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Mon 1 Jan 2007 12:25 PM

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Herpes zoster & Postherpetic neuralgia

The encore of the varicella zoster virus and its most common complication.

Herpes zoster, commonly referred to as shingles, results from the reactivation of latent varicella zoster virus from dorsal root or cranial ganglia, acquired during the primary infection with varicella (chicken pox). While varicella is commonly a disease of childhood, the incidence of herpes zoster increases with age, affecting approximately half of all people who live to 85 years of age. Herpes zoster is uncommon in persons less than 15 years old.

Most cases of herpes zoster can be managed within primary care, with the most common complication being postherpetic neuralgia - pain that persists well after the rash has healed, and that can be highly debilitating. This article reviews the diagnosis and treatment of herpes zoster, and the management of postherpetic neuralgia.

Risk factors

Any person who has been infected with the varicella zoster virus can develop herpes zoster, but it is uncommon before age 50. Women may be more prone to herpes zoster than men, although this is uncertain. After primary infection, the virus is probably often reactivated, but adequate cell mediated immunity, boosted by exposure to people with active varicella, prevents clinical disease. These asymptomatic reactivations may also enhance immunity.

The sharp rise in age and zoster incidence is thought to be caused by a normal decline in cell mediated immunity, related to age. Additional risk factors include disease states that affect cell mediated immunity; such as HIV infection, lymphoma, treatment of malignancy; such as chemotherapy or radiotherapy, and use of immunosuppressant drugs, such as steroids.

Childhood vaccination against varicella was introduced in the US in 1995 (it is now in use in several countries), and it is hoped that this will help reduce the overall incidence of zoster. The FDA also approved the first herpes zoster vaccine in early 2006 (see ‘At a glance: Zostavax) for use in adults aged 60 and over, which may also aid in lowering incidence. It should be noted that, although herpes zoster is not as contagious as the primary varicella infection, persons with active infection can transmit varicella zoster to nonimmune contacts.

Pathophysiology

During primary infection with varicella zoster (chicken pox), the virus enters the sensory ganglia. How it does so, is not completely understood. The virus then becomes latent, potentially for decades, because of cell mediated immunity acquired during the primary infection and boosted periodically through life. Reactivation of the virus occurs because of a decrease in this cell mediated immunity. It is thought the reactivated virus then travels down the sensory nerve, causing inflammation and generating the characteristic dermatomal distribution of acute pain and skin lesions.

Presentation

In many cases, the first indication of herpes zoster is pain, tingling, or an unpleasant sensation within the affected dermatome that heralds the onset of lesions. This prodromal stage typically lasts between one to three days, and may be accompanied by other symptoms including headache, malaise, myalgia and fever. During the prodromal stage of herpes zoster the symptoms may be mistaken for other conditions, but the subsequent development of the distinctive shingles rash is virtually diagnostic.

The eruptive phase is characterised by the emergence of vesicular eruptions. As in the prodromal phase, patients may also experience symptoms such as malaise, myalgia, headache, and fever.

The lesions begin as a maculopapular rash that follows a dermatomal arrangement, referred to as a ‘belt-like pattern' (the word shingles comes from the Latin cingulum, which means belt or girdle), and develop into vesicles. In about 10%-25% of cases, the rash affects the face near the eyes. Once they form vesicles, lesions progress through stages in which they rupture, release their contents, ulcerate, and finally crust over and become dry. Lesions typically heal within 10-15 days but in elderly and immunocompromised patients, the eruptive phase is commonly longer and more extensive. Patients are infectious until lesions have dried.

Pain accompanies the rash in nearly all adults, and is the most common reason for seeking medical help. It is often described as ‘burning' or ‘stinging' and can be intense, particularly in women and the elderly.

There are several serious complications of herpes zoster (these can be ophthalmic, splanchnic, cerebral or motor) but the most common in immunocompentent adults is postherpectic neuralgia. Ophthalmic herpes zoster will occur in approximately 10-20% of all herpes zoster cases and doctors should be alert for eye complications if skin lesions are located in dermatome of the nasociliary nerve (the tip of the nose, the skin at the inner corner of the eye, and the rood and side of the nose). Early treatment with oral antiviral drugs is required at the first sign of disease, to reduce the risk of eye disorders. Hutchinson's sign (involvement of the tip of the nose) in the early phase of ophthalmic zoster, a red eye or visual complaints are signs for referral to an opthalmologist.

Diagnosis

In almost all cases, herpes zoster can be diagnosed by history and physical examination. The appearance of herpes zoster is sufficiently distinctive that a clinical diagnosis is usually accurate.

In difficult cases, where the virus or viral DNA must be identified to confirm the diagnosis, laboratory diagnostics may be required. Polymerase chain reaction (PCR) is a rapid, highly sensitive method that is most often used to identify varicella zoster virus. Virus culture is the most specific method for testing, but it is both expensive and time consuming and so not as widely used.

Treatment

The treatment of herpes zoster has two major objectives; to control acute symptoms and to prevent complications. Antiviral agents have been demonstrated to decrease the duration of herpes zoster lesions, reduce the severity of pain associated with the rash, and lessen the chance of postherpetic neuralgia. However, because antiviral agents prevent the virus from replicating, they are unlikely to be helpful if not given within 72 hours of the onset of the rash. Acyclovir (Zovirax), valacyclovir (Valtrex), and famciclovir (Famvir) appear equally safe and effective. In practice, valacyclovir and famciclovir may be preferable to orally-administered acyclovir, which has lower bioavailability. Patients are also more likely to comply with the lower dosing frequency (valacyclovir and famciclovir are taken three times a day for seven days, while acyclovir is taken five times a day for 7-10 days).

Orally administered corticosteroids are commonly used in combination with antiviral agents in the treatment of herpes zoster. Corticosteriods have been demonstrated to reduce pain (specifically prednisone in conjunction with acyclovir), although their benefit in reducing the incidence of postherpetic neuralgia is debatable. The use of corticosteroids for herpes zoster without concomitant antiviral therapy is not recommended.

The pain associated with herpes zoster ranges from mild to acute. Over-the-counter pain analgesics are not strong enough to relieve acute pain during the outbreak period. Opioid analgesics, specifically oxycodone, methodone, and morphine, may help reduce neuropathic pain but they can be addictive and are not always effective.

Tricyclic antidepressants such as amitriptyline (Elavil), nortriptyline (Pamelor), and desipramine (Norpramin, Pertofrane) have demonstrated effective pain management in clinical trials. In five clinical trials to determine the efficacy of TCAs for pain management in postherpetic neuralgia patients, 47% to 67% of TCA-treated patients reported "moderate-to-excellent" pain relief. However, TCAs may take several weeks to become effective.

Anticonvulsants Gabapentin and pregabalin have also been used to treat neuropathic pain in herpes zoster, and appear to be equally effective in reducing discomfort.

There are no specific lifestyle recommendations, although an early return to normal social and domestic activities should be encouraged.

Postherpetic neuralgia

Despite adequate antiviral therapy, some zoster patients continue to experience prolonged pain long after the rash has healed. The prevalence of postherpetic neuralgia (PHN) is difficult to determine as definitions can vary. Some authors define PHN as pain occurring more than 30 days after the onset of rash, whilst others have defined the syndrome as pain three to six months after the acute episode. Others now use the term "zoster associated pain" to encompass all pain in association with herpes zoster.

The mechanism of PHN is not completely known, but it is thought that nerve damage triggered by an inflammatory response during acute herpes zoster may play a role. This damage culminates in neuropathic pain. Neuropathic pain caused by PHN is usually accompanied by a number of somatosensory abnormalities, including dysesthesia (an unpleasant abnormal sensation that can be spontaneous or evoked), allodynia (pain evoked by a normally innocuous stimulus such as light touch), and hyperalgesia (pain of exaggerated severity in response to normally painful stimulation).

As with the risk for herpes zoster, PHN increases with age. About 40% of herpes zoster patients over age 50 have some degree of PHN, as do 50% of those over 60 and 75% of those over 75. Other established risk factors for PHN include a greater severity of acute pain during zoster, more severe rash and a prodrome of dermatomal pain before onset of the rash. Patients with all of these risk factors have at least a 50% chance of having postherpetic neuralgia for six months or more.

It should be noted that PHN is generally a self-limited condition, and should subside in time. However, for its duration, PHN can have a marked impact on quality of life in older adults, with pain hindering the basic activities of daily living. Patients may present with chronic fatigue, insomnia and weight loss, and anxiety and depression are also common.

Treating postherpetic neuralgia

Treating in PHN is directed at pain control. The antiviral agents used to treat herpes zoster have no effect on postherpetic neuralgia; and alleviating pain often requires a certain amount of trial and error and a combination of medications. A drug that is effective in one patient may not help someone else.

There are currently five main types of drug therapy available for pain management in patients with PHN; transdermal lidocaine, topical capsaicin, tricyclic antidepressants (TCAs), anticonvulsants, and opioid analgesics.

Lidocaine patches, first approved by the FDA in 1999 for the treatment of PHN, can provide pain relief with minimal side effects and may be used in conjunction with oral medication. Several studies have shown that the lidocaine patch reduces pain intensity for short periods of time, typically 12 hours. Topical capsaicin applied to the affected area three to five times daily, has been shown to be more effective than placebo, but not necessarily more so than other conventional treatments. The application of capsaicin depletes substance P from pain fibers of sensory nerves. Complete depletion of substance P results in analgesia. However, the burning sensation that occurs during application may be too painful for some patients with PHN.

As previously mentioned, tricyclic antidepressants are a useful component of pain management in PHN patients. By blocking the reuptake of serotonin, norepinephrine, or both in spinal neurons, these agents block pain perception. However, TCAs share common side effects and should be closely monitored, as there are several risks associated with their use in elderly patients.

Opioid analgesics (oxycodone, methodone, and morphine) are common forms of treatment for PHN although, as with TCAs, require caution and monitoring; patients may develop analgesic tolerance or physical dependence.

Gabapentin and pregabalin are the two most common anticonvulsants used to treat neuropathic pain associated with PHN. Both appear to be equally effective in reducing neuropathic pain, and large clinical trials have demonstrated that sleep, mood and overall quality of life improve with gabepentin therapy. Some patients may not respond to one agent or another, but a lack of response to one agent does not predict the response to the other. Appropriate selection may involve some trial and error.

Conclusion

Herpes zoster and postherpetic neuralgia are relatively common conditions, primarily seen in older or immunocompromised patients. Use of an antiviral medication as swiftly as possible following diagnosis can lessen the chance that pain will be prolonged as postherpetic neuralgia.

While therapeutic approaches to the treatment of PHN have brought relief to some patients, it is hoped that the combination of varicella zoster vaccination and herpes zoster vaccination will, in the future, prevent the virus from making a reappearance.

At a glance: Zostavax

In May 2006, the US Food and Drug Administration approved the first vaccine for herpes zoster for use in adults age 60 and over.

Zostavax, manufactured by Merck & Co, was found to halve the rate of herpes zoster in persons 60 or older and reduce the rate of postherpetic neuralgia by 66.5%. The results of the Shingles Prevention Study, which included 38,546-patients, were reported in the New England Journal of Medicine.

During the 5.5-year-study, 19,270 patients were randomised to the active vaccine. The vaccine reduced the burden of illness due to herpes zoster by 61.1%, reduced the rate of postherpetic neuralgia by 66.5%, and reduced the rate of herpes zoster by 51.3%.

However, under current FDA rulings, patients between 50 and 59, an at-risk group, are not eligible for the one dose injection. Further contraindications include a history of primary or acquired immunodeficiency states, meaning that an estimated one in 10 older patients are not candidates for the vaccine.

In addition, the duration of protection after vaccination with Zostavax is unknown. In the Shingles Prevention Study, protection from zoster was demonstrated through four years of follow-up, but it is unclear whether revaccination will be required at a later date.

This article is provided courtesy of Harvard Medical International. © 2006 President and Fellows of Harvard College

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