Herpes Zoster

Herpes zoster (shingles) is an acute, cutaneous viral infection caused by the reactivation of varicella-zoster virus (VZV), a herpesvirus that is the cause of varicella (chickenpox). Differences in clinical manifestations between varicella and herpes zoster apparently depend on an individual's immune status; those with no previous exposure to VZV, most commonly children, develop the clinical syndrome of varicella, whereas those with circulating varicella antibodies develop a localized recrudescence, zoster.

Zoster probably results most often from a failure of the immune system to contain latent VZV replication. Whether other factors, such as radiation, physical trauma, certain medications, other infections, and stress, also can trigger zoster has not been determined with certainty. Nor is it entirely clear why circulating varicella antibodies and cell-mediated immune mechanisms do not prevent recurrent overt disease, as is common with most other viral illnesses.

The incidence of zoster appears to be inversely correlated with the host’s capacity to mount a cellular immune response. However, many patients with zoster apparently have normal immunity. In these patients, zoster is postulated to occur when VZV antibody titers and cellular immunity drop to levels that no longer are completely effective in preventing viral invasion. Evidence for this hypothesis includes the observation that pediatricians, who presumably are routinely reexposed to VZV and thus maintain high levels of immunity, seldom develop zoster.

Herpes zoster manifests in many ways. It should not be considered simply a self-limited dermatomal rash with pain. VZV infection is an acute neurologic disease that warrants immediate evaluation. That VZV is always a benign disorder is a common misperception. Once VZV infection resolves, many individuals continue to suffer pain—a condition known as postherpetic neuralgia (PHN).

VZV infection gives rise to two distinct syndromes. The primary infection, chickenpox, is a contagious and usually benign febrile illness. After this infection resolves, viral particles remain in the dorsal root or other sensory ganglia, where they may lay dormant for years to decades.

In this latent period, host immunologic mechanisms suppress replication of the virus, but VZV reactivates when the host mechanisms fail to contain the virus. Such failure may result from a wide spectrum of conditions, ranging from stress to severe immunosuppression; occasionally, it follows direct trauma. VZV viremia occurs frequently with chickenpox but also may arise with herpes zoster, albeit with a lower viral load.

Once VZV is activated at the spinal root or cranial nerve neurons, an inflammatory response occurs that also encompasses the leptomeninges; both plasma cells and lymphocytes are noted. This inflammation in the dorsal root ganglion can be accompanied by hemorrhagic necrosis of nerve cells. The result is neuronal loss and fibrosis.

The frequency of dermatologic involvement is correlated with the centripetal distribution of the initial varicella lesions. This pattern suggests that the latency may arise from contiguous spread of the virus during varicella from infected skin cells to sensory nerve endings, with subsequent ascent to the ganglia. Alternatively, the ganglia may become infected hematogenously during the viremic phase of varicella, and the frequency of the dermatome involvement in herpes zoster may reflect the ganglia most often exposed to reactivating stimuli.

The appearance of the cutaneous rash due to herpes zoster coincides with a profound VZV-specific T-cell proliferation. Production of interferon alfa appears with the resolution of herpes zoster. In immunocompetent patients, specific antibodies (immunoglobulins G, M, and A [IgG, IgM, and IgA]) appear more rapidly and reach higher titers during reactivation (herpes zoster) than during the primary infection. The patient has a long-lasting, enhanced, cell-mediated immunity response to VZV.[8, 9, 10]

The anatomic location of the involved dermatome often determines the specific manifestations. When cervical and lumbar roots are involved, motor involvement, which is often overlooked, may be evident, depending on the virulence or extent of migration. In at least 1 case of motor neuron involvement, lymphocytic infiltration and myelin breakdown were observed with preservation of axons.

This infection is contagious to persons with no previous immunity to VZV. However, it is estimated to be only one third as contagious as primary varicella. It is transmitted either via direct contact with the lesions or via the respiratory route.

Herpes virus infections may occur together in the same host. Of more than 100 types of Herpesviridae viruses, eight are of particular interest in humans: herpes simplex viruses (HSVs)–1 and 2, VZV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesviruses 6, 7, and 8 (HHV-6, HHV-7, HHV-8).[11] Postmortem examination of trigeminal and/or facial ganglia detected these viruses in 30 (63.8%) of 47 subjects, with HHV-6 being the most prevalent, identified in 46.8% of them, followed by HSV-1 in 14.9%, VZV in 8.5%, EBV in 8.5%, HSV-2 in 4.3%, and CMV in 2.1%.

Organ system involvement

Central nervous system

Whereas herpes zoster is classically described in sensory (dorsal root) ganglia, it can spread to affect any portion of the central nervous system (CNS). Involvement of the anterior horn cells can produce muscular weakness, cranial nerve palsies, diaphragmatic paralysis, neurogenic bladder, and colonic pseudo-obstruction. Wider involvement of the spinal cord can produce Guillain-Barré syndrome, transverse myelitis, and myositis.

In severely ill or immunocompromised patients, general CNS involvement can be observed in the form of meningoencephalitis or encephalitis. Such presentations may be indistinguishable from those of other forms of meningoencephalitis, though other evidence of acute zoster usually is present.[12] Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis without elevated protein. These infections can be life-threatening.

Optical system

Herpes zoster ophthalmicus (HZO), a potentially devastating form of acute herpes zoster, results from the reactivation of VZV in the trigeminal (fifth cranial) nerve. Any branch of the nerve may be affected, though the frontal branch within the first division of the trigeminal nerve is most commonly involved. This branch innervates nearly all of the ocular and periocular structures.

Polymerase chain reaction (PCR) nerve studies have detected latent trigeminal VZV in as many as 87% of patients.[13] Clinical disease has been reported in as few as 8% and as many as 56% of patients in studies focused on ophthalmic involvement.[14]

Auditory system

Herpes zoster oticus (also known as Ramsay Hunt syndrome, geniculate neuralgia, or herpes zoster auricularis) is caused by VZV reactivation involving the facial and auditory nerves. This syndrome may go unnoticed and be difficult to diagnose, especially in elderly patients.

Vesicular eruptions may manifest on the pinna, tragus, or tympanic membrane or in the auditory canal, as well as anywhere in the facial nerve distribution. The patient may experience hearing impairment, nystagmus, vertigo, or a facial nerve palsy mimicking Bell palsy.[15] Patients may lose taste sensation in the anterior two thirds of the tongue.[15]

Clinical phases of disease

The clinical manifestations can be divided into the following three phases:

• Preeruptive phase (preherpetic neuralgia)

• Acute eruptive phase

• Chronic phase (PHN)

The preeruptive phase is characterized by unusual skin sensations or pain within the affected dermatome that heralds the onset of lesions by 48-72 hours. During this time, patients may also experience other symptoms, such as malaise, myalgia, headache, photophobia, and, uncommonly, fever. Trigeminal herpes zoster and Ramsay Hunt syndrome were described in an elderly man with a prodromal toothache.[16]

The acute eruptive phase is marked by the emergence of vesicular eruptions. Patients may also experience some of the other symptoms seen in the preeruptive phase. Lesions begin as erythematous macules and papules that quickly develop into vesicles. New lesions tend to form over a period of 3-5 days, sometimes coalescing to form bullae. After they form vesicles, lesions progress through stages in which they rupture, release their contents, ulcerate, and finally crust over and become dry. Patients remain infectious until the lesions have dried.

During this phase, almost all adult patients experience pain (ie, acute neuritis). A few experience severe pain without any evidence of a vesicular eruption (ie, zoster sine herpete), and a small number have a characteristic eruption but do not experience pain. Symptoms and lesions in the acute eruptive phase tend to resolve over 10-15 days. However, lesions may require up to a month to completely heal, and the associated pain may become chronic.

PHN, the chronic phase, is characterized by persistent or recurring pain lasting 30 or more days after the acute infection or after all lesions have crusted. It is the most frequent complication, observed in 9-45% of all cases.[4] Most people report a deep burning or aching pain, paresthesia, dysesthesia, hyperesthesia, or electric shock–like pains. The pain can be severe and incapacitating, and may take a long time to resolve, especially in the elderly; it lasts longer than 12 months in nearly 50% of patients older than 70 years.[5]

Herpes zoster (shingles) is caused by VZV infection. VZV is an enveloped, double-stranded DNA virus belonging to the Herpesviridae family; its genome encodes approximately 70 proteins. In humans, primary infection with VZV occurs when the virus comes into contact with the mucosa of the respiratory tract or conjunctiva. From these sites, it is distributed throughout the body. After primary infection, the virus migrates along sensory nerve fibers to the satellite cells of dorsal root ganglia where it becomes dormant.

Reactivation of VZV that has remained dormant within dorsal root ganglia, often for decades after the patient’s initial exposure to the virus in the form of varicella (chickenpox), results in herpes zoster.[1] Exactly what triggers this reactivation has not yet been determined precisely, but likely candidates (alone, or in combination) include the following:

• External reexposure to the virus

• Acute or chronic disease processes (particularly malignancies and infections)

• Medications of various types

• Emotional stress

The reason why one dorsal root ganglion experiences reactivation of its stored viral load preferentially over another ganglia is unclear. Diminished cellular immunity seems to increase the risk of reactivation, in that the incidence increases with age and in immunocompromised persons.[17]

Zoster can be a presenting symptom of hyperparathyroidism, and it occurs twice as often (frequency, 3.7%) among patients with hypercalcemia as it does among age-matched cohorts of patients older than 40 years who have normal calcium levels.[18]

The cause of PHN also remains a mystery. Rapid initiation of treatment decreases the incidence of PHN substantially, an effect that can be explained by the theory that incessant pain of active zoster sets up a positive feedback loop within the thalamus and the cortex, creating a central pain syndrome similar to phantom leg pain. According to this theory, prompt treatment breaks the loop by providing pain-free periods early in the disease course.

Risk factors

Known risk factors for developing herpes zoster relate to the status of cell-mediated immunity to VZV. Risk factors in children and adults include the following:

• VZV-specific immunity and cell-mediated immunity, which generally declines with age

• Immunosuppression (eg, by HIV infection or AIDS)[17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31]

• Immunosuppressive therapy[32, 33]

• Primary VZV infection in utero or in early infancy, when the normal immune response is decreased

• Anti-tumor necrosis factor (TNF)-a agents (may pose an increased risk)[34]

• Immune reconstitution inflammatory syndrome (IRIS)

• Acute lymphocytic leukemia and other malignancies

IRIS is a paradoxical deterioration in clinical status that develops in a patient receiving antiretroviral treatment despite satisfactory control of viral replication and improvement of the patient’s CD4 count. Such patients may have signs and symptoms of a previously subclinical and unrecognized herpes zoster infection, as a paradoxical worsening of treatment response several weeks into therapy in the context of immune recovery on antiretroviral therapy (ART).

The appearance of herpes zoster within an 8- to 12-week period after initiation of ART should prompt consideration of IRIS. Early recognition and prompt treatment, along with continuation of highly active ART, are especially important in such cases.[35]

Research indicates that patients with inflammatory bowel disease (IBD) are at significantly increased risk for herpes zoster.[8] In an analysis of more than 108,000 IBD patients and 430,000 matched controls, the overall annual incidence per 100,000 person-years was 734 among IBD patients, compared with 437 in non-IBD patients. The elevated risk in IBD patients remained after adjustment for comorbidities and other factors. Treatment with thiopurines, corticosteroids, and biologic antitumor necrosis factor–alpha (anti-TNF) agents was independently associated with an increased risk of herpes zoster.[36, 37]

Patients with multiple myeloma and colon cancer treated with arsenic trioxide may have a propensity to develop herpes zoster (shingles). Arsenic compounds have been suggested as a possible predisposing factor for herpes viral reactivation in these patients.[38]

Ambilateral reactivation of herpes zoster after cataract operations on both eyes has been described.[39]

In a population-based case-control study from the United Kingdom aimed at quantifying the effects risk factors at various ages, 144,959 adults diagnosed with herpes zoster between 2000 and 2011 were compared with 549,336 age-, sex-, and practice-matched control subjects (median age, 62 years).[40] The following factors were associated with increased risk of zoster:

• Rheumatoid arthritis (2.1% vs 1.5%)

• Inflammatory bowel disease (1.3% vs 0.9%)

• Chronic obstructive pulmonary disease (4.7% vs 3.7%)

• Asthma (7.1% vs 5.8%)

• Chronic kidney disease (6.0% vs 5.4%)

• Depression (4.7% vs 4.0%)

For many of the risk factors evaluated, the relative effects were greater in younger individuals.[40] The greatest risk of zoster was observed in patients with severely immunosuppressive conditions (eg, lymphoma and myeloma), but current vaccines are contraindicated in these individuals.

United States statistics

In the United States, approximately 95% of adults—and 99.5% of adults aged 40 years or older—have antibodies to VZV and thus are vulnerable to reactivation of infection.[41] A person of any age with a previous varicella infection may develop zoster, but the incidence increases with advancing age as a consequence of declining immunity.

Approximately 4% of patients develop a recurrent episode later in life.[42] Recurrent zoster occurs almost exclusively in people who are immunosuppressed. Approximately 25% of patients with HIV and 7-9% of those receiving renal transplantation or cardiac transplantation experience a bout of zoster.

HZO represents 10-15% of all cases of HZ. Approximately half of these patients develop complications of HZO. The risk of ophthalmic complications in patients with herpes zoster does not seem to correlate with age, sex, or severity of the rash.

Before the advent of widespread vaccination, an estimated 4 million cases of primary VZV infection occurred annually in the United States alone.[41] Infection was nearly universal by the end of the teenage years, with studies showing only 10% of persons older than age 15 years as remaining susceptible to infection.[42]

Over the period of a lifetime, 10-20% of those with primary infections went on to experience episodes of herpes zoster.[43] High-risk groups, such as elderly populations and immunocompromised people, might experience cumulative incidences as high as 50%.[44] The estimated annual number of cases in the United States is approximately 1 million.[18]

Since the introduction of widespread vaccination for varicella in 1995, the incidence of primary VZV infection in the United States has been reduced by up to 90%.[41] However, the effect of this vaccination, as well as that of the subsequently approved vaccination for herpes zoster, on the current and future incidence of herpes zoster remains to be determined.

International statistics

Internationally, the incidence of zoster has not been well studied, but it is probably in the same range as that reported in the United States.[45] A German study of data on patients in the country’s statutory health system (SHI) for the year 2010 estimated that the mean annual incidence was 5.79 cases per 1000 person-years, equivalent to 403,625 cases annually in the SHI population (which comprised about 85% of the total German population).[46]

Age-related demographics

It is rare in children and young adults, except in younger patients with AIDS, lymphoma, other malignancies, and other immune deficiencies and in patients who have received bone marrow or kidney transplants. Fewer than 10% of zoster patients are younger than 20 years, and only 5% are younger than 15 years. Even though zoster is primarily a disease of adults, it has been noted as early as the first week of life, occurring in infants born to mothers who had primary VZV infection (chickenpox) during pregnancy.

The incidence increases with age.[47] In the general population, the lifetime incidence rate is 10-20%, which rises to 50% in those individuals surviving to age 85 years.[17] More than 66% of patients are older than 50 years. The incidence of PHN also rises with advancing age.[48]

Sex-related demographics

It generally has not been considered to have a sex predilection. However, one study reported a higher prevalence in women than in men.[49] Ertunc et al suggested both that zoster frequency is higher in right-handed patients and that the rash appears more frequently on the left side in females.[50] The pathophysiology for these differences is uncertain.

Race-related demographics

Blacks are reported to have a significantly lower risk of developing zoster than whites do; however, zoster has been reported as an early manifestation of HIV infection in young Africans. Research has shown that elderly blacks are up to 75% less likely to develop herpes zoster than elderly whites.[44] Similar findings have been demonstrated in children.[51] In a meta-analysis of controlled herpes zoster clinical trials, a nonwhite racial group was found to be associated with a younger age at zoster onset.[47]

The rash usually resolves within 10-15 days. The prognosis for younger and otherwise healthy patients is excellent. Elderly people have a significantly increased risk of complications.

It rarely causes fatalities in patients who are immunocompetent, but it can be life-threatening in severely debilitated or immunocompromised patients. Disseminated zoster in immunocompromised patients can lead to death from encephalitis, hepatitis, or pneumonitis. Patients with active lymphoproliferative malignancies are at particular risk. Mortality rate from disseminated herpes zoster is between 5% and 15%.[43]

Morbidity usually is confined to pain within the affected dermatome, which can range in intensity from uncomfortable to debilitating. PHN can persist well beyond the duration of active disease, though most cases eventually resolve.

Variant presentations of zoster (eg, keratitis and myelitis) may carry additional morbidity. Eye involvement (HZO) can cause temporarily or permanently decreased visual acuity or blindness. Complications such as secondary infection and meningeal or visceral involvement can produce further morbidity in the form of infections and scarring.

A 2017 propensity score–matched analysis indicates that newly diagnosed herpes zoster significantly raises the risk of myocardial infarction and stroke.[52, 53] Results showed a 41% increased risk of composite cardiovascular events. Antiviral treatment and vaccination may decrease risks, but further research is needed. Rationing of health care so that there is an 80-year upper age limit on vaccinations enhances the burden of disease.[54]

Patients should be informed about the natural progression of herpes zoster, its potential complications, and the value of vaccinations. Motivational interviewing has been successful in increasing adult vaccinations using supermarket chain pharmacies.[55]

During the acute phase, patients are infective and contagious to others and should be instructed to avoid contact with elderly people, people who are immunocompromised, pregnant women, people with no history of chickenpox infection. It is especially contagious to infants and babies.

In regard to treatment, patients should be instructed that treatment should be started within 72 hours of onset if at all possible, not only to speed resolution of the shingles itself but also to prevent PHN. Once PHN begins, treatment is much more difficult and often unsuccessful. Patients should also be told not to scratch the lesions; doing so may predispose them to secondary bacterial infections.

For patient education resources, see the Infections Center, as well as Shingles and Chickenpox. Additionally, an informational video is provided below.

Herpes zoster (shingles) may begin with a systemic response (eg, fever, anorexia, and lassitude), though symptoms frequently are mild and may not be associated by either patient or physician with the classic manifestations of the condition.

Symptoms typically include prodromal sensory phenomena along 1 or more skin dermatomes lasting 1-10 days (average, 48 hours), which usually are noted as pain or, less commonly, itching or paresthesias.[3] Prodromal pain typically is described as muscle or toothachelike in origin but may simulate headache, iritis, pleurisy, brachial neuritis, cardiac pain, appendicitis or other intra-abdominal disease, or sciatica. This simulation can result in incorrect tentative diagnoses; however, the dermatomal distribution usually helps clarify the diagnosis.

The prodromal interval of pain prior to onset of cutaneous findings has been believed to represent spread of varicella-zoster virus (VZV) particles along sensory nerves; however, approximately 10% of patients report the simultaneous onset of pain and rash.

After the onset of prodromal symptoms, the following signs and symptoms occur:

• Patchy erythema, occasionally accompanied by induration, in the dermatomal area of involvement

• Regional lymphadenopathy, either at this stage or subsequently

• Grouped herpetiform vesicles developing on the erythematous base (the classic finding)

• Pain in the dermatomal area of involvement may remain the same as in prodrome or may change in character and intensity with the onset of other symptoms; many patients describe the pain as burning, throbbing, or stabbing in nature; it may be severe, mild, constant, rare, or felt as another sensation such as pruritus; the involved area may be tender to palpation[1]

• Vesicular involution – Vesicles initially are clear but eventually cloud, rupture, crust, and involute, a process that may be greatly accelerated by treatment

• After vesicular involution, slow resolution of the remaining erythematous plaques, typically without visible sequelae – Note, however, that scarring can occur if deeper epidermal and dermal layers have been compromised by excoriation, secondary infection, or other complications

Unfortunately, resolution of the associated pain does not always accompany resolution of erythema and vesiculation. Postherpetic neuralgia (PHN), which usually is confined to the area of original dermatomal involvement, can persist for weeks, months, or years and is often severe. Severe prodromal pain and the density of the herpetic eruption have been characterized as risk factors and predictors for PHN.[56]

The reason why some patients with zoster experience PHN and others do not is not fully understood, but it is clear that patients who are older (> 60 years), particularly those who are debilitated or arteriosclerotic, are affected far more frequently than younger patients are. In addition, PHN is observed more frequently after cases of herpes zoster ophthalmicus (HZO) and in instances of upper-body dermatomal involvement.

Other less common postherpetic sequelae include hyperesthesia or, more rarely, hypoesthesia or anesthesia in the area of involvement.

Herpes zoster oticus (Ramsay Hunt syndrome) may produce an acute jugular foramen syndrome.[57] It is characterized by acute-onset dysphagia and dysphonia, often accompanied or preceded by cranial, cervical, or pharyngeal pain. Herpetic vesicles on the skin or mucosa may or may not occur, may be noted late after onset, or may go undetected.

Classic physical findings include painful grouped herpetiform vesicles on an erythematous base confined to the cutaneous surface innervated by a sensory nerve (see the first image below). Typically, the condition affects a single dermatome, most commonly a thoracic dermatome, on one side of the body (see the second, third, and fourth images below). Regional lymphadenopathy may be present.

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

Herpes zoster, unilateral, on trunk.

Herpes zoster on lateral part of abdomen.

Suspected zoster of the hand.

After a prodromal illness, erythematous macules and papules appear (see the image below) and progress to vesicles within 1 day. The vesicles eventually cloud, rupture, crust, and involute. Patients may experience pain and sensory loss in the distribution of the rash. Motor weakness, especially in lumbar and cervical radicular distributions, is often present but unrecognized and represents viral activity beyond the sensory root. Because the weakness often is not diagnosed accurately, the incidence and prevalence are uncertain.

Maculopapular rash due to herpes zoster in child with history of leukemia. Image courtesy of Centers for Disease Control and Prevention (CDC).

Note that zoster may present in multiple dermatomes and possibly bilaterally (ie, zoster multiplex). The frequency of multiple, disseminated, and visceral zoster is increased in the immunocompromised population. Occasionally, patients experience paresthesias and pain in a dermatomal distribution without a rash (ie, zoster sine herpete).

Many clinical variations are possible. The following is a summary of the more important variations.

Herpes zoster ophthalmicus

HZO results from viral invasion of the Gasserian ganglion and accounts for 10-15% of zoster cases.[58] In addition to the classic symptoms and lesions of herpes zoster, common manifestations of HZO include conjunctivitis, scleritis, episcleritis, keratitis iridocyclitis, Argyll-Robertson pupil, glaucoma, retinitis, choroiditis, optic neuritis, optic atrophy, retrobulbar neuritis, exophthalmos, lid retraction, ptosis, and extraocular muscle palsies.

HZO develops when cranial nerve (CN) V (ie, the trigeminal nerve) is involved in viral reactivation. For unknown reasons, involvement of the ophthalmic branch of this nerve (V1) is 5 times as common as involvement of the maxillary branch (V2) or the mandibular branch (V3). HZO is easily recognized on the basis of vesicular and erythematous involvement of the CN V1 dermatome, ipsilateral forehead, and upper eyelid (see the image below). When lesions are found in the CN V1 dermatome, a slit-lamp examination is done to identify corneal findings.

Herpes zoster in ophthalmic (V1) distribution of trigeminal nerve. Note unilateral distribution of rash and how V1 distribution may extend to tip of nose. Though at risk for keratitis with zoster in this distribution, patient had normal ocular examination. Patient consented to picture distribution for educational use; written permission on file. Image courtesy of JS Huff.

Ipsilateral preauricular and, occasionally, submaxillary nodal involvement is a common prodromal event in HZO and often is valued equivalently with pain, vesiculation, and erythema in establishing a diagnosis. Prodromal lymphadenopathy should not be confused with the later reactive adenopathy caused by secondary infection of vesicles. Headaches, nausea, and vomiting also are common prodromal symptoms.

Signs of meningeal irritation may be present; therefore, meningitis must be excluded. CN V1 (with ciliary ganglion) sends branches to the tentorium (the recurrent nerve of Arnold), as well as to CN III, CN VI, and occasionally CN IV. This may account for the frequency of meningeal signs and the occasional CN III and CN VI nerve palsies associated with HZO.

Aggressive treatment and follow-up monitoring are required for HZO because of the possibility of eye involvement, which occurs in about 50% of HZO patients. Traditionally, nasociliary branch involvement, characterized by vesicles at the tip of the nose, has indicated that eye involvement is present or imminent (the Hutchinson rule). This rule is now being disputed, with some experts claiming that eye and nasociliary branch involvement can be present without such vesiculation. In our experience, eye lesions are rare in the absence of distal nose lesions.

In the absence of prompt detection and treatment, eye involvement poses a risk to vision. The presence of orbital edema is an ophthalmologic emergency, and patients must be referred immediately for specialized ophthalmic evaluation and treatment. Iritis, iridocyclitis, glaucoma, and corneal tissue ulcerations are possible in these cases. Involvement of the area below the palpebral fissure alone, without upper eyelid or nasal involvement, is considered less likely to result in ocular complications, in that the superior maxillary nerve innervates the lower eyelid.

Postherpetic complications are more common in HZO than in other manifestations of zoster.[59] In particular, PHN is observed in well over 50% of patients with HZO and can be severe and long-lasting. Scarring also is more common, probably as a result of severe destructive inflammation.

As noted (see above), palsy of CN III and, occasionally, of CN IV and CN VI may occur. Rarely, simultaneous involvement of other CNs has been reported. The most common such event is CN VII involvement, which may produce facial palsy.

Svozilkova et al reported 1 case of varicella-caused retinal necrosis after ocular trauma.[60]

Intraoral herpes zoster

HZO may involve the skin or the oral cavity, or both simultaneously. Trigeminal herpes zoster with Ramsay Hunt syndrome may produce cutaneous, intraoral, and otic vesicles; hearing loss; and mild facial palsy.[16] Herpes zoster of the maxillary division of the trigeminal nerve may begin with toothache during its prodromal stage, followed by its vesicular eruption.[61] Herpes zoster maxillaris may involve a unilateral maxillary canine to resemble pulpal necrosis and apical periodontitis. Thus, gingival herpes zoster may be evident as painful desquamative vesicles or a pulpal disorder.[62]

Herpes zoster of maxillary branch of CN V

Involvement of CN V2 is localized to the ipsilateral cheek, the lower eyelid, the side of the nose, the upper eyelid, the upper teeth, the mucous membrane of the nose, the nasopharynx, the tonsils, and the roof of the mouth. At times, only the oral mucous membrane is involved, and there are no cutaneous manifestations. Early preeruptive herpetic pain can simulate a severe toothache and result in unnecessary oral surgery or dental treatment.

Herpes zoster of mandibular branch of CN V

Areas of CN V3 involvement include the side of the head, the external ear and external auditory canal, the lower lip, and a portion of the oral mucosa. As when other branches of CN V are involved, prodromal pain in affected areas can result in incorrect diagnoses.

Herpes zoster oticus

Herpes zoster oticus (also termed geniculate zoster, zoster auris, Ramsay Hunt syndrome, or Hunt syndrome) may develop if the geniculate ganglion is involved. This condition is considered rare but more likely is just rarely recognized. It often is mistaken for eczema, Ménière disease, Bell palsy, stroke, and abscess of the ear.

Classically, herpes zoster oticus begins with otalgia and herpetiform vesicles in the external ear canal or on the tympanic membrane, with or without features of facial paralysis resulting from facial nerve (CN VII) involvement, auditory symptoms (eg, deafness), and vestibular symptoms in variable combinations. The syndrome also may result from zoster originating from CN IX or CN X; the external ear has complex innervation that includes branches of several CNs (CN V, CN VII, CN IX, and CN X), as well as vertebral nerve C2 and possibly C3.

Glossopharyngeal and vagal herpes zoster

Glossopharyngeal zoster (herpes pharyngis) and vagal zoster (herpes laryngis) involve the jugular and petrosal ganglia, which are adjacent and often involved in some combination; however, individual involvement of both ganglia has been observed. Painful vesicular rash typically involves the palate, posterior tongue, epiglottis, tonsillar pillars, and, occasionally, the external ear. A unilateral distribution can distinguish this variation of zoster from herpes simplex and herpangina.

Herpes occipitocollaris (vertebral nerves C2 and C3 involvement)

Herpes occipiticollaris involves the posterior scalp, the nuchal area, portions of the ear, and portions of the lower mandible and anterior neck (see the image below). Vertebral nerves C2 and C3 often are involved together. Branches of these 2 vertebral nerves communicate with CN VII and CN X, sometimes causing symptoms related to these cranial nerves as well.

Herpes zoster on neck.

Nuchal or scalp involvement occasionally is confused with folliculitis, furunculosis, cellulitis, erysipelas, or acne keloidalis nuchae. The painful prodrome can result in confusion and misdiagnosis until the classic vesicular rash appears.

Herpes zoster encephalomyelitis

Herpes zoster encephalomyelitis may give rise to localized mild leptomeningitis in the region of neurologic involvement. This is more common than is generally recognized and often results in pleocytosis in the cerebrospinal fluid (CSF). Leptomeningitis most likely occurs when CNs (especially CN V) are involved because of the presence of the recurrent nerve of Arnold, which branches from CN V1 to the tentorium. For this reason, meningeal symptoms (eg, headache, changes in sensorium, fever, and neck stiffness) are most common with HZO.

Rarely, symptoms of meningoencephalitis may be significant; at times, they may be severe enough to cause death. Westenend and Hoppenbrouwers reported fatal hemorrhagic encephalitis in an otherwise healthy woman.[63] Zoster encephalomyelitis may be mistaken for acute poliomyelitis. The spread of VZV to the central nervous system (CNS) also may occur during suppression of host resistance by neoplasms, by cytotoxic drugs, and, possibly, by radiation therapy.

Herpes zoster myelitis

That VZV can produce encephalomyelitis is well documented. More rarely, the myelitis lesion predominates or is the sole feature. The clinical picture is one of acute onset of paraplegia resulting from a diffuse involvement of the spinal cord. The picture is that associated with acute transverse myelopathy.

Spinal cord involvement becomes apparent within 2-3 weeks of the initial rash, with myelopathic findings (usually bilateral) on examination. The disease may progress for 3 weeks, though a few cases of progression for as long as 6 months have been reported in patients with AIDS. Recurrent zoster myelitis is rare, though one case has been reported of a previously healthy young woman who developed recurrent myelopathy at the same spinal level. The condition resolved fully with intravenous (IV) acyclovir treatment.

Disseminated herpes zoster

Disseminated herpes zoster is usually defined as a generalized eruption of more than 10-12 extradermatomal vesicles occurring 7-14 days after the onset of classic dermatomal herpes zoster. Typically, it is clinically indistinguishable from varicella (chickenpox). Dissemination occurs in approximately 2% of zoster cases in the general population but has been observed in as many as 35% of patients who are hospitalized or immunocompromised.

Dissemination often is an indication of depressed cell-mediated immunity caused by various underlying clinical situations, including malignancies, radiation therapy, cancer chemotherapy, organ transplants, and long-term use of systemic corticosteroids (short-term use of low-to-moderate doses of corticosteroids does not increase the incidence of dissemination). Patients in whom zoster has disseminated must be observed carefully for the development of pneumonitis and encephalitis, which can be life-threatening.

Unilateral herpes zoster involving multiple dermatomes

Involvement of more than 1 dermatomal distribution in unilateral zoster is rare and usually is considered a harbinger of significant compromise of the immune system caused by AIDS, malignancy, chemotherapy, and other factors. Involvement of 2 dermatomes may be referred to as zoster duplex, and involvement of 3 or more may be referred to as zoster multiplex.

Bilateral herpes zoster

On rare occasions, herpes zoster manifests bilaterally. Bilateral presentations should always raise concern for disseminated disease (and immunocompromise) or for alternate diagnosis, specifically for herpes simplex.

In cases of bilateral zoster, it is not unusual for 1 or 2 adjacent dermatomes to be involved. Unlike examples of multiple dermatomal involvement in unilateral disease (see above), involvement in adjacent dermatomes is not typically a sign of underlying disease (eg, malignancy).

Recurrent herpes zoster

Recurrences of herpes zoster do occur rarely and are not limited to those who are immunocompromised.[64] The incidence rate of herpes zoster is 5.1 cases per 1000 person years; its recurrence rate was calculated at 12 cases per 1000 person years. Risk factors include old age (51-70 years) and zoster-related pain longer than 30 days. Many reputed cases of recurrent zoster involve other entities, usually herpes simplex in a linear distribution.

Herpes zoster involving urinary bladder

Rarely, zoster involving the dermatomes of the buttock area (vertebral nerves L1, L2, S2, S3, S4) may be associated with vesicles in the bladder, which can cause severe dysuria and urinary frequency. This picture is easily mistaken for that of cystitis. If vesicles rupture in the bladder, hematuria (another common symptom of cystitis) may occur. Transient bladder paralysis resulting from zoster involving the gluteal and sacral regions and lumbar sympathetic segments has been reported, and acute urinary retention is possible if a motor component exists.

Herpes zoster involving other internal structures

Vesicular involvement has been reported in bronchi, pleural spaces, and the gastrointestinal (GI) tract. Zoster pneumonia also has been reported. Such involvement frequently is found in individuals with significantly compromised immune systems. Pain in these areas, like pain on the cutaneous surface, may be referred and does not necessarily indicate the presence of vesicles.

Herpes zoster with motor complications

Although VZV typically invades only sensory nerves (for unknown reasons), viral particles occasionally cross over to the anterior horn of the involved ganglion and cause motor symptoms. These symptoms range from weakness to total paralysis, depending on how many roots of the involved nerve plexus are affected. Whereas most motor involvement (like most sensory involvement) is self-limited, partial or complete paresis can persist indefinitely, particularly when cranial (CN V or VII), phrenic, and extremity nerves are affected.

Paresis may be seen in extraocular muscles, any area of facial innervation, and anywhere along the spinal cord, including the phrenic nerve. Paresis most commonly is observed when muscles of an arm or leg are involved; however, this may be because it is detected most easily at those locations.

Fabian et al reported a patient who had a left upper arm monoplegia after zoster multiplex involving C4, C5, and C6 nerves.[65] The authors believed that the brachial plexus inflammation was an extension of a dorsal ganglionitis. They found that the motor neuropathy was an inflammatory demyelinating process.

Truncal motor involvement may be more common than generally is believed, because both physician and patient easily may overlook a small area of muscle weakness of the central trunk. Paralysis of abdominal musculature can cause a hernial bulge.

Zoster sine herpete

Some cases of VZV reactivation result in a condition known as zoster sine herpete. Patients experience pain and weakness in a dermatomal distribution, and a tender, erythematous, unilateral patch or plaque is apparent, but there are no visible signs of cutaneous vesicles. Like typical herpes zoster (shingles), zoster sine herpete tends to be preceded by dysesthesias.

This condition presents a diagnostic dilemma; however, VZV DNA may be detected by polymerase chain reaction (PCR) assay of oropharyngeal swabs in patients with zoster peripheral facial palsy. Because such studies are not routine, the true incidence and prevalence are unknown. Furuta et al found that VZV could be demonstrated in 8-25% of patients with acute peripheral facial palsy without cutaneous vesicles.[66]

Although it is rarely, if ever, fatal in itself, it may be considered a contributing factor to death in some individuals who are severely debilitated. Westenend and Hoppenbrouwers reported fatal hemorrhagic encephalitis in an otherwise healthy female.[63] The condition has numerous potential nonfatal complications, as follows.

PHN is the most common complication, affecting as many as 50% of patients older than 60 years. It may develop as a continuation of the pain that accompanies acute zoster, or it may develop after apparent resolution of the initial zoster reactivation. The pain may last for months to years.[5] The underlying pathophysiology of PHN may involve peripheral nerve damage or continued viral activity.

Herpes zoster involving CN V1 (ie, HZO) may be associated with conjunctivitis, keratitis, corneal ulceration, iridocyclitis, glaucoma, and decreased visual acuity or blindness. With ocular involvement, long-term antiviral treatment may be required.

Complications of herpes zoster oticus (Ramsay Hunt syndrome)—that is, zoster involving CN V, CN IX, and CN X)—may include peripheral facial nerve weakness and deafness. This condition may also produce an acute jugular foramen syndrome.[57]

It may be associated with a secondary bacterial infection at the site of the rash (typically streptococcal or staphylococcal). Necrotizing fasciitis is a possible and devastating complication.

Meningoencephalitis secondary to herpes zoster is more likely to be seen in immunocompromised patients than in immunocompetent patients. Other CNS complications may include myelitis, cranial nerve palsies, and granulomatous angiitis. Granulomatous angiitis may result in the development of a cerebrovascular accident.

Disseminated zoster may be seen in immunocompromised patients. In such cases, hematogenous spread may result in the involvement of multiple dermatomes.

Visceral involvement can also occur. Hong and Elgart have reported GI complications.[67]

Guillain-Barré syndrome is a rare complication from reactivation of latent VZV. Cresswell et al reported that Guillain-Barré syndrome also resulted from primary VZV infection in an adult.[68]

VZV is being investigated for its possible role in least some cases of chronic fatigue syndrome.[69]

Severe herpes zoster after varicella vaccination in immunocompetent young children as a rare complication has been described, with these children at low risk of developing meningoencephalitis.[70] In children, VZV infection may produce a facial palsy[71] ; it may also result in zoster sine herpete, doing so more frequently in children than adults. Ramsay Hunt syndrome (herpes zoster oticus) tends to be found more often in school-aged children, whereas zoster sine herpete is more likely to be found in preschool children.

Childhood varicella zoster virus infections have been linked with an increased risk of arterial ischemic stroke and may precipitate a childhood arterial ischemic stroke.[72, 73]

Diagnosis of herpes zoster (shingles) is based primarily on the history and physical findings—specifically, the characteristic location and appearance of the skin eruption in association with localized pain. Systemic manifestations are uncommon and usually are confined to patients in whom the immune system has been compromised by other disease processes or chemotherapy.

In most patients, confirming the diagnosis via laboratory testing usually has no utility, because most tests are time consuming, lack specificity, or are unavailable outside of research facilities. In select patient populations, however, the presentation can be atypical and may require additional testing. This is particularly true in immunocompromised patients.

Zoster has been considered a harbinger of other occult disease (eg, malignancies in older patients). Both zoster and malignancy are common in elderly individuals; therefore, most experts currently consider the association to be purely coincidental. There also appears not to be an increased incidence of malignancy in children with herpes zoster. Approximately 3% of pediatric cases occur in children with malignancies. Accordingly, a malignancy workup is not indicated in an otherwise healthy child who has herpes zoster.

Although varicella-zoster virus (VZV) can be cultured, its growth rate is usually too slow for culturing to make a timely contribution to diagnosis.

One of the least expensive and simplest laboratory diagnostic methods for VZV and other herpesviruses is the Tzanck smear. The Tzanck smear is performed by obtaining a scraping from the base of a fresh vesicular lesion after it has been unroofed, spreading and drying the collected material on a glass slide, staining the result with Giemsa, and examining the material with a microscope for the characteristic presence of multinucleated giant cells.

The Tzanck smear confirms that the lesion is herpetic but cannot differentiate between VZV and other herpesviruses. Further, this test has a limited sensitivity compared with other diagnostic methods, such as polymerase chain reaction (PCR) assay. Therefore, a negative result does not rule out a herpes virus infection and should not preclude empiric treatment in patients.[76]

When acute diagnostic confirmation is desired, modern tests, such as direct fluorescent antibody (DFA) testing or PCR (if available), are preferred to the Tzanck smear. DFA testing of vesicular fluid or a corneal lesion can yield the VZV antigen. Both DFA and PCR have far greater sensitivity and specificity than the Tzanck smear and allow differentiation between herpes simplex virus (HSV) and VZV infections.

PCR assay of vesicular fluid or a corneal scraping can yield the VZV nucleic acid. Detection of VZV DNA in plasma can facilitate the early recognition of VZV infection in immunocompromised hosts.[77] [#WorkupSkinBiopsyFindings]In cases of zoster sine herpete, DNA analysis by means of PCR appears more useful than the standard assays, especially for early diagnosis.

It is seen approximately 7 times more frequently in patients with HIV infection; therefore, when clinically indicated, an HIV test should be ordered.

No imaging tests are indicated in typical cases of cutaneous herpes zoster infection. Magnetic resonance imaging (MRI) may be used in cases of myelopathy or encephalopathy as a means of excluding other etiologies.

A small percentage of patients, particularly those with cranial nerve (CN) involvement, may develop headache and neck stiffness, necessitating a lumbar puncture to exclude meningitis. Because the inflammatory response involves the leptomeninges, cerebrospinal fluid (CSF) may show increased protein and a pleocytosis.

Because the diagnosis can almost always be made on clinical grounds, skin biopsy is seldom necessary; as a rule, it is reserved for cases that are difficult to diagnose (eg, atypical lesions).

On rare occasions when skin biopsy is necessary, histologic findings are similar to those of herpes simplex and varicella. Ballooning degeneration and acantholysis of keratinocytes result in an intraepidermal vesicle. Multinucleated giant cells with accentuation of nuclear material at the periphery of nuclei are characteristic.[78] Underlying leukocytoclastic vasculitis often is a prominent finding and helps differentiate zoster from other herpetic infections.

Lymphocytes may be found in the lower part of the epidermis, accompanied by a combination of spongiosis and vacuolar alteration. The papillary dermis is often edematous. Extravasated erythrocytes in variable numbers are a common finding. A brisk lymphocytic infiltrate is present in the upper dermis.

Some of these lymphocytes may have large and polygonal nuclei. They are dense, perivascular, and sparse interstitial, superficial, and deep collections, sometimes assuming a patchy, lichenoid pattern. The lymphocytes may be prominent in and around adnexal structures, often peppering follicles, sebaceous glands, and eccrine glands.

Neutrophils and nuclear dust are occasionally seen; eosinophils are rare.

Conventional microscopy is routinely used to confirm infection by herpesviruses, though on occasion, PCR assay may then be used to demonstrate herpesvirus-specific DNA.

Episodes of herpes zoster (shingles) are generally self-limited and resolve without intervention; they tend to be more benign and mild in children than in adults. An enormous number and variety of therapeutic approaches have been proposed over the years, most of which are probably ineffective.[79] Some effective therapies do exist, however, and these can reduce the extent and duration of symptoms, and possibly the risk of chronic sequelae (eg, postherpetic neuralgia [PHN]) as well.

Therapeutic choices generally depend on the host’s immune state and on the presentation of zoster. Conservative therapy includes nonsteroidal anti-inflammatory drugs (NSAIDs); wet dressings with 5% aluminum acetate (Burow solution), applied for 30-60 minutes 4-6 times daily; and lotions (such as calamine).

Treatment is of greatest benefit in those patient populations at risk for prolonged or severe symptoms, specifically, immunocompromised people and persons older than 50 years. The benefit of treating younger and healthier populations is unclear.

Uncomplicated zoster does not require inpatient care. Hospital admission should be considered for patients with any of the following:

• Severe symptoms

• Immunosuppression

• Atypical presentations (eg, myelitis)

• Involvement of more than 2 dermatomes

• Significant facial bacterial superinfection

• Disseminated herpes zoster

• Ophthalmic involvement

• Meningoencephalopathic involvement

Patients with disseminated disease or severe immunosuppression or who are 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.

Medications used include steroids, analgesics, anticonvulsants, and antiviral agents. Surgical care is not generally indicated, though it may be required to treat certain complications (eg, necrotizing fasciitis). Rhizotomy (surgical separation of pain fibers) may be considered in cases of extreme, intractable pain.

Varicella-zoster virus (VZV) vaccine is used for preventive purposes. Varicella-zoster immune globulin (VZIG) is used to prevent or modify clinical illness in susceptible persons who are exposed to varicella or zoster.

There are a variety of topic treatments, including topical acyclovir 5% cream, lidocaine, and capsaicin.[80, 81] The latter, applied at least 5 times a day, depletes neurotransmitters at involved nerve endings. Topical lidocaine can also be used to treat patients with PHN.[82] For acute HZO, a good approach is wet-to-dry dressings with sterile saline solution or Burow solution (a pharmacologic preparation made of 5% aluminum acetate dissolved in water), which should be applied to the affected skin for 30-60 minutes 4-6 times daily. A modified form of Burow solution is commercially sold as Domeboro powder packets, which need to be dissolved in water. The acyclovir cream is often applied 5 times a day for 4 days. Calamine lotion, a mixture of zinc oxide with about 0.5% iron (III) oxide, may be used as an antipruritic 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 weeping or oozing blisters. There is, however, no proof that calamine lotion has any real therapeutic effect on rashes and itching. Topical ozone therapy may be beneficial in diminishing pain and shortening the course, with few if any adverse effects.[83]

The goals of therapy are as follows:

• To shorten the clinical course

• To provide analgesia

• To prevent complications

• To decrease the incidence of PHN

Corticosteroids

Whether steroids are essential or even helpful for zoster remains subject to debate. Many practitioners have long used oral prednisone and similar medications to reduce acute pain.[84] Some have also hoped to decrease the incidence of PHN, presumably by reducing inflammation in dorsal root ganglia and involved sensory nerves. Whereas some studies have provided evidence that the early use of steroids may decrease the incidence of PHN, others have failed to show benefit. Additional study is needed.

A substantial dose (40-60 mg every morning) typically is administered as early as possible in the course of the disease and is continued for 1 week, followed by a rapid taper over 1-2 weeks. Dissemination of viral particles beyond dermatomal limits always has been a theoretical concern, but clinically, it almost never is observed in individuals with intact immune systems. Typical risks inherent in the use of systemic steroids, such as adrenocortical suppression and femoral osteonecrosis, must be kept in mind.

Two controlled studies evaluated the addition of oral corticosteroids to acyclovir therapy.[85, 86] In comparison with antiviral agents alone, the combined regimen was were found to accelerate the resolution of acute neuritis and to yield a clear improvement in quality-of-life measures. The use of oral steroids had no effect on the development or duration of PHN.

A study involving a single epidural injection of steroids and local anesthetics given in conjunction with a standard regimen of oral antivirals and analgesics was found to yield a modest improvement in zoster-associated pain for 1 month as compared with treatment without steroids.[87] No effect in preventing PHN was noted.

In view of the potential adverse effects of and contraindications to corticosteroid use, it has been suggested that these agents should be limited to cases of moderate to severe zoster pain or cases in which significant neurologic symptoms (eg, facial paralysis) or central nervous system (CNS) involvement is present and the use of corticosteroids is not otherwise contraindicated.[1]

The optimal duration of steroid therapy is not known. It seems reasonable that if such therapy is prescribed, it should be administered concurrently with antiviral therapy. The duration of steroid use should not extend beyond the period of antiviral therapy. Steroids should not be given alone (without antiviral therapy).

Agents for pain control

The majority of patients with acute herpes zoster experience pain, and this pain is usually the most debilitating symptom of the disease. Accordingly, efforts should be made to reduce patients’ pain and suffering, even if opioid therapy is required. Failure to do so is problematic, especially in view of emerging evidence that providing adequate pain control on an acute basis may reduce the incidence of PHN.

Primary medications for acute zoster-associated pain include the following:

• Narcotic and nonnarcotic analgesics (both systemic and topical)

• Neuroactive agents (eg, tricyclic antidepressants [TCAs])

• Anticonvulsant agents

The efficacy of these treatments for general neuropathic pain has been well established, but only a few of them have been evaluated specifically for acute zoster-associated pain in controlled studies.

The oral narcotic oxycodone and the oral anticonvulsant gabapentin, as well as the topical analgesics aspirin and lidocaine, proved capable of reducing acute zoster-associated pain in double-blind, placebo-controlled studies.[88, 89, 7, 90, 91] On the other hand, the oral anticonvulsant pregabalin had no statistically significant effect in relieving acute zoster pain in a small double-blind, placebo-controlled study. However, other controlled studies showed this medication to be effective in treating the pain of PHN.[92]

Corticosteroids (see above) and antiviral agents (see below) have also been shown to accelerate the resolution of zoster-associated pain.[42, 1, 93, 94, 95, 96, 85, 97]

Nonpharmacologic therapies that may be considered for acute zoster-associated pain include sympathetic, intrathecal, and epidural nerve blocks and percutaneous electrical nerve stimulation. Although well-controlled studies are few, meta-analyses and clinical trials suggest that these treatments are effective in treating acute zoster-associated pain.[4, 98, 99]

Antiviral agents

Many studies have found acyclovir and its derivatives (valacyclovir, famciclovir, penciclovir, and desciclovir, which is not available in the United States) to be safe and effective in treating active disease and preventing PHN. Their mechanism of action involves preventing VZV replication through inhibition of viral DNA polymerase.[43, 100] Valacyclovir and famciclovir are not approved by the US Food and Drug Administration (FDA) for treatment of herpes zoster in children; acyclovir is more commonly used.

Antiviral therapy may decrease the length of time for new vesicle formation, the number of days to attain complete crusting, and the days of acute discomfort. Usually, the earlier antiviral medications are started, the more effective they are in shortening the duration of zoster and in preventing or decreasing the severity of PHN. Ideally, therapy should be initiated within 72 hours of symptom onset.

Controlled studies of antiviral use have only evaluated the efficacy of initiation of therapy within 48-72 hours of rash onset, demonstrating no loss of effectiveness when medications are started at any point during that period.[100] Several observational studies found antiviral therapy to be capable of reducing zoster pain even when started beyond the traditional 72-hour therapeutic window.[101, 102] Thus, antiviral therapy should be considered for acute zoster treatment regimens, regardless of the time of presentation.

Clinical trials showed that oral acyclovir, famciclovir, and valacyclovir reduce viral shedding and accelerate resolution of symptoms (eg, pain) in uncomplicated herpes zoster. Some studies suggested that valacyclovir and famciclovir may be superior to acyclovir in resolving pain and accelerating cutaneous healing. In addition, both agents have greater bioavailability than acyclovir and thus require less frequent dosing.[42, 1, 93, 94, 95, 96] Moreover, acyclovir-resistant viral strains are emerging, suggesting a potentially increased role for newer agents.

The duration of antiviral treatment in studies has ranged from 7 to 21 days. For immunocompetent patients, a 7- to 10-day course of acyclovir or a 7-day course of one of the newer agents is probably appropriate; longer courses may be needed in immunocompromised patients.

The evidence of benefit notwithstanding, there remains some debate about the use of antivirals in this setting. For example, a study by Kubeyinje concluded that acyclovir did not decrease acute pain duration or the incidence of complications in healthy young adults with typical herpes zoster.[103] However, these results cannot be extrapolated to the elderly, who are at greater risk of PHN.

Immunocompromised states

Individuals with altered cell-mediated immunity, due either to an immunosuppressive condition (eg, HIV infection or cancer) or to a treatment (eg, extended corticosteroid use), are at increased risk. Furthermore, presentations in the immunocompromised population can be complicated by disseminated disease and visceral organ involvement.[1, 104]  Unsurprisingly, the risk of developing multiple myeloma, leukemia, and lymphoma is increased in patients with herpes zoster.[105]

Antiviral therapy has been demonstrated to halt progression and dissemination of acute herpes zoster in immunocompromised patients, even when initiated more than 72 hours after rash onset.[106] Accordingly, such therapy is recommended for all immunocompromised patients who present before the full crusting of all lesions.

IV acyclovir remains the drug of choice for the following populations of immunocompromised patients:

• Patients with evidence of disseminated disease or visceral organ involvement

• Patients with ophthalmic involvement

• Patients with advanced HIV/AIDS who harbor active opportunistic infections or exhibit prominent wasting

• Transplant recipients who have just undergone transplantation or are being treated for rejection

Patients without such risk factors can be treated with oral antiviral agents. Data on adjunctive therapy with corticosteroids are insufficient to permit a recommendation recommended. Antiviral therapy should be continued until all lesions have resolved.[106]

Herpes zoster ophthalmicus

A study by Morgan and King showed that the eye was the most common site of zoster involvement in patients requiring hospital admission.[107] Pain was the main complaint.

Two trials comparing oral acyclovir with famciclovir or valacyclovir in patients with herpes zoster ophthalmicus (HZO) found outcomes to be comparable with any of the regimens.[108, 109] Patients with diagnosed or suspected HZO should receive antiviral therapy and should be promptly referred to an ophthalmologist.

If a patient complains of severe pain at any point at or beyond the appearance of crusted vesicles, the clinician should strongly suspect that PHN has developed. Once established, the pain is notoriously difficult to alleviate with traditional analgesics, including narcotics. Consequently, treatment of PHN is complex; a multifaceted, patient-specific approach is important.

It should be noted that whereas acute zoster pain and PHN are believed to result from different pathophysiologic mechanisms, it is clinically and experimentally impossible to determine precisely when the 2 types of pain cross over. Accordingly, some workers use the term zoster-associated pain to describe both acute and chronic pain as a continuum.

The only consistently successful method of treating PHN is to prevent it via prompt treatment of acute zoster and its associated pain. Initiation of antiviral therapy as early as possible in the course of acute zoster, and definitely within 72 hours of onset, has been shown to be effective in alleviating acute pain and preventing PHN in most patients (though treating already-established PHN with antivirals appears not to be beneficial[110] ). Consultation with pain specialists may also be required.[5, 111, 112, 113]

Once PHN has developed, various treatments are available, including the following:

• Neuroactive agents (eg, TCAs)[6]

• Anticonvulsant agents (eg, gabapentin[7] and pregabalin)

• Narcotic and nonnarcotic analgesics, both systemic (eg, opioids) and topical

Two placebo-controlled studies that evaluated gastroretentive gabapentin in 357 patients with PHN found that more of the patients in the gabapentin group felt better and exhibited a response to treatment.[114] The reduction in PHN pain with gabapentin was noted as early as day 2 of therapy and lasted for at least 10 weeks.

Topical capsaicin can be helpful; its active ingredient depletes neurotransmitters at involved nerve endings. However, the cream must be applied at least 5 times daily, and pain may increase upon application for the first few days as accumulated neurotransmitters are released. Once neurotransmitter reserves have been depleted, any resultant pain relief is temporary.

Topical lidocaine is occasionally used to treat patients with PHN, though the data are insufficient to allow it to be recommended as a first-line agent for PHN with allodynia.[115] In one small study, administration of lidocaine 4% ophthalmic eyedrops produced a significant reduction in eye and forehead pain.[82]

The use of oral or epidural corticosteroids in conjunction with antiviral therapy has been found to be beneficial in treating moderate-to-severe acute zoster but to have no effect on the development or duration of PHN.[85, 97, 87] Intrathecal administration of corticosteroids has also been attempted[116] but is not currently recommended.

Combination therapies have shown promise for relieving PHN, but clinical evidence to support such approaches is limited.[117]

Pavan-Langston has proposed the following protocol for treatment of PHN[118] :

• TCAs – Nortriptyline, amitriptyline, or desipramine 25 mg; adjust up to 75 mg at bedtime; continue for several weeks if necessary

• Topical treatment with either capsaicin ointment (once or 4 times daily) or lidocaine patches

• Gabapentin (30-600 mg 3 times daily), sustained-release oxycodone (10-20 mg twice daily), or both[119, 120, 121]

Although anesthesia-based interventions such as local anesthetic blocking of sympathetic nerves or stellate ganglion blockade may produce transient relief, their effectiveness in reducing the protracted pain of PHN remains to be determined. Transcutaneous electric nerve stimulation (TENS) and, if necessary, neurosurgery (eg, thermocoagulation of substantia gelatinosa Rolandi) have been found to be helpful in exceptional cases.

No specific dietary changes are recommended.

Patients with shingles can perform activities as tolerated. Most are capable of self-restricting their activities on the basis of any limitations that may be imposed by pain; additional advice from physicians is rarely, if ever, necessary.

During the acute phase, patients are contagious should be counseled to avoid direct skin contact with immunocompromised persons, pregnant women, and individuals with no history of chickenpox infection. Infants and babies are especially vulnerable at the acute, contagious stage. If the patient is hospitalized, contact isolation measures should be considered.

Varicella-zoster virus vaccine

It has been proposed that zoster occurs when varicella antibody titers and varicella-specific cellular immunity drop to a level at which they no longer are completely effective in preventing viral invasion. Evidence for this hypothesis includes observation that pediatricians, who presumably are reexposed to varicella virus routinely and thus maintain high levels of immunity, seldom develop zoster. It follows that there is a rationale for vaccination.

Since 1995, live attenuated VZV vaccine (Varivax) has been available in the United States and has been up to 99% effective in protecting susceptible children from varicella infection. The higher-potency live attenuated VZV vaccine introduced in 2006 (Zostavax) demonstrated a reduction in shingles in adults by 51.3% during 3 years of follow-up in one study.[122]

The routine use of the live attenuated varicella vaccine has led to a remarkable reduction in the incidence of primary varicella infection. Furthermore, vaccinated children have demonstrated lower rates of herpes zoster than those infected through natural exposure to VZV.[123, 124] However, the effect of childhood vaccination on the incidence of herpes zoster in adult populations remains to be fully elucidated.

Prevention or attenuation is particularly desirable in older patients because zoster is more frequent and is associated with more complications in older populations and because declining cell-mediated immunity in older age groups is associated with an increased risk of zoster. A zoster vaccine immunization program in older adults may be cost effective and has the potential to decrease the incidence or reduce its severity.[125, 126]

In February 2018, the Centers for Disease Control and Prevention (CDC) approved the 2018 adult immunization schedules. Changes to this year’s schedule regarding zoster vaccines includes the following[127, 128] :

• Administer two doses of recombinant zoster vaccine (RZV) (Shingrix) 2-6 months apart to adults aged 50 years or older regardless of past episodes of herpes zoster or receipt of zoster vaccine live (ZVL) (Zostavax)
• Administer two doses of RZV 2-6 months apart to adults who previously received ZVL at least 2 months after ZVL
• For adults aged 60 years or older, administer either RZV or ZVL (RZV is preferred)

In 2006, on the basis of the findings from the Shingles Prevention Study,[122] the US Food and Drug Administration (FDA) approved Zostavax for prevention of herpes zoster in people aged 60 years and older. This randomized, double-blind, placebo-controlled trial of the vaccine enrolled more than 38,000 adults older than 60 years. The vaccine reduced the incidence by 61.1% and the incidence of PHN by 66.5%.

Shortly thereafter, the CDC recommended that the zoster vaccine be given to all nonimmunocompromised, nonpregnant people aged 60 years of age and older, including those who have had a previous episode of zoster.[122]

In 2011, the FDA lowered the approved age for use of Zostavax to 50-59 years. Approval was based on a multicenter study, the Zostavax Efficacy and Safety Trial (ZEST), which was conducted in the United States and 4 other countries and included 22,439 subjects aged 50-59 years.[129] Participants were divided into 2 equal groups and randomly assigned to receive either Zostavax or placebo, then monitored for at least 1 year for development of shingles. Zostavax reduced the risk of developing zoster significantly (approximately 70%).

Persons with a reported history of zoster can be vaccinated. Repeated zoster has been confirmed in immunocompetent persons soon after a previous episode. Although the precise risk for and severity of zoster as a function of time after an earlier episode are unknown, some studies suggest it may be comparable to the risk in persons without a history of zoster. Furthermore, no laboratory evaluations exist to test for the previous occurrence of zoster, and any reported diagnosis or history might be erroneous.

The live attenuated VZV vaccine demonstrated a reduction in the incidence rate of herpes zoster, preventing both herpes zoster and postherpetic neuralgia.[130] More recently, the safety of this recombinant zoster vaccine has been judged as favorable,[130] even in those with immune-mediated inflammatory diseases.[131]

In October 2017, the FDA approved Shingrix (zoster vaccine recombinant, adjuvanted) for the prevention of shingles in adults aged 50 years and older. Approval is based on findings from a phase III clinical trial program assessing its efficacy, safety, and immunogenicity in 38,000 patients. Data from a pooled analysis of two clinical trials demonstrated efficacy against shingles greater than 90% across all age groups, as well as sustained efficacy over a follow-up period of 4 years.[132, 133]

The first trial, ZOE-50, was a randomized, placebo-controlled study conducted in 18 countries in Europe, North America, Latin America, and Asia-Australia. The study evaluated the efficacy, immunogenicity, and safety of the HZ/su vaccine in adults aged 50 years or older. Participants were randomly assigned in a 1:1 ratio to receive either HZ/su vaccine (0.5 mL at month 0 and 2) or placebo. Two doses of HZ/su administered 2 months apart had a vaccine efficacy of 97.2%, compared with placebo, in reducing the risk of herpes zoster in adults aged 50 years or older. The vaccine efficacy was similar among the three age groups.[132]

The second trial, ZOE-70, studied the safety and efficacy of HZ/su in adults aged 70 years or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster was 89.8% and was similar in participants aged 70-79 years (90.0%) and participants aged 80 years or older (89.1%). In pooled analyses of data from participants aged 70 years or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% and vaccine efficacy against postherpetic neuralgia was 88.8%.[133]

The two vaccines, the discontinued zoster vaccine live (ZVL; Zostavax) and the currently available nonlive adjuvanted recombinant zoster vaccine (RZV; Shingrix), differ in efficacy and durable response.[134] Vaccination with RZV in immunocompetent adults aged 50 years or older is recommended, including those previously vaccinated with ZVL. The cost-effectiveness of vaccinating US adults aged 60 years and older, previously vaccinated with ZVL, was evaluated. Compared with revaccinating with ZVL, vaccination with RZV is highly desirable.

Other methods of prevention of initial infection include contact and respiratory isolation of infected patients until full crusting of lesions is achieved, as well as postexposure prophylaxis with VZIG in select populations.

Varicella-zoster immune globulin

The CDC recommends administration of VZIG to prevent or modify clinical illness in persons with exposure to varicella or herpes zoster who are susceptible or immunocompromised. It should be reserved for patients at risk for severe disease and complications, such as neonates and patients who are immunocompromised or pregnant.[135]

VZIG provides maximum benefit when administered as soon as possible after the presumed exposure, but it may be effective if administered as late as 96 hours after exposure. Protection after VZIG administration lasts for an average of approximately 3 weeks, according to the CDC.

Consultation is rarely necessary in cases of uncomplicated zoster. Consultation with the appropriate specialist may be indicated when symptoms point toward meningitis (HZO), dental disease (zoster of the maxillary branch), ear infections or deafness (Ramsay Hunt syndrome), oropharyngeal infections, meningoencephalitis, or encephalomyelitis; when the patient is immunocompromised; when the rash is atypical; when motor complications are present; or when the urinary bladder, the lungs, or the gastrointestinal tract is involved.

Typical cases of zoster may be treated in the outpatient setting and do not require extensive follow-up. Patients should be informed about the natural progression of herpes zoster and its potential complications. Initial evaluation should address the possibility of atypical manifestations. Pain relief should be a primary concern.

After initial treatment, further care consists solely of monitoring the patient and remaining alert for complications (eg, secondary infection, eye involvement, and meningeal or visceral involvement) and for sequelae such as PHN. Patients who develop PHN should be seen regularly and should receive emotional support in addition to medical therapy.

Since there is an increased risk of developing multiple myeloma, leukemia, and lymphoma, an appropriate screening with physical examination and laboratory test should be considered.[105]

The following organizations have issued guidelines for the management of herpes zoster and its complications:

• International Association for the Study of Pain (IASP)[1]

• American Academy of Family Physicians (AAFP)[136]

• Infectious Disease Society of America (IDSA)[137, 138]

• American Academy of Neurology (AAN)[139]

• European Federation of Neurological Societies (EFNS)[140]

• Centers for Disease Control and Prevention (CDC)[127, 141]

The 2007 International Association for the Study of Pain (IASP) recommendations for the management of herpes zoster offer the most comprehensive guidance covering treatment of both immunocompromised and immunocompetent patients.

IASP recommendations for immunocompetent patients are as follows[1] :

• Topical antiviral therapy is not recommended.

• Oral antiviral therapy is recommended for first-line treatment for patients 50 years or older, moderate or severe pain, moderate or severe rash, or those who have non truncal involvement.

• Oral antiviral therapy should be considered for patients younger than 50 years with mild pain and rash and truncal involvement because of the risk of developing postherpetic neuralgia (PHN).

• Brivudin, famciclovir, and valacyclovir show greater efficacy than acyclovir.

• Antiviral therapy should be initiated within 72 hours of the onset of the rash, but it may be considered for patients presenting more than 72 hours after the onset of the rash when there are cutaneous, motor, neurologic, or ocular complications or in patients of advanced age or in severe pain.

• Pain management approaches should be individualized based on pain severity, underlying conditions, and prior response to specific medications.

• For mild to moderate pain, acetaminophen or NSAIDs may be used alone or in combination with weak opioids such as codeine or tramadol.

• For moderate to severe pain, strong opioids such as oxycodone or morphine may be used.

• If moderate to severe pain has not responded rapidly to treatment with an opioid analgesic, the addition of gabapentin or pregabalin, tricyclic antidepressants (TCAs) (especially nortriptyline), or corticosteroids (eg, prednisone) may be considered.

• For those patients with moderate or severe pain who are unable to tolerate an opioid analgesic, treatment with gabapentin or pregabalin, TCAs (especially nortriptyline), or corticosteroids (eg, prednisone), alone and in combination, can be considered.

• For patients with pain that is inadequately controlled by antiviral agents in combination with oral analgesic medications and/or corticosteroids, referral to a pain specialist to evaluate eligibility for neural blockade.

IASP recommendations for immunocompromised patients are as follows[1] :

• Intravenous acyclovir is the therapy of choice for allogeneic hematopoietic stem cell transplant recipients within 4 months of transplantation, hematopoietic stem cell transplant recipients with moderate-to-severe acute or chronic graft versus host disease, or any transplant recipient receiving aggressive antirejection therapy.

• For less severely immunosuppressed patients, oral therapy with acyclovir, valacyclovir, or famciclovir, coupled with close clinical observation, is a reasonable option.

• Brivudin is not recommended for patients undergoing chemotherapy with 5-fluoropyrimidines.

• For highly immunocompromised patients who present with herpes zoster ophthalmicus, intravenous acyclovir and evaluation by an ophthalmologist is recommended.

The 2011 American Academy of Family Physicians (AAFP) guidelines include the following key recommendations[136] :

• Antiviral therapy should be initiated within 72 hours of the onset of the rash in patients with acute herpes zoster (level A).

• Based on individual patient characteristics, a TCA, tramadol, long-acting opioid, or anticonvulsant (ie, gabapentin or pregabalin) should be selected to decrease the pain of PHN (level A).

• Capsaicin cream or a lidocaine patch may decrease pain in patients with PHN (level B).

In its 2014 update of practice guidelines for the diagnosis and management of skin and soft tissue infections, the Infectious Disease Society of America (IDSA) offered recommendations for management in immunocompromised patients. Recommendations include the following[137] :

• The treatment of choice is high-dose intravenous acyclovir for immunocompromised patients.

• Oral acyclovir, famciclovir, and valacyclovir is recommended for mild cases in patients with transplant immune suppression or for patients who have shown a clinical response to intravenous acyclovir.

• Recipients of bone marrow transplants should take oral acyclovir or valacyclovir during the first year for prevention of herpes zoster.

The 2007 International Association for the Study of Pain (IASP) recommendations for the management of herpes zoster ophthalmicus are as follows[1] :

• Famciclovir or valacyclovir for 7-10 days, with intravenous acyclovir given as needed for retinitis

• Pain medications, as for immunocompetent patients

• Cool-to-tepid wet compresses (if tolerated)

• Antibiotic ophthalmic ointment administered twice daily (eg, bacitracin-polymyxin) to protect the ocular surface

• Topical steroids (eg, 0.125-1% prednisolone 2-6 times daily) prescribed and managed only by an ophthalmologist for corneal immune disease, episcleritis, scleritis, or iritis

• No topical antivirals

• Mydriatic/cycloplegia as needed for iritis (eg, 5% homatropine twice daily)

• Ocular pressure–lowering drugs given as needed for glaucoma

• Systemic steroids indicated in the presence of moderate to severe pain or rash

The 2004 American Academy of Neurology (AAN) practice parameter for the treatment of postherpetic neuralgia (PHN) was last reaffirmed in 2008 and includes the following recommendations[139] :

• Tricyclic antidepressants (TCAs) (eg, amitriptyline, nortriptyline, desipramine, and maprotiline), gabapentin, pregabalin, opioids, and topical lidocaine patches are effective in the treatment of PHN (level A, class I and II).

• Preservative-free intrathecal methylprednisolone may be considered in the treatment of PHN if available (level A, class I and II).

• No benefit was found with the use of acupuncture, benzydamine cream, dextromethorphan, indomethacin, epidural methylprednisolone, epidural morphine sulfate, iontophoresis of vincristine, lorazepam, vitamin E, and zimelidine (level B, class II).

• Unproven interventions include carbamazepine, nicardipine, biperiden, chlorprothixene, ketamine, He:Ne laser irradiation, intralesional triamcinolone, cryocautery, topical piroxicam, extract of Ganoderma lucidum, dorsal root entry zone lesions, and stellate ganglion block (level U, single class II study and class IV studies).

  In 2010, the European Federation of Neurological Societies (EFNS) updated its 2005 guidelines on the pharmacological treatment of neurological pain, which included the following recommendations for the treatment of PHN[140] :

• TCA or gabapentin/pregabalin is recommended as first-line treatment (level A).

• Topical lidocaine (level A, less consistent results) may be considered first line in elderly patients, especially if there are concerns regarding the adverse CNS effects with oral medications.

• Strong opioids (level A) and capsaicin cream are second-line choices.

• Capsaicin patches show promise (level A), but the long-term effects of repeated applications, particularly on sensation, are unclear.

Starting in 2008, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination of all people 60 years or older with a single-dose zoster vaccine. Zoster vaccination is not indicated to treat acute herpes zoster or postherpetic neuralgia (PHN) or to prevent the development of PHN in patients with acute herpes zoster. Serologic testing for varicella immunity is not required prior to vaccination. In 2011 and 2013, after a review of the cost-benefit analysis, the ACIP declined to recommend the vaccine be administered to persons aged 50-59 years.[141]

Additional 2018 recommendations include the following[127] :

• The preferred (RZV) zoster vaccine may be given simultaneously with other vaccines recommended for people 60 years or older, such as the Td, Tdap, and pneumococcal polysaccharide vaccines.

• Zoster vaccination is not recommended for persons of any age who have received varicella vaccine.

• Patients with a history of herpes zoster can be vaccinated.

• For patients initiating immunosuppressant treatments, the zoster vaccine should be given at least 14 days before the initiation of immunosuppressive therapy

• Acyclovir, famciclovir, or valacyclovir should be discontinued at least 24 hours before administration of the "live virus" zoster vaccine, if possible. These medications should not be used for at least 14 days after vaccination, by which time the immunologic effect should be established. Note this does not apply in the use of the new recombinant zoster vaccine.

• The zoster vaccine is contraindicated for persons who have a history of an anaphylactic reaction to any component of the vaccine, including gelatin and neomycin.

• The zoster vaccine should not be administered to persons with primary or acquired immunodeficiency.

The 2013 Infectious Disease Society of America (IDSA) clinical practice evidence-based guidelines for vaccination of immunocompromised patients includes the following recommendations for the vaccine[138] :

• The zoster vaccine should be given to patients 60 years and older if it can be administered 4 weeks or more before beginning highly immunosuppressive therapy (strong, low).

• The zoster vaccine should be given to patients aged 60 years and older who are receiving therapy considered to induce a low level of immunosuppression (strong, low).

• The zoster vaccine is not recommended for highly immunocompromised patients (strong, very low).

The IDSA differs from the CDC ACIP in recommending that the zoster vaccine should be considered for patients with a history of varicella or zoster infection or who are varicella–zoster virus seropositive with no previous doses, aged 50-59 years, if it can be administered 4 weeks or more before beginning immunosuppressive therapy (weak, low).

Whereas there were once no effective therapies for herpes zoster (shingles), the advent of oral antiviral agents has made the treatment of this condition possible. Acyclovir and its derivatives (famciclovir, penciclovir, and valacyclovir) have been shown to be safe and effective in the treatment of active disease and the prevention of postherpetic neuralgia (PHN). Low-dose gabapentin used in acute disease did not appear effective in preventing PHN.[142]  Other agents used in management include corticosteroids, analgesics, tricyclic antidepressants (TCAs), and vaccines.

Class Summary

Antiviral agents exert a direct antiviral effect on varicella-zoster virus (VZV). Nucleoside analogues initially are phosphorylated by viral thymidine kinase, eventually forming a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

The goals of antiviral therapy are to decrease pain, to inhibit viral replication and shedding, to promote healing of skin lesions, and to prevent or reduce the severity of postherpetic neuralgia. Antiviral therapy may decrease the length of time for new vesicle formation, the number of days to attain complete crusting, and the days of acute discomfort. Initiate treatment as soon as possible because treatment is most effective within 72 hours of eruption.

Acyclovir (Zovirax)

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including HSV type 1 (HSV-1), HSV-2, VZV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). In cell cultures, acyclovir has the highest antiviral activity against HSV-1, followed, in decreasing order of potency, by HSV-2, VZV, EBV, and CMV.

Treatment with acyclovir is indicated in patients with involvement of the first branch of the trigeminal nerve, those who are immunocompromised, or those with increased risk for major complications from a varicella infection (ie, patients older than 13 years, those receiving long-term corticosteroid or aspirin therapy, and those with chronic cutaneous or pulmonary diseases). Zoster in adolescents may be treated with oral acyclovir if it is initiated within 72 hours of eruption.

Famciclovir

Famciclovir is a prodrug that, once ingested, is rapidly biotransformed into the active compound penciclovir and phosphorylated by viral thymidine kinase. By competition with deoxyguanosine triphosphate, penciclovir triphosphate inhibits viral polymerase. Activity against HSV-1, HSV-2, and VZV has been demonstrated.

Therapy should be initiated as soon as herpes zoster is diagnosed. No data are available on the efficacy of treatment started 72 hours after rash onset. The dosage should be adjusted in patients with renal insufficiency or hepatic disease.

Valacyclovir (Valtrex)

Valacyclovir is an L-valyl ester of acyclovir. It is rapidly converted to acyclovir, which has demonstrated antiviral activity against HSV-1, HSV-2, VZV, and other viruses.

Therapy should be initiated at the earliest sign or symptom; it is most effective when started within 48 hours of the onset of zoster rash. No data are available on the efficacy of treatment started 72 hours after rash onset.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body’s immune response to diverse stimuli. Some authors find benefit in the short-term use of steroids to help manage herpes zoster, and some evidence exists to suggest a decreased incidence of PHN in patients who received steroids. Other studies find no benefit from the use of steroids.

Prednisone (Deltasone, Rayos)

Although steroid use is controversial, it remains a therapeutic option. Prednisone is inactive and must be metabolized to the active metabolite prednisolone. Conversion may be impaired in patients with liver disease.

Class Summary

These agents are used to induce active immunity.

Zoster vaccine recombinant (Shingrix)

The agent is a nonlive, recombinant subunit vaccine intended for intramuscular injection in two doses. It consists of glycoprotein E, an antigen, and AS01B, an adjuvant system, intended to induce a strong and sustained immune response to help overcome reduced immunity that comes with age. It is indicated for the prevention of shingles (herpes zoster) in adults aged 50 years or older.

Class Summary

Topical analgesics containing capsaicin have been shown to be effective for temporary relief of neuropathic pain.

Capsaicin (Capzasin-P, Zostrix)

Capsaicin is derived from plants of the Solanaceae family. It is a transient receptor potential vanilloid-1 (TRPV1) agonist indicated for neuropathic pain associated with PHN. TRPV1 is an ion channel–receptor complex expressed on nociceptive skin nerve fibers. Topical capsaicin causes initial TRPV1 stimulation that may cause pain, followed by pain relief via a reduction in TRPV1-expressing nociceptive nerve endings. Neuropathic pain may gradually recur over several months, an event thought to be caused by TRPV1 nerve fiber reinnervation of the treated area.

Capsaicin transdermal patch (Qutenza)

Capsaicin is a TRPV1 agonist indicated for neuropathic pain associated with postherpetic neuralgia. Topical capsaicin causes initial TRPV1 stimulation that may cause pain, followed by pain relief via a reduction in TRPV1-expressing nociceptive nerve endings. Neuropathic pain may gradually recur over several months; this recurrence is thought to be caused by TRPV1 nerve fiber reinnervation of the treated area.

Class Summary

These agents stabilize the neuronal membrane so the neuron is less permeable to ions. This prevents the initiation and transmission of nerve impulses, thereby producing the local anesthetic action.

Lidocaine transdermal (Lidoderm, Ztlido)

Lidocaine transdermal is indicated for pain associated with postherpetic neuralgia. Lidoderm 5% transdermal patch contains 700 mg of lidocaine per patch. ZTlido 1.8% transdermal patch contains 36 mg per patch. Pharmacokinetic studies have demonstrated bioequivalence of the 2 patches. The ZTlido 1.8% patch is engineered to provide improved adhesion and flexibility to provide targeted transdermal absorption, so a lower amount of lidocaine can be used.

Class Summary

Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and facilitate physical therapy. Most oral narcotic analgesics have sedating properties that are beneficial for patients who have skin lesions.

Oxycodone (OxyContin, Roxicodone, Oxecta)

Oxycodone is a narcotic analgesic that is indicated for the relief of moderate to severe pain. Patients with herpes zoster usually experience pain. Antiviral and steroid therapies provide relatively minor relief of pain, and narcotic analgesics are often needed.

Acetaminophen (Tylenol, APAP 500, FeverAll)

Acetaminophen is indicated for use in patients with mild pain or fever. It is the drug of choice for the treatment of pain in patients who (1) have documented hypersensitivity to aspirin or NSAIDs, (2) have upper gastrointestinal (GI) disease, or (3) are taking oral anticoagulants. Acetaminophen reduces fever via direct action on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating.

Ibuprofen (Advil, Motrin, Caldolor)

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is the drug of choice for treatment of mild to moderately severe pain, if no contraindications exist. It inhibits inflammatory reactions and pain, probably by decreasing the activity of the enzyme cyclooxygenase and thereby, in turn, inhibiting prostaglandin synthesis. Ibuprofen is one of the few NSAIDs that are indicated for fever reduction.

Naproxen (Aleve, Naprosyn, Naprelan, Anaprox)

Naproxen another NSAID that is commonly used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, an effect that results in a decrease of prostaglandin synthesis.

Class Summary

Although they are most often used as antiepileptics, certain anticonvulsants are also effective for treating neuropathic pain.

Gabapentin (Neurontin, Gralise)

Gabapentin is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter gamma-amino butyric acid (GABA), which paradoxically is thought not to exert an effect on GABA receptors. Gabapentin appears to exert its effect via the α2δ1 and α2δ2 auxiliary subunits of voltage-gated calcium channels. It is used to manage pain and provide sedation in neuropathic pain. Gabapentin is primarily used for the treatment of PHN. It has also been used to treatment the pain of acute zoster.

Pregabalin (Lyrica, Lyrica CR)

Pregabalin is a structural derivative of GABA. It binds with high affinity to the α2-δ site (a calcium channel subunit). In vitro, it reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. It is approved by the US Food and Drug Administration (FDA) for neuropathic pain associated with diabetic peripheral neuropathy or PHN and as adjunctive therapy in partial-onset seizures.

Class Summary

TCAs have been shown to play a role in the treatment of PHN.

Amitriptyline

Amitriptyline blocks the reuptake of norepinephrine and serotonin. It decreases pain by inhibiting spinal neurons involved in pain perception.

Desipramine (Norpramin)

Desipramine is a tricyclic antidepressant that, of the first-generation TCAs, has the least adverse effects. These agents have been found to be effective in relieving PHN.