Varicella Zoster Virus Central Nervous System Infection—A Retrospective Study from a Tertiary Center in Greece
1
Internal Medicine Department, University Hospital of Heraklion, Heraklion, PC 71110, Greece
2
School of Medicine, University of Crete, Heraklion, PC 71003, Greece
3
Laboratory of Clinical Virology, School of Medicine, University of Crete, Heraklion, PC 71003, Greece
*
Author to whom correspondence should be addressed.
GERMS 2024, 14(3), 267-276; https://doi.org/10.18683/germs.2024.1437
Submission received: 31 May 2024
/
Revised: 20 June 2024
/
Accepted: 12 September 2024
/
Published: 30 September 2024
Abstract
Introduction: Central nervous system (CNS) infection due to the varicella zoster virus (VZV) can complicate the primary infection or the reactivation, leading to significant mortality and morbidity. This study aimed to describe the clinical, laboratory, and radiological characteristics of patients with confirmed VZV CNS infection in a tertiary hospital in Greece. Methods: Data about patients hospitalized from January 2018 to September 2023 with CNS infection by VZV, confirmed by a syndromic polymerase chain reaction in the cerebrospinal fluid (CSF), were retrospectively collected and evaluated. Results: In total, 14 patients were recorded. The median age was 49 years, and 35.7% were male. Headache was present in 71.4%, a rash in 57.1%, and fevers, nausea or vomiting, and disorientation in 35.7%. The CSF showed lymphocytic pleocytosis in all patients. Brain magnetic resonance imaging was performed in 53.8%. Empirical antivirals were given in 69.2%, and intravenous acyclovir was given to all patients after identification of VZV in the CSF. Only 7.1% (1 patient) required intensive care unit admission, and 7.1% (1 patient) died. Patients presenting without a rash may be slightly younger, have a slightly lower Charlson comorbidity index, be more likely to present with photophobia or phonophobia, and have lower serum CRP. Conclusions: Patients presenting with VZV CNS infection have lymphocytic pleocytosis in the CSF and usually have a favorable outcome with antiviral treatment. Those presenting without a rash may have a different overall clinical phenotype from those with a rash; however, this must be evaluated in larger studies in the future.
Introduction
Varicella zoster virus (VZV), also known as human herpesvirus-3 (HHV-3), is the cause of chickenpox (varicella) in the case of primary infection or shingles (herpes zoster), in the case of reactivation, with the latter typically presenting with pain and rash with a dermatomal distribution; however, in some cases, pain in a dermatomal distribution without a rash may occur (zoster sine herpete). Chickenpox is the primary infection caused by VZV and primarily affects children in temperate climates, causing a typical febrile illness and a rash characterized by pruritic papulovesicular lesions. It has a worldwide distribution and is highly contagious, spreading from one infected person to another through close contact. A vaccine against chickenpox can significantly reduce the likelihood of contracting the disease. Herpes zoster mostly occurs in adults after reactivation of VZV in the dorsal root ganglia, where it may remain dormant for years after primary infection. Its incidence varies and is approximately up to 9 cases per 1,000 people. Though it is less contagious than chickenpox, direct contact with vesicular fluid may transmit the virus. Zoster sine herpete is a variation of herpes zoster where VZV causes typical pain with dermatomal distribution without the development of a rash, thus making clinical diagnosis difficult [1].
Central nervous system infection due to VZV can complicate either the primary infection or reactivation, leading to increased mortality and morbidity [2,3]. These manifestations are particularly significant in the context of the constantly growing older and immunocompromised populations [4]. Furthermore, atypical clinical presentations, such as central nervous system (CNS) infection without skin manifestations, can pose significant clinical challenges for timely diagnosis [5,6].
Despite being one of the most common infectious causes of encephalitis and aseptic meningitis, VZV infection may be underreported in the literature [7]. Moreover, treatment recommendations are not based on randomized controlled trials but rather on small-scale studies, highlighting the need for further research on the subject [1].
The objective of this study was to provide a comprehensive description of the clinical, laboratory, and radiological characteristics, as well as the outcomes, of patients with confirmed VZV central nervous system infection in a tertiary hospital in Crete, Greece.
Methods
This is a retrospective cohort study of patients hospitalized in the University Hospital of Heraklion, Crete, Greece. Patients of any age with a positive polymerase chain reaction (PCR) for VZV nucleic acid in the cerebrospinal fluid (CSF) along with pleocytosis (more than five enucleated cells/mm3) in the CSF, negative CSF cultures for bacteria and compatible clinical presentation (at least one of the following: headache, fever, altered mental status, behavioral changes, nuchal rigidity, nausea or vomiting, seizures or focal neurological symptoms) were considered to have CNS infection due to VZV and were included in the analysis [8]. Patients who were not hospitalized at the University Hospital of Heraklion were excluded. Data on positive PCR were retrieved from the Laboratory of Clinical Virology of the University Hospital of Heraklion from January 1st 2018, to September 30th 2023. The molecular identification of VZV was performed using the FilmArray Meningitis/Encephalitis (ME) Panel (BioFire Diagnostics, USA). Clinical and laboratory data were retrieved from the hospital's electronic medical record. Demographical characteristics, initial clinical presentation, physical examination, and laboratory data were obtained. Only the laboratory values were retrieved and evaluated when no clinical data were available. The study was conducted following the Declaration of Helsinki and approved by the Institutional Review Board of the University Hospital of Heraklion (protocol code 08/24-03-2021).
Descriptive statistics were performed with GraphPad Prism 6.0 (GraphPad Software, Inc., USA). Qualitative data are presented as counts and percentages. Data are presented as numbers (%) for categorical variables and medians [interquartile range (IQR)].
Results
Characteristics of patients with CNS infection by VZV
During the study, 31 patients with a CNS infection due to the VZV were diagnosed. Only 14 were hospitalized at the University Hospital of Heraklion, Crete, Greece; the rest were hospitalized in other hospitals. Thus, the 14 patients for whom data were available were included in the analysis. The median age was 49 years (range: 1-88 years), and 35.7% (five patients) were male. The most common comorbidities were hypertension in 21.4% (three patients), active cancer (solid or hematological) in 21.4% (three patients), cerebrovascular disease in 21.4% (three patients), previous history of cancer (solid or hematological) in 14.3% (two patients), chronic pulmonary disease in 14.3% (two patients), dementia in 14.3% (two patients) diabetes mellitus in 7.1% (one patient), dyslipidemia in 7.1% (one patient), chronic kidney disease in 7.1% (one patient), heart failure in 7.1% (one patient), and rheumatological disease in 7.1% (one patient). All 14 VZV- positive patients were negative for other pathogens of the multiplex PCR. The rest of the pathogens were tested by the FilmArray ME panel.
Clinical characteristics of patients with CNS infection by VZV
Headache was present in 71.4% (10 patients), a rash in 57.1% (eight patients), fever in 35.7% (five patients), nausea or vomiting in 35.7% (five patients), disorientation in 35.7% (five patients), nuchal rigidity in 28.6% (four patients), focal neurological signs in 28.6% (four patients), photophobia in 28.6% (four patients), phonophobia in 14.3% (two patients), behavioral changes in 14.3% (two patients), and seizures in 7.1% (one patient). The Glasgow Coma Scale (GCS) was 15 out of 15 in all patients except for one, where it was 14 out of 15. Regarding the rash, the most common type was a typical zoster rash, with blisters along the area of a dermatome. In 7.1% (one patient), Ramsay-Hunt syndrome was diagnosed with a rash involving the ear, while in 7.1% (one patient), facial zoster was diagnosed involving the dermatome of the fifth cranial nerve. No patient presented with chickenpox. The epidemiological and clinical characteristics of the patients are shown in Table 1 and Table 2.
Laboratory characteristics of patients with CNS infection by VZV
The CSF was more commonly retrieved in the emergency department in 35.7% (five patients), the internal medicine department in 28.6% (four patients), the neurology department in 21.4% (three patients), the dermatology department in 7.1% (one patient), and the pediatric intensive care unit (ICU) in 7.1% (one patient). The CSF glucose to serum glucose was lower than 50% in 50% of the patients (seven patients). The CSF protein was increased (higher than 60 mg/dL) in 85.7% (12 patients). All 14 patients had an increased white cell number in the CSF, and lymphocyte predominance was present in all patients. The characteristics of the CSF and the rest of the laboratory exams are shown in Table 3. In 50% (seven patients), C- reactive protein (CRP) was increased (higher than 0.5 mg/dL).
PCR for VZV was positive in the CSF of all patients. However, in most cases, the result was not quantitative. Quantitative PCR was performed in four patients; median copies were 7100/mL. VZV antibodies were examined only in eight patients, with IgM antibodies being positive only in one patient and IgG antibodies being negative only in one patient.
Treatment of patients with CNS infection by VZV
Empirical antivirals were given in 69.2% (nine out of 13 patients with available data), and antivirals were given to all after identification of VZV genetic material with PCR. Acyclovir was the antiviral used in all cases. In 66.7% (eight out of 12), an intravenous-to-oral transition was performed with a change from acyclovir to valacyclovir. The median duration of intravenous therapy was ten days (range: 2-14), and the median duration of treatment, regardless of route of administration, was 14 days (range: 5-24). In 50% (six out of 12 with available data), antibiotics for bacterial infection were given empirically for the CNS infection; however, in all cases, they were stopped after the negative CSF culture and the positive PCR for VZV. In 25% (three patients), antibiotics were administered for another concomitant presumed source of bacterial infection. One patient (7.1%) required ICU admission, and one patient (7.1%) died.
Brain imaging of patients with CNS infection by VZV
Brain magnetic resonance imaging (MRI) was performed in 53.8% (seven out of 13 patients with available data). In five of those, abnormal findings were found. These findings were leukoencephalopathy in 60% (three patients), trigeminal nerve inflammation in 20% (one patient), and mild meningeal inflammation in 20% (one patient).
Comparison of patients presenting with and without a rash
Table 2 and Table 3 compare patients presenting with CNS infection by VZV with and without a rash. Patients who presented with zoster rash differed from those who did not, being slightly older, having a slightly higher Charlson comorbidity index, not having photophobia or phonophobia, and higher serum CRP.
Discussion
In the present study, 14 patients with CNS infection due to VZV during six years are presented. The most common clinical presentation included headache and rash. Patients who presented with zoster rash differed slightly from those who did not, being slightly older, having a slightly higher Charlson comorbidity index, not having photophobia or phonophobia, and having higher serum CRP. All patients were treated with intravenous acyclovir, and mortality was low, with only one patient dying overall.
VZV, an alphaherpesvirus (also known as human herpesvirus-3, HHV-3) with neurotropic attributes that can remain dormant in the autonomic nervous system ganglia, is an essential cause of viral meningitis and encephalitis. Disseminated VZV infection can affect a wide range of patients across the age and immunosuppression spectrum [9], such as patients with hematological malignancy [10], allogenous stem cell transplant [11], solid organ transplantation [12], and patients undergoing immunosuppressive treatment for other reasons such as those treated with fingolimod, anti-TNF factors, corticosteroids, tacrolimus or cyclophosphamide [13,14]. Notably, VZV central nervous system infection was recognized as an important diagnostic consideration for patients with HIV infection as early as the early 1990s [15]. That is still true in the antiretroviral era, with a multicenter study by Reimer-McAtee et al. demonstrating an increased risk of being diagnosed with VZV-related central nervous system infection in patients living with HIV who presented with encephalitis [16].
On the other hand, there is mounting evidence that VZV-related central nervous system infection can manifest in patients without any cause of immunosuppression [5]. In a retrospective analysis of aseptic meningitis in 177 otherwise healthy patients, 14.1% were diagnosed with VZV. Of note, those with VZV were older than those diagnosed with enterovirus-related aseptic meningitis (which was the leading cause of identifiable viruses, with 38.4%) [17]. On a smaller scale, Gaudin et al. reported five cases of confirmed PCR VZV central nervous system infection in young patients. Of note, only three presented with a rash, and all had favorable outcomes [18].
Recent analyses also report various degrees of immunosuppression among their study populations. In a retrospective analysis of 16 patients by Alvarez et al., five out of 16 patients with VZV central nervous system infection were immunocompromised [19]. In another analysis by Pahud et al. of 26 patients, 20 were immunocompromised [20], whereas in an analysis by Tabaja et al., only three out of 20 patients had any degree of immunosuppression (i.e., active malignancy, chemotherapy or biological agents)[21] and in an analysis by Becerra et al. two out of 11 were immunocompromised [22]. Lenfant et al. reported 42% immunosuppression in their analysis [23].
Therefore, our data are comparable with these analyses since, in the present study, only 28.6% of patients were immunocompromised, with three having an active malignancy and one having a rheumatologic condition under long- term corticosteroid treatment. Interestingly, none of our patients had a diagnosis of HIV infection.
Varicella zoster virus reactivation, resulting in central nervous system disease, seems to affect people of all ages. However, older patients are at a higher risk. Petitgas et al. analyzed patients enrolled in the ENCEIF cohort, a French cohort of older patients with encephalitis, and the incidence of VZV-related encephalitis increased with age, with 30% of cases in those over 80 years old, 15% of cases in the 65-79 years of age group and 7% in those younger than 65 years of age [24]. These findings are consistent with the findings of Arruti et al., where 23 cases of confirmed VZV presented in a population over 65 years of age. In that analysis, VZV encephalitis was the most common cause of viral encephalitis, ahead of HSV. Arruti et al. also reported increased mortality with increasing age or time elapsed from the onset of symptoms to treatment initiation and a high percentage of neurologic sequelae at discharge (40%) [25]. Also consistent are the findings of Herlin et al., who described 92 patients in Denmark where the median age was 75, there was a high percentage of immunocompromised patients. Unfavorable outcomes were 69% at discharge, whereas three- month mortality was up to 11% [26]. Our study differs in that the median age was below 55 (even when excluding the youngest, an infant with acute leukemia, from the analysis); however, the representation of older people was strong, with five out of 14 patients over 65 years.
The presence of VZV central nervous disease in the absence of dermatological findings is increasingly recognized. In a retrospective analysis of 11 people living with HIV and VZV CNS infection, only four presented with skin findings [15]. This also seems to be the case in immunocompetent populations, as shown in previously mentioned analyses [2]. This analysis, however, is consistent with the traditional clinical course of VZV reactivation, with eight out of 14 patients presenting with vesicular lesions. Of note was that the rash preceded the neurological image in only five patients.
The absence of inflammatory syndrome is an important finding that is also being observed. In the present study, two patients (excluding a case of acute leukemia) presented with WBC over 10,000/mm3 and none above 15,000. Of note, only four had CRP levels higher than 1 mg/dL, and only five presented with fever before hospitalization. These findings are consistent with the literature. In the analysis by Becerra et al., over half of the population presented with absent inflammatory syndrome, and in the analysis by Tabaja et al., 79% had a WBC count of less than 11,000/mm3 [21,22]. Herlin et al. and Han et al. also reported median values of WBCs below 10,000/mm3 [17,26]. Lenfant et al. report a broader range of inflammatory markers as expressed by CRP; however, in their between- groups comparison (favorable versus unfavorable outcomes), there was no statistical significance [23]. This is consistent with the findings of Yuan et al. [27]
In the present study, a subanalysis was performed among patients who presented with zoster rash and those who presented without such a rash. Patients who had a rash differed slightly from those who did not, being slightly older, having a slightly higher Charlson comorbidity index, not having photophobia or phonophobia, and having higher serum CRP. However, the small number of patients presented herein may have affected the power of the analysis. Thus, larger studies are needed to evaluate whether these differences were due to chance. Independently of whether presentation without a rash constitutes a different disease phenotype, the absence of the rash could be misleading, making clinicians think that VZV infection is unlikely, thus making them less likely to empirically treat with antivirals for VZV CNS infection [20]. This could lead to significant delays in appropriate treatment, possibly affecting the disease outcome [20].
The management of central nervous system infections is based on administering intravenous acyclovir; however, guidelines suggest that it is not based on large-scale trials. Guidelines from the Infectious Diseases Society of America (IDSA) refer only to encephalitis, with the recommendation of acyclovir having a rating of B-III (moderate evidence, based on expert opinions/clinical experience/descriptive studies). Based on that guideline, the preferred regimen is acyclovir, with ganciclovir being an alternative. No recommendation is made for the use of corticosteroids [28]. Valacyclovir, an oral agent with good bioavailability, is also used in some cases and has been successfully used in the treatment of VZV encephalitis [21]. In the present study, all 14 patients were initially treated with intravenous acyclovir. Eight of them received oral valacyclovir later on. Recovery from infection was noted for 13 out of 14 patients. The only patient who died probably succumbed to the primary cause that was associated with his immunosuppression (acute leukemia in an infant that required intensive care).
Cognitive impairment after VZV infection is a significant complication after the resolution of the infection. Grahn et al. demonstrated this in a case-control study of 14 patients who experienced VZV central nervous system infection as compared to healthy individuals, finding that the study population had significant long-term cognitive impairment [29]. In a series of 23 patients with VZV meningitis, Liu et al. also demonstrated cognitive decline, and the Montreal Cognitive Assessment (MoCA) scores of these patients were significantly lower than those of the control group. Additionally, cellular metabolism, as demonstrated by MRI in that series, was impaired in the hippocampal regions bilaterally [30]. Moreover, the overall functional status can be affected after VZV central nervous system infection is resolved. In a retrospective multicenter analysis of 72 patients, Lenfant et al. showed that although aseptic meningitis had a better prognosis, increased protein levels in the cerebrospinal fluid were associated with a steeper decline in neurological functionality estimates (as expressed via the modified Rankin scale). In that same analysis, 60% of the patients had unfavorable outcomes, and of those who completed follow-up, 12.9% died [23].
This study has some notable limitations. First, it is a single-center study with quite a small number of patients. Thus, the results should be read with caution since they represent the patterns of a specific geographical area. The small number of patients precluded the conduction of statistical analysis. Moreover, data about patients hospitalized in other hospitals whose cerebrospinal fluid samples were positive during the study period were not included in the present study. Third, some information about the included patients may have been missed. Additionally, diagnosing VZV CNS infection was based on PCR, identifying VZV’s genetic material. However, in most cases, the technique used was qualitative; thus, the data about the DNA quantity is unavailable for all patients. Finally, repeat serology was not performed, even though it is not the suggested method for diagnosing zoster or VZV CNS infection.
Conclusions
Patients presenting with VZV CNS infection in the present study had lymphocytic pleocytosis in the CSF and usually had a favorable outcome with antiviral treatment. The clinical presentation may not include the development of a typical zoster rash in almost half the cases. These patients may be slightly younger, have slightly lower Charlson comorbidity index, be more likely to present with photophobia or phonophobia, and have lower serum CRP. Those presenting without a rash may have a different overall clinical phenotype from those with a rash; however, this must be evaluated in larger studies in the future.
Author Contributions
KA contributed to the investigation, data analysis, and preparation of the original draft. PI the data analysis, visualization, and preparation of the original draft. GS contributed to the investigation and preparation of the original draft. DK contributed to the preparation of the original draft, the project administration, and the supervision. All authors read and approved the final version of the manuscript.
Funding
None to declare.
Institutional Review Board Statement
The study was conducted following the Declaration of Helsinki and approved by the Institutional Review Board of the University Hospital of Heraklion (protocol code 08/24-03-2021).
Conflicts of Interest
All authors – none to declare.
References
- Andrei, G.; Snoeck, R. Advances and perspectives in the management of varicella-zoster virus infections. Molecules. 2021, 26, 1132. [Google Scholar] [CrossRef] [PubMed]
- Chamizo, F.J.; Gilarranz, R.; Hernández, M.; Ramos, D.; Pena, M.J. Central nervous system infections caused by varicella-zoster virus. J Neurovirol. 2016, 22, 529–532. [Google Scholar] [CrossRef]
- Le Bot, A.; Ballerie, A.; Pronier, C.; et al. Characteristics and outcome of varicella-zoster virus central nervous system infections in adults. Eur J Clin Microbiol Infect Dis. 2021, 40, 2437–2442. [Google Scholar] [CrossRef]
- Petitgas, P.; Tattevin, P.; Mailles, A.; et al. Infectious encephalitis in elderly patients: a prospective multicentre observational study in France 2016-2019. Infection. 2023, 51, 859–867. [Google Scholar] [CrossRef]
- Platanaki, C.; Leonidou, L.; Siagkris, D.; Giannopoulou, Ι.; Paliogianni, F.; Velissaris, D. Varicella-zoster virus aseptic meningitis: an atypical presentation in an immunocompetent male patient. Oxf Med Case Reports. 2021, 2021, omab035. [Google Scholar] [CrossRef]
- Nguyen, A.; Bauler, L.; Hoehn, C.; Mastenbrook, J. varicella zoster virus meningoencephalitis with an atypical presentation of chest pain, impaired memory, and seizure. J Emerg Med. 2020, 59, e175–e178. [Google Scholar] [CrossRef]
- Wilken, M.; Ameghino, L.; Cammarota, Á.; Nogués, M.A.; Del Castillo, M.; Farez, M.F. Clinical and cerebrospinal fluid findings contribute to the early differentiation between infectious and noninfectious encephalitis. Medicina (B Aires). 2017, 77, 214–221. [Google Scholar]
- Hong, H.L.; Lee, E.M.; Sung, H.; Kang, J.K.; Lee, S.A.; Choi, S.H. Clinical features, outcomes, and cerebrospinal fluid findings in adult patients with central nervous system (CNS) infections caused by varicella-zoster virus: comparison with enterovirus CNS infections. J Med Virol. 2014, 86, 2049–2054. [Google Scholar] [CrossRef] [PubMed]
- Andrei, G.; Snoeck, R. Advances and perspectives in the management of varicella-zoster virus infections. Molecules. 2021, 26, 1132. [Google Scholar] [CrossRef]
- Tu, R.; Liu, J.; Cheng, F.; et al. Case report: unusual varicella-zoster virus meningoencephalitis with meningomyelitis mimicking central nervous system leukemia. Front Med (Lausanne). 2022, 9, 847219. [Google Scholar] [CrossRef] [PubMed]
- Yamashita, Y.; Kusakabe, S.; Toda, J.; et al. Sequential onset of varicella-zoster virus encephalomeningitis and progressive multifocal leukoencephalopathy in an allogeneic hematopoietic stem cell transplant recipient. Exp Clin Transplant. 2018, 16, 628–630. [Google Scholar]
- Benavente, K.; Kozai, L.; Silangcruz, K.; Banerjee, D. The risks of rejection vs. infection: Ramsay Hunt syndrome, Gradenigo syndrome, and varicella meningoencephalitis in a heart transplant patient. Eur Heart J Case Rep. 2023, 7, ytad373. [Google Scholar] [CrossRef]
- Issa, N.P.; Hentati, A. VZV encephalitis that developed in an immunized patient during fingolimod therapy. Neurology. 2015, 84, 99–100. [Google Scholar] [CrossRef]
- Tao, T.; Chen, J.; Long, K.; et al. Severe varicella-zoster virus meningoencephalomyelitis coexisting with visceral disseminated varicella-zoster virus infection in a patient with lupus nephritis: a case report. Medicine (Baltimore). 2023, 102, e33459. [Google Scholar] [CrossRef]
- Gray, F.; Bélec, L.; Lescs, M.C.; et al. Varicella-zoster virus infection of the central nervous system in the acquired immune deficiency syndrome. Brain 1994, 117, 987–999. [Google Scholar] [CrossRef]
- Reimer-Mcatee, M.; Ramirez, D.; Mcatee, C.; Granillo, A.; Hasbun, R. Encephalitis in HIV-infected adults in the antiretroviral therapy era. J Neurol. 2023, 270, 3914–3933. [Google Scholar] [CrossRef] [PubMed]
- Han, S.; Choi, H.; Kim, J.; Park, K.; Youn, Y.C.; Shin, H. Etiology of aseptic meningitis and clinical characteristics in immune-competent adults. J Med Virol. 2016, 88, 175–179. [Google Scholar] [CrossRef] [PubMed]
- Gaudin, M.; Theïs, C.; Mrozek, N.; et al. Varicella zoster virus and meningitis in immunocompetent patients: specificity and questions. Clin Infect Pract. 2022, 13, 100125. [Google Scholar] [CrossRef]
- Alvarez, J.C.; Alvarez, J.; Tinoco, J.; et al. Varicella-zoster virus meningitis and encephalitis: an understated cause of central nervous system infections. Cureus. 2020, 12, e11583. [Google Scholar] [CrossRef] [PubMed]
- Pahud, B.A.; Glaser, C.A.; Dekker, C.L.; Arvin, A.M.; Schmid, D.S. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J Infect Dis. 2011, 203, 316–323. [Google Scholar] [CrossRef]
- Tabaja, H.; Sharara, S.L.; Abi Aad, Y.; et al. Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon. Med Mal Infect. 2020, 50, 280–287. [Google Scholar] [CrossRef] [PubMed]
- Becerra, J.C.L.; Sieber, R.; Martinetti, G.; Costa, S.T.; Meylan, P.; Bernasconi, E. Infection of the central nervous system caused by varicella zoster virus reactivation: a retrospective case series study. Int J Infect Dis. 2013, 17, e529–e534. [Google Scholar] [CrossRef] [PubMed]
- Lenfant, T.; L'Honneur, A.S.; Ranque, B.; et al. Neurological complications of varicella zoster virus reactivation: prognosis, diagnosis, and treatment of 72 patients with positive PCR in the cerebrospinal fluid. Brain Behav. 2022, 12, e2455. [Google Scholar] [CrossRef] [PubMed]
- Petitgas, P.; Tattevin, P.; Mailles, A.; Fillâtre, P.; Stahl, J.P. Infectious encephalitis in elderly patients: a prospective multicentre observational study in France 2016-2019. Infection. 2023, 51, 859–867. [Google Scholar] [CrossRef]
- Arruti, M.; Piñeiro, L.D.; Salicio, Y.; Cilla, G.; Goenaga, M.A.; López de Munain, A. Incidence of varicella zoster virus infections of the central nervous system in the elderly: a large tertiary hospital-based series (2007-2014). J Neurovirol. 2017, 23, 451–459. [Google Scholar] [CrossRef]
- Herlin, L.K.; Hansen, K.S.; Bodilsen, J.; et al. Varicella zoster virus encephalitis in denmark from 2015 to 2019-a nationwide prospective cohort study. Clin Infect Dis. 2021, 72, 1192–1199. [Google Scholar] [CrossRef]
- Yuan, Y.; Wang, J.; Zhang, Y.; Liu, H.; Yan, Y. Factors predictive of varicella zoster virus encephalitis/meningitis: a single-center, retrospective study. Med Sci Monit. 2022, 28, e938057. [Google Scholar] [CrossRef]
- Tunkel, A.R.; Glaser, C.A.; Bloch, K.C.; et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008, 47, 303–327. [Google Scholar] [CrossRef]
- Grahn, A.; Bergström, T.; Runesson, J.; Studahl, M. Varicella-zoster virus (VZV) DNA in serum of patients with VZV central nervous system infections. J Infect. 2016, 73, 254–260. [Google Scholar] [CrossRef]
- Liu, H.; Wang, J.; Yuan, Y.; Gu, J.; Yan, Y. Hippocampal metabolic alterations and cognitive dysfunction in varicella zoster virus meningitis: a single-center case series study. Med Sci Monit. 2023, 29, e939670. [Google Scholar] [CrossRef]
Table 1.
Characteristics of individual patients with varicella zoster virus central nervous system infection.
Table 1.
Characteristics of individual patients with varicella zoster virus central nervous system infection.
| Patient number | Age (years) and gender | Medical history | Charlson comor- bidity index | Duration of symptoms until presentation (days) | Symptoms | Empirical antivirals for CNS infection | Duration of treatment in total (and IV) | Outcome |
|---|---|---|---|---|---|---|---|---|
| 1 | 23F | None | 0 | NR | NR | NR | NR | Survived |
| 2 | 1F | Leukemia | 2 | 1 | AMS. Fever, rash | Yes | NA (4) | Died |
| 3 | 83F | Malignancy (non- active), hypothyroidism | 4 | 5 | Rash, FNS, fever, headache | No | 14 (14) | Survived |
| 4 | 47M | MS, HTN | 1 | 4 | Headache, nausea, AMS, rash | Yes | 14 (2) | Survived |
| 5 | 31F | None | 0 | 5 | Fever, photophobia, neck stiffness. headache | Yes | 14 (9) | Survived |
| 6 | 40F | Malignancy (active) | 0 | 4 | Headache, neck stiffness, photophobia, phonophobia, nausea, fever | No | 14 (10) | Survived |
| 7 | 44F | None | 0 | 15 | Rash, headache | Yes | 14 (9) | Survived |
| 8 | 58M | CVD, malignancy (active) | 9 | 0 | Headache, AMS, FNS, behavioral changes, seizures | No | NR | Survived |
| 9 | 86M | CVD, AF, dementia, COPD, malignancy (non-active) | 8 | 3 | Rash, AMS, nausea | Yes | 5 (9) | Survived |
| 10 | 88M | DM, COPD, CVD, HF, AF, HTN, CKD | 10 | 2 | Headache, AMS, rash | Yes | 14 (14) | Survived |
| 11 | 76F | Dementia | 4 | 10 | Rash, FNS, behavioral changes | No | 24 (14) | Survived |
| 12 | 69F | CTD, HTN, dyslipidemia | 3 | 4 | Headache, nausea, neck stiffness, fever, rash | Yes | 21 (14) | Survived |
| 13 | 44F | Hypothyroidism, depression | 0 | 10 | FNS, photophobia, AMS, neck stiffness, headache | Yes | 14 (14) | Survived |
| 14 | 51M | None | 2 | 1 | Headache, photophobia, phonophobia | Yes | 14 (10) | Survived |
AF – atrial fibrillation; AMS – altered mental status; CKD – chronic kidney disease; CNS – central nervous system; COPD – chronic obstructive pulmonary disease; CTD – connective tissue disorder; CVD – cerebrovascular disease; DM – diabetes mellitus; F – female; FNS – focal neurological symptoms; HF – heart failure; HTN – hypertension; IV – intravenously; M – male; MS – multiple sclerosis; NA – not applicable; NR – not reported.
Table 2.
Clinical and epidemiological characteristics of patients with varicella zoster virus central nervous system infection in total and in regards to whether they had a rash.
Table 2.
Clinical and epidemiological characteristics of patients with varicella zoster virus central nervous system infection in total and in regards to whether they had a rash.
| Characteristic | All patients (n=14) | Patients with a rash (n=8) | Patients without a rash (n=6) |
|---|---|---|---|
| Male gender, n (%) | 5 (35.7) | 3 (37.5) | 2 (33.3) |
| Age, years, median (IQR) | 49 (37.8-77.8) | 72.5 (44.8-85.3) | 42 (29-52.8) |
| Charlson comorbidity index, median (IQR) | 2 (0-5) | 3.5 (1.3-7) | 0 (0-3.8) |
| Hypertension, n (%) | 3 (21.4) | 3 (37.5) | 0 (0) |
| Active cancer, n (%) | 3 (21.4) | 1 (12.5) | 2 (33.3) |
| CVD, n (%) | 3 (21.4) | 2 (25) | 1 (16.7) |
| Previous cancer, n (%) | 2 (14.3) | 2 (25) | 0 (0) |
| Dementia, n (%) | 2 (14.3) | 2 (25) | 0 (0) |
| COPD, n (%) | 2 (14.3) | 2 (25) | 0 (0) |
| Diabetes mellitus, n (%) | 1 (7.1) | 1 (12.5) | 0 (0) |
| CKD, n (%) | 1 (7.1) | 1 (12.5) | 0 (0) |
| Dyslipidemia, n (%) | 1 (7.1) | 1 (12.5) | 0 (0) |
| Rheumatologic disease, n (%) | 1 (7.1) | 1 (12.5) | 0 (0) |
| Heart failure, n (%) | 1 (7.1) | 1 (12.5) | 0 (0) |
| Clinical characteristics | |||
| Duration of symptoms (days), median (IQR) | 4 (1.5-7.5) | 4 (2.3-8.8) | 4 (0.5-7.5) |
| Headache, n (%) | 10 (71) | 5 (62.5) | 5 (83.3) |
| Rash, n (%) | 8 (57.1) | 8 (100) | 0 (0) |
| Nausea/vomiting, n (%) | 5 (35.7) | 3 (37.5) | 2 (33.3) |
| Disorientation, n (%) | 5 (35.7) | 4 (50) | 1 (13.3) |
| Fever, n (%) | 5 (35.7) | 3 (37.5) | 2 (33.3) |
| Focal neurologic signs, n (%) | 4 (28.6) | 2 (25) | 2 (33.3) |
| Photophobia, n (%) | 4 (28.6) | 0 (0) | 4 (66.7) |
| Phonophobia, n (%) | 2 (14.3) | 0 (0) | 2 (33.3) |
| Behavioral changes, n (%) | 2 (14.3) | 0 (0) | 2 (33.3) |
| Seizures, n (%) | 1 (7.1) | 0 (0) | 1 (16.7) |
| Empirical antivirals for CNS infection, n (%) | 9 (69.2) | 6 (75) | 3 (60) |
| Antivirals after diagnosis, n (%) | 13 (100) | 8 (100) | 5 (100) |
| Intravenous to oral antiviral switch, n (%) | 8 (66.7) | 5 (62.5) | 3 (75) |
| Duration of intravenous treatment, days, med (IQR) | 10 (7-14) | 11.5 (5.3-14) | 10 (7-12) |
| Duration of treatment, days, median (IQR) | 14 (14-14) | 14 (14-21) | 14 (14-14) |
| ICU admission, n (%) | 1 (7.1) | 1 (12.5) | 0 (0) |
| Duration of hospitalization, days, median (IQ | 9.5 (7.5-14.5) | 11 (5-16) | 9.5 (7.5-12.5) |
| Mortality, n (%) | 1 (7.1) | 1 (12.5) | 0 (0) |
CKD – chronic kidney disease; COPD – chronic obstructive pulmonary disease; CVD – cerebrovascular disease; ICU – intensive care unit; IQR – interquartile range; NA – not applicable.
Table 3.
Laboratory characteristics of patients with varicella zoster virus central nervous system infection in total and in regards to whether they had a rash.
Table 3.
Laboratory characteristics of patients with varicella zoster virus central nervous system infection in total and in regards to whether they had a rash.
| Characteristic | All patients (n=14) | Patients with a rash (n=8) | Patients without a rash (n=6) |
| CSF glucose, mg/dL, median (IQR) | 57.5 (50.5-67.8) | 57 (49.5-79) | 59 (48.5-64) |
| Serum glucose, mg/dL, median (IQR) | 115 (98.5-127.8) | 120.5 (103.8-139.8) | 104.5 (92.3-117) |
| CSF to serum glucose ratio, median (IQR) | 50.8 (46.8-55.1) | 48.9 (44.7-53.9) | 54.1 (46.7-62.4) |
| CSF protein, mg/dL, median (IQR) | 118 (89.8-207.3) | 97.3 (65-165.8) | 161 (109.4-245) |
| CSF WBCs, /mm3, median (IQR) | 164 (35.8-435.8) | 98.5 (26-331) | 416 (119.8-588) |
| CSF lymphocytes among white cells, %, median (IQR) | 88 (72-92) | 87 (67.5-91) | 88 (71.3-93) |
| WBCs in blood, /mm3, median (IQR) | 8,250 (5,175-10,100) | 8,250 (5,150-13,100) | 8,050 (5,100-10,100) |
| Neutrophils in blood, /mm3, median (IQR) | 4,750 (3,325-6,725) | 4,550 (2,975-5,175) | 5,550 (3,450-8,075) |
| Lymphocytes in blood, /mm3, median (IQR) | 1,550 (650-2,325) | 1,600 (425-2,475) | 1,300 (775-1,925) |
| Platelets, /mm3, median (IQR) | 193,000(175,800- 257,800) | 183,500 (171,300- 233,500) | 248,500 (189,000- 372,300) |
| CRP upon admission, mg/dL, median (IQR) | 0.59 (0.1-2.3) | 1.4 (0.3-5.6) | 0.1 (0.5-0.8) |
| Creatinine upon admission, mg/dL, median (IQR) | 0.81 (0.69-1) | 0.9 (0.7-1.4) | 0.8 (0.7-0.9) |
| Urea upon admission, mg/dL, median (IQR) | 26.5 (18.8-44.8) | 34.5 (19.5-62.8) | 23 (18.8-31.8) |
| Sodium upon admission, mEq/L, median (IQR) | 138 (134.8-140) | 137.5 (134.3-140.5) | 138 (134.8-140) |
| MRI done, n (%) | 7 (53.8) | 4 (57.1) | 3 (50) |
| Abnormal findings in MRI, n (%) | 5 (71.4) | 3 (75) | 2 (66.7) |
CSF – cerebrospinal fluid; IQR – interquartile range; MRI – magnetic resonance imaging; NA – not applicable; WBC – white blood cells.
© GERMS 2024.
Share and Cite
MDPI and ACS Style
Alexakis, K.; Ioannou, P.; Sourvinos, G.; Kofteridis, D.P. Varicella Zoster Virus Central Nervous System Infection—A Retrospective Study from a Tertiary Center in Greece. GERMS 2024, 14, 267-276. https://doi.org/10.18683/germs.2024.1437
AMA Style
Alexakis K, Ioannou P, Sourvinos G, Kofteridis DP. Varicella Zoster Virus Central Nervous System Infection—A Retrospective Study from a Tertiary Center in Greece. GERMS. 2024; 14(3):267-276. https://doi.org/10.18683/germs.2024.1437
Chicago/Turabian StyleAlexakis, Konstantinos, Petros Ioannou, George Sourvinos, and Diamantis P. Kofteridis. 2024. "Varicella Zoster Virus Central Nervous System Infection—A Retrospective Study from a Tertiary Center in Greece" GERMS 14, no. 3: 267-276. https://doi.org/10.18683/germs.2024.1437
APA StyleAlexakis, K., Ioannou, P., Sourvinos, G., & Kofteridis, D. P. (2024). Varicella Zoster Virus Central Nervous System Infection—A Retrospective Study from a Tertiary Center in Greece. GERMS, 14(3), 267-276. https://doi.org/10.18683/germs.2024.1437
