasts 7–10 days, though skin may not heal completely for 2–4 weeks
- 3 clinical presentations
  - Unilateral vesicular eruption within a dermatome (most frequently between T3 and L3)
  - Zoster ophthalmicus (involvement of ophthalmic branch [V1] of the trigeminal nerve)
    - Pain and rash in the distribution of V1
    - Involvement of the eye is an ophthalmologic emergency.
    - Can lead to blindness if untreated
  - Ramsay Hunt syndrome (involvement of the facial nerve [cranial nerve VII])
    - Pain and vesicles appear in external auditory canal.
    - Ipsilateral facial palsy (upper and lower half of the face, resembling Bell’s palsy)
    - Loss of taste in the ipsilateral anterior two-thirds of the tongue
- Immunocompromised host
  - Similar clinical presentations, though, can be more prolonged and more severe.
  - In immunocompromised patients who develop disseminated cutaneous zoster, there is the risk of involvement of the lungs (pneumonitis), central nervous system (meningoencephalitis), liver, and other organs.
    - Rarely fatal
Postherpetic neuralgia
- Persistent pain and paresthesias in the dermatomal distribution of previous zoster rash
  - May be sharp, stabbing, burning, or aching
  - Can have either hypoesthesia or hyperesthesia on examination
  - Extreme sensitivity to touch and temperature changes

Differential Diagnosis

Zoster
- Coxsackievirus infections
  - Can also produce a dermatomal vesicular rash
- Herpes simplex virus infections
- Contact dermatitis, for instance poison oak or poison ivy
- Prodromal pain can sometimes be confused with angina, appendicitis, duodenal ulcer, or colic (biliary or renal).
Postherpetic neuralgia
- Trigeminal neuralgia
- Mononeuritis
- Traumatic peripheral nerve lesions
- Atypical facial pain

Diagnostic Approach

Zoster
- Diagnosis is almost always made by clinical assessment alone without additional laboratory confirmation.
- Unilateral vesicular lesions in a dermatomal pattern should suggest diagnosis.
- In prodromal stage, diagnosis can be difficult and may be made only after lesions have appeared or by retrospective serologic assessment.
- Occurrence of zoster without a rash can occur (zoster sine herpete).
- Unequivocal confirmation is possible only through 1 of the following:
  - Isolation of VZV in susceptible tissue-culture cell lines
  - Demonstration of either seroconversion or a > 4-fold rise in antibody titer between convalescent- and acute-phase serum specimens
  - Detection of VZV DNA by polymerase chain reaction (PCR)

Postherpetic neuralgia
- Clinical diagnosis: pain syndrome in zoster-affected dermatome following vesicular rash consistent with zoster infection

Laboratory Tests

Zoster
- Serology
  - Unequivocal confirmation of VZV infection if > 4-fold rise in antibody titer between convalescent- and acute-phase serum specimens
  - Most frequently employed serologic tools for assessing host response are:
    - Immunofluorescent detection of antibodies to VZV membrane antigens
    - Fluorescent antibody to membrane antigen (FAMA) test
    - Immune adherence hemagglutination
    - Enzyme-linked immunosorbent assay (ELISA)
  - FAMA test and ELISA appear to be the most sensitive.
- PCR
  - PCR technology for detection of viral DNA in vesicular fluid
    - Available in a limited number of diagnostic laboratories
- Tissue cultures
  - Isolation of VZV in susceptible tissue-culture cell lines gives unequivocal confirmation of diagnosis.
Postherpetic neuralgia
- No laboratory tests are indicated.

Imaging

Routine imaging is not indicated.

Diagnostic Procedures

Zoster
- Tzanck smear
  - Tzanck smear of scraping from base of lesions to demonstrate multinucleated giant cells is rapid but has low sensitivity (~60%).
- Cerebrospinal fluid analysis usually is not indicated unless central nervous system involvement is suspected.
  - Asymptomatic meningitis may be present.
    - Pleocytosis
    - Moderately elevated protein levels

Treatment Approach

Zoster

Immunocompetent hosts
- Oral antiviral agents
  - Accelerated lesion healing and resolution of zoster-associated pain
Immunocompromised hosts
- Intravenous antivirals (oral antivirals insufficient)
  - Reduce occurrence of visceral complications
  - No effect on healing of skin lesions or pain
Management of complications (in addition to antiviral therapy)
- Acute neuritis/postherpetic neuralgia
  - Management directed toward pain control
- Zoster ophthalmicus
  - Immediate referral to ophthalmologist
  - Managed with analgesics and atropine
- Ramsay Hunt syndrome
  - Oral glucocorticoids often given with oral antiviral agents
  - Eye protection to avoid corneal abrasions

Specific Treatments

Zoster: immunocompetent host

General
- Hygiene and skin care
  - Aluminum acetate soaks
  - Lotions
Oral antiviral therapy
- Increases the rate of healing and decreases the pain caused by the acute rash
- Most beneficial when initiated within 72 hours of symptom onset
- Acyclovir 800 mg 5 times daily for 7–10 days or
- Famciclovir 500 mg tid for 7 days or
- Valacyclovir 1 g tid for 5–7 days

Zoster: immunocompromised host

Severely immunocompromised hosts (e.g., transplant recipients, patients with lymphoproliferative malignancies, AIDS patients)
- Oral acyclovir therapy is not recommended.
- Intravenous antiviral therapy
  - Acyclovir 10–12.5 mg/kg q8h for 7 days
- Attempt to wean from any preexisting immunosuppressive treatment
Low-risk immunocompromised hosts
- Oral therapy with valacyclovir or famciclovir appears beneficial.

Acute neuritis and postherpetic neuralgia

Analgesics
- Nonnarcotics, especially NSAIDs
- Narcotic derivatives
Additional medications that may be beneficial for pain relief are:
- Gabapentin
  - Titrate gradually from 300 mg on day 1 to 300 mg bid on day 2 to 300 mg tid on day 3, to a maximum of 3500 mg/day.
  - Benefit is often seen several weeks after initiating therapy.
- Amitriptyline
  - Start at 10–25 mg daily, gradually increasing to 50–75 mg daily over 2– 3 weeks.
- Venlafaxine[1]
  - Start at 75 mg/day in 2–3 divided doses; may increase by up to 75 mg/day every 4 days, up to 225 mg/day (not to exceed 375 mg/day in 3 divided doses)
  - In studies of this drug for neuropathic pain, the higher doses (at least 150–225 mg/day) are often necessary to get a good effect.
- 5% lidocaine patches
  - Applied locally over affected region of skin
- Oral glucocorticoids (for acute neuritis during active zoster, not postherpetic neuralgia)
  - May decrease duration of acute pain and shorten time of return to usual activity, but there is no clear benefit in reducing risk of developing postherpetic neuralgia.
  - Given likely marginal benefit, older patients with underlying comorbid conditions (e.g., diabetes mellitus, hypertension, osteoporosis) are poor candidates for glucocorticoid therapy.
  - Should consider only in healthy patients with moderate or severe pain at presentation
  - Typical dosing schedule for prednisone
    - 60 mg/d on days 1–7
    - 30 mg/d on days 8–14
    - 15 mg/d on days 15–21
  - Should not be given without concurrent antiviral therapy

Monitoring

Zoster
- Monitor for complications (e.g., disseminated varicella infection, secondary bacterial infection) or for occurrence of postherpetic neuralgia.
Postherpetic neuralgia
- Monitor response to treatment.

Complications

Zoster

Postherpetic neuralgia
- Most debilitating and frequent complication of zoster
Central nervous system involvement may rarely follow localized zoster.
- Symptomatic meningoencephalitis
  - Headache
  - Fever
  - Photophobia
  - Meningeal signs
  - Vomiting
Transverse myelitis with or without motor paralysis
Granulomatous angiitis
- Vasculitis of the ipsilateral internal carotid artery, occurring weeks to months after resolution of zoster ophthalmicus, produces ipsilateral stroke and thus hemiplegia contralateral to the side of the original zoster rash.
Systemic involvement, including pneumonitis and hepatitis
- Rare in immunocompetent patients
- Highest risk populations: Hodgkin’s disease, non-Hodgkin’s lymphoma, bone marrow transplant recipients
Zoster ophthalmicus
- Can result in unilateral blindness that can be prevented with antiviral therapy.
Ramsay Hunt syndrome
- In addition to postherpetic neuralgia, patient can have persistent facial weakness and loss of taste on ipsilateral anterior two-thirds of tongue.

Prognosis

Zoster
- Rarely fatal, even in immunocompromised patients with disseminated disease
- Immunocompromised patients are at greatest risk for progressive herpes zoster.
  - Patients with Hodgkin’s and non-Hodgkin’s lymphoma
  - Bone marrow transplant recipients
    - Postherpetic neuralgia, scarring, and bacterial superinfection are especially frequent following zoster occurring within 9 months of transplantation.
    - Concomitant graft-versus-host disease increases chances of dissemination and/or death.
    - Mortality is 10%.
- Recurrent herpes zoster is exceedingly rare except in immunocompromised hosts, especially those with AIDS.
Postherpetic neuralgia
- Successful treatment of pain from postherpetic neuralgia is limited, but generally pain should subside over time.

Prevention

Live attenuated varicella vaccine

Vaccine studies with live attenuated VZV vaccine in individuals > 60 years of age have demonstrated a decrease in incidence (by 51%) and severity (by 61%) of herpes zoster and a reduction in risk of postherpetic neuralgia (by 66%).
The U. S. Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommends universal vaccination for those 60 years of age and older, including those who have experienced previous episodes of shingles.
Special note: Initial concerns that the varicella vaccine now offered to children who have not had chickenpox might lead to an increase in the incidence of herpes zoster have not been substantiated.

Varicella-zoster immune globulin

Limited availability
Indications
- Susceptible individuals who are at high risk for developing the complications of varicella (primary infection) and who have had a significant exposure
Should be given within 96 hours (preferably within 72 hours) of exposure
Exposure criteria: exposure to person with chickenpox or zoster
- Household: residence in the same household
- Playmate: face-to-face indoor play
- Hospital: varicella
  - Same 2- to 4-bed room or adjacent beds in large ward
  - Face-to-face contact with infectious staff member or patient
  - Visit by a person deemed contagious
- Hospital: zoster
  - Intimate contact (e.g., touching or hugging) with a person deemed contagious
- Newborn infant
  - Onset of varicella in the mother < 5 days before delivery or < 48 hours after delivery
  - Not indicated if mother has zoster.
Candidates (provided they have significant exposure)
- Immunocompromised susceptible children without history of varicella or varicella immunization
- Susceptible pregnant women
- Newborn infants whose mother had onset of chickenpox within 5 days before or within 48 hours after delivery
- Hospitalized premature infant (> 28 weeks of gestation) whose mother lacks a reliable history of chickenpox or serologic evidence of protection against varicella
- Hospitalized premature infant (< 28 weeks of gestation or < 1000-g birth weight), regardless of maternal history of varicella or VZV serologic status

Prophylactic antiviral treatment for primary infection

Indications
- High-risk patients who are ineligible for vaccine or who are beyond the 96-hour window after direct contact
Antiviral medication
- Decreases severity of or prevents disease entirely
- Start therapy 7 days after exposure (host is midway into the incubation period) with 1 of the following antiviral medications:
- Acyclovir
  - Adults: 800 mg PO q 4 hr 5 times/day for 7–10 days
- Valacyclovir
  - Adults 1 g PO tid for 7 days
- Famciclovir
  - Adults 500 mg PO q 8 hr for 7 days

ICD-9-CM

053.19 Herpes zoster with other nervous system complications (includes postherpetic neuralgia, not elsewhere classified)
053.9 Herpes zoster without mention of complication (includes shingles)