Zoster sine herpete (ZSH) is one of the atypical clinical manifestations of herpes zoster (HZ) [1,2]. ZSH and HZ are both induced by reactivation of the neurotropic varicella-zoster virus (VZV) [3,4]. VZV infection and reactivation in the nervous system, such as cranial nerve and spinal nerve, can spread to the innervated target tissue (skin, cornea, laryngeal mucosa, etc.) and cause rash (shingles) eruption. Once the shingle appears, the diagnosis of HZ is apparent from its clinical manifestation. Unfortunately, VZV reactivation does not always cause shingles, and can occur in the enteric nervous system, such as the viscera or autonomic nerve, which do not project to the skin. This kind of reactivation with no shingles after the initial VZV infection is called ZSH [5].

ZSH is likely to be missed or misdiagnosed, and patients may not receive timely antiviral treatment. This causes continuous activation of the VZV, which may induce lasing herpetic neuralgia, and even postherpetic neuralgia (PHN) if much damage was cause to the affected nerves [6]. More seriously, continuous VZV reactivation can lead to fatal sequelae such as encephalitis, cerebrovasculopathy, and stroke [7,8]. The literature about ZSH manifestations, especially the diagnosis of ZSH with VZV reactivation, are reviewed in this article.

At present, there is no epidemic data about ZSH. However, considering the high infection rate of VZV, and the epidemiology of HZ and PHN in populations, the incidence of ZSH cannot be low.

In America, there are almost one million cases of HZ each year, with an annual rate of 0.3% to 0.4% [9,10]. In China, the prevalence of HZ is 7.7% in hospital patients aged ≥ 40 years [11]. In the old (≥ 50 yr), immunocompetent, unvaccinated population, the HZ incidence rate was ~10/1,000 person-years [12]. In North America and Europe, more than 95% of young adults are positive for the VZV, which means they are at risk for ZSH and HZ [13]. Of note, the incidence of HZ is expected to increase in the future because of the gradually aging world, and developments of medicine (e.g., immunosuppressive agents) [14,15]. Therefore, ZSH is very likely underreported and underrated, which may be the reason of some neuropathic pain of unknown origin.

VZV, the pathogen of ZSH and HZ, is transmitted by direct contact or by inhalation of aerosols from vesicular fluid or infected respiratory tract secretions [9]. The VZV can travel retrogradely along sensory neuron fibers to the spinal dorsal root ganglion or cranial ganglion and stay dormant [16]. When the VZV-specific immunity decreases, the latent virus in the ganglions reactivates, replicates, and then various HZ or ZSH symptoms appear [4]. Many factors affecting cellular immunity may cause the reactivation of the VZV [17]. These risk factors for VZV reactivation include: old age, cellular immunodeficiency, genetic susceptibility, trauma, systemic diseases (such as diabetes, kidney disease, fever, hypertension, etc.), mental stress, fatigue, and so on [18-20].

The specific mechanisms of VZV reactivation are not fully understood [21]. VZV-specific memory T cells are present after the initial recovery from VZV infection. However, as time goes by, the immune function of memory T cells declines. When it falls below the theoretical “zoster threshold”, the risk of ZSH or HZ increases accordingly [22]. After being recognized by its recognition receptors, the VZV activates the signaling in the body and induces the gathering of inflammatory cells to combat the VZV, and indirectly activates T cells, which jointly cause the damage of skin and nerve tissues, and result in neuralgia and other symptoms of ZSH or HZ [23].

Evidence suggests that persistent radicular pain from ZSH can be caused by chronic activation of the VZV and ganglionitis. In a patient who had experienced chronic trigeminal neuralgia for more than 1 year, the trigeminal ganglionic mass was removed and the pathological and virological analyses discovered active VZV ganglionitis [24]. In another study, active VZV ganglionitis was found in the trigeminal ganglia of a patient who experienced chronic trigeminal neuralgia for months before death [25]. Using human dorsal root ganglia xenografts in immunodeficient mice, Zerboni and Arvin [26] demonstrated VZV replication in mechanoreceptive neurons; They also found that the VZV in the dorsal root ganglia triggers release of pro-inflammatory cytokines that cause neuronal damage. These findings may help to explain the neurologic sequelae in ZSH, HZ, and PHN patients.

Evidence indicates that VZV infection and reactivation are more common than previously realized. VZV reactivation, displaying no cutaneous vesicles, has been demonstrated in 8% to 25% of patients with acute peripheral facial palsy by serological examination [27]. The VZV latency and reactivation in neurons, including those of the enteric nervous system that do not project to the skin, can cause serious and variable ZSH clinical features [28]. ZSH patients not only complain of different kinds of neuropathic pain, but also display lesions at hidden places other than the skin, as well as various manifestations of nerve injury [29,30].

As early as 1958, Lewis [5] proposed a diagnosis method of ZSH in patients with radicular pain in the skin, based on a variety of syndromes: (1) unilateral segmental pain of a sclerotomal or dermatomal type, or both, with complete recovery in a few weeks; (2) certain painful unilateral muscular paresis of obscure origin; (3) unilateral segmental pain associated with certain visceral disturbances of short duration and complete resolution; (4) unilateral ophthalmic neuralgia with involvement of the eyeball, or with paresis of the ocular muscles, or both; (5) unilateral otalgia without evidence of middle-ear disease and associated with facial palsy, hyperacousis, or loss of taste sensation on the anterior two-thirds of the tongue; (6) cases presenting as an acute labyrinthitis, or Menier’s syndrome, with evidence of the involvement of adjacent nerves, particularly the seventh cranial nerve; (7) unilateral paralysis of the soft palate, pharyngeal muscles, or vocal cord of obscure origin, especially when associated with otalgia or with an inflammatory reaction in, or around, the entrance to the larynx.

Symptoms and signs of ZSH can be covert, and ZSH should be considered in patients with a history of radicular pain, peripheral facial palsy, or muscle paralysis without a rash, especially when other causes are excluded. For example, ZSH of the trigeminal nerve should be considered in patients with neuropathic pain in the trigeminal nerve innervating area, if they do not demonstrate other appreciable findings such as tumor or HZ [34]. A high level of suspicion of ZSH is needed for prompt diagnosis and treatment in undiagnosed patients with neuropathic pain, especially in immunosuppressed patients, and it is very necessary to take a thorough medical history including recurrent pain and recent use of medications.

Diagnosis with symptom alone may lead to misdiagnosis, and thus it is necessary to find evidence of VZV reactivation to diagnose ZSH, which primarily depends on laboratory investigation [6]. Several kinds of approaches are available to confirm VZV infection. For a while, the “gold standard” for VZV infection detection was virus isolation, which is costly and time consuming. In addition, the VZV is a labile virus, so cultures can fail in VZV infected patients. Therefore, VZV isolation is rarely used for confirming infection today [39]. At present, there are two widely used methods to detect VZV reactivation: VZV DNA detection with polymerase chain reaction (PCR), and an enzyme linked immunosorbent assay (ELISA) examination of anti-VZV antibodies, i.e., anti-VZV immunoglobulin (IgG and IgM) (Table 1).

Because of VZV reactivation, ZSH can cause many neurological diseases [29,49,60]. In fact, more and more neurological disorders have been found to be associated with VZV reactivation in ZSH. Some of them are even fatal, especially when VZV reactivation and invasion take place in the central nervous system.

HZ vaccine is a major breakthrough for the prevention of HZ. It should be able to effectively reduce ZSH and complications such as PHN caused by HZ and ZSH. In 2006, zoster vaccine live (Zostavax) has been recommended for those ≥ 60 years old, who have no contraindications, and in 2011, the indication has been extended to everyone ≥ 50 years [70]. The other zoster vaccine Shingrix, a subunit vaccine containing VZV glycoprotein-E and the AS01B adjuvant, was approved by the Food and Drug Administration for adults ≥ 50 years old in 2017 [71]. Since the advent of these vaccines, it was reported that the burden of HZ in the United States has begun to dissipate [72].

Due to very limited literature and lack of random control trial studies of ZSH treatment, there are no guidelines about the treatment of ZSH at present. Once the diagnosis is established, it is reasonable to treat it with an antiviral agent (acyclovir or vacyclovir) combined with pain management (e.g., intercostal nerve block) and specialized treatment for various sequelae [1]. Furuta et al. [52] achieved a 100% cure rate of 13 facial palsy patients with ZSH after acyclovir-prednisone treatment. If no special sequela displayed, the treatment for ZSH can be the same as that for HZ [34]. The main purposes of HZ and ZSH treatment including pain relief, rapid healing, and avoiding sequela. Once a diagnosis is made, to reduce the intensity of acute pain and the duration and severity of reactivation, antivirals should be started as soon as possible [73]. Aciclovir, valaciclovir, or famciclovir can be used as the antiviral agents. Non-steroidal anti-inflammatory drugs, tramadol, opioids, ligands of the α2δ subunit of the calcium channel (gabapentin or pregabalin), tricyclic antidepressants, or corticosteroids can be used to relieve herpetic neuralgia [73]. Other kinds of therapy include local management of skin lesions, epidural neural blockade, and traditional Chinese medicine [74]. Of note, in order to reduce the replication of VZV and the subsequent neuropathological damage, ZSH should be treated as soon as possible [75].

PHN also requires timely and active treatment when it is diagnosed. PHN should be considered and treated according to PHN guidelines [76] for patients with recurrent neuralgia at the same site. Long-term PHN torment can lead to complications such as anxiety and depression [77,78], and can cause structural and functional abnormalities in the brain of PHN patients [79-81].

ZSH, a special form of VZV reactivation, often leads to misdiagnosis due to the lack of typical clinical manifestations. ZSH should be considered in patients with unilateral, single-root neuralgia and diagnosed with VZV DNA and/or anti-VZV IgG/IgM. As one sequela of ZSH, PHN should be considered and treated in patients with recurrent neuralgia in the same site. Accurate diagnosis method, timely antiviral therapy, more ZSH related studies and guidelines will be beneficial for ZSH diagnosis and treatment.