Synonyms: herpes zoster and varicella zoster

Shingles is caused by the human herpesvirus-3 (HHV-3).

Primary infection usually occurs in childhood, producing chickenpox (varicella) although it can be subclinical. After this the virus lies dormant in the sensory nervous system in the geniculate, trigeminal or dorsal root ganglia. It may lie dormant for many years or many decades, kept in check by the immune system,¹ before flaring up in a single dermatome segment.

When this happens, the virus travels down the affected nerve over a period of 3 to 4 days, causing perineural and intraneural inflammation along the way. There is not always a clear reason for a flare-up but associations include ageing (most patients are over 50 years old), immunosuppressive illness, new stress (including physical trauma)² or new medical treatments.³

Typically affected dermatomes include:

• Thoracic (56%)
• Cervical (17%)
• Trigeminal nerve (12%)
• Lumbar (10%)
• Sacral (5%)
• Ophthalmic herpes, which is more common in elderly males⁴

Epidemiology

At least 90% of children have been exposed to chickenpox before they are 16. Shingles is seen as a disease of older people but it can affect all ages including children. The incidence and severity increase with age. This may be due to a decline in cellular rather than humoral immunity.⁵ Figures available are unreliable and in those quoted below there are no figures for the those aged between 50 and 80. They do at least show the expected upward trend with age.

• Under 20 years - 0.4 to 1.6 cases per 1,000 persons.
• Age 20 to 50 years - 2.0 to 3.0 cases per 1,000 persons.
• Over 80 years - 4.5 to 11.0 cases per 1,000 persons.
• About 20% of people will have shingles at some stage in their lives.

There is no sex difference in incidence but women are more susceptible to postherpetic neuralgia (PHN).

PHN and intractable pain increase with age. It affects 27% of untreated adults aged 55 years, 47% of untreated adults aged 60 years and 73% of untreated adults aged 70 years. Pain lasting for more than 1 year occurs in 48% of patients older than 70 years.

Patients might suggest that elderly people should be kept away from children with chickenpox in case they catch shingles. This is a misconception. Chickenpox can rarely be acquired from a patient with active shingles as the lesions shed virus⁶ (transmission is by direct contact or droplet spread) but shingles is not caught from contact with a person with chickenpox.

Risk factors

• Increasing age increases the incidence and morbidity of shingles.
• Incidence and risk are increased in the immunocompromised patient.
• Diseases such as HIV, Hodgkin's lymphoma and bone marrow transplants all have a high risk.
• If anyone presents with shingles affecting more than one dermatome, think of immune system compromise. This also applies to patients younger than 50 years old presenting with the condition.⁷

Presentation

The disease can be divided into the pre-eruptive phase, acute eruptive phase and chronic phase - postherpetic neuralgia (PHN).

Pre-eruptive phase

• In the pre-eruptive phase there is no skin lesion to see but 80% of patients complain of burning, itching or paraesthesia in one dermatome.
• This usually lasts for a day or two but it can be over a week before the characteristic eruption appears.
• The patient may feel unwell with malaise, myalgia, headache and fever but these symptoms may abate as the eruption appears.
• In the pre-eruptive phase the skin may be tender but there are no lesions to see. There may be lymphadenopathy.
• Diagnosis is difficult before the characteristic rash appears.

Eruptive phase

• The eruptive phase is when the skin lesions appear. Most, but not all, adults have acute, neuritic pain in this phase. A few have severe pain without any eruption, called zoster sine herpete. Young adults and children are most likely to be free of pain.
• Crust formation and drying occurs over 7 to 10 days and is followed by resolution at 14 to 21 days.
• Patients are infectious until lesions are dried.
• In the eruptive phase the rash first appears as a patch of erythematous, swollen plaques with clusters of small vesicles. This eruption is virtually diagnostic of shingles. It may not affect the whole dermatome but it will not extend outside it. Hence any rash that crosses the midline is not shingles.
• More vesicles may erupt over the next 5 to 7 days. They form crusts that fall off inside 3 weeks.
• In elderly and immunocompromised patients, the eruptive phase is longer and more extensive. It occasionally results in haemorrhagic blisters, skin necrosis, and secondary bacterial infections.

Chronic phase

• Chronic phase or PHN is persistent or reoccurring pain lasting 30 days or more after the acute infection or after all lesions have crusted.

Variations

Ophthalmic shingles

Synonyms: herpes zoster ophthalmicus (HZO), ophthalmic herpes zoster

• Acute lesions of the orbit or globe develop within three weeks of the onset of the rash. They may resolve swiftly or linger and recur over years.
• Patients may have a red eye, decreased visual acuity, epiphora, photophobia and forehead tenderness.
• Other problems affect various parts of the eye:
  • Lids - bilateral eyelid oedema can develop, giving the erroneous impression of a bilateral problem⁹ as well as blepharitis and ptosis.¹⁰
  • Conjunctiva - giving rise to a follicular conjunctivitis.
  • Episclera and sclera - resulting in inflammation (episcleritis and scleritis).
  • Cornea - keratitis occurs in ~65% of all cases;² multiple features may occur, e.g. multiple small epithelial dendrites (seen after instilling fluorescein), stromal and neurotrophic keratitis, raised mucous plaques and so on. This is one of the sites where significant visual loss can occur.¹⁰
  • Anterior part of the eye - uveitis, paralysis ± atrophy of the iris and secondary glaucoma (about 10% of cases).¹¹
  • Posterior part of the eye - retinitis, choroiditis and optic neuritis.
• Nerve damage can include oculomotor palsies² and neuralgia.
• Tissue scarring can include lid deformities, neuralgia, and lipid keratopathy.

Ramsay Hunt's syndrome

See separate article Herpes Zoster Oticus

• This is caused by zoster of the geniculate ganglion affecting the mandibular division of the facial nerve. Whilst it is a general tenet of shingles that it affects the sensory and not the motor system, this is the notable exception. It may present as a Bell's palsy and it is not until the rash appears that the diagnosis is apparent. Involvement of the auditory nerve can impair hearing or paralysis of the tensor tympani can cause hyperacusis. Vesicular eruptions may appear on the pinna, in the auditory canal, on the tympanic membrane, or occasionally on the hard palate. There may be unilateral loss of taste of the anterior two thirds of the tongue.
• CNS involvement is uncommon in those with normal immunity but it can be devastating.¹² Direct invasion of adjacent structures may occur leading to involvement of the anterior horn neurons, resulting in muscular weakness, cranial nerve palsies, diaphragmatic paralysis, neurogenic bladder, and pseudo-obstruction of the colon. In the absence of a rash, diagnosis can be very difficult.
• The cerebrospinal fluid may have pleocytosis and increased protein content suggestive of CNS inflammation. Some patients may have very mild encephalitis but most have only a headache. Significant meningoencephalitis is rare but has a 20% mortality.

Differential diagnosis

• Before the rash appears the pain may be thought to originate from under that dermatome and so it must be considered as a possible cause of chest or abdominal pain.
• Cluster headaches or migraine - consider in the prodromal phase.
• The Ramsey-Hunt's syndrome may present as Bell's palsy before the rash appears.
• The rash, especially if without pain, may be mistaken for atopic eczema, contact dermatitis, herpes simplex or impetigo. This may lead to this viral infection being treated with steroid cream.
• Consider the differentials of the acute red eye where there is no rash (e.g. conjunctivitis, corneal abrasion, keratitis).
• If you strongly suspect herpes zoster ophthalmicus (HZO), look for a rash or evidence of a previous rash, such as pigmentary changes along the hairline or consider zoster sine herpete.

Investigation³

The diagnosis is usually clinical, based on typical lesions in a single dermatome. Various techniques to detect the virus or antibody detection may be possible after consultation with a microbiologist. Tzanck smears may yield results (although they may not distinguish varicella zoster virus (VZV) from other herpes viruses) but scraping for smears and cultures are usually negative as the viruses are difficult to recover from the scrapes. A direct immunofluorescence assay can be used; it is more sensitive than viral culture and can differentiate herpes simplex viral infections from VZV infections.

Where the presentation is atypical (e.g. a young patient, severe disease or a rash extending beyond one dermatome), the patient needs to be investigated for immunocompetency.

Management

Topical therapy

Although some advocate the use of topical treatment (aciclovir or penciclovir cream and a steroid-antibiotic combination, e.g. Fucidin-H, three times a day), evidence suggests treatment is inadequate compared with oral therapy and adds no further benefit.¹³ As secondary bacterial conjunctivitis is a risk, a better case can be made for antibiotic eyedrops. Warm compresses to the skin may help relieve discomfort.

Oral antiviral therapy

Oral aciclovir has been shown to shorten the duration of signs and symptoms, as well as to reduce the incidence and severity of herpes zoster ophthalmicus (HZO) complications,³ notably post herpetic neuralgia.¹⁴

• The drugs that are used are aciclovir 800 mg five times a day (seven to ten days), valaciclovir 1000 mg three times a day or famciclovir 500 mg three times a day, both for seven days.⁶ (The effectiveness of the second generation antivirals in reducing eye complications is less well studied than with aciclovir but patients may be more likely to comply with the treatment regime).⁸
• Longer and more intense (intravenous) treatments may be required in the elderly and the immunocompromised.³
• Early and effective treatment reduces complications.¹⁵

Management of ocular problems

• Where there is intraocular involvement, various agents are used depending on which tissue is involved. An ophthalmologist should be involved to carry out a detailed assessment and tailor a management plan accordingly.
• Patients may benefit from long-term application of ocular lubricants, and cool compresses are advised for the conjunctivitis in the acute phase. Epithelial defects are sometimes treated with additional chloramphenicol ointment.
• Patients may also require cycloplegics to help pain relief and intraocular pressure-lowering drugs.
• Where there is retinitis, choroiditis or optic neuritis, the patient may need admission for intravenous antivirals.^10,11
• Topical steroids may only be started under ophthalmic supervision (these are beneficial in certain specific cases and harmful in others).
• Where neurotrophic ulcers develop, botulinum toxin administration to produce a protective ptosis may be considered (the effects wear off after about 3 months). Other options available to manage these ulcers include bandage contact lenses, tissue glue and tarsorrhaphy (the lids are sutured together; depending on the type of procedure, this may or may not be irreversible).
• Treatment may go on for many months or even years.
• Corneal scarring may require penetrating keratoplasty (corneal transplant).⁶

Analgesia

It may be necessary to give quite strong analgesia if there is pain. If the pain is severe beyond the moment that the vesicles have crusted over, post-herpetic neuralgia has probably developed (see 'Postherpetic neuralgia', below).³ Do not treat corneal pain with topical anaesthetics - these are toxic to the cornea. A combination approach may be required, especially in the elderly.¹⁹

Referral¹

• Refer all patients with a red eye or reduced visual acuity within the same day or, at the very latest, the next morning.
• If the eye is not red but Hutchinson's sign is present, refer the patient to be seen within one to two weeks, as there is a high risk of eventual ocular involvement.
• Refer patients within cranial nerve palsies within one to two weeks.
• Any patient with known immunodeficiency (including those with organ transplants and patients on systemic immunosuppression or chemotherapy) should be seen by physicians in an infectious disease unit.
• More severe disease, recurrence or multiple dermatomal involvement should raise suspicions of underlying immunosuppression; actively look for causes. Consider HIV in patients under 65 years of age.²⁰
• Patients with extensive associated cellulitis need to be admitted for intravenous antibiotics.
• Patients with more severe or persistent neuralgia should be referred early to a pain clinic before the condition becomes chronic.

Complications

General complications

• Bone marrow recipients with visceral dissemination have a mortality rate of approximately 10%.
• Morbidity associated with postherpetic neuralgia (PHN) increases with age.
• Haematogenous dissemination to the viscera occurs in 1 or 2% of immunocompetent patients but is more frequent in immunocompromised patients.

Complications of ophthalmic shingles

• Ocular complications occur in 50% of cases. Of these, pain occurs in 93% of these patients and is still present at 6 months in 31%. Of those affected, anterior uveitis occurs in 92% and varieties of keratitis in 52%. At 6 months, 28% of involved eyes have long-term disease, with chronic uveitis, keratitis, and neuropathic ulceration being the most common.²¹
• Lid complications include ptosis, trichiasis, scarring of the skin and madarosis (loss of lashes).
• Rare ocular complications include optic neuritis, retinitis and ocular cranial-nerve palsies. There is a complete or near resolution of ophthalmoplegia in about 65% of cases.²² Sight is threatened by neuropathic keratitis, perforation, secondary glaucoma, posterior scleritis, optic neuritis, and acute retinal necrosis. Neurological complications are rare (one series reported this in 5.5% of patients) with meningoencephalitis being noted in a few patients.²³
• Long-term complications may be related to poor sensation of the cornea and poor motor function of the eyelid. This may put the eye at risk during episodes of impaired consciousness. There is risk of neuropathic ulceration and exposure keratopathy. There is also a risk of complications common to the disease elsewhere, like PHN. The risk of long-term problems is such that it is recommended that a history of ophthalmic herpes zoster should remain in the problems section of the medical record. There is a 6 to 14% chance of recurrence.⁸
• Permanent sequelae of ophthalmic zoster infection may include chronic ocular inflammation, loss of vision, and debilitating pain.¹⁰ Gradual clouding of the cornea may occur.

Postherpetic neuralgia

See related article Post herpetic neuralgia.

This constant or intermittent pain occurs in about 7% of patients and is said to have occurred if pain persists beyond 3 months.¹⁰ Although it does generally improve with time, it may go on for months or years and, in some unfortunate individuals, indefinitely. It can also be refractory to treatment. In severe cases, it can lead to depression and even suicidal ideation. It is described as a deep, burning or aching pain, paraesthesia, dysaesthesia, hyperaesthesia, or electric shock-like pains. Referral to a pain clinic is appropriate in severe or recalcitrant cases.

The most important risk factor for PHN is age. At age 60, approximately 60% of patients with shingles develop PHN, and at age 70, 75% develop PHN. The affected area may show evidence of scarring and sensation may be different. The risk is greatest in the trigeminal area, especially the ophthalmic division.

A systematic review²⁴ of the treatment of established PHN found that no single best treatment is known:

• In the first instance, skin hypersensitivity can be addressed with a protective layer over the skin (if possible) and cool compresses may help with pain, alongside paracetamol alone or with codeine. Capsaicin cream 0.025%-0.075% four times a day, after skin lesions have healed, may help but about 30% of these patients report a burning sensation or erythema.²
• Low-dose tricyclic antidepressants (e.g. amitriptyline, imipramine or nortriptyline) or antiepileptics (e.g. gabapentin or carbamazepine) may then be offered according to the patient's medical background. Doses are titrated upwards according to effect.
• These are effective for alleviating pain but long-term, clinically meaningful benefits are uncertain and side-effects are common.
• If pain is refractory to these therapies there may be benefit from intrathecal methylprednisolone.²⁵
• Little evidence is available regarding treatment of PHN of less than 6 months' duration.
• Although an RCT found benefit from administration of amitriptyline from the onset of shingles,²⁶ instead of waiting for the neuralgia, it has been criticised as being of poor quality, as there was no control about the simultaneous administration of antiviral therapy.

Prognosis

• The prognosis for younger and otherwise healthy patients is excellent.
• Pregnant women and immunosuppressed patients have the highest risk of serious sequelae.
• Elderly people have a significantly increased risk of complications, including postherpetic neuralgia (PHN), bacterial infections, and scarring.
• Immune compromise carries poorer prognosis.

Prevention

In the USA, vaccination against chickenpox has become routine and cases have dropped by 80%. It is a very effective vaccine.²⁷ It reduces the incidence of herpes zoster in children with leukaemia.²⁸ In the UK, a vaccine is available to at-risk groups, including those who are not immune but work in a setting where they may be infected.

There are two causes of concern about vaccination in the UK. One is that immunisation of children may result in a susceptible adult population later on and, if adults contract the wild disease, it is far more serious than in children. The other is concern that there may be a temporary increase in the incidence of shingles.²⁹ In view of these concerns, current policy is to wait and see what happens elsewhere, especially in the USA where immunisation has been routine for a number of years.³⁰

Document references

1. Lam FC, Law A, Wykes W; Herpes zoster ophthalmicus. BMJ. 2009 Aug 13;339:b2624. doi: 10.1136/bmj.b2624.
2. Jackson TL; Moorfields Manual of Ophthalmology, Mosby (2008)
3. Diaz MM et al, Herpes Zoster Ophthalmicus, Medscape, March 2011
4. Ragozzino MW, Melton LJ 3rd, Kurland LT, et al; Population-based study of herpes zoster and its sequelae. Medicine (Baltimore). 1982 Sep;61(5):310-6. [abstract]
5. Burke BL, Steele RW, Beard OW, et al; Immune responses to varicella-zoster in the aged. Arch Intern Med. 1982 Feb;142(2):291-3. [abstract]
6. Denniston AKO, Murray PI. Oxford Handbook of Ophthalmology (OUP), 2008
7. Gurwood AS, Savochka J, Sirgany BJ; Herpes zoster ophthalmicus. Optometry. 2002 May;73(5):295-302. [abstract]
8. Opstelten W, Zaal MJW; Managing ophthalmic herpes zoster in primary care. BMJ 2005;331(7509):147.
9. Kanski J. Clinical Ophthalmology, A Systematic Approach, 5th Ed, Butterworth Heinemann (2003)
10. Shaikh S, Ta CN; Herpes zoster ophthalmicus, American Family Physician, November 2002; comprehensive text and pictures
11. Kunimoto DY, Kanitkar KD, Makar MS; The Wills Eye Manual, 4th Edition, Lippincott, Williams and Wilkins (2004)
12. Flamholc L; Neurological complications in herpes zoster. Scand J Infect Dis Suppl. 1996;100:35-40. [abstract]
13. Neoh C, Harding SP, Saunders D, et al; Comparison of topical and oral acyclovir in early herpes zoster ophthalmicus. Eye. 1994;8 ( Pt 6):688-91. [abstract]
14. Tyring S, Barbarash RA, Nahlik JE, et al; Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med. 1995 Jul 15;123(2):89-96. [abstract]
15. Severson EA, Baratz KH, Hodge DO, et al; Herpes zoster ophthalmicus in olmsted county, Minnesota: have systemic antivirals made a difference? Arch Ophthalmol. 2003 Mar;121(3):386-90. [abstract]
16. Shingles, Clinical Knowledge Summaries (2008)
17. Alper BS, Lewis PR; Treatment of postherpetic neuralgia: a systematic review of the literature. J Fam Pract. 2002 Feb;51(2):121-8. [abstract]
18. Whitley RJ, Weiss H, Gnann JW Jr, et al; Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med. 1996 Sep 1;125(5):376-83. [abstract]
19. Bajwa ZH, Ho CC; Herpetic neuralgia. Use of combination therapy for pain relief in acute and chronic herpes zoster. Geriatrics. 2001 Dec;56(12):18-24. [abstract]
20. Yoganathan K; Herpes zoster ophthalmicus. Don't forget HIV. BMJ. 2009 Sep 14;339:b3621. doi: 10.1136/bmj.b3621.
21. Harding SP; Management of ophthalmic zoster. J Med Virol. 1993;Suppl 1:97-101. [abstract]
22. Sanjay S, Chan EW, Gopal L, et al; Complete unilateral ophthalmoplegia in herpes zoster ophthalmicus. J Neuroophthalmol. 2009 Dec;29(4):325-37. [abstract]
23. Srinivasan S, Ahn G, Anderson A; Meningoencephalitis-complicating herpes zoster ophthalmicus infection. J Hosp Med. 2009 Jul;4(6):E19-22. [abstract]
24. Alper BS, Lewis PR; Does treatment of acute herpes zoster prevent or shorten postherpetic neuralgia? J Fam Pract. 2000 Mar;49(3):255-64. [abstract]
25. Kotani N, Kushikata T, Hashimoto H, et al; Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med. 2000 Nov 23;343(21):1514-9. [abstract]
26. Bowsher D; The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage. 1997 Jun;13(6):327-31. [abstract]
27. Vazquez M, LaRussa PS, Gershon AA, et al; The effectiveness of the varicella vaccine in clinical practice. N Engl J Med. 2001 Mar 29;344(13):955-60. [abstract]
28. Hardy I, Gershon AA, Steinberg SP, et al; The incidence of zoster after immunization with live attenuated varicella vaccine. A study in children with leukemia. Varicella Vaccine Collaborative Study Group. N Engl J Med. 1991 Nov 28;325(22):1545-50. [abstract]
29. Welsby PD; Chickenpox, chickenpox vaccination, and shingles. Postgrad Med J. 2006 May;82(967):351-2. [abstract]
30. Edmunds WJ, Brisson M; The effect of vaccination on the epidemiology of varicella zoster virus. J Infect. 2002 May;44(4):211-9. [abstract]

Internet and further reading

• Shingles, Clinical Knowledge Summaries (2008)
• Post Herpetic Neuralgia, Clinical Knowledge Summaries (2008)
• Wareham DW, Breuer J; Herpes zoster. BMJ. 2007 Jun 9;334(7605):1211-5.
• Moon JE, Hospenthal DR; Herpes Zoster. eMedicine, November 2009.
• McElveen WA et al, Postherpetic Neuralgia, Medscape, Jul 2010