Herpes Zoster

INTRODUCTION

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Background: Herpes zoster was known to the ancient Greeks and Romans, but it was not until 1885 that von Bokey noted the association between varicella zoster virus (VZV) and shingles. VZV is the causative agent of both varicella (chickenpox) and herpes zoster (shingles). Chickenpox is the primary infection, whereas herpes zoster represents reactivation of previous infection.

Chickenpox is a common and generally benign illness of childhood that is characterized by an exanthematous vesicular rash. Approximately 90% of US children are exposed by age 15 years. Following this primary infection, VZV becomes latent in dorsal root ganglia. Generally, a decrease in cellular immunity is believed to trigger the reactivation of the virus.

Herpes zoster presents as a vesicular rash in a dermatomal distribution that usually is associated with pain. After resolution of the acute eruptive phase, patients may develop postherpetic neuralgia, a sometimes incapacitating pain that can last for months.

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Pathophysiology: VZ belongs to the herpes family, which includes the herpes simplex viruses (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes viruses 6 and 7. It is the most infectious of the human herpes viruses.

Once attached to target cells via specific receptors, the capsid penetrates through the cell wall and releases the viral genome. Upon completion of viral double-stranded DNA replication, capsid and membrane synthesis take place. After the primary infection, the virus migrates along sensory nerve fibers and becomes latent in satellite cells of dorsal root ganglia. It remains there for the remainder of the patient's life. Zoster is caused by reactivation of the dormant virus.

Reactivation typically occurs in elderly and immunocompromised patients when cellular immunity is decreased. VZ reappears in neurons and satellite cells and spreads to the skin through peripheral nerves. Skin biopsy specimens during the acute phase of shingles reveal inflammation and partial denervation. Inflammation, hemorrhagic necrosis, and neuronal loss also are observed in dorsal root ganglia.

Inflammation in involved peripheral nerves can persist for months and lead to demyelination, wallerian degeneration, and sclerosis. This can lead to scarring of the dorsal root ganglia, peripheral nerves, and skin. In addition, degenerative and inflammatory changes also can occur in the central nervous system.

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Frequency:
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• In the US: Cumulative incidence is 20%, or an annual rate of 3-5 cases per 1000 persons. Incidence increases with age and impaired immune status. Second episodes occur in immunosuppressed hosts but are rare in immunocompetent people. Most recurrent herpes zoster episodes actually are dermatomal HSV. Immunosuppressed adults (human immunodeficiency virus [HIV] infection and malignancy) have a much higher risk of zoster. Incidence in adults with HIV infection is estimated at 3-4 episodes per 100 patient-years. Approximately 45% of bone marrow transplant recipients have cutaneous or visceral dissemination.

• Internationally: No accurate data are available, but incidence likely is similar to that in the United States. Varicella tends to occur at an older age in the tropics. In sub-Saharan Africa and south and Southeast Asia, incidence of herpes zoster virus in association with HIV is increasing.

Mortality/Morbidity: Cutaneous herpes zoster very rarely causes fatality in patients who are immunocompetent but can be life threatening in immunocompromised patients.

• Bone marrow recipients with visceral dissemination have a mortality rate of approximately 10%.

• Long-term complications of ophthalmic zoster with corneal involvement occur in over 20% of such patients and may result in blindness.

• Morbidity associated with postherpetic neuralgia increases with age.

Race: No clear predominance exists among any race or ethnic group.

Sex: Although no significant sex predominance has been observed in HZ, women may have increased risk of postherpetic neuralgia.

Age: All ages can be affected, but zoster primarily is a disease of elderly people. Incidence and severity increase with age.

• People younger than 20 years - 0.4-1.6 cases per 1000 persons

• People aged of 20-50 years - 2.0-3.0 cases per 1000 persons

• People older than 80 years - 4.5-11.0 cases per 1000 persons

CLINICAL

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History: The clinical manifestations of herpes zoster can be divided into the pre-eruptive phase (pre-herpetic neuralgia), acute eruptive phase, and chronic phase (postherpetic neuralgia).

• Preeruptive phase

• This phase is characterized by unusual skin sensations.

• As many as 80% of patients experience burning, itching, or paraesthesia that typically is localized to a dermatomal distribution. These symptoms usually last for several days but occasionally can last for longer than a week before the cutaneous eruption appears.

• The burning pain prior to the characteristic eruptions may present a diagnostic dilemma because it can simulate any number of painful conditions, including migraine headache, cholecystitis, hepatitis, renal colic, appendicitis, pleurisy, pulmonary embolism, or myocardial ischemia.

• During this time, patients also may experience malaise, myalgia, headache, and fever.

• These symptoms may precede the eruptive phase by several days to a week or more and gradually resolve as cutaneous eruptions appear.

• Eruptive phase

• This phase is marked by the emergence of vesicular eruptions and possible constitutional symptoms.

• Almost all adult patients experience pain (acute neuritis) during the eruptive phase. A few experience severe pain, without any evidence of a vesicular eruption (zoster sine herpete), and a small number of patients have a characteristic eruption but do not experience pain.

• Crust formation and drying occur over 7-10 days and are followed by resolution at 14-21 days.

• Patients are infectious until lesions are dried. Anyone who has not previously had varicella is at risk of acquiring this readily transmitted virus. Pregnant women and immunosuppressed patients have the highest risk of serious sequelae.

• Herpes zoster may be the earliest clinical sign of acquired immunodeficiency syndrome (AIDS); therefore, patients should be assessed for HIV risk factors. HIV testing should be considered in patients younger than 40 years.

• Patients are not more likely to have an underlying malignancy.

• Chronic phase (postherpetic neuralgia)

• Postherpetic neuralgia is persistent or reoccurring pain lasting 30 or more days after the acute infection or after all lesions have crusted.

• Pain resolves gradually in most patients but can persist for years.

• Most people report a deep, burning or aching pain, paraesthesia, dysesthesia, hyperesthesia, or electric shock-like pains.

• The pain can be extremely severe and incapacitating, leading to depression and even suicide.

• Postherpetic neuralgia and intractability of pain increase with age, from 27% of untreated adults aged 55 years to 47% of untreated adults aged 60 years to 73% of untreated adults aged 70 years.

• Pain lasting for more than 1 year occurs in 48% of patients older than 70 years.

Physical: Presentation with a characteristic rash facilitates making the diagnosis of herpes zoster. Other findings can include lymphadenopathy and sensory changes.

• Preeruptive phase

• Paraesthesia or other sensory changes over a dermatomal distribution

• Lymphadenopathy

• Eruptive phase

• The initial rash presents as a swath of patchy, erythematous, swollen plaques from which clusters of small vesicles arise. This eruption is virtually diagnostic of shingles.

• The extent of dermatomal involvement varies among patients and may involve all or part of a dermatome.

• It usually affects a single dermatome and rarely crosses the body midline. Eruptions in a bilateral distribution are very rare.

• Patients may have as many as 25 vesicles distributed outside the primarily affected dermatome; more than 25 lesions in noncontiguous dermatomes suggests disseminated zoster.

• The vesicles arise in clusters and many become purulent by day 4. Variation in size is common.

• Only be a few vesicles may be present initially, but successive eruptions for 5-7 days may occur.

• Vesicles either umbilicate or erupt prior to drying and crusting. Crusts will fall off within 3 weeks.

• In elderly and immunocompromised patients, the eruptive phase is longer and more extensive. It occasionally results in hemorrhagic blisters, skin necrosis, and secondary bacterial infections.

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• Typically affected dermatomes include thoracic (56%), cervical (17%), trigeminal nerve (12%), lumbar (10%), and sacral (5%).

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• Hematogenous dissemination to the viscera or extradermatomal skin occurs in 1-2% of immunocompetent patients but is more frequent in immunocompromised patients.

• Herpes zoster ophthalmicus

• The trigeminal nerve (CN V) has 3 branches—ophthalmic, maxillary, and mandibular. The ophthalmic nerve further divides into frontal, lacrimal, and nasociliary nerves.

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• Herpes zoster ophthalmicus occurs if involvement of any of the ophthalmic branches occurs, and it accounts for approximately 7-10% of all zoster cases.

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• Furthermore, HZ may be confined to a single branch of the trigeminal nerve.
• When the nasociliary branch is involved, vesicles appear on the tip or side of the nose (Hutchinson sign). This presentation often is associated with more serious complications and may lead to orbital involvement.

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• Involvement of other sensory branches of the trigeminal nerve usually results in periocular distribution with sparing of the orbit.

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• Involvement of the eye presents with acute lesions of the globe and orbit that develop within 3 weeks of the rash. They may rapidly resolve or become chronic. These lesions can reappear years after the initial episode.

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• Approximately 28% of people develop long-term sequelae.

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• Complications resulting from inflammatory changes include keratitis, episcleritis, iritis, ischemic papillitis, and orbital vasculitis.

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• Nerve damage can include ocular motor palsies and neuralgia.

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• Tissue scarring can include lid deformities, neuralgia, and lipid keratopathy.

• Central nervous system involvement

• Latent VZV is restricted to the sensory ganglia.

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• During reactivation, a direct invasion of adjacent structures may occur. This may lead to involvement of the anterior horn neurons, resulting in muscular weakness, cranial nerve palsies, diaphragmatic paralysis, neurogenic bladder, and colon pseudo-obstruction.

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• A further local invasion may result in myelitis with secondary paraparesis, urinary retention, and other visceral motor neuropathies.

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• The cerebrospinal fluid (CSF) may have pleocytosis and increased protein content suggestive of CNS inflammation. While some of these patients may have very mild encephalitis, most have only a headache. Significant meningoencephalitis is rare.

• Ramsay-Hunt syndrome

• Also known as herpes zoster oticus, geniculate neuralgia, or herpes zoster auricularis, it is caused by VZV reactivation involving the facial and auditory nerves.

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• It may present with hearing impairment; vertigo; facial nerve palsy (mimicking Bell palsy); and vesicular eruptions on the pinna, in the auditory canal, on the tympanic membrane, or occasionally on the hard palate.

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• Patients may lose taste sensation in the anterior two thirds of the tongue.

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• It accounts for more than 50% of the cephalic motor neuropathies.

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• It may be unnoticed and difficult to diagnose, especially in elderly patients.

• Zoster sine herpete

• It is characterized by pain in a dermatomal distribution without vesicle eruptions or other forms of rash.

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• Prevalence is difficult to estimate because definitive diagnosis is problematic.

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• Viral detection by a polymerase chain reaction may be helpful in establishing the diagnosis.

Causes:

• The cause of herpes zoster is the reactivation of VZV.

• No identifiable environmental, genetic, or social factors exist.

WORKUP

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Lab Studies:
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• Although usually diagnosed clinically, several laboratory tests are available for confirmation, differentiation, and subtyping.

• Tzanck smear

• Provides an inexpensive and rapid means for confirming suspected infection and can be obtained readily in the office or at the bedside. It does not distinguish between HZV and HSV.

• It is most sensitive when obtained from a new vesicle, followed by a pustule, then by a crusted lesion. If a crusted lesion is used for smear preparation, it will be necessary to remove the crust and make the smear by scraping the base of the lesion.

• The slide can be fixed in alcohol and Papanicolaou stain. Other stains include methylene blue, toluidine blue, Giemsa, and Wright.

• Under light microscopy, the pathognomonic triad includes multinucleated giant cell formation, ground glass appearance of the nuclear chromatin, and nuclear contours that appear molded together.

• A 1992 study demonstrated that, in the hands of experienced dermatologists, a Tzanck smear has 84% sensitivity.

• Electron microscopy

• Very sensitive in experienced hands

• Does not distinguish between HZV and HSV

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• Not readily available due to cost and therefore has a limited role in diagnosis

• Direct immunofluorescence with fluorescein-tagged antibody directed against viral antigen

• Improved sensitivity and specificity as compared to the Tzanck smear in vesicular lesions but is less sensitive in crusted lesions

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• Rapid results

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• Can differentiate HSV and HZV

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• Requires a fluorescence microscope and an experienced technician

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• Must be submitted frozen or fixed

• Immunoperoxidase techniques

• Can distinguish between HZV and HSV

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• Relatively inexpensive and rapid

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• Can be performed on both fixed and fresh specimens

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• More labor intensive and less sensitive (sensitivity of 67%) than immunofluorescence

• Serologic tests include Western blot analysis, complement fixation, and neutralization test.

• Limited role in diagnosis

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• Evaluation for VZV antibodies can be performed to verify immune status but are not of diagnostic value in either varicella or zoster diagnosis.

• Viral culture

• Viral culture remains the criterion standard for diagnosis of herpes zoster.

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• A high false-negative rate (20-80%) is due to inappropriate transport conditions, sampling the wrong area of the lesion, and inadequate viral concentration.

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• Due to the poor sensitivity and lack of readily available virology laboratories with VZV culture capability it generally is not useful.

• Polymerase chain reaction

• Polymerase chain reaction is rapid and highly sensitive.

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• It can diagnose infection from a wide spectrum of specimens, such as Tzanck smear debris, vesicle fluid, crusts, fixed tissue specimens, and CSF.

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• Reported sensitivity is 97-100% but is somewhat lower with fixed-tissue specimens.

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• Contamination can lead to false-positive results. This can be minimized by using controls and meticulous laboratory techniques.

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• Due to its high sensitivity and specificity, rapid turn around time, and versatility with a variety of specimens, it eventually may replace the older laboratory tests for the diagnosis of herpes zoster.

Imaging Studies:
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• Imaging studies are not useful in the diagnosis of shingles.

Procedures:
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• Punch biopsy

• Punch biopsy is useful when lesions are atypical.

• It is easier to interpret than the Tzanck smear.

• Punch biopsy is more invasive.

• Overall sensitivity and specificity are similar to the Tzanck smear.

Histologic Findings: During the acute phase, significant inflammation of the skin, dorsal root ganglia, and peripheral nerves is present. Evidence for early denervation of skin tissue, hemorrhagic necrosis, and neuronal loss in dorsal root ganglia is present. Inflammatory changes may persist for months and lead to scarring.

TREATMENT

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Medical Care: Medical therapy will be discussed in 3 scenarios that include the treatment of acute herpes zoster, prevention of postherpetic neuralgia, and treatment of postherpetic neuralgia.

• Acute herpes zoster

• Topical therapy can include cool tap water compresses several times a day, especially with extensive eruptions.

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• Corticosteroids: Use is controversial because no conclusive evidence indicates that steroids shorten the course of acute infection, decrease pain, or have any effect on postherpetic neuralgia. One study demonstrated that acute neuritis resolved more quickly in patients receiving high doses of prednisone compared to patients who received a placebo or acyclovir. Because corticosteroids have demonstrated some improvement in the quality of life, their administration in combination with antivirals should be considered for high-risk patients with no contraindications. The addition of antiviral agents provides a reasonable safeguard against corticosteroid-induced enhancement of viral replication.

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• Injections: Lidocaine injections may eliminate pain during the eruptive stage. Use higher concentrations (1%) for more severe pain. A combination of triamcinolone and lidocaine has also been successful.

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• Nerve blocks: Sympathetic nerve blocks are useful for treating pain. A series of 3 injections with 0.25% bupivacaine is administered. Usually, fast improvement in pain occurs, with total resolution by the third injection. Although effective for immediate pain relief, no evidence indicates that they prevent or treat postherpetic neuralgia.

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• Antiviral therapy: Antiviral therapy is effective for acute cutaneous or ophthalmic herpes zoster in immunocompetent patients. Therapy should be initiated within 72 hours of onset.

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  • Acyclovir: Both oral and IV acyclovir have been shown to decrease inflammation, vesicle formation, viral shedding, and pain during the acute phase of infection. It is most effective when started within 48 hours of onset. It always is indicated with ocular involvement or with immunosuppressed and debilitated patients with extensive cutaneous involvement. In immunocompromised patients, IV acyclovir is effective in the treatment of disseminated herpes zoster. Therapy can be changed to oral as they improve. Immunocompromised patients who receive long-term acyclovir are predisposed to acyclovir-resistant herpes zoster. If acyclovir resistance is suspected, obtain cultures for sensitivity testing and treat with foscarnet.

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  • Valacyclovir: It is the prodrug of acyclovir with very high bioavailability. It is as effective as acyclovir in during the acute phase. It has a more convenient dosing regimen than acyclovir.

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  • Famciclovir: It is a prodrug of penciclovir. When taken orally, it is as effective as acyclovir for treating uncomplicated cases. Like valacyclovir, it provides the advantage of 3 times a day dosing, which may improve compliance.

• Prevention of postherpetic neuralgia

• Nerve blocks: No definitive studies are available. In a large retrospective study and a small placebo-controlled study, sympathetic nerve blocks showed no preventative effects.

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• Corticosteroids: Use is controversial. Small randomized-controlled studies have shown some effect in the reduction of pain, but other larger studies demonstrated no effectiveness.

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• Antivirals: Results are inconclusive. Most placebo-controlled acyclovir trials show a relatively short-lived effect on pain reduction. A 1991 analysis of placebo-controlled trials of oral acyclovir demonstrated a reduction of postherpetic neuralgia and pain from 86 to 49 days. In a study comparing valacyclovir and acyclovir, a smaller proportion of patients treated with valacyclovir experienced pain for more than 6 months (19.3% versus 25.7%). No differences in pain intensity or quality-of-life measures were found. A placebo-controlled study of famciclovir showed it to significantly shorten the duration of postherpetic neuralgia. In a direct comparison, famciclovir and acyclovir appear to be equally effective.

  Combination therapy with antivirals and corticosteroids may provide some temporary relief of pain, but these combinations have not been shown to prevent postherpetic neuralgia.

• Postherpetic neuralgia

• Analgesics: Some patients obtain relief from aspirin, NSAIDs, and narcotic medications, but they generally have a limited role in the treatment of neuropathic pain. In anecdotal reports, topical formulations of aspirin; indomethacin and lidocaine; and locally injected lidocaine, procaine, and mepivacaine have provided relief.

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• Capsaicin: It is a chemical that depletes substance P (pain impulse transmitter) and prevents its resynthesis with nerves. It is available without a prescription. It can be applied daily but may cause moderate burning during application. It has been shown to decrease postherpetic neuralgia pain by 21% after 4 weeks.

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• Neuroactive agents: Tricyclic antidepressants have an established role in the treatment of postherpetic neuralgia. Amitriptyline provides moderate-to-excellent pain relief. Desipramine also is effective. Early treatment is almost twice as successful as late treatment. Treatment should be started at low doses at bedtime and increased weekly until pain resolves or adverse effects become unacceptable. Full results may not be evident for weeks after the onset of treatment. Serotonin-selective reuptake inhibitors and lorazepam have been studied but are of limited use.

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• Anticonvulsant drugs: Agents such as phenytoin, valproate, carbamazepine, and gabapentin have shown some benefit in the reduction of shooting pain but no reduction of continuous pain. Nontraditional therapies such as acupuncture, nerve stimulation, hypnosis, and biofeedback may be effective with intractable pain. Emotional support is very important. Patients with postherpetic neuralgia may become depressed and withdrawn.

Surgical Care:

• Surgical care should be reserved as the last treatment option.

• Candidates include patients with severe postherpetic neuralgia pain who do not respond to any conventional therapy.

• In extreme cases of neuropathic pain when all other forms of medical therapy fail, rhizotomy (surgical separation of pain fibers) may be considered.

Consultations:

• Consultation with a dermatologist or infectious disease specialist should be obtained if diagnosis is in doubt.

• Consult a pain specialist for severe postherpetic neuralgia.

Diet: No specific dietary changes are recommended.

Activity:

• Patients with shingles can perform activities as tolerated.

• During the acute phase, avoid direct skin contact with immunocompromised persons, pregnant women, and individuals with no history of chickenpox infection.

MEDICATION

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The goal of drug therapy is to suppress inflammation, pain, and infection. Multiple drug regimens have been studied for the treatment of acute herpes zoster and the neuropathic pain that persists after the resolution of cutaneous eruptions (postherpetic neuralgia).
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Drug Category: Antivirals -- Reduce pain and time to lesion resolution during the acute phase of shingles and may reduce risk or duration of postherpetic neuralgia.

Drug Category: Corticosteroids -- Have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. May help reduce pain, but reports are inconclusive.

Drug Category: Topical anesthetics -- Decrease pain associated with postherpetic neuralgia.

Drug Category: Tricyclic antidepressants -- Have been shown to have a role in the treatment of postherpetic neuralgia.

FOLLOW-UP

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Further Inpatient Care:
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• Inpatient care is recommended for immunocompromised patients, debilitated patients with severe cutaneous involvement, and ophthalmic zoster.

• Any patient at risk for dissemination or requiring IV medications should be admitted.

Further Outpatient Care:
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• Follow up until symptoms resolve.

• Inform patients about the natural progression of herpes zoster and its potential complications.

• Pain relief should be a primary concern.

• Patients who develop postherpetic neuralgia should be seen regularly and should receive emotional support in addition to medical therapy.

Transfer:
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• Patients with disseminated disease, severe immunosuppression, or those unresponsive to therapy should be transferred to a higher level of care.

• If consultation is required but not available at the initial facility, patients should be transferred to a tertiary-care medical center.

Complications:
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• Postherpetic neuralgia

• Although no clear predictive factors exist, this severe intractable pain is the main cause of morbidity.

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• It occurs in 73% of patients older than 70 years; incidence increases with age.

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• Most patients will improve eventually, but the pain may persist for months to years.

• Dissemination

• Immunocompromised patients are especially likely to develop disseminated zoster.

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• Mortality rates approach 25%.

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• Besides cutaneous involvement, these patients may develop dissemination to the brain, lungs, and other organs.

• Ophthalmic

• Although acute lesions involving the globe or orbit of the eye can resolve within a few weeks of treatment, they can become chronic.

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• Patients can develop keratitis, episcleritis, iritis, papillitis, vasculitis, ocular motor palsies, and nerve damage.

• Nervous system

• Cranial nerve palsies, peripheral muscle weakness, diaphragmatic dysfunction, neurogenic bladder, colonic pseudo-obstruction, and other visceral neuropathies are possible complications.

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• Significant encephalitis, although rare, carries a 10-20% mortality rate.

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• Minimally symptomatic aseptic meningitis is common.

• Infection and scarring

• Immunosuppressed, elderly, and debilitated patients have a higher risk of bacterial superinfections.

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• More extensive skin involvement may result in hypertrophic scarring and disfiguration.

Prognosis:
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• The prognosis for younger and otherwise healthy patients is excellent.

• Elderly people have a significantly increased risk of complications, including postherpetic neuralgia, bacterial infections, and scarring.

Patient Education:
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• During the acute phase, patients are infective to others and should be instructed to avoid contact with elderly people, people who are immunocompromised, pregnant women, or people with no history of chickenpox infection.

• Patients should be instructed to not scratch the lesions, which may predispose to bacterial infections.

MISCELLANEOUS

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Medical/Legal Pitfalls:
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• Misdiagnosis or failure to treat patients with involvement of the trigeminal nerve may lead to long-term ophthalmic complications.

• Take special care with immunocompromised and debilitated patients. Err on the side of admitting immunosuppressed patients and those with eye or symptomatic CNS involvement.