Shingles is caused by the varicella-zoster virus (VZV), which primarily affects the dorsal root ganglia (DRG) of the spinal nerves or trigeminal nerve. A single DRG is commonly affected, but a small number of adjacent DRGs may be affected, usually on the same side.

Acute herpetic neuralgia is defined as pain during the first 30 days after the eruption of the rash. If the pain resolves within the next 4 months, it is defined as subacute herpetic neuralgia. Pain persisting beyond this time frame is called postherpetic neuralgia (PHN). Although spontaneous resolution of herpes zoster may be expected in many patients, a significant number of patients develop chronic intractable pain of PHN.

Herpes zoster most frequently occurs in adults who previously have had chickenpox. The virus remains dormant in the DRG until, many years later, it is reactivated, producing herpes zoster because of decreased cell-mediated immunity. The decrease in immunity that permits the reactivation may be caused by infection or malignancy, or it may be iatrogenic. Persistent stress and untreated depression are thought to lower immunity, hence increasing the likelihood of shingles with severe pain, increasing the risk of chronic PHN.^1,2

Although the DRGs of the spinal and cranial nerves are involved most commonly, any part of the central nervous system (CNS) can be affected. For example, the anterior motor horn may be involved, or the patient may have myelitis or encephalomyelitis. It has been suggested that T-cell recognition of VZV proteins is a likely mechanism involved in the control of reactivation of the virus from latency.^3–5

The incidence of herpes zoster in the U.S. population indicates a steep increase in the general population over the past 30 years.⁶ The incidence of herpes zoster is low in immunocompetent children⁷ but is higher in immunosuppressed children.⁸ The disease is more common in elderly adults, and the risk increases proportionately with age. The best incidence data for PHN in older patients come from the placebo arm of a large randomized trial that evaluated vaccination against VZV.⁹ In 334 patients from 60 to 69 years of age who developed herpes zoster, PHN occurred in 6.9%. In contrast, among 308 patients age 70 years or older who developed herpes zoster, PHN occurred in 18.5%.

The virus may be recovered from early vesicles and has been recovered from blood, lung, liver, and cerebrospinal fluid (CSF) but only occasionally from the oropharynx. Scrapings also provide cellular material containing multinuclear giant cells. Acidophilic intranuclear inclusions can be seen in the Tzanck smear stained with hematoxylin and eosin, Giemsa, Papanicolaou, or Paragon multiple stain. A punch biopsy for electron microscopic examination provides even more reliable material; the more reliable material may permit a diagnosis before the vesicular stage develops (Table 49-1).

ACUTE HERPES ZOSTER

The diagnosis of herpes zoster is difficult to make before the rash develops. After the lesions appear, the clinical features are so typical that the diagnosis is easy. Before eruption, herpes zoster often is mistaken for other pain-causing conditions, such as trigeminal neuralgia, cluster headache, coronary artery disease, pleurisy, cholecystitis, and painful spine conditions.

Epithelial cells with eosinophilic intranuclear inclusions and multinucleated giant cells can be identified in material scraped from the base of a vesicle. The leukocyte count is normal in uncomplicated herpes zoster. Mononuclear pleocytosis is present in the CSF of patients with herpes zoster, particularly those with cranial nerve involvement.

Acute herpes usually has pain that is localized to the dermatomal distribution of one or more affected DRGs. Typically, herpes zoster occurs in one or two adjacent dermatomes, usually in the thoracic area. The ophthalmic division of the trigeminal nerve is the most common single nerve affected. The pain may be accompanied by fever and malaise. It may be mild at onset, becoming severe over the next few days. It can be dull, sharp, burning, aching, or shooting with paresthesia.

It starts with redness and swelling followed by red papules that become vesicles, blebs, and pustules and then to the crusting stage over 2 to 3 weeks. The lesions typically are unilateral, appearing along a dermatome. In mild cases, the skin lesions may not affect the whole dermatome, but sensory involvement of the whole dermatome usually is present. In severe cases, larger blebs usually cover the entire dermatome and tend to coalesce.

The lesions appear in thoracic dermatomes in more than 50% of patients. The next region where they commonly are seen is the trigeminal distribution, with an incidence of 3% to 20%. The ophthalmic division is involved in 75% of these patients. Lumbar and cervical eruptions occur in 10% to 20% of patients, with a sacral distribution being much less common. With advancing age, the incidence of trigeminal (ophthalmic) zoster increases, and that of spinal zoster declines. Bilateral zoster occurs in less than 1% of patients. Recurrent zoster is reported in a small percentage of patients usually in the same or adjacent dermatomes.

If the trigeminal (gasserian) ganglion is affected, the symptoms usually include pain in the nerve distribution, headache, and weakness of the eyelid muscles. Lesions may appear on the face, cornea, mouth, and tongue. Scarring and anesthesia of the cornea may occur. The first division of the trigeminal nerve most often is affected. If there is involvement of the geniculate ganglion, the patient may develop Bell’s palsy, vertigo, disorders of hearing, and lesions of the external ear and canal and the anterior portion of the tongue. Pink scars eventually become hypopigmented, with persistent pain despite sensory loss.

Risk factors for severe, persistent pain associated with acute herpes zoster include prodromal symptoms, age greater than 50 years, and moderate to severe pain at presentation.¹⁰ The duration of pain has been shown to correlate with severity of lesions at worst phase and the involved region, with age over 60 years and those with trigeminal involvement most likely to have significantly longer durations of pain.¹¹

POSTHERPETIC NEURALGIA

Postherpetic neuralgia also can be confused with other problems, but the patient usually has a history of a previous unilateral skin eruption, and there may be residual scarring of the skin. Hyperesthesia, dysesthesia, and anesthesia also may be present in the affected areas. Skin eruption may be minimal in some cases, and few or even no scars may be present with PHN (zoster sine herpete). In these patients, the CNS was damaged by the original infection, resulting in neuralgia without producing any scars to the skin. A rising zoster antibody titer in the acute stage confirms the infectious agent.

POSTHERPETIC ITCH

In 10% to 50% of patients with herpes zoster, pain and hyperesthesia persist after the lesions are healed. Herpes zoster–related pain (HZRP) ranges in severity from a mild, bothersome discomfort to a debilitating and agonizing condition. Severe HZRP is commonly described as aching, burning, and lancinating. It may occur spontaneously, continuously without stimulation, and intermittently with stimulation. Itch that arises from disease located at any point along the afferent pathway is called neuropathic itch. Patients may experience a deep aching or burning pain, unbearable itching, a paresthesia that may be painful (dysesthesia), an exaggerated response to stimuli (hyperalgesia), or electric shock–like pains. These abnormal sensations may resolve or persist unpredictably.

Relief usually is found during sleep. In chronic PHN, the patient commonly has hyperpathia, often associated with damage to a peripheral nerve, the spinothalamic tract, or the thalamus. It may be caused by a reduction in the number and proportion of conducting nerve fibers.

Dysesthesia often is interpreted as pain. Uncomfortable unpleasant sensations make the patient unable to bear the lightest contact with the skin. Some patients even cut holes in their clothing to minimize the problem. A slight breath of wind can incite a paroxysm of pain. Curiously, most patients can tolerate firm pressure on the affected area but not light pressure. They may wear especially tight clothing or keep their hands pressed over the painful region. Patients may complain about a feeling of worms under the skin or of ants crawling over the skin (formication).

Itch can be present as well. Theoretically, it is possible that the few remaining cutaneous neurons may have been itch fibers from adjacent unaffected dermatomes. This possible discriminatory preservation of peripheral itch fibers that have unusually large innervation territories can become sensitized by ongoing tissue inflammation. The products of chronic inflammation perpetuate sensitization of itch fibers.

Another possible explanation independent of peripheral inflammation is that itch could also be generated by central itch neurons firing excessively when deprived of afferent input (phantom itch). Centrally mediated herpes zoster–related itch may include electrical hyperactivity of deafferented central itch–specific neurons, imbalances between excitation, and inhibition of second-order sensory neurons. Preservation of a few scattered sensory neurons after a herpes zoster eruption may have allowed activation of occasional second-order neurons without concomitant recruitment of inhibitory interneurons.

PREVENTION

Clinical trials have demonstrated that zoster vaccine reduces the incidence of zoster and PHN. Specifically, a 2012 meta-analysis evaluated the efficacy of the zoster vaccine in eight randomized trials that included 52,269 individuals 60 years of age or older, the majority of whom came from the Shingles Prevention Study (SPS), a placebo-controlled clinical trial of 38,546 adults 60 years of age or older, using a live attenuated Oka/Merck VZV vaccine.¹² A similar reduction in herpes zoster was observed as was seen in the SPS. Thus, individuals who are 60 years of age or older are strongly recommended to receive zoster vaccination to decrease the risk of zoster and PHN. Preliminary data also suggest that zoster vaccine is effective in reducing the incidence of zoster and preventing PHN in persons 50 to 59 years of age.¹³

ACUTE HERPES ZOSTER

The goals are aggressive treatment of acute zoster and prevention of PHN, which is shown to reduce the incidence and severity of PHN.¹⁴ Pain should be treated aggressively, especially in elderly and immunosuppressed patients, who are prone to PHN.^15,16

Drug Therapy

The various drugs used in the treatment of the acute stage of herpes zoster are summarized in Table 49-2.

Antiviral Agents

Antiviral agents are now the standard preferred therapy for acute herpes zoster infections. The VZV, similar to all viruses, is a parasite that takes over healthy cells and uses their DNA to reproduce itself. It is believed that if viral DNA synthesis can be slowed or inhibited, then specific host immune systems might have more time to help control the viral infection. Some substances that grossly inhibit DNA synthesis were developed as possible anticancer drugs and have been found to have more significant antiviral than anticancer activity. Theoretically, these agents could either kill the virus or alter its replication. To be effective, the agents must be given before significant tissue damage occurs. Such agents include acyclovir, cytarabine, vidarabine, idoxuridine, sorivudine, famciclovir, valaciclovir, and brivudine. The nucleoside analogues acyclovir, famciclovir, and valacyclovir are the current preferred antivirals.

Acyclovir masquerades as one of the building blocks of the DNA needed by the herpesvirus to reproduce itself. This stops the chain, and the virus ceases to replicate. Although acyclovir accelerates cutaneous changes in herpes zoster, the intensity and duration of acute herpetic neuralgia appear to be directly related to time of therapy initiation (not later than 6 days after onset).¹⁴ The author of a meta-analysis of 30 clinical trials in immunocompetent patients found five homogeneous, randomized, placebo-controlled trials that showed that oral acyclovir, 800 mg/day within 72 hours of rash onset, may reduce the incidence of residual pain at 6 months by 46%.¹⁷

Although acyclovir has been shown to be effective in shortening the duration of zoster pain, other newer agents may offer some advantages. Sorivudine has compared favorably with acyclovir in terms of accelerating cutaneous healing¹⁸ and preventing recurrences and new episodes.¹⁹

Famciclovir has been shown to be efficacious in treating herpes zoster.^20–22 A placebo-controlled clinical trial was conducted in 419 immunocompetent adults (mean age, 50 years) with uncomplicated zoster to evaluate the efficacy of standard dose famciclovir (500 mg three times daily) or high-dose famciclovir (750 mg three times daily) for the treatment of acute zoster and prevention of PHN.²¹ All patients were initiated on the intervention or placebo within 72 hours of rash and were treated for 7 days. After 5 months of monthly follow-up, the intention-to-treat analysis demonstrated that famciclovir was associated with modest improvement in lesion healing rates (median, 5–6 days with low- and high-dose famciclovir) compared with placebo (median, 7 days). In addition, compared with placebo, the median duration of PHN was reduced by approximately 2 months with famciclovir therapy, regardless of dose (62 and 55 days with low- and high-dose famciclovir, respectively, compared with 119 days with placebo). In addition, famciclovir may be as or more effective than acyclovir in prevention of reactivation from latency for genital herpes.²³

Valacyclovir may be even more efficacious in treating herpes zoster than acyclovir, shortening the time to complete resolution of herpes zoster–associated pain.^24,25 It may even offer cost benefits.²⁶ In a randomized, double-blind study of 1141 immunocompetent adults with herpes zoster (mean age, 68 years), the efficacy and safety of valacyclovir (1000 mg orally three times daily for 7 or 14 days) were compared with acyclovir (800 mg orally five times daily for 7 days) over 6 months of follow-up.²⁷ An intent-to-treat analysis demonstrated that valacyclovir for 7 or 14 days accelerated the resolution of acute neuritis (median duration of pain, 38 and 44 days, respectively) compared with acyclovir (median, 51 days). The proportion of patients with pain persisting for 6 months was modestly lower in the combined valacyclovir arms (19%) than the acyclovir arm (26%). No additional benefit was observed with a longer duration of valacyclovir.