1 herpes zoster and postherpetic neuralgia 台北市立聯合醫院皮膚科林瑞宜

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Herpes zoster and Postherpetic neuralgia

台北市立聯合醫院皮膚科林瑞宜

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學經歷• 1972 年國立台灣大學醫學部醫科畢業• 1973 年國立台灣大學醫科附設醫院皮膚科住院醫師• 1977 年台灣台北市立和平醫院皮膚科主任• 1980 年國立台灣大學醫科附設醫院皮膚科兼任講師 (~ 現在 )• 1980-2007 年 : 台灣皮膚科醫學會理事 ( 曾任常務理事，理事長 )• 1984 年美國哈佛大學麻省總醫院皮膚病理研究所 (1984/07~1985/0

6)• 1993 年台灣台北市立和平醫院皮膚科主治醫師• 1995 年台灣台北市立性病防治所所長• 1998 年台灣台北市立和平醫院院長 • 2001 年台灣台北市立和平醫院顧問醫師兼皮膚科主治醫師 , • 2005 年台灣台北聯合醫院皮暨和平院區皮膚科主任 (~ 現在 ) • 2008 年衛生署藥害審議委員會委員

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Epidemiological Features and Costs of Herpes Zoster in Taiwan:

A National Study 2000 to 2006 Acta Derm Venereol 2009; 89: 612–616

• Overall, 34,280 patients were diagnosed with zoster (incidence 4.89/1000 person-years)

• A total of 4543 patients (13.3%) had persistent neuralgia one month after the start of the zoster rash (incidence 0.64/1000 person-years),

• 2944 patients (8.6%) developed postherpetic neuralgia 3 months after the start of the zoster rash (incidence 0.42/1000 person-years).

• overall hospitalization rate for zoster was 16.1 cases per 100,000 person-years.

• The cost for each home care case and per hospitalized case were approximately $NT1655 and $NT38,051, respectively

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goals of therapy for herpes zosterJ Am Acad Dermatol 2007;57:S136-42

• The goals of therapy for herpes zoster are – to accelerate healing, – limit the severity and duration of pain, – reduce complications, which include, in additi

on to postherpetic neuralgia, encephalitis, myelitis, cranial and peripheral palsies, a syndrome of delayed contralateral hemiparesis, and acute retinal necrosis.

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Management and prevention of herpes zoster: a Canadian perspective.

• Varicella-zoster virus reactivation leads to herpes zoster – the main complication of which is postherpetic neuralgia (PHN).

• Rapid antiviral therapy initiated within 72 hwithin 72 h of rashof rash onset has been shown to – accelerate rash healing, – reduce the duration of acute pain and, – to some extent, attenuate the development an

d duration of PHN.

Can J infect dis Med Microbiol 2010;21(1):45-52.

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Pathogenesis and diagnosis

• Varicella-zoster virus (VZV), a member of the Herpesviridae family

• Following an incubation period of 14 to 21 days, the primary infection is varicella (chickenpox).

• The virus then migrates via retrograde axonal transport to sensory ganglia, where it establishes lifelong latency.

• VZV reactivations can be asymptomatic or symptomatic leading to the development of zoster, which typically occurs many decades after primary infection.

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Clinical manifestation of Herpes zoster

• A typical zoster rash in an immunocompetent individual involves one or two adjacent dermatomes, and usually lasts seven to 10 days. – Thoracic dermatomes up to 50% of cases,– Ophthalmic areas in 1% to 10%

• About 75% patients report having prodromal pain (zoster sine herpete)– can precede the rash by days to weeks

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Clinical manifestation of Herpes zoster

• Because zoster rash is so typical, diagnosis can be made clinically in most instances.

• In very early stage, red edematous plaque may be confused with cellulitis or contact dermatitis.

• While few papular lesions only, differentiate from herpes simplex virus (HSV) or conditions such as impetigo, folliculitis, insect bites etc..

• The rash may be atypical dissemination or chronicity in immunocompromised patients.

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Laboratory diagnostic test of Herpes zoster

• Swabs and cell scrapings from the base for – Direct fluorescent antibody staining (DIF), 90% positiv

e in vesicular stage (DDx VZV/HSV) – Cell culture : 60% to 75%, need one week– Polymerase chain reaction (PCR)

• the mostsensitive diagnostic method to distinguish wild-type VZV from the vaccine Oka strain

– Tzanck cytology : ballooning cells and multinucleated giant cells

• Cytopathic viral infection

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Herpes zoster

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Complication of Herpes zoster

• Pain is the most frequent complication. – Acute pain occurring within 30 days after rash onset, – subacute pain (between 30 days and 90 to 120 days) – postherpetic neuralgia (PHN), significant pain and per

sists longer than 90 to 120 days after rash onset.

• Keratitis, 2/3 in Hepes zoster ophthalmicus • neurological complications

– Ramsay Hunt syndrome: HZ of the facial nerve, with vesicles on the ear, palate or tongue leading to facial paresis, hearing loss and vertigo.

– Others: myelitis, aseptic meningitis, Bell’s palsy, etc..

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• Visceral dissemination: fatality rate of 5% to 15%,even with antiviral therapy– cellular immunodeficiency : HIV, hematologica

l malignancies, solid tumours, and following stem cell or organ transplantation,

• 皮蛇繞身體一圈後，病人可能沒救了 ?

• Soft tissue infection, ? After NSAID

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Postherpetic Neuralgia (PNH)

• The risk of PHN, given an episode of zoster, increases with age.– 10% of patients with zoster– in one-third of zoster patients > 60 y/o– incidence of 14 cases per 10,000 person-years

• In addition to advancing age, the severity of acute pain and rash, prodromal pain, ophthalmic location and possibly female sex are also risk factors for PHN

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Antiviral Treatment for Herpes zoster

• The main objectives of antiviral treatment are: – to reduce viral replication, – To reduce duration of rash and acute pain – to prevent complications seen mostly in immunocompromised

patients. – early antiviral therapy may also attenuate development of PHN.

健保規定為 :•發生皮疹的 72hours 內•一般人治療為五天

•Famciclovir 250mg • TID x 5

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10.7.1.1. 全身性抗疱疹病毒劑1. Acyclovir ： (98/11/1 、 100/7/1) 使用本類製劑應以下列條件為限：

1. 疱疹性腦炎。2. 帶狀疱疹或單純性疱疹侵犯三叉神經第一分枝 VI皮節，可能危及眼角膜者。

3. 帶狀疱疹或單純性疱疹侵犯薦椎 S2皮節，將影響排泄功能者。4. 免疫機能不全、癌症、器官移植等病患之感染帶狀疱疹或單純性疱疹者。5. 新生兒或免疫機能不全患者的水痘感染。6. 罹患水痘，合併高燒 (口溫 38℃以上 ) 及肺炎 (需Ｘ光顯示 ) 或腦

膜炎，並需住院者（ 85/1/1 ）。7. 帶狀疱疹或單純性疱疹所引起之角膜炎或角膜潰瘍者。8. 急性視網膜壞死症 (acute retina necrosis) 。9. 帶狀疱疹發疹三日內且感染部位在頭頸部、生殖器周圍之病人，可給予五日內之口服或外用藥品 (86/1/1 、 87/4/1) 。

10.骨髓移植術後病患得依下列規定預防性使用 acyclovir ：（ 87/11/1 ）1.限接受異體骨髓移植病患。2.接受高劑量化療或全身放射治療 (TBI) 前一天至移植術後第卅天為止。

其中Ⅰ與Ⅵ應優先考慮注射劑型的 acyclovir 。疱疹性腦炎得使用 14至 21 天。（ 95/6/1 、 100/7/1 ）

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10.7.1.1. 全身性抗疱疹病毒劑2.Famciclovir ； valaciclovir ： (100/7/1)• 使用本類製劑應以下列條件為限：• 帶狀疱疹或單純性疱疹侵犯三叉神經第一分枝 VI皮節，可能危及眼角膜者。

• 帶狀疱疹或單純性疱疹侵犯薦椎 S2皮節，將影響排泄功能者。• 免疫機能不全、癌症、器官移植等病患之感染帶狀疱疹或單純性疱疹者。• 帶狀疱疹或單純性疱疹所引起之角膜炎或角膜潰瘍者。• 急性視網膜壞死症 (acute retina necrosis) 。• 帶狀疱疹發疹 3日內且感染部位在頭頸部、生殖器周圍之病人，可給予5日內之口服或外用藥品。

• 骨髓移植術後病患得依下列規定預防性使用 acyclovir ：• A. 限接受異體骨髓移植病患。• B. 接受高劑量化療或全身放射治療 (TBI) 前一天至移植術後第 30天為

止。3. Acyclovir 、 Famciclovir 及 valaciclovirt 除上述特別規定外，使用

療程原則以 10天為限，口服、注射劑及外用藥膏擇一使用，不得合併使用。（ 95/6/1 、 100/7/1 ）

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Antiviral Treatment for Herpes zoster

In Taiwan, the usual dosage for Famciclovir is 250mg TID

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Usage of Famciclovir for Herpes zoster

• Equal efficacy is noted in RCT 559 immunocompetent adults treated for 7 days (initiated within 72 hours of onset of zoster skin lesions) – famciclovir (750 mg QD, 500 mg BID, or 250 mg TID) – acyclovir (800mg x5/day ).J Clin Virol 2004;29:248-53

• Famciclovir, like acyclovir, has also been shown to reduce the duration of postherpetic neuralgia by a median of 2 months. Ann Intern Med 1995;123:89-96

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Rash severity in herpes zoster: Correlates and relationship to postherpetic neuralgia

J Am Acad Dermatol 2002;46:834-9

26BRITISH MEDICAL JOURNAL 293: 1529, 1986

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Frequently descriptions in Textbook or Review Articles

• Antiviral drugs have been consistently found to effectively reduce the severity and duration of herpes zoster, and are safe and well tolerated with minimal adverse effects.

• They do not, however, reliably prevent the development of postherpetic neuralgia.

28ANTIMICROB AGENTS CHEMOTHERA 39:1546–1553, 1995

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In Canada

• Oral therapy with one of the three antivirals is recommended as first-line treatment for all immunocompetent patients who – consult rapidly (preferably within 72 h of rash onset) – who fulfill any of the following criteria:

• 50 years of age or older; • moderate or severe acute pain; • moderate or severe rash; • Nontruncal involvement

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Late antiviral treatment

• Of note, the 72 h inclusion criterion has been arbitrarily chosen in randomized clinical trials and may not be optimal in clinical practice.

• The presence of new vesicles, which reflect active viral replication, may be an alternative way to select patients for antiviral treatment.

• Ophthalmic zoster should be treated more aggressively, including referral for eye assessment and starting of antiviral therapy even beyond the 72 h period.

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Usage of corticosteroids in HZ

• Although showing some benefits in acute zoster pain, corticosteroids do not provide added value over acyclovir in reducing PHN, and are thus not recommended in the initial management of HZ .

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Acute pain associated with herpes zoster

• Defined as pain before and during blister eruption.

• Prodromal pain can consist of various symptoms, e.g. itching, burning, tingling, stubbing, tenderness superficial and deep pain.

• Usually moderate-to-severe acute pain caused by acute neuritis, can last for nearly a month.

• Pathogenesis of acute pain– an abnormal discharge in the dorsal horn, – by the inflammation of the dorsal root ganglion, – by the extent of the neuritis and the dermal vasculitis.

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Use of NSAID in VZV infection

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NSAID may induce more infection

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Use of NSAID in VZV infectionRESULTS• In patients with varicella, there were 386 cases of severe skin or soft

tissue complications (rate 2.8 per 1000) during the 2month follow-up period (mean age 10.7 years). The rate of complications associated with exposure to NSAIDs was increased (rate ratio 4.9; 95% CI 2.1, 11.4).

• In patients with zoster disease, there were 681 cases of severe skin or soft tissue complications (rate 6.3 per 1000) during the 2month follow-up (mean age 60.9 years).

• The rate ratio of complications associated with exposure to NSAIDs was 1.6 (95% CI 1.1, 2.4). In both conditions, there was no increased risk of complication associated with a current exposure to paracetamol.

CONCLUSIONS• The use of NSAIDs is associated with an elevated risk of severe ski

n and soft tissue complications of varicella zoster virus infection, mostly in children with varicella.

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Zoster-Associated Pain/Postherpetic Neuralgia pain

• Pain that persists beyond a defined period of time is referred to as postherpetic neuralgia.

• from 9–14%, Usually in elder, rare in < 50y/o• Although the overall incidence of chronic pain is l

ow, its incidence and severity increases with rising age.

37BMJ 2000;321:1–4

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BMJ 2000;321:1–4

39Journal of Antimicrobial Chemotherapy (1998) 41, 549–556

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Zoster Brief Pain InventoryOrigin: J Pain 2004;5:344-56.

1. Have you had any pain caused by your shingles in the last 24 h?

(yes, no)2. Shade in the areas where you

feel pain on the diagram (face and back body anatomy diagrams)

3. Rate your worst pain in the last 24 h (scale of 0–10)

4. Rate your least pain in the last 24 h (scale of 0–10)

5. Rate your average pain in the last 24 h (scale of 0–10)

6. Rate your current pain (scale of 0–10)

7. Are you receiving treatments or medication for your shingles pain? (yes, no)

8. How much relief have these treatments provided in the last 24 h? (scale of 0%–100%)

9. How your shingles pain has interfered with (last 24 h):A. General activityB. MoodC. Walking abilityD. Normal workE. Relations with other peopleF. SleepG. Enjoyment of life

(scale of 0–10 for each item)

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Management of Zoster-assocoated Pain(ZAP)

• ZAP : Acute pain associated with rash and PHN. • ZAP may be described as continuous or paroxysmal,

evoked or spontaneous, burning or lancinating, and other sensory abnormalities in the skin.

• Different (2) pain mechanisms . – Increased excitability of damaged primary afferent neurons

causing irritable nociceptors and central sensitization, resulting in pain and allodynia;

– Degeneration of nociceptive neurons in dorsal root ganglia or the spinal cord, leading to deafferentation with central hyperactivity, causing pain but typically without allodynia .

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Treatment regimensRasi et al. - Acyclovir in treatment of post-herpetic pain J Infect Dev Ctries 2010; 4(11):754-760

• All patients took acyclovir, 800 mg five times a day, for the first four days of the first week, followed by three treatment-free days. In the cases evidence of pain reduction but not CPR, a second course of treatment with the same dosage was offered. The patients were followed for three months without medication

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The efficacy of time-based short-course acyclovir therapy in treat

ment of post-herpetic pain J Infect Dev Ctries 2010; 4(11):754-760.

• Group 1 :within 72 hrs, Group 2: after 72 hrs• acyclovir, 800 mg five times a day, x 4 days of the first week,

followed by three treatment-free days. If no complete response, treating again.

No significant difference (or no therapeutic effect ?)

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Management of ZAP

• Perform a medical and psychosocial evaluation and targeted physical examination to confirm the diagnosis, document comorbid illness and provide a basis for treatment.

• Elderly patients may be socially isolated, may have cognitive impairment, depression or other life stressors that may impact treatment compliance and outcome.

• Anxiety or depression may also develop secondary to severe ZAP and can influence suffering.

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Management of ZAP

Patient education and general measures: • The disease and its time course should be explai

ned, including the risk of viral transmission to individuals who have not had varicella.

• The rash should be kept clean and dry to reduce the risk of secondary bacterial infection.

• Acute skin discomfort may be reduced by sterile wet dressings.

• Topical antibiotic dressings with adhesives that can cause irritation and delay rash healing should be avoided.

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Management of ZAP

Pharmacological agents: • ZAP should be assessed early and treatment

should begin promptly. • The principles of optimum pain management

– use of standardized pain measures, – scheduled analgesia, – consistent and frequent follow-up to adjust

dosing to the needs of the patient,

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Management of ZAP

Pharmacological agents:

• It is important to recognize that ZAP changes over time and can become more severe as the acute infection progresses.

• The initial choice of treatment approaches depends on the patient’s pain severity, comorbid conditions and on any previous known response to specific medications.

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In Taiwan

• 2008 年 Herpes zoser 病人

• (ICD 9 053): 6488 其中使用 Neurotin 617 人

• (ICD 9 053.1X): 2709 其中使用 Neurotin 320人

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健保用藥給付規定• 1.1.6. Gabapentin 、 lidocaine 貼片劑（ 97/12/1 、 98/4/1 、 9

8/9/1 ）限使用於帶狀疱疹皮膚病灶後神經痛，並符合下列條件：

• 1. 使用其他止痛劑或非類固醇抗發炎劑（ NSAIDs ）藥品治療後仍無法控制疼痛或有嚴重副作用者。 (97/12/1 、 98/4/1)

• 2. Gabapentin 成分口服製劑，限每日最大劑量為 3,600mg ，且日劑量超過 2,400mg 時，需於病歷記載理由。臨床症狀改善，應逐步調低劑量。限使用 Neurontin 、 Gapatin 、 Gatine 、Gaty 、 Carbatin 。 (97/12/1 、 98/4/1 、 98/9/1)

• 3. Lidocaine 貼片劑，限每日最大劑量為 3 片，且日劑量超過 2 片時，需於病歷記載理由。臨床症狀改善，應逐步調低劑量。限使用 Lidopat Patch 。（ 98/9/1 ）

• 4. Lidopat 貼片劑不得與 Gabapentin 成分口服製劑併用。（ 98/9/1 ）

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Vaccination for Herpes zoster

• Zoster vaccine licensed for 60 years of age and older .– not licensed for immunocompromised individuals, pregnant wom

en or children. • vaccine is a lyophilized live, attenuated Oka VZV strain. • Boost cellular immunity in older adults through a range of

subcutaneous doses with a good safety profile .• SPS randomly assigned > 38,000 people to zoster vacci

ne or placebo . – reduced the burden of illness by 61%, – Reduce the incidence of zoster by 51%– Reduce the incidence of PHN by 67% – 60 to 69 years of age vs > 70 years of age :vaccine efficacy 63.9

% versus 37.6%, respectively– However, the reduction in incidence of PHN was similar in these

two age groups.

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Principles of analgesics for postherpetic neuralgia

• Grade 1 = non-opioids as a rule (pain NRS 1–4); • Grade 2 = nonopioids and/or low potency opioids in com

bination with analgesics (pain NRS 5–8); • Grade 3 = high potency opioids, individual combination

with the above mentioned analgesics (pain NRS 9–10); • NRS = numerical rating scale.

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AAN Evidence-Based Guideline Summary of Treatment for Postherpetic Neuralgia

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Thank You for Your Attension

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1 herpes zoster and postherpetic neuralgia 台北市立聯合醫院皮膚科 林瑞宜

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1 herpes zoster and postherpetic neuralgia 台北市立聯合醫院皮膚科林瑞宜