INTRODUCTION: In Parts I & II we presented background on the involvement of varicella zoster virus (VZV) with the enteric nervous system (ENS). The conclusion of our three-part series will outline the diagnostic approaches to detect VZV reactivations without the external signs of shingles (Zoster sine herpete-ZSH) as outlined by Zhou et al1.

DISCUSSION: The two methods for detecting VZV with no signs of shingles (either DNA or antibodies) each have their own advantages. PCR detection is more sensitive and is more likely to detect the virus in the early phases of reactivation but requires more specialized equipment and proper controls to rule out false positives. The use of antibodies for detection with an ELISA test is easier to perform with the kits available and the detection of IgM antibodies would be an indication of a reactivation in it’s early phase, while IgG would be an indication of a reactivation in it’s mid to later stages. In ZSH patients, rising anti-VZV antibody titers serve as a marker for active viral infection. The presence of anti-VZV IgG antibody in cerebral spinal fluid (CSF) or serum can be used to diagnose ZSH. Anti-VZV IgG in the CSF, and the reduced serum/CSF ratios of VZV IgG compared with the normal level of serum/CSF for albumin and total IgG, reflect the intrathecal synthesis of anti-VZV IgG (Morita et al)2. At the beginning of VZV reactivation, anti-VZV IgM elevates in the CSF or serum. However, even at the beginning of ZSH, IgM may not be as sensitive as IgG in ZSH diagnosis. In a cohort of 45 ZSH patients with acute peripheral facial paralysis that occurred within 7 days, all of the patients were anti-VZV IgG positive after blood tests, however, only 7 patients were anti-IgM positive (Lee et al)3. In some cases, it has been reported that a ZSH patient was negative for VZV DNA, while anti-VZV IgG was positive and evidently reduced serum/CSF ratios of anti-VZV IgG, which indicated intrathecal synthesis (Blumenthal et al)4. These comparisons indicate that the outcome of VZV DNA or anti-VZV antibodies detection is related to the sample type and the detection timepoint during the course of ZSH. More studies are needed to determine the better method and sample, as well as the best timepoint to confirm if the VZV reactivation exists in different kinds of ZSH patients.

CONCLUSION: The introduction of vaccines for preventing shingles was a major breakthrough in the prevention of Herpes Zoster (Zostavax™ in 2006 and Shingrix™ 2017). The recently released zoster vaccine, Shingrix™, is a subunit vaccine containing VZV glycoprotein-E and the ASO1B adjuvant, and was approved by the FDA for adults age 50 and above, in 2017. Since the introduction of these vaccines, it has been reported that the burden of HZ in the United States has begun to decline, although an uptick in cases has been seen during the SARS-CoV-2 pandemic. Even so, the accurate detection of HZ in the absence of outward physical indications is still an area of great interest.



  1. Zhou, J., J. Li, L. Ma, and S. Cao. (2020). Zoster sine herpete: a review. Korean J Pain 33(3):208-215.
  2. Morita, Y., Y. Osaki, Y., Doi, B. Forghani, and DH Gilden. (2003). Chronic active VZV infection manifesting as zoster sine herpete, zoster paresis and myelopathy. J. Neurol Sci. 212: 7-9. https://org/10.1016/s0022-510x(03)00081-9
  3. Lee, H.Y., M.G. Kim, D.C. Park, M.S. Park, J.Y. Byun, and S.G. Yeo. (2012). Zoster sine herpete causing facial palsy. Am J Otolaryngol 33:565-571.
  4. Blumenthal, D.T., E. Shacham-Shmueli, F. Bokstein, D.S. Schimd, R.J. Cohrs, M.A. Nagel, R. Mahalingham, and D. Gilden. (2011). Zoster sine herpete: virologic verification by detection of anti-VZV IgG antibody in CSF. Neurology 76:484-5.

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