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]. These have not been well studied and are not widely used in clinical practice.

Oral medications effective in treating postherpetic neuralgia include antiepileptic drugs, antidepressants, and opioid analgesics. The anticonvulsants gabapentin and pregabalin are approved by the Food and Drug Administration for treatment of postherpetic neuralgia. Both gabapentin and pregabalin are calcium channel ligands. Gabapentin can provide statistically significant improvement in daily pain rating, sleep, mood, and quality of life for patients with postherpetic neuralgia [24,25]. Pregabalin acts like gabapentin and is similarly useful in postherpetic neuralgia [26–28].

Whereas amitriptyline has been most studied, secondary amine tricyclics such as nortriptyline are usually preferred because of the side effect profile [28–30].

Use of opioids and opioid-like analgesics including tramadol, oxycodone, morphine, and methadone can also reduce severe pain in postherpetic neuralgia [31–33]. Use of opioids and opioid-like analgesics requires caution and close monitoring for side effects and medication abuse.

There are a number of guidelines for treatment of postherpetic neuralgia, with slight variations in recommended protocols [10,34,35]. Most would consider topical lidocaine, tricyclic antidepressants, and gabapentin or pregabalin first-line agents. Topical capsaicin, tramadol, and opioid analgesics are second- or third-line therapies [34,35]. Combination therapy may provide superior pain management while minimizing medication side effects [36,37].

Rehabilitation

Ultrasound may be effective in relieving acute zoster pain. In a clinical trial of acute zoster pain, more than 80% of participants receiving ultrasound were pain free at the end of the treatment compared with 46% in the placebo group [38]. The treatment parameters used in areas adjacent to the vertebral column were 1 MHz frequency, 25% pulsed cycle, applied for 1 minute per effective radiating area of the transducer at 0.8% W/cm² intensity and around the periphery of the vesicles at 0.5 W/cm².

Transcutaneous electrical nerve stimulation (TENS) is a widely used nonpharmacologic treatment thought to reduce nociception from small delta fibers and nonmyelinated fibers by stimulating larger, myelinated afferent nerve fibers, although its exact mechanism of action is still not well understood [39]. When TENS was applied to the second digit compared with the third and fifth digits in patients with carpal tunnel syndrome, fMRI showed temporarily decreased pain-related cortical activation [40]. When applied to the superficial radial nerve in healthy volunteers, TENS was found to increase the heat pain threshold [40a]. In a small RCT, patients with postherpetic neuralgia receiving a combination of TENS and oral pregabalin reported superior pain relief compared with those receiving a combination of sham TENS and pregabalin [40b]. In another combination therapy RCT, patients with postherpetic neuralgia reported significant pain reduction from baseline after receiving 8 weeks of TENS combined with local cobalamin injection [40c]. In summary, although there is theoretical support for TENS as a treatment for neuropathic pain and it has been recently studied in combination with other drugs, there is a need for studies comparing TENS alone against placebo in patients with postherpetic neuralgia. Although there is no consensus about voltage, pulse duration, or pulse frequency, TENS is thought to be most effective when applied at the maximum setting that is not uncomfortable.

Desensitizing treatments, such as alternating exposure to heat and cold, vibration, and repeated light tapping of the affected area, may be helpful but are not well studied.

In cases of ophthalmic involvement, occupational therapists can instruct in scanning techniques for low vision and decreased peripheral vision. If the geniculate ganglion is affected, occupational therapists may work on techniques for hearing impairment or vestibulocochlear dysfunction. Occupational therapists can also assist with fall risk reduction, such as by removal of loose rugs, improvement in lighting, and decrease of clutter in the home and work environment.

Other practical measures to improve function include rearrangement of workstations to reduce contact of sensitive areas with seat backs and armrests, use of low-friction fabrics such as silk, use of a hand-held showerhead to direct water flow away from painful dermatomes, and modification of sexual positions.

Procedures

Subcutaneous botulinum toxin injection has been successful in relieving postherpetic neuralgia pain in two small randomized, double-blind, placebo-controlled studies [41,42]. One study not only showed decreased pain, but patients who received botulinum toxin also had improved sleep and reduced opioid use compared with subcutaneous 0.5% lidocaine and placebo with 0.9% saline [42].

Retrospective studies on the effect of sympathetic nerve blocks have reported reduced duration of acute herpes zoster pain as well as short-term improvement with postherpetic neuralgia. However, the long-term effect of sympathetic nerve block in postherpetic neuralgia has not been established [43, 43a].

Paravertebral injection of bupivacaine and methylprednisolone may be helpful as adjuvant therapy to conservative management. A randomized study of 132 herpes zoster patients compared standard therapy of oral antivirals and analgesics or standard therapy with adjuvant paravertebral injections. The incidence of postherpetic neuralgia was 2% in the intervention group compared with 16% with standard treatment [44].

Epidural injection of steroids may provide modest, short-term pain relief in postherpetic neuralgia. In a randomized, controlled trial of 598 patients receiving standard oral antiviral and analgesic therapy with and without epidural steroid injection, the injection of bupivacaine and methylprednisolone was found to have a modest effect in reducing the pain of postherpetic neuralgia for 1 month but did not prevent long-term postherpetic neuralgia [45].

Intrathecal administration of methylprednisolone and lidocaine has led to significant decrease in pain intensity and area in a randomized trial of 277 patients with intractable postherpetic neuralgia. Patients in the intrathecal steroid group also had decrease in nonsteroidal anti-inflammatory drug use [46].

Other interventions, such as greater occipital nerve block, deep cervical nerve blocks, stellate ganglion blocks, and Jaipur block with subcutaneous lidocaine, bupivacaine, and methylprednisolone, have occasionally improved symptoms in case reports and observational studies [47–50]. The effects of cryotherapy, percutaneous nerve stimulation, and radiofrequency have not been well established. Spinal cord stimulation may be of benefit in medically complicated patients with multiple drug sensitivities, polypharmacy, and serious comorbid conditions [51]. Although these interventions have not been adequately studied, they may have some efficacy in treatment of recalcitrant postherpetic neuralgia symptoms.

Surgery

Surgery is not indicated for postherpetic neuralgia.

Potential Disease Complications

Acute optic neuritis from ophthalmic zoster may lead to permanent loss of vision, usually due to virus-induced impairment in retinal perfusion, leading to retinal necrosis. Retinal necrosis generally occurs in severely immunocompromised patients [52].

Herpes zoster ophthalmicus has also been associated with orbital apex syndrome, an inflammation of the oculomotor nerve thought to be related to secondary vasculitis within the orbital apex. This syndrome can cause impaired eye motility and often is manifested as dysconjugate gaze and diplopia.

Similarly, Ramsay Hunt syndrome may lead to permanent facial nerve paralysis and vestibulocochlear dysfunction.

Potential Treatment Complications

Topical lidocaine is generally well tolerated with only mild to moderate localized skin reactions reported [21]. However, topical capsaicin may cause greater local skin reaction including redness, burning pain, and itching [22].

The most common side effects of gabapentin and pregabalin are dizziness and somnolence. All tricyclic antidepressants may cause fatigue or sedation, dizziness, dry mouth, blurry vision, constipation, urinary retention, orthostatic hypotension, and QT prolongation or cardiac arrhythmias. Side effects of opioids and opioid-like analgesics include typical narcotic medication adverse effects of nausea, diarrhea, and constipation.

Gastrointestinal, hepatic, and renal complications may arise from prolonged use of acetaminophen, antiviral medications, or nonsteroidal anti-inflammatory drugs.

All interventional procedures carry a risk of pain, infection, and bleeding. Sympathetic nerve blocks may also cause hypotension, bradycardia, unintentional motor blockade, and neuropathic deafferentation pain. Epidural injections and paravertebral injection may result in hematoma or abscess formation. Complications of intrathecal methylprednisolone include hypotension, nerve root irritation, arachnoiditis, transverse myelitis, and chemical meningitis.

Spinal cord stimulation adverse effects include infection, dural puncture, pain from stimulator component, equipment failure, and dislocation. These may require reoperation or removal procedures.