Aseptic Meningitis in HZ Patients

pISSN 1013-9087eISSN 2005-3894

Ann Dermatol Vol. 29, No. 3, 2017 https://doi.org/10.5021/ad.2017.29.3.283

ORIGINAL ARTICLE

Risk Factors for Aseptic Meningitis in Herpes Zoster

Patients
Sang-Hoon Kim*, Seong-Min Choi*, Byeong C. Kim, Kang-Ho Choi, Tai-Seung Nam, Joon-Tae Kim,
Seung-Han Lee, Man-Seok Park, Seong J. Kim1

Departments of Neurology and 1Dermatology, Chonnam National University Medical School, Gwangju, Korea

Background: Herpes zoster (HZ) is caused by reactivation of tome involvements. Additional logistic regression analysis
latent varicella-zoster virus (VZV) infection. HZ-associated resulted in a fading between gender difference (p=0.050)
aseptic meningitis, a rare complication of HZ, can require and craniocervical involvement having an OR of 5.667 for
hospitalization and a long treatment period. Objective: A ret- aseptic meningitis (p=0.006). Conclusion: In HZ patients,
rospective study was performed to identify potential factors skin rash with craniocervical distribution and male gender
associated with HZ-associated aseptic meningitis development. were associated with a higher risk of aseptic meningitis. (Ann
Methods: We included all outpatients and patients admitted Dermatol 29(3) 283287, 2017)
in the neurology and dermatology departments of a single
tertiary center, who were diagnosed with HZ for two years. -Keywords-
Among 818 patients, 578 patients were eligible for analysis. Herpes zoster, Herpesvirus 3, human, Meningitis, aseptic,
Results: The demographics and potential risk factors were Risk factors
compared between the uncomplicated HZ group (n=554)
and aseptic meningitis group (n=24). Among the potential
factors, the dermatological distribution of skin rash and INTRODUCTION
gender showed statistically significantly different between
the two groups. Patients with craniocervical distribution of Herpes zoster (HZ) is a disease caused by reactivation of
HZ accounted for 87.5% (n=21) of the aseptic meningitis the latent varicella-zoster virus (VZV) that remains latent in
group and 54.3% (n=301) of the uncomplicated HZ group the dorsal root and cranial nerve ganglia; this latency is
(p=0.043). The aseptic meningitis group had more men known to be life-long1,2. Once reactivated, the virus spreads
(66.7%, n=16) than the uncomplicated HZ group (42.8%, along the involved nerves and the corresponding cuta-
n=237, p=0.033). Patients with craniocervical distribution neous dermatome. The incidence of HZ has increased in
had an odds ratio (OR) of 5.884 (p=0.001) for developing the last two decades: 3.6 per 1,000 person-years in the
aseptic meningitis when compared with the other derma- United States, with an increase from 3.2 to 4.1 per 1,000
person-years from 1996 to 20013.
Received April 26, 2016, Revised August 18, 2016, Accepted for Numerous complications have been associated with HZ,
publication August 22, 2016
*These authors contributed equally to this work. including postherpetic neuralgia, meningitis, myelitis, en-
Corresponding author: Byeong C. Kim, Department of Neurology, Chonnam cephalitis, and arteritis4. In a previous study of 859 pa-
National University Hospital, 42 Jebong-ro, Dong-gu, Gwangju 61469, tients with HZ, the postherpetic neuralgia occurred in
Korea. Tel: 82-62-220-6123, Fax: 82-62-228-3461, E-mail: byeong.kim7@ 7.9% within 60 days of the onset of HZ; superinfection,
gmail.com
2.3%; ocular complications, 1.6%; motor neuropathy, 0.9%;
This is an Open Access article distributed under the terms of the Creative
Commons Attribution Non-Commercial License (http://creativecommons. meningitis, 0.5%; and HZ oticus, 0.2%5. Old age and co-
org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, morbid conditions that may impair cell-mediated im-
distribution, and reproduction in any medium, provided the original work
munity including diabetes, cancer, connective tissue dis-
is properly cited.
ease, chronic obstructive pulmonary disease, inflammatory
Copyright The Korean Dermatological Association and The Korean
Society for Investigative Dermatology bowel disease, human immunodeficiency virus infection,

Vol. 29, No. 3, 2017 283

SH Kim, et al

organ transplantation, and psoriasis have been reported to

Case definition
be associated with higher risk of complications in HZ pa-
tients5. HZ-associated aseptic meningitis is considered a HZ was diagnosed by dermatologists in patients with char-
rare complication of HZ, and it usually requires hospital- acteristic distribution and appearance of skin lesions ac-
ization and a long period of treatment. companied by localized pain. Tzanck smear was utilized
Clinically, HZ-associated aseptic meningitis is relatively to support the diagnosis of HZ. HZ-associated aseptic
common in comparison to other complications involving meningitis was defined as follows: 1) signs and/or symp-
the central nervous system. In HZ patients with headaches toms of meningeal irritation without brain parenchymal in-
accompanied by nausea, vomiting, neck stiffness, fever or volvement in patients within 4 weeks of HZ diagnosis; 2)
chills complicated meningitis should be suspected. It is CSF leukocyte count over 5106/L; 3) a negative CSF
thought that the involvement of cranial nerves may con- stain and culture for bacteria, tuberculosis, and fungus;
tribute to a higher risk of aseptic meningitis. In a previous and 4) no other explainable non-infectious aetiology.
report of patients with systemic cancer, cases of HZ-asso-
Statistical analyses
ciated meningoencephalitis, although small in number,
were all associated with trigeminal or disseminated zos- Descriptive statistics were performed using IBM SPSS
ter6. However, the clinical characteristics and potential Statistics ver. 20.0 (IBM Co., Armonk, NY, USA). Fishers
risk factors that may predispose patients with HZ to com- exact test and bimodal logistic regression were used in the
plicated aseptic meningitis have been poorly studied. The analysis of the collected data. All tests performed were
aim of this study was to identify the possible risk factors two-tailed and differences were considered significant at
and related clinical characteristics in patients with HZ for p0.05.
developing HZ-associated aseptic meningitis.
RESULTS
MATERIALS AND METHODS
The demographics and potential risk factors were com-
Study design
pared between the uncomplicated HZ group (n=554) and
This retrospective study was based on a review of elec- HZ-associated aseptic meningitis group (n=24) (Table 1).
tronic medical records from patients diagnosed with HZ. The mean age was 56.8 years in the uncomplicated group,
This study was approved by the institutional review and 51.1 years in the aseptic meningitis group. The asep-
boards of Chonnam National University Hospital (IRB no. tic meningitis group was 5.7 years younger; however, this
CNUH-2015-150). difference was not significant (p=0.296). Age stratification
showed that patients over the age of 60 years accounted
Patients
for half of the uncomplicated HZ group and the aseptic
We included all outpatients as well as all patients admit- meningitis group (49.9% and 50.0% respectively). Among
ted in the neurology and dermatology departments of a the potential risk factors, the dermatological distribution of
single tertiary centre who were diagnosed with HZ in skin rash and gender were significantly different between
2013 and 2014. A total of 818 patients were initially the two groups. Patients with craniocervical distribution of
included. After the electronic medical records were thor- HZ accounted for 87.5% (n=21) of the aseptic meningitis
oughly reviewed, 578 patients were eligible for analysis as group and 54.3% (n=301) of the uncomplicated group
the excluded 240 cases lacked a definite diagnosis or had (p=0.043). When a comparison was made between cra-
insufficient medical records for analysis. Dermatologists niocervical distributions versus the rest, patients with cra-
examined skin lesions including Tzanck smears. Patients niocervical distribution had an odds ratio of 5.884 (95%
with symptoms of headache, fever or meningeal irritation confidence interval [CI], 1.73519.953; p=0.001) for de-
signs were suspected to have meningitis and underwent veloping HZ-associated aseptic meningitis. The aseptic
spinal tapping for evaluation of the cerebrospinal fluid meningitis group had a higher proportion of men (66.7%,
(CSF). Among the medical records, data pertaining to age, n=16) than the uncomplicated group (42.8%, n=237,
gender, involved dermatomes, and other medical con- p=0.033). The frequency of hypertension, diabetes melli-
ditions (hypertension, diabetes mellitus, pregnancy, con- tus, use of immunosuppressants, and concurrent malig-
current malignancy, liver cirrhosis, chronic kidney disease, nancy or hematologic disorder was not significantly differ-
and immunosuppressant use) were used for evaluation ent between the two groups. The frequency of liver cir-
and analysis. rhosis and chronic kidney disease was also insignificant
(Table 1). The interval between onset of HZ and symp-

284 Ann Dermatol

 Aseptic Meningitis in HZ Patients

Table 1. Demographics and clinical characteristics of patients with uncomplicated herpes zoster and herpes zoster-associated aseptic
meningitis (n=578)
HZ-associated
Variable Uncomplicated HZ OR (95% CI) p-value
aseptic meningitis
No. 554 24

Mean age (yr) 56.8219.020 51.1322.27 0.296
Male 237 (42.8) 16 (66.7) 2.68 (1.1266.355) 0.033*
Hypertension 134 (24.2) 6 (25.0) 1.05 (0.4062.686) 1.000
Diabetes mellitus 63 (11.4) 4 (16.7) 1.56 (0.5164.707) 0.508
Malignancy/hematologic 13 (2.3) 0 1.000
Pregnancy 20 (3.6) 0 1.000
Immunosuppressant use 22 (4.0) 2 (8.3) 2.20 (0.4869.942) 0.262
Liver cirrhosis 7 (1.3) 0 1.000
Chronic kidney disease 8 (1.4) 0 1.000
Dermatome distribution
,
Craniocervical 301 (54.3) 21 (87.5) 5.88 (1.73519.953) 0.001*
Thoracic 176 (31.8) 3 (12.5)
Lumbar 55 (9.9) 0
Sacral 16 (2.9) 0
Disseminated 6 (1.1) 0
Values are presented as number only, number (%), or meanstandard deviation unless otherwise indicated. HZ: herpes zoster, OR:

odds ratio, CI: confidence interval. *Indicates statistical significance, p-values for the Fishers exact test, p-values for the Mann-Whitney

U test, Craniocervical involvement vs. others.

Table 2. Relative odds of herpes zoster-associated aseptic DISCUSSION

meningitis in patients with herpes zoster: logistic regression model
Variable OR 95% CI p-value In this retrospective study of the potential risk factors for
the development of aseptic meningitis in patients with HZ,
Male 2.439 0.9995.953 0.050
Age 0.983 0.9621.005 0.132 patients with skin lesions on craniocervical distribution
Craniocervical involvement 5.667 1.65919.365 0.006* had higher odds for the development of HZ-associated
Hypertension 1.048 0.3333.299 0.936 aseptic meningitis. Among the trigeminal branches, the in-
Diabetes mellitus 1.306 0.3554.804 0.688 volvement of the ophthalmic branch (V1) was associated
Immunosuppressant use 2.322 0.47811.264 0.296 with higher risk of complicated meningitis. In a previous
OR: odds ratio, CI: confidence interval. *Indicates statistical study by Galil et al.5, the involvement of the V1 derma-
significance. tome increased the risk of developing any complication in
HZ patients, which is more or less consistent with our
finding. The association between skin lesions with cranio-
toms of meningitis was 5.3 days in average, ranging from cervical distribution and aseptic meningitis has been de-
0 to 30 days. In 20 of the cases (83.3%), the meningitis scribed in a previous report on systematic cancer patients,
symptoms manifested within 6 days from onset of HZ skin in which all patients with meningoencephalitis had trige-
lesions. minal or disseminated zoster6. This relation can be ex-
To adjust for confounding effects, logistic regression analy- plained by considering the anatomical distance between
sis was performed. The gender difference between the two the brain meninges and the region of the involved
groups faded (95% CI, 0.9995.953; p=0.050) and the dermatome. A closer anatomical distance may facilitate vi-
craniocervical involvement had an odds ratio of 5.667 for ral invasion to the brain meninges and cause clinical
the complication of aseptic meningitis (95% CI, 1.659 symptoms of meningitis. A previous case of a HIV-positive
19.365; p=0.006) (Table 2). Among the craniocervical VZV meningoencephalitis patient showed histopatho-
dermatomes, the V1 trigeminal dermatome was most fre- logical evidence of necrotizing vasculitis predominant in
quently involved in the meningitis group (p=0.003) with the meninges in postmortem autopsy7. This finding in-
4-fold increased risk (OR, 4.4; 95% CI, 1.75611.048; dicates that vasculitis is a pathogenic mechanism in men-
p=0.002) compared to the involvement of other derma- ingitis associated with VZV, and hematogenous invasion
tomes. the virus may play a role in CNS VZV infections. Another

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SH Kim, et al

previous study revealed CSF findings in 46 patients with and chronic kidney disease) were not significantly asso-
HZ that 21 patients presented with leukocytosis and ciated with HZ-associated aseptic meningitis in the current
one-third had positive PCR results for VZV or anti-VZV study. Although patients with chronic kidney disease have
IgG within the first week, after the onset of skin lesions8. been reported to have a higher risk for HZ compared to
These findings demonstrate that subclinical invasion of the general population16,17, the association between com-
CSF by VZV seems common. Therefore, the increased risk plicated aseptic meningitis and chronic kidney disease
with craniocervical involvement cannot solely be attrib- was not significant. Future study with a larger sample size
uted to the anatomical proximity. may reveal significance of the previously mentioned co-
In a previous retrospective analysis of central nervous sys- morbidities in relation to HZ-associated meningitis.
tem VZV reactivation, 71% of aseptic meningitis cases The strength of our study is that we enrolled a relatively
were noted in male patients9. In regards to the study of HZ large number of patients for analysis. However, there are
prevalence, a Swedish analysis revealed a female predom- also several limitations. First, given that this was a retro-
inance10, and a systematic review of European data by spective study, the associations observed cannot be con-
11
Pinchinat et al. also reported higher incidence rates in sidered as definitive evidence of a causal relationship.
female patients. In the current study, 56.2% of the total Further study with a prospective design is needed. Second,
HZ cases were noted in women and although not statisti- 240 patients were excluded from the analysis due to in-
cally significant, male predominance in the aseptic menin- sufficient medical records or lack of proper diagnosis,
gitis group was observed. Female predominance is a trend which may have influenced analysis of the results. Third,
for HZ, but the complication rate of HZ-associated aseptic the etiology of complicated aseptic meningitis cases was
meningitis is higher in male patients. This is presumed to not confirmed by VZV PCR in the current study. Patients
be due to immunological and hormonal differences be- with aseptic meningitis caused by other viral agents may
tween genders. Further study is needed to clarify the rela- have been included in the analysis, as enterovirus is the
tionship between gender and incidence of HZ-associated most common causative pathogen and VZV accounts for
aseptic meningitis and the underlying mechanisms con- only 8% of aseptic meningitis cases in adults18.
tributing to this difference. In HZ patients, a skin rash with craniocervical distribution
HZ-associated aseptic meningitis accounted for 4.15% of is associated with a higher risk of HZ-associated aseptic
the total HZ cases in our study, which is higher than the meningitis. Closer observation is needed to detect signs
previous report: 0.5%5. This may be due to the increasing and symptoms of meningitis in patients with HZ infection
proportion of the elderly population, resulting in older HZ with this risk factor. Clinicians should take this in-
patients who bear higher risk of complications. In our formation into account when treating patients with HZ.
study, however, the mean age was younger in the aseptic
meningitis group (51.1 years vs. 56.8 years in the un- ACKNOWLEDGMENT
complicated HZ group). The relatively small number of
the meningitis patients (24 cases) compared with the other All persons who have made substantial contribution, but
group (554 cases) may have contributed to the contra- who are not eligible as authors are named in acknow-
dictory age difference between the two groups. A larger ledgment. This study was supported by a grant from the
sample size may yield a contrasting result. Immunosup- Brain Research Program through the National Research
pression is associated with increased risk of not only HZ Foundation of Korea funded by the Ministry of Science,
and its complications3,12-14. Our results did not show sig- ICT & Future Planning NRF-2014M3C7A1046041 (to
nificant difference in immunocompromised hosts, which B.K.) and a grant from Chonnam National University
include patients with concurrent malignancy, hematologic Hospital CRI 13902-22.4 (to B.K.).
disease, or chronic immunosuppressant use, between the
uncomplicated HZ group and the Hz-associated aseptic CONFLICTS OF INTEREST
meningitis group. These results may be indicating reduced
incidence of HZ complications in immunocompromised The authors have nothing to disclose.
population of our study, probably due to active diagnosis
and early antiviral treatment at initial stage of HZ in these REFERENCES
patients and increased prophylactic use of antiviral agents
especially in patients undergoing hematopoietic cell trans- 1. Ku CC, Padilla JA, Grose C, Butcher EC, Arvin AM. Tropism
plantation15. Previous comorbidities or medical conditions of varicella-zoster virus for human tonsillar CD4(+) T
(hypertension, diabetes mellitus, pregnancy, liver cirrhosis, lymphocytes that express activation, memory, and skin

286 Ann Dermatol

 Aseptic Meningitis in HZ Patients

homing markers. J Virol 2002;76:11425-11433. zoster in Sweden--predominance in the elderly and in

2. Chen JJ, Gershon AA, Li ZS, Lungu O, Gershon MD. Latent women-a register based study. BMC Infect Dis 2013;
and lytic infection of isolated guinea pig enteric ganglia by 13:586.
varicella zoster virus. J Med Virol 2003;70 Suppl 1:S71-S78. 11. Pinchinat S, Cebrin-Cuenca AM, Bricout H, Johnson RW.
3. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Similar herpes zoster incidence across Europe: results from
Sy LS. A population-based study of the incidence and a systematic literature review. BMC Infect Dis 2013;13:170.
complication rates of herpes zoster before zoster vaccine 12. Antonelli MA, Moreland LW, Brick JE. Herpes zoster in
introduction. Mayo Clin Proc 2007;82:1341-1349. patients with rheumatoid arthritis treated with weekly,
4. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, low-dose methotrexate. Am J Med 1991;90:295-298.
Mahalingam R, Cohrs RJ. Neurologic complications of the 13. Korelitz BI, Fuller SR, Warman JI, Goldberg MD. Shingles
reactivation of varicella-zoster virus. N Engl J Med 2000; during the course of treatment with 6-mercaptopurine for
342:635-645. inflammatory bowel disease. Am J Gastroenterol 1999;
5. Galil K, Choo PW, Donahue JG, Platt R. The sequelae of 94:424-426.
herpes zoster. Arch Intern Med 1997;157:1209-1213. 14. Miller GG, Dummer JS. Herpes simplex and varicella zoster
6. Hughes BA, Kimmel DW, Aksamit AJ. Herpes zoster- viruses: forgotten but not gone. Am J Transplant 2007;
associated meningoencephalitis in patients with systemic 7:741-747.
cancer. Mayo Clin Proc 1993;68:652-655. 15. Kim DH, Messner H, Minden M, Gupta V, Kuruvilla J,
7. Kleinschmidt-Demasters BK, Mahalingam R, Shimek C, Wright J, et al. Factors influencing varicella zoster virus
Marcoux HL, Wellish M, Tyler KL, et al. Profound cere- infection after allogeneic peripheral blood stem cell trans-
brospinal fluid pleocytosis and Froin's syndrome secondary plantation: low-dose acyclovir prophylaxis and pre-transplant
to widespread necrotizing vasculitis in an HIV-positive diagnosis of lymphoproliferative disorders. Transpl Infect Dis
patient with varicella zoster virus encephalomyelitis. J 2008;10:90-98.
Neurol Sci 1998;159:213-218. 16. Kuo CC, Lee CT, Lee IM, Ho SC, Yang CY. Risk of herpes
8. Haanp M, Dastidar P, Weinberg A, Levin M, Miettinen A, zoster in patients treated with long-term hemodialysis: a
Lapinlampi A, et al. CSF and MRI findings in patients with matched cohort study. Am J Kidney Dis 2012;59:428-433.
acute herpes zoster. Neurology 1998;51:1405-1411. 17. Wu MY, Hsu YH, Su CL, Lin YF, Lin HW. Risk of herpes
9. Becerra JC, Sieber R, Martinetti G, Costa ST, Meylan P, zoster in CKD: a matched-cohort study based on admini-
Bernasconi E. Infection of the central nervous system strative data. Am J Kidney Dis 2012;60:548-552.
caused by varicella zoster virus reactivation: a retrospective 18. Kupila L, Vuorinen T, Vainionp R, Hukkanen V, Marttila
case series study. Int J Infect Dis 2013;17:e529-e534. RJ, Kotilainen P. Etiology of aseptic meningitis and ence-
10. Studahl M, Petzold M, Cassel T. Disease burden of herpes phalitis in an adult population. Neurology 2006;66:75-80.

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