Annals of Long-Term Care: Clinical Care and Aging. 2016;24(1):31-34.
Received June 6, 2014; accepted September 2, 2015.
Iris Tio-Matos MD
Puget Sound Health Care System
9600 Veterans Drive SW, A-182-GEC
Tacoma, WA 98493
The authors report no relevant financial relationships.
1Geriatrics and Extended Care Service,VA
2Puget Sound Health Care System, American Lake Division, Tacoma, WA
The authors would like to acknowledge the work of George R. Merriam, MD, who served as an advisor to both authors.
Zoster sine herpete is a less frequent presentation of the Varicella zoster virus. Varicella zoster virus is the common agent for varicella (chickenpox); after years of dormancy, the virus may reactivate, causing shingles. This occurs with increasing frequency in older adults. Zoster sine herpete presents with severe pain in a dermatomal distribution, but it does not involve the appearance of a painful herpetiform rash. As such, diagnosing this condition can pose a challenge. Even without the presence of a rash, post-herpetic neuralgia is the most common complication, and the chronic pain can lessen patients’ overall quality of life. The authors present the case of an 89-year-old woman with prolonged pain located over her right hemithorax that was irritated by touching the area. After a number of misdiagnoses, the woman was confirmed to have zoster sine herpete. Tactics for treatment and prevention are also discussed.
Key words: zoster sine herpete, shingles, varicella zoster virus, herpes zoster vaccine
Varicella zoster virus (VZV) is an alpha herpes virus that causes epidemic varicella (chickenpox), most commonly in preschool and school aged children. After the primary infection, VZV remains latent in the ganglia of cranial, dorsal root, and autonomic nerves along the entire neural axis. Cell-mediated immunity prevents reactivation for many years, but, as immunity declines with age, VZV may reactivate, causing zoster sine herpete, otherwise known as shingles. The exact mechanism of VZV reactivation is not completely understood, but it is thought to be a result of the gradual decline in T-cell–mediated immunity associated with aging.1 Studies of simian models suggest that VZV latency and reactivation are probably regulated by changes in the innate immune response involving cytokines and/or chemokines.1
The incidence of shingles in the United States is only 15–30% of adults older than 65 years of age, but it is rising.2 Rates of shingles are probably underreported due to the difficulty of diagnosis, though better testing methods have recently become available and have improved diagnosis. Shingles is, for the most part, a self-limited, localized cutaneous eruption associated with neuralgic pain along the dermatomal distribution of the affected nerve. Most clinicians easily recognize the typical presentation of shingles. However, as this case illustrates, atypical presentations can present a diagnostic challenge.
Mrs. D is an 89-year-old white female with a history of arterial hypertension and mild cognitive impairment but is otherwise very functional and independent. She received the varicella zoster vaccine in 2009. In early 2013, she developed sudden onset pain over her right hemithorax, which extended in a half-belt fashion from below the lower portion of the scapula, radiating forward along the right costal margin to the right upper quadrant of the abdomen. The pain was a constant, deep burning sensation that was not associated with meals and worsened at night. Analgesics, antacids, or bowel movements did not relieve it. It was made worse by touching the affected area, even by the rubbing of her clothing. There were no skin abnormalities present.
The patient presented to her local emergency room, where the workup included ultrasound and CT scans, both of which were noncontributory. She was discharged home with no additional treatment other than analgesic agents. She returned to geriatric primary care clinic 7 days later, because the pain and discomfort were not resolved. Again, the work up was unrevealing. She was given a prescription for codeine plus acetaminophen. She returned to the geriatric clinic within 10 days, because her pain was unchanged. Again, other than the very sensitive area on her thorax, there were no signs of a rash or other abnormalities. A broader set of diagnostic laboratory tests were performed, including a polymerase chain reaction (PCR) for VZV.
Mrs. D was ultimately diagnosed with herpes zoster shingles variant, zoster sine herpete, on the basis of her clinical presentation and the description of her pain. Her differential diagnoses initially included liver and/or gallbladder disease or radiculopathic pain. Because an etiology for her pain was not determined at presentation, treatment was delayed for several weeks, during which she endured significant discomfort. The fact that she had received the varicella zoster vaccine may have suppressed the appearance of the shingles rash, which would have provided a strong clue to the diagnosis. By the time serologic studies were reported as positive for VZV, more than 3 weeks had elapsed since her initial presentation. Because the area was still very painful, we chose to treat with prednisone 40 mg per day and tapered over a 2-week period; due to her age, this is lower than the suggested treatment course of 60 mg per day and tapered over a 3-week period. In addition, she received gabapentin 200 mg three times per day for 6 weeks. Mrs. D reported significant pain reduction within 1.5 weeks. Three months later, she was symptom-free, suggesting she was not afflicted with post-herpetic neuralgia.
Zoster sine herpete was first described in 1958 by British physician GW Lewis, who published the case of a physician with acute trigeminal pain without a rash.3 Before the advent of polymerase chain reaction (PCR) technology, the diagnosis was not completely certain and was limited to a high index of suspicion. However, the advent of VZV DNA sequencing and anti-VZV antibody detection have improved clinical diagnosis, helping to identify a range of symptoms and signs now known as sequelae of VZV, including vasculopathy, myelitis, meningoencephalitis, cerebellar ataxia, and polyneuritis cranialis. Indeed, all of the neurologic complications of VZV reactivation can occur without a rash.4
Due to the lack of the characteristic skin rash associated with typical shingles, which excludes the use of a Tzank smear, for example, the test of choice for the diagnosis of zoster sine herpete is PCR. It has replaced direct fluorescent assay as the assay of choice in many large laboratories. PCR has high sensitivity (95%) and specificity approaching 100%, with no cross-reactivity to other herpes viruses.5 It is rapid and relatively inexpensive. The specimen can be obtained from cerebrospinal fluid, bronchoalveolar lavage, saliva, serum, or whole blood, as well as from skin lesions, were they to be present. Performing PCR in saliva is an interesting possibility in the diagnosis of zoster sine herpete due to its easy access and noninvasive nature, but more studies on the accuracy and sensitivity of identifying VZV DNA in saliva are needed.6 VZV-specific antibodies may also be used for the diagnosis of atypical herpes zoster. In cases involving cranial nerves and meningoencephalitis, analyses should include tests for both anti-VZV IgG and PCR-amplifiable VZV DNA in cerebrospinal fluid, as well as examination of blood monocytes for VZV DNA.6 Patients with zoster sine herpete have rising titers of VZV-specific antibodies in both serum and CSF and have VZV DNA in CSF and peripheral blood mononuclear cells detectable by PCR.1 PCR is also useful in identifying a wild-type viral infection from the strains used in vaccines, vOka. This becomes useful when an episode of shingles occurs shortly after vaccination and is thus blamed on the vaccine, because the identity of the causative virus can be determined.6 Other diagnostic tests that take skin lesion material for examination, such as a Tzank smear and direct fluorescence, are not as useful due to the lack of vesicular lesions.
Post-herpetic neuralgia (PHN) is the most common and dreaded complication from the reactivation of herpes zoster. Defined as pain that persists for longer than 6 weeks after the onset of a herpes rash, PHN can persist for months and, in some cases, for years. Although it is benign in nature and eventually resolves, the chronic pain associated with PHN can greatly impair quality of life and lead to interrupted sleep, weight loss, and depression. The incidence of PHN increases with age. In a randomized trial completed in 2003 to assess the efficacy of the VZV vaccine, Oxman et al found that PHN developed in 6.9% of patients aged 60–69 years. In patients older than 70 years, the incidence of PHN was 18.5%.7 Despite the absence of a rash in zoster sine herpete, the severe pain can lead to the development of PHN, but there is lack of data as to the real incidence of PHN in patients with zoster sine herpete. Neurologic complications after zoster sine herpete will depend on the affected cranial or peripheral nerves. These may include aseptic meningitis or encephalitis, Bell’s palsy, transverse myelitis, transient ischemic events, and stroke.2
Once reactivation of the virus occurs and shingles is diagnosed, oral antiviral agents with or without oral corticosteroids may shorten duration of the acute phase but do not significantly reduce the risk of PHN.8 Treatment complications of zoster sine herpete are very similar to classic shingles; however, the delay in diagnosis may delay initiation. Ideally, treatment should begin within 72 hours of onset.9 A few FDA-approved antiviral agents are available, including acyclovir, valacyclovir, and famciclovir. Antiviral therapy is recommended for patients older than 50 years or for any immunocompromised patients with moderate to severe rash and pain, who have ophthalmic or facial involvement or other neurologic complications of herpes zoster, because these patients have greater risk of complications and long-term sequelae.10
If the disease persists or there are serious complications such as Bell’s palsy, oral corticosteroids at a dose of 1 mg/kg per day or 40–60 mg for 3–5 days or longer are suggested. Their use for uncomplicated cases remains controversial. Several studies have demonstrated a benefit for the reduction of acute pain, but there is no evidence that their use prevents the development of PHN.5,11
Pain associated with active disease can be controlled with nonsteroidal anti-inflammatories, narcotics, and/or lidocaine patches. Established PHN can be treated with topical capsaicin, lidocaine patches, oral anticonvulsants such as gabapentin or pregabalin, and tricyclic antidepressants. Severe acute pain or PHN may require a nerve block.
Herpes zoster vaccination is the single most important strategy for the prevention of complications related to herpes zoster and has been available since 2007. The Centers for Disease Control and Prevention recommends immunization of adults older than 60 years of age.12 In the VA Collaborative Shingles Prevention Study, a randomized placebo controlled trial during 1998–2003, three end points were assessed over 4 years of post-vaccination follow-up. Participants in this study were older than 60 years of age and immunocompetent. In the vaccinated population, the incidence of herpes zoster was reduced by 51.3% (95% CI, 44.2–57.6%), the incidence of PHN was reduced by 66.5% (95% CI, 47.5–57.6%), and the burden of illness due to herpes zoster was reduced by 61.1% (95% CI, 51.1–69.1%). Of note, one limitation to this study was that fewer than 7% of subjects were older than 80 years.7
In a study by Murray et al, the VZV vaccine and placebo had similar safety profiles in terms of serious adverse events during the 6 months after vaccination.12 In a follow up to the VA Shingles Prevention Study, it was found that the vaccine could be administered safely even if there was a prior history of herpes zoster infection.13
The long-term effectiveness of the herpes zoster vaccination has been questioned, however. In a recently published study, Schmader et al re-enrolled 7320 vaccine recipients and 6950 placebo recipients from the more than 38,000 participants of the Shingles Prevention Study.14 The vaccine’s effectiveness was then assessed for the same three end points during the next 7 years after vaccination. By Year 7, the vaccine showed decreased efficacy in the reduction of herpes zoster incidence (from 51.3% to 39.6%), in the prevention of PHN (from 66.5% to 60.1%), and in the reduction of the burden of illness (61.1% to 50.1%) by the 7th year.14
For the majority of shingles patients, appearance of the characteristic herpetiform rash prompts diagnosis and initiation of treatment. When shingles occurs despite vaccination, the extent of the rash and the severity of the neuropathic pain may be less. Although this suppression of the virus may benefit the patient, ironically, it can also confound the diagnosis.
In patients who present with severe pain and allodynia (pain due to a stimulus which does not typically cause pain) or with a more limited rash and less pain, atypical shingles should be considered in the differential diagnosis. Prompt, appropriate treatment can limit the duration of the discomfort. For up to 5 years, vaccination with attenuated HZV reduces the risk of shingles by about half, but the long-term persistence of effectiveness is unknown.14 In the future, as more data arise from the Long-Term Shingles Vaccine Persistence study, this question will be addressed. This study should also shed light on whether a booster will be necessary and, if so, how long after primary vaccination. Until then, vaccination remains the most effective means of avoiding shingles and its consequences. As with childhood varicella, re-emergent shingles infection itself provides the equivalent of a potent booster. How long this post-shingles immunity persists is not known precisely, but, fortunately, very few patients develop shingles more than once.14 In our clinical experience, we have recently found an increase in atypical zoster presentations in immunocompetent vaccinated elderly patents. A literature search yielded evidence suggesting a correlation between atypical breakthrough varicella and varicella immunization in children,15 but we have not found studies addressing a similar correlation between the shingles vaccine and atypical herpes zoster in adults. More research is needed in this regard.