VZV Foundation - A Decade Of Leadership In The Fight Against VZV Infections

	Diagnosing and Managing Shingles & PHN © 1997 VZV Research Foundation PLEASE BE ADVISED THAT THIS SECTION CONTAINS INFORMATION FOR SCIENTISTS AND MEDICAL PROFESSIONALS, AND IS NOT INTENDED FOR THE GENERAL PUBLIC. Shingles or herpes zoster is a painful and sometimes debilitating viral disease that afflicts nearly one million Americans annually. The incidence of herpes zoster increases with age and among the immunocompromised; the highest incidence of shingles is among those over age 75, and the majority of shingles patients are between 55 and 75 years of age [1]. As the U.S. population ages and more people are immunocompromised by AIDS, cancer treatment and organ transplantation, physicians can anticipate a rise in the number of shingles cases they treat. As a result, the physician can expect an increase in patients with post-herpetic neuralgia (PHN), a painful complication of zoster. Like zoster, the incidence of PHN increases with age. Between nine and 15 percent of zoster patients suffer from PHN. [2] *Immediate Attention Is Imperative* The challenge to the physician is the prompt and proper diagnosis and treatment of shingles. Herpes zoster is difficult to diagnose in its prodromal stage and may often be misdiagnosed in its acute phase. Early recognition is paramount; when treated within 72 hours of eruption of vesicular rash -- and preferably well before 72 hours -- the severity and duration of shingles is significantly lessened. Acute pain responds to prompt treatment of herpes zoster, and immediate therapy lessens the duration of pain in PHN patients. *The Cause: Varicella-Zoster Virus* Herpes zoster, an acute infection of the nervous system, is caused by the varicella-zoster virus (VZV), the same virus responsible for chickenpox. Whereas itching is the key symptom of the rash of varicella (chickenpox), pain is the overriding characteristic of zoster. More than 90 percent of Americans over age 15 have experienced chickenpox [3], making them all susceptible to shingles at a later time. It is estimated that between 10 to 25 percent of the population will experience herpes zoster. It is unusual for children and young adults to develop shingles. While chickenpox is highly contagious, zoster itself is not transmissible. However, the lesions of shingles contain infectious VZV and individuals who have not had chickenpox can develop varicella from exposure to patients with shingles. Following a bout of varicella, VZV remains dormant in the sensory ganglia, usually for decades. Shingles is the often painful result of the reactivation of the dormant virus in these nerves. This reactivation is due to the decline in cellular immunity to VZV that can be the result of aging and immunosuppression. The incidence and severity of herpes zoster and PHN increase with advanced age. Some hypothesize that psychological stress may play a role in the development of PHN [4]. It is not known what triggers VZV to reactivate. Gender does not affect the incidence of shingles or PHN [5], and no genetic cause or association has been shown. A multi-center study is underway to determine whether re-exposing the elderly to VZV, through vaccination, will boost VZV immunity and thus lessen the frequency and severity of herpes zoster in this population [6]. *Symptoms - Zoster* The major and most common symptom of zoster is pain that can be severe and persistent. In the prodromal stage - on average 48 to 72 hours before the presence of rash -- diagnosis can be difficult. Typical symptoms can include: Localized numbness; Localized tingling, burning or shooting pain that may be constant or intermittent; Localized itching; and, Fever, headache, chills and nausea. The eruptive stage is characterized by a painful rash of blistered skin that typically is limited to a band on one side of the body, often localized to the trunk, face or forehead. Thus the names, Zoster, which is Greek for belt, and Shingles, which comes from "cingulum," Latin for girdle or belt. The skin lesions of zoster resemble those of varicella (progressing to vesicles, pustules and scabs), but, unlike varicella, are usually painful and not disseminated widely. When the eye is affected, unilateral blindness can result [7]. Diagnosis in the eruptive stage is not always self-evident. The rash of zoster has been misdiagnosed as allergic reactions and insect bites. A rapid and specific diagnosis can be made by performing an indirect immunofluorescence stain on a smear of cells recovered from the lesion and transferred to a microscope slide. New lesions may appear for up to five days. In the immunocompetent patient, healing is usually complete within two to four weeks. Individuals who are immunocompromised are most susceptible to more prolonged and even repeat bouts of shingles [8]. *Post-Herpetic Neuralgia* Post-herpetic neuralgia (PHN) is the name given to the pain that persists one to three months or longer after the shingles rash has healed [9]. The risk of developing PHN is directly related to the patient's age when shingles appears, and patients with ophthalmic zoster may be at increased risk. PHN is one of the most severe and intractable of chronic pains, lasting months or years after the disappearance of zoster blisters [10]. The pain of PHN may be sharp, piercing, throbbing or stabbing. It is the result of injury to the peripheral nerves and resultant changes in the signal processing of the central nervous system [11]. The pain may extend beyond the margins of the original zoster eruption [12]. The skin may be unusually sensitive to even the lightest touch (as from clothing), to the smallest breeze, and to changes in temperature (either hot or cold). The severity and duration of pain appears to increase with age. The devastating effect of PHN on quality of life for many patients cannot be underestimated. Most debilitating can be allodynia, pain triggered by otherwise trivial stimula, with some individuals remaining housebound because they cannot tolerate the touch of clothing. *Treatment Options - Zoster* In selecting therapies to treat shingles and PHN, the patient's age and health status should be taken into account. For example, immunocompromised patients may fare better with an intravenous, rather than an oral, antiviral drug. Zoster: Use of antiviral drugs is a key therapy because drugs may limit the replication and spread of the reactivated virus within the ganglion to the skin. Treatment with an orally-administered antiviral drug within 72 hours of shingles eruption in healthy elderly patients speeds healing of zoster blisters and the resolution of pain. The earlier antiviral therapy is begun, the better the outcome. Oral antivirals include acyclovir, famciclovir, and valaciclovir. FDA approved dosages are: acyclovir, 800 mg five times a day for 10 days; famciclovir, 500 mg t.i.d. for seven days; and valaciclovir, 1000 mg t.i.d. for seven days [13]. These antivirals generally are well tolerated. Side effects may include nausea, headache, diarrhea, and vomiting [14]. Corticosteroids, taken in combination with an antiviral, lessen the duration of pain in the acute phase of zoster, allow the patient to resume normal activity and restore uninterrupted sleep [15]. Corticosteroids are only recommended for healthy, elderly individuals who experience moderate or severe pain; this population seems to derive the greatest benefit [16]. Post-Herpetic Neuralgia: Some tricyclic antidepressants -- notably amitriptyline, desipramine, nortriptyline and maprotiline -- are effective as "analgesics" in treating PHN [17]. Recent studies have also shown that some nonopioids, opioids and adjuvant analgesic drugs are also effective in treating PHN pain. Selective seratonin uptake inhibitors (e.g., fluoxetine, sertraline, paroxetine) are less effective as analgesics, and conventional analgesics such as ibuprofin are ineffective [18]. Patients should be informed that a tricyclic drug is being prescribed for its analgesic - not antidepressant - properties. Once an appropriate dose level is attained, it may take up to 10 days for the analgesic effect of the drug to be felt, and that dosage may need to be adjusted. Narcotic analgesics seem to benefit some patients with PHN. Cold packs may offer temporary relief of pain. Because the pain of PHN can be debilitating, negatively affecting relationships and severely limiting professional and personal activities, patients should be encouraged to consult a specialist in pain treatment. Cognitive-behavior modification, biofeedback and relaxation training are among the approaches used by these specialists. *About the VZV Research Foundation* The urgent need for increased research and education on chickenpox, shingles and PHN led to the formation of the VZV Research Foundation (VZVRF) in 1991. This publicly-supported charity serves as an important information resource to thousands of VZV sufferers, their families and their physicians. The Foundation also sponsors international scientific conferences on VZV and awards research grants to investigate the reasons for the virus' reemergence, to develop new vaccines to prevent chickenpox and shingles in the immunocompromised, and to seek out new treatments for PHN pain. VZVRF is guided by its Board of Directors and has a Scientific Advisory Board consisting of more than 30 internationally renowned experts on VZV. For further information on the Foundation or its activities, please contact: VZV Research Foundation 40 East 72nd Street New York, NY 10021 Tel. 212-472-3181 800-472-VIRUS (1-800-472-8478) Fax: 212-861-7033 E-MAIL: VZV@VZVFoundation.org The VZV Research Foundation is a tax-exempt, charitable organization under section 501(c)(3) of the Internal Revenue Code, identification number 13-3601316. Gifts to the Foundation are tax deductible to the full extent permitted by law. Footnotes: Ragozzino, M.W., Melton L.J. III, Kurland L.T. et al., "Population-Based Study of Herpes Zoster and Its Sequelae," Medicine, 1982, Vol. 62, pp. 310-316. Hope-Simpson, R.E., "The Nature of Herpes Zoster: A Long-Term Study and a New Hypothesis," Proc R Soc Med, 1965, Vol. 58, pp. 9-20; Burgoon, C.F., Jr., Baldridge, G.D., "The Natural History of Herpes Zoster," Journal of the American Medical Association, 1957, Vol. 164, pp. 264-265. Straus, Stephen, "Shingles: Sorrows, Salves and Solutions," Journal of the American Medical Association, April 14, 1993, Vol. 269, p. 1836. Dworkin, Robert, "Identifying the Likelihood of PHN: A Research Update," VZV Focus, Vol. III, No. 1, Summer/Fall 1995, p. 4. Ragozzino, M.W., "Incidence of Herpes Zoster Per 100,000 Person Years" (figure), Archives of Dermatology, 1957, Vol. 75, pp. 193-196. Oxman, Michael, "Immunization To Reduce the Frequency and Severity of Herpes Zoster and Its Complications," Neurology, Vol. 45, No. 12, Supplement 8, p. S45. Pavan-Langston, Deborah, "Herpes Zoster Ophthalmicus," Neurology, Vol. 45, No. 12, Supplement 8, pp. S50-51. Shingles, National Institute of Neurological Disorders and Stroke, October 1996. Nurmikko, Turo, "Clinical Features and Pathophysiologic Mechanisms of Postherpetic Neuralgia," Neurology, Vol. 45, No. 12, Supplement 8, p. S54. Kost, Rhonda, Straus, Stephen, "Postherpetic Neuralgia: Pathogenesis, Treatment and Prevention," New England Journal of Medicine, July 4, 1996, Vol. 335, No. 1, p. 32. Ibid., p. 33. Ibid. Physicians' Desk Reference 1996 Edition, Medical Economics, pp. 1196, 1220, 2488. Ibid., pp. 1195, 1225, 2488. Kost, Rhonda, Straus, Stephen, "Postherpetic Neuralgia: Pathogenesis, Treatment and Prevention," New England Journal of Medicine, July 4, 1996, Vol. 335, No. 1, p. 37. Whitley, Richard J., et al., Annals of Internal Medicine, 1996, 125:376-383. Kost, Rhonda, Straus, Stephen, "Postherpetic Neuralgia: Pathogenesis, Treatment and Prevention," New England Journal of Medicine, July 4, 1996, Vol. 335, No 1, p. 36; Watson, C. Peter, "The Treatment of Post-Herpetic Neuralgia," Neurology, December 1995, Vol. 45, No. 12, Supplement 8, pp. S58-59. Ibid.

Diagnosing and Managing Shingles & PHN
© 1997 VZV Research Foundation

PLEASE BE ADVISED THAT THIS SECTION CONTAINS INFORMATION FOR SCIENTISTS AND MEDICAL PROFESSIONALS, AND IS NOT INTENDED FOR THE GENERAL PUBLIC.

Shingles or herpes zoster is a painful and sometimes debilitating viral disease that afflicts nearly one million Americans annually. The incidence of herpes zoster increases with age and among the immunocompromised; the highest incidence of shingles is among those over age 75, and the majority of shingles patients are between 55 and 75 years of age [1]. As the U.S. population ages and more people are immunocompromised by AIDS, cancer treatment and organ transplantation, physicians can anticipate a rise in the number of shingles cases they treat. As a result, the physician can expect an increase in patients with post-herpetic neuralgia (PHN), a painful complication of zoster. Like zoster, the incidence of PHN increases with age. Between nine and 15 percent of zoster patients suffer from PHN. [2]

Immediate Attention Is Imperative

The challenge to the physician is the prompt and proper diagnosis and treatment of shingles. Herpes zoster is difficult to diagnose in its prodromal stage and may often be misdiagnosed in its acute phase. Early recognition is paramount; when treated within 72 hours of eruption of vesicular rash -- and preferably well before 72 hours -- the severity and duration of shingles is significantly lessened. Acute pain responds to prompt treatment of herpes zoster, and immediate therapy lessens the duration of pain in PHN patients.

The Cause: Varicella-Zoster Virus

Herpes zoster, an acute infection of the nervous system, is caused by the varicella-zoster virus (VZV), the same virus responsible for chickenpox. Whereas itching is the key symptom of the rash of varicella (chickenpox), pain is the overriding characteristic of zoster.

More than 90 percent of Americans over age 15 have experienced chickenpox [3], making them all susceptible to shingles at a later time. It is estimated that between 10 to 25 percent of the population will experience herpes zoster. It is unusual for children and young adults to develop shingles. While chickenpox is highly contagious, zoster itself is not transmissible. However, the lesions of shingles contain infectious VZV and individuals who have not had chickenpox can develop varicella from exposure to patients with shingles.

Following a bout of varicella, VZV remains dormant in the sensory ganglia, usually for decades. Shingles is the often painful result of the reactivation of the dormant virus in these nerves. This reactivation is due to the decline in cellular immunity to VZV that can be the result of aging and immunosuppression. The incidence and severity of herpes zoster and PHN increase with advanced age. Some hypothesize that psychological stress may play a role in the development of PHN [4]. It is not known what triggers VZV to reactivate.

Gender does not affect the incidence of shingles or PHN [5], and no genetic cause or association has been shown. A multi-center study is underway to determine whether re-exposing the elderly to VZV, through vaccination, will boost VZV immunity and thus lessen the frequency and severity of herpes zoster in this population [6].

Symptoms - Zoster

The major and most common symptom of zoster is pain that can be severe and persistent. In the prodromal stage - on average 48 to 72 hours before the presence of rash -- diagnosis can be difficult. Typical symptoms can include:

Localized numbness;

Localized tingling, burning or shooting pain that may be constant or intermittent;

Localized itching; and,

Fever, headache, chills and nausea.

The eruptive stage is characterized by a painful rash of blistered skin that typically is limited to a band on one side of the body, often localized to the trunk, face or forehead. Thus the names, Zoster, which is Greek for belt, and Shingles, which comes from "cingulum," Latin for girdle or belt. The skin lesions of zoster resemble those of varicella (progressing to vesicles, pustules and scabs), but, unlike varicella, are usually painful and not disseminated widely. When the eye is affected, unilateral blindness can result [7].

Diagnosis in the eruptive stage is not always self-evident. The rash of zoster has been misdiagnosed as allergic reactions and insect bites. A rapid and specific diagnosis can be made by performing an indirect immunofluorescence stain on a smear of cells recovered from the lesion and transferred to a microscope slide.

New lesions may appear for up to five days. In the immunocompetent patient, healing is usually complete within two to four weeks. Individuals who are immunocompromised are most susceptible to more prolonged and even repeat bouts of shingles [8].

Post-Herpetic Neuralgia

Post-herpetic neuralgia (PHN) is the name given to the pain that persists one to three months or longer after the shingles rash has healed [9]. The risk of developing PHN is directly related to the patient's age when shingles appears, and patients with ophthalmic zoster may be at increased risk. PHN is one of the most severe and intractable of chronic pains, lasting months or years after the disappearance of zoster blisters [10].

The pain of PHN may be sharp, piercing, throbbing or stabbing. It is the result of injury to the peripheral nerves and resultant changes in the signal processing of the central nervous system [11]. The pain may extend beyond the margins of the original zoster eruption [12]. The skin may be unusually sensitive to even the lightest touch (as from clothing), to the smallest breeze, and to changes in temperature (either hot or cold). The severity and duration of pain appears to increase with age.

The devastating effect of PHN on quality of life for many patients cannot be underestimated. Most debilitating can be allodynia, pain triggered by otherwise trivial stimula, with some individuals remaining housebound because they cannot tolerate the touch of clothing.

Treatment Options - Zoster

In selecting therapies to treat shingles and PHN, the patient's age and health status should be taken into account. For example, immunocompromised patients may fare better with an intravenous, rather than an oral, antiviral drug.

Zoster:
Use of antiviral drugs is a key therapy because drugs may limit the replication and spread of the reactivated virus within the ganglion to the skin. Treatment with an orally-administered antiviral drug within 72 hours of shingles eruption in healthy elderly patients speeds healing of zoster blisters and the resolution of pain. The earlier antiviral therapy is begun, the better the outcome.

Oral antivirals include acyclovir, famciclovir, and valaciclovir. FDA approved dosages are: acyclovir, 800 mg five times a day for 10 days; famciclovir, 500 mg t.i.d. for seven days; and valaciclovir, 1000 mg t.i.d. for seven days [13]. These antivirals generally are well tolerated. Side effects may include nausea, headache, diarrhea, and vomiting [14].

Corticosteroids, taken in combination with an antiviral, lessen the duration of pain in the acute phase of zoster, allow the patient to resume normal activity and restore uninterrupted sleep [15]. Corticosteroids are only recommended for healthy, elderly individuals who experience moderate or severe pain; this population seems to derive the greatest benefit [16].

Post-Herpetic Neuralgia:
Some tricyclic antidepressants -- notably amitriptyline, desipramine, nortriptyline and maprotiline -- are effective as "analgesics" in treating PHN [17]. Recent studies have also shown that some nonopioids, opioids and adjuvant analgesic drugs are also effective in treating PHN pain. Selective seratonin uptake inhibitors (e.g., fluoxetine, sertraline, paroxetine) are less effective as analgesics, and conventional analgesics such as ibuprofin are ineffective [18]. Patients should be informed that a tricyclic drug is being prescribed for its analgesic - not antidepressant - properties. Once an appropriate dose level is attained, it may take up to 10 days for the analgesic effect of the drug to be felt, and that dosage may need to be adjusted.

Narcotic analgesics seem to benefit some patients with PHN. Cold packs may offer temporary relief of pain.

Because the pain of PHN can be debilitating, negatively affecting relationships and severely limiting professional and personal activities, patients should be encouraged to consult a specialist in pain treatment. Cognitive-behavior modification, biofeedback and relaxation training are among the approaches used by these specialists.

About the VZV Research Foundation

The urgent need for increased research and education on chickenpox, shingles and PHN led to the formation of the VZV Research Foundation (VZVRF) in 1991. This publicly-supported charity serves as an important information resource to thousands of VZV sufferers, their families and their physicians. The Foundation also sponsors international scientific conferences on VZV and awards research grants to investigate the reasons for the virus' reemergence, to develop new vaccines to prevent chickenpox and shingles in the immunocompromised, and to seek out new treatments for PHN pain.

VZVRF is guided by its Board of Directors and has a Scientific Advisory Board consisting of more than 30 internationally renowned experts on VZV.

For further information on the Foundation or its activities, please contact:

VZV Research Foundation
40 East 72nd Street
New York, NY 10021
Tel. 212-472-3181
800-472-VIRUS (1-800-472-8478)
Fax: 212-861-7033
E-MAIL: VZV@VZVFoundation.org
The VZV Research Foundation is a tax-exempt, charitable organization under section 501(c)(3) of the Internal Revenue Code, identification number 13-3601316. Gifts to the Foundation are tax deductible to the full extent permitted by law.

Footnotes:

Ragozzino, M.W., Melton L.J. III, Kurland L.T. et al., "Population-Based Study of Herpes Zoster and Its Sequelae," Medicine, 1982, Vol. 62, pp. 310-316.

Hope-Simpson, R.E., "The Nature of Herpes Zoster: A Long-Term Study and a New Hypothesis," Proc R Soc Med, 1965, Vol. 58, pp. 9-20; Burgoon, C.F., Jr., Baldridge, G.D., "The Natural History of Herpes Zoster," Journal of the American Medical Association, 1957, Vol. 164, pp. 264-265.

Straus, Stephen, "Shingles: Sorrows, Salves and Solutions," Journal of the American Medical Association, April 14, 1993, Vol. 269, p. 1836.

Dworkin, Robert, "Identifying the Likelihood of PHN: A Research Update," VZV Focus, Vol. III, No. 1, Summer/Fall 1995, p. 4.

Ragozzino, M.W., "Incidence of Herpes Zoster Per 100,000 Person Years" (figure), Archives of Dermatology, 1957, Vol. 75, pp. 193-196.

Oxman, Michael, "Immunization To Reduce the Frequency and Severity of Herpes Zoster and Its Complications," Neurology, Vol. 45, No. 12, Supplement 8, p. S45.

Pavan-Langston, Deborah, "Herpes Zoster Ophthalmicus," Neurology, Vol. 45, No. 12, Supplement 8, pp. S50-51.

Shingles, National Institute of Neurological Disorders and Stroke, October 1996.

Nurmikko, Turo, "Clinical Features and Pathophysiologic Mechanisms of Postherpetic Neuralgia," Neurology, Vol. 45, No. 12, Supplement 8, p. S54.

Kost, Rhonda, Straus, Stephen, "Postherpetic Neuralgia: Pathogenesis, Treatment and Prevention," New England Journal of Medicine, July 4, 1996, Vol. 335, No. 1, p. 32.

Ibid., p. 33.

Ibid.

Physicians' Desk Reference 1996 Edition, Medical Economics, pp. 1196, 1220, 2488.

Ibid., pp. 1195, 1225, 2488.

Kost, Rhonda, Straus, Stephen, "Postherpetic Neuralgia: Pathogenesis, Treatment and Prevention," New England Journal of Medicine, July 4, 1996, Vol. 335, No. 1, p. 37.

Whitley, Richard J., et al., Annals of Internal Medicine, 1996, 125:376-383.

Kost, Rhonda, Straus, Stephen, "Postherpetic Neuralgia: Pathogenesis, Treatment and Prevention," New England Journal of Medicine, July 4, 1996, Vol. 335, No 1, p. 36; Watson, C. Peter, "The Treatment of Post-Herpetic Neuralgia," Neurology, December 1995, Vol. 45, No. 12, Supplement 8, pp. S58-59.

Ibid.