Definition

Varicella-zoster virus is a lipid-enveloped, double-stranded DNA herpesvirus that coevolved with ancestral primates for more than 70 million years [1]. It expresses its genes sequentially, leading to expression of nonstructural proteins, nonstructural protein enzymes, and late structural proteins [2]. Late structural proteins encapsulate the DNA core, infect host cells, and replicate in host cell nuclei.

Acute varicella-zoster infection is the initial activation of the virus manifested with a diffuse pruritic, vesicular rash. This is commonly known as chickenpox. Two viremic phases are thought to occur in acute zoster infection. Animal studies suggest that the first viremia occurs in regional lymph nodes and viscera, approximately 5 days after exposure [3]. The second viremia, approximately 14 days after exposure, promotes viral spread to the nasopharynx and the skin, causing the hallmark rash [4]. The virus usually infects children and spreads by aerosol droplets and skin-to-skin exposure to the vesicles, which contain large amounts of virus.

Herpes zoster, or shingles, is the reactivation of latent varicella-zoster virus. After acute herpes zoster infection, the virus remains dormant and resides in sensory ganglia, including the dorsal roots and cranial nerves [5]. Reactivation generally results from immunocompromised states such as stress, disease, or advanced age. The virus typically migrates along dermatomes, manifesting as a painful rash. The virus may spread to the spinal sensory nerves, dorsal horn, or cranial nerves. It is a painful condition with a highly age-related incidence, affecting about 50% of individuals who survive to the age of 85 years [6]. It affects men and women equally. Involvement of motor nerves is extremely rare.

Postherpetic neuralgia is pain persisting in affected dermatomes despite resolution of the rash. Although the timeline may be variable, many define postherpetic neuralgia as persistent pain 4 months or more after resolution of acute herpes zoster [7]. The likelihood for development of postherpetic neuralgia increases with older age, female sex, presence of a prodrome, greater rash severity, and greater acute pain severity [8]. It is the most common complication after an acute episode of shingles.

Symptoms

Prodromal symptoms may precede varicella-zoster reactivation by a few days up to 1 week. These include low-grade fever and malaise with hyperesthesia, dysesthesia, paresthesia, or pruritus along the distribution of affected dermatomes.

Fulminant shingles is marked by the emergence of erythematous macules accompanied by severe burning, stinging pain in a single sensory or cranial nerve distribution. This is followed by the eruption of fluid-filled papules, clusters, and vesicles. New skin eruptions generally continue to appear for 3 to 5 days. Thoracic dermatomes are most frequently affected. During this period, prodromal low-grade fever and malaise may continue to persist, and lymphadenopathy may also be present.

Zoster affecting exposed areas may result in sun or wind sensitivity. Sensitivity to light touch, intolerance to wearing of clothes over the erupted area, and brief jolts of shooting pain are also common.

Of the cranial nerves, the ophthalmic branch of the trigeminal nerve is the most often affected. If there is ophthalmic involvement, photophobia may be present. This is known as herpes zoster ophthalmicus and can result in monocular blindness. It has an incidence of 1% in the general population [9].

In very rare cases, zoster of the geniculate ganglion occurs, affecting the seventh and eighth cranial nerves. Symptoms include otalgia, vertigo, tinnitus, ataxia, loss of hearing, loss of taste, and even ipsilateral facial paralysis. This is known as Ramsay Hunt syndrome (herpes zoster oticus).

In most cases, symptoms tend to resolve shortly after healing of the rash. However, in more than 25% of patients, neuralgia persists for longer than 1 month after resolution of the rash [10]. This pain is commonly described as sharp, burning, aching, or shooting and may be accompanied by allodynia and hyperalgesia.

Physical Examination

In shingles, typical skin eruptions follow a dermatomal distribution, appearing as raised, fluid-filled vesicles. Once the vesicles burst and release fluid that contains live virus, they crust. Once the vesicles have crusted, the patient is no longer infectious. Lesions are often exquisitely tender to light touch. If deeper dermal involvement is present, scarring and discoloration may be seen.

Ophthalmic zoster is usually accompanied by a rash in the dermatomal distribution of the nasociliary nerve, along the side of the nose (Hutchinson sign). Periorbital edema, petechial hemorrhages, conjunctivitis, scleritis, and corneal sensitivity are also commonly associated with ophthalmic zoster [9]. Hutchinson sign and an unexplained red eye are indications for ophthalmologic consultation.

Ramsay Hunt syndrome is manifested as a rash on the auricle and external ear accompanied by exquisite otalgia, vestibulocochlear dysfunction, and facial nerve palsy. Any suspicion for Ramsay Hunt syndrome should lead to an urgent otolaryngology consultation.

With postherpetic neuralgia, there are no visible skin abnormalities on inspection. However, the patient may describe allodynia or hyperalgesia on even very gentle palpation.

Functional Limitations

Functional limitations due to herpes zoster include difficulty with activities involving pressure or heat exposure to the affected area. If the facial divisions of the trigeminal nerve or areas by the ear are affected, individuals may not tolerate wearing of protective headgear or facemasks and facial exposure to sun or wind. If the thoracic dermatomes are affected, clothing or even touching of the back against an office chair may increase pain. Both sex and contact sports may be intolerable. Difficulty in sleeping may arise from discomfort from sheets touching the skin. Bathing and toweling often exacerbate pain along the affected dermatome.

If the optic nerve or the ophthalmic branch to the trigeminal nerve is affected by shingles, monocular low vision may result in impaired depth perception and decreased field of view. If the patient has herpes zoster oticus, hearing, balance, tasting, and facial muscle movements are impaired. Thus, driving may be affected by zoster involvement of the trigeminal nerve or the geniculate ganglion.

Diagnostic Studies

Zoster is usually easy to diagnose on the basis of history and physical examination. In general, laboratory tests for diagnosis of reactivation of herpes zoster virus are not clinically useful [11]. For atypical cases, the Centers for Disease Control and Prevention guidelines suggest direct fluorescent antibody testing for rapid diagnosis [10]. To obtain a specimen, apply a sterile cotton swab to the base of an open lesion or, less preferably, a lesion crust.

Prevention is important in this condition. Varicella vaccination in childhood is primary prevention for chickenpox. Zoster vaccination, recommended by the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices for people 60 years of age or older [12], prevents herpes zoster reactivation as shingles. In a randomized double-blind placebo-controlled trial of the zoster vaccine, there was reduction of herpes zoster incidence by 51.3% and postherpetic neuralgia incidence by 66.5% [13]. However, there is still insufficient evidence for vaccination in the long-term prevention of postherpetic neuralgia [14].

If given within 72 hours of symptom onset, antiviral medication with oral acyclovir, valacyclovir, or famciclovir has been shown to relieve acute zoster pain and shorten rash duration, although there is no consistent evidence that it reduces the incidence of postherpetic neuralgia [15].

For patients with immunocompromise or malabsorption, the intravenous route of antiviral medication delivery is preferred to the oral route. There is limited evidence that a course of intravenous followed by oral antiviral treatment reduces pain in patients with postherpetic neuralgia of more than 3 months’ duration [19].

Topical therapies that are approved by the Food and Drug Administration for postherpetic neuralgia include lidocaine and capsaicin. Lidocaine is available both as a 5% patch and in a gel cream form. A double-blind placebo-controlled efficacy and safety study with lidocaine patch has shown improvements in pain, allodynia, quality of life, and sleep measures [20,21].

Topical capsaicin is an extract of hot chili peppers that works as an agonist of the vanilloid receptor TRPV1. Capsaicin is available as an 8% patch and as different cream formulations. A small randomized double-blind controlled study with capsaicin showed a decrease in the numerical pain rating scale scores of patients by 33.8% compared with a 4.9% increase in controls [22]. Application of capsaicin should lead to desensitization of the unmyelinated epidermal nerve fibers and reduced hyperalgesia with repeated applications.

Other topical treatments that have been studied include topical aspirin, indomethacin, and diclofenac [23