Infection of the central nervous system caused by varicella zoster virus reactivation: a retrospective case series study

Open AccessPublished:April 08, 2013DOI:https://doi.org/10.1016/j.ijid.2013.01.031

      Summary

      Background

      Recent data suggest that varicella zoster virus (VZV)-associated complications of the central nervous system (CNS) are more common and diverse than previously thought. The main purpose of this article is to describe the clinical characteristics and the outcome of patients suffering from meningitis and encephalitis caused by VZV reactivation.

      Methods

      A retrospective case study of adult patients (≥16 years old) diagnosed with a VZV reactivation in the CNS was performed. The cases were identified by a qualitative PCR DNA assay of the cerebrospinal fluid (CSF) at the Regional Hospital of Lugano between January 1, 2003 and July 31, 2010.

      Results

      Eleven out of 519 CSF samples (2.1%), submitted from patients with a clinical diagnosis of viral meningitis or encephalitis, were positive for VZV. A vesiculo-pustular skin eruption was observed in only five patients (45%). In six cases (55%), a systemic inflammatory syndrome was absent. The clinical outcome was favorable in eight patients (73%). Only one out of 11 patients (9%) died. The four patients with encephalitis had a less favorable prognosis: one patient recovered without residual neurological sequelae; two had a chronic neuropsychological handicap, speech difficulties, facial nerve palsy, and focal seizures; one patient died. We estimated an annual incidence rate of VZV infection of the CNS of 1.02/100 000 inhabitants for southern Switzerland.

      Conclusions

      Screening of CSF for VZV by PCR is recommended for all patients with encephalitis and for those with viral meningitis of unclear origin in order to better target antiviral treatment.

      Keywords

      1. Introduction

      Varicella zoster virus (VZV) is ubiquitous throughout the world. Initial infection with VZV results in chickenpox (varicella), which is typically seen in children aged 1–9 years. In most temperate climates, more than 90% of people are infected before adolescence.
      • Mueller N.H.
      • Gilden D.H.
      • Cohrs R.J.
      • Mahalingam R.
      • Nagel M.A.
      Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency.
      Recent data suggest that central nervous system (CNS) complications caused by VZV reactivation are more common than previously thought.
      • Kleinschmidt-DeMasters B.K.
      • Gilden D.H.
      Varicella-zoster virus infections of the nervous system: clinical and pathologic correlates.
      VZV is the third most frequent causal agent of viral meningitis after enterovirus and herpes simplex virus type 2, with a frequency ranging from 5% to 29%.
      • Frantzidou F.
      • Kamaria F.
      • Dumaidi K.
      • Skoura L.
      • Antoniadis A.
      • Papa A.
      Aseptic meningitis and encephalitis because of herpesviruses and enteroviruses in an immunocompetent adult population.
      • Koskiniemi M.
      • Rantalaiho T.
      • Piiparinen H.
      • von Bonsdorff C.H.
      • Färkkilä M.
      • Järvinen A.
      • et al.
      Infections of the central nervous system of suspected viral origin: a collaborative study from Finland.
      • Kupila L.
      • Vuorinen T.
      • Vainionpää R.
      • Hukkanen V.
      • Marttila R.J.
      • Kotilainen P.
      Etiology of aseptic meningitis and encephalitis in an adult population.
      Since the introduction of DNA amplification by PCR for the diagnosis of VZV in the CNS at the beginning of the 1990s, the number of diagnosed cases has increased.
      • DeBiasi R.L.
      • Tyler K.L.
      Molecular methods for diagnosis of viral encephalitis.
      However, only a few epidemiological studies are available in which clinical characteristics and outcome are described.
      Infectious manifestations referring to the CNS are multiple and include myelopathy, encephalitis, meningitis, and vasculopathy.
      • Kleinschmidt-DeMasters B.K.
      • Gilden D.H.
      Varicella-zoster virus infections of the nervous system: clinical and pathologic correlates.
      The possibility of infectious reactivation without the characteristic vesicular rash (zoster sine herpete) makes the diagnosis even more difficult.
      The main purpose of this article is to describe the clinical characteristics and the outcome of patients suffering from meningitis and encephalitis caused by VZV reactivation seen at a community-based hospital.

      2. Methods

      2.1 Study design

      This was a retrospective study based on the review of the clinical characteristics of adults (≥16 year old) suffering a VZV reactivation in the CNS diagnosed by VZV PCR in the cerebrospinal fluid (CSF).

      2.2 Data collection

      We collected clinical information on patients with infection of the CNS caused by VZV admitted to the emergency department of the Regional Hospital of Lugano between January 1, 2003 and July 31, 2010. The decision to perform a PCR test for VZV was taken by the emergency physician. Patients with neurological symptoms, detectable VZV DNA in the CSF, and available clinical records were included in the study.
      The Regional Hospital of Lugano is a 280-bed facility and the main referral hospital for about 134 000 inhabitants.
      • DeBiasi R.L.
      • Tyler K.L.
      Molecular methods for diagnosis of viral encephalitis.
      Lugano is the largest city of the Canton of Ticino, a region of southern Switzerland with a population of 340 000.

      Republica del Canton Ticino. Ufficio di Statistica. Popolazione residente permanente al 31 dicembre, secondo il sesso, 2007 e 2008, e a metà dell’anno, 2008. Available at: http://www.ti.ch/DFE/USTAT/DATI_COMUNI [accessed 19.11.12].

      PCR for the detection of VZV DNA was developed in the early nineties, but its use has become widespread in the last 10 years. Virological diagnosis is performed at the Bellinzona's Cantonal Institute of Microbiology, a laboratory that has offered VZV PCR in the CSF since 2001 and processes all samples of suspected cases in Ticino. This enabled us to estimate the average annual incidence of infections of the CNS caused by VZV for our region.

      2.3 Case definition

      Viral meningitis was defined as: symptoms and/or signs of meningeal inflammation without evidence of brain parenchymal involvement; CSF leukocyte count over 5 × 106/l; a negative CSF bacterial culture; and the absence of a non-infectious etiology to explain the clinical findings. Encephalitis was diagnosed if the patient presented signs of cerebral parenchymal involvement, i.e. acutely altered consciousness or personality changes, epileptic seizures or focal neurologic signs, and either an elevated CSF white blood cell count (WBC) (over 5 × 106/l) or protein level >40 mg/l, or neuroradiological and electroencephalogram (EEG) findings consistent with encephalitis.
      In the absence of an immunocompromising disease or immunosuppressive drugs, the patients were considered to be immunocompetent.
      Descriptive statistics were performed by means of Excel software (Microsoft Corp.).

      2.4 VZV nucleic acid extraction, PCR, and melting curve analysis

      Nucleic acids were extracted from a 0.2-ml volume of CSF by total nucleic acid protocol on a MagNA Pure Compact instrument (Roche Molecular Biochemical) in accordance with the manufacturer's instructions. DNA was eluted in a final volume of 100 μl. All samples were amplified by LightCycler PCR (Roche) with primers directed to ORF 29 of the virus: sense, 5′-TGT CCT AGA GGA GGT TTT ATC TG-3′; antisense primer, 5′-CAT CGT CTG TAA GAC TTA ACC AG-3′, as previously described.
      • Espy M.J.
      • Teo R.
      • Ross T.K.
      • Svien K.A.
      • Wold A.D.
      • Uhl J.R.
      • et al.
      Diagnosis of varicella-zoster virus infections in the clinical laboratory by LightCycler PCR.
      The composition of the master mix was as previously described,
      • Espy M.J.
      • Teo R.
      • Ross T.K.
      • Svien K.A.
      • Wold A.D.
      • Uhl J.R.
      • et al.
      Diagnosis of varicella-zoster virus infections in the clinical laboratory by LightCycler PCR.
      except for the use of FastStart DNA Master SYBR Green and the addition of dUTP/uracil glycosylase for the prevention of carry-over contaminations.
      For the assay, a 5-μl aliquot of nucleic acid extract was added to 15 μl of PCR mixture in each reaction capillary. All capillaries were then sealed and amplified using the following protocol: 37 °C for 10 min for one cycle, 95 °C for 10 min for one cycle to activate HotStart Taq polymerase, followed by denaturation at 95 °C for 10 s, 10 s of annealing at 62 °C, and 12 s of primer extension at 72 °C for 45 cycles.
      To demonstrate the specificity of the PCR product, a melting curve analysis was performed following PCR amplification. Starting at 54 °C, the temperature in the thermal chamber was slowly raised (0.2 °C/s) to 95 °C, and fluorescence measured continuously. PCR products of the expected amplified fragment of gene 29 produce a melting curve peaking at 66–68 °C.

      3. Results

      During the study period, 11 cases were diagnosed out of 519 CSF samples tested for VZV (2.1%). We observed a progressive increase in the requests for a VZV test for CNS infections following the introduction of the specific DNA PCR technique at our microbiology laboratory. Despite this increased diagnostic activity, the incidence of identified cases remained unchanged. The average annual incidence of CNS infections caused by VZV during the period 2003–2010 stands at 1.02 (standard deviation 0.79) cases for 100 000 inhabitants.
      The median age of patients with VZV reactivation in the CNS was 48 years (range 27–75 years), with only three patients over the age of 60 years. Seven patients (64%) were men (Table 1). The most frequent symptoms and signs were headache (64%), fever (54%), and neck stiffness (27%). In six patients (55%), a systemic inflammatory syndrome (WBC >10 × 106/l and C-reactive protein (CRP) >5 mg/l) was absent. A vesiculo-pustular skin eruption was observed in five patients (45%) (Table 1, Table 2). Only two patients (18%) were immunodeficient. One patient had an advanced HIV disease (Centers for Disease Control and Prevention (CDC) stage C), the second was receiving immunosuppressive therapy with azathioprine and cyclosporine after renal transplantation. The median length of hospital stay was 14 days (range 2–43 days). Ten patients (91%) received the recommended treatment with intravenous acyclovir (10–15 mg/kg body weight every 8 h for 10 days). The course was favorable in eight cases (73%). Only the patient with advanced HIV disease died; death occurred on the second day after admission. He displayed behavioral changes with no rise in CSF WBC and therefore he did not receive a specific antiviral treatment.
      Table 1Annual distribution of cases of CNS infections caused by VZV, 2003–2010
      YearTotal number of positive samplesPositive sample results
      200342 (8.1%)2 (18%)
      200440 (7.7%)2 (18%)
      200571 (13.6%)3 (27%)
      200675 (14.4%)0
      200780 (15.4%)1 (9%)
      200875 (14.4%)0
      200993 (17.9%)1 (9%)
      Until May 201043 (8.2%)2 (18%)
      Total519 (100%)11 (100%)
      CNS, central nervous system; VZV, varicella zoster virus.
      Table 2Clinical manifestations, laboratory results, and therapy of the patients suffering from VZV reactivation in the CNS, 2003–2010
      DiagnosisYearSexAgeClinical manifestationsRashHIV statusOther immunosuppressive conditionsWBC, ×109/lPCR, mg/lLeukocytes in CSF, ×106/lProtein in CSF, mg/lDuration of hospital stay, daysOutcomeTherapy
      Meningitis2003M59Headache, feverPresentNegNo71.9360127011No neurological sequelaeAcyclovir IV
      Meningitis2004M49Headache, feverPresentNegNo10.83826005No neurological sequelaeAcyclovir IV
      Meningitis2005M36HeadacheAbsentNegNo11.12115721806No neurological sequelaeAcyclovir IV
      Meningitis2005F48Headache, feverPresentNegNo8.3023774014No neurological sequelaeAcyclovir IV
      Meningitis2005M28Headache, fever, neck stiffnessAbsentNegNo100.512073021No neurological sequelaeAcyclovir IV
      Meningitis2009M27Headache, photophobia neck stiffnessAbsentNegNo100.5403129215No neurological sequelaeAcyclovir IV and valacyclovir PO
      Meningitis2010F68Headache feverPresentNegNo8.7442689411No neurological sequelaeAcyclovir IV
      Encephalitis2004F48Fever, drowsiness, dysarthriaAbsentNDNo14.135.8228014Neuropsychological sequelaeAcyclovir IV
      Encephalitis2006M36Altered consciousnessAbsentPosNo2.7124.322802DiedNo
      Encephalitis2007M66Ocular pain, focal seizures at EEGPresent (herpes ophthalmicus)NegImmunosuppressive therapy with azathioprine and cyclosporine216.61747543Focal seizuresAcyclovir IV
      Encephalitis2010F75Headache, VII cranial nerve palsyHerpes oticusNegNo12.9416773524No neurological sequelaeAcyclovir IV and valacyclovir PO
      CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; F, female; IV, intravenous; M, male; ND, not determined; PCR, polymerase chain reaction; PO, per os (oral); VZV, varicella zoster virus; WBC, white blood cell count.
      Seven patients (64%) fulfilled the criteria for aseptic meningitis (Table 1). The median age of these patients was 48 years (range 27–68 years), five (71%) were males. All had headache, five (71%) had fever, and two (29%) had neck stiffness. The characteristic rash was absent in three (43%) of the cases. In three patients (43%), the systemic inflammatory parameters were normal. The median CSF WBC was 398 × 106/l (range 82–1167 × 106/l) and the protein concentration was 1101 mg/l (range 600–2180 mg/l). Six patients underwent neuroimaging: three magnetic resonance imaging (MRI) and three computed tomography (CT) scan. All the radiological findings were reported as normal or showing abnormalities consistent with pre-existing lesions. The median length of hospital stay was 11 days (range 5–21 days). The outcome was favorable in 100% of the meningitis cases.
      Four patients (36%) fulfilled the criteria for encephalitis (Table 1). The median age of these patients was 57 years (range 28–66 years) and two were males. The neurological manifestations of encephalitis were multiple: three displayed focal symptoms including speech difficulties, central facial palsy, and focal seizures. One patient had headache and another had fever. The median length of hospital stay in the encephalitis group was 19 days (range 2–43 days). Only two cases had the characteristic rash, whereas a systemic inflammatory syndrome was present in all cases. The median WBC in CSF was 47 × 106/l (range 2–167 × 106/l) and the protein concentration was 442 mg/l (range 280–735 mg/l). In two patients the leukocyte count in the CSF was normal. All patients had neuroimaging studies. Two had an MRI and two a CT scan. All the radiological images were found to be normal or showing abnormalities consistent with pre-existing lesions. One of the patients had an advanced HIV infection (CDC stage C3). The median length of hospital stay was 19 days (range 2–43 days). The diagnosis of encephalitis was associated with a worse outcome. Only one patient recovered without neurological sequelae. Two patients demonstrated important neuropsychological deficiencies and one patient died.

      4. Discussion

      Varicella zoster reactivation in the CNS is associated with a variety of serious and potentially lethal complications in both immunocompetent and immunocompromised individuals. In contrast to the classic textbook descriptions,
      • Persson A.
      • Bergström T.
      • Lindh M.
      • Namvar L.
      • Studahl M.
      Varicella-zoster virus CNS disease—viral load, clinical manifestations, and sequels.
      the present case series is characterized by the predominance of immunocompetent patients aged <60 years. Our results are therefore comparable to those reported by Persson et al. in Sweden,
      • Persson A.
      • Bergström T.
      • Lindh M.
      • Namvar L.
      • Studahl M.
      Varicella-zoster virus CNS disease—viral load, clinical manifestations, and sequels.
      Pahud et al. in California,
      • 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.
      and Pollak et al. in Israel,
      • Pollak L.
      • Dovrat S.
      • Book M.
      • Mendelson E.
      • Weinberger M.
      Varicella zoster vs. herpes simplex meningoencephalitis in the PCR era. A single center study.
      where the percentages of patients with immunodeficiency were 38%, 12%, and 10%, respectively.
      Another important difference between our study and earlier publications is the frequent absence of skin lesions, which were reported in only 45% of cases, as well as a missing systemic inflammatory syndrome in 55% of cases in the present study. In this respect, our results are comparable to those observed in the studies carried out by Persson et al.
      • Persson A.
      • Bergström T.
      • Lindh M.
      • Namvar L.
      • Studahl M.
      Varicella-zoster virus CNS disease—viral load, clinical manifestations, and sequels.
      and Pahud et al.,
      • 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.
      in populations with similar percentages of patients with an immunodeficiency.
      Traditionally, the vesicular rash is regarded as a characteristic finding for viral reactivation. However, several recent studies have confirmed the low sensitivity of this clinical sign, which is absent in more than a third of cases of CNS infection (Table 3).
      Table 3Clinical features and outcome of patients with CNS infection caused by VZV reactivation in the medical literature, 2000–2011
      YearCountryDesign of studyNumber of patientsWomenImmunocompromised patientsPresence of rash in VZV casesPatients with VZV encephalitisPatients with VZV meningitisOther clinical presentationsOutcome of patients with VZV encephalitisOutcome of patients with VZV meningitisMortalityRef.
      2012IsraelRetrospective2012 (60%)0100%12 (60%)8 (40%)02 (10%) mild neurological sequelaeFavorable012
      2011USAProspective2650%10 (38.4%)11 (42%)13 (50%)10 (38.4%)3 (11.5%) ADEMNAVNAVNAV11
      2009SwedenRetrospective97NAV12 (12.3%)62 (63.9%)34 (35%)28 (28.9%)39 (40.2%) encephalopathy, cerebrovascular disease10 (29.4%) severe neurological sequelae7 (25%) mild neurological sequelae2 (2%)10
      2009AustraliaRetrospective5926NAVNAVNAV226 (3.8%)NAPNAPNAVNAPNAP21
      2009FranceProspective25339%NAVNAV20 (7.9%)NAP0NAVNAP3 (1.1%)22
      2008UKRetrospective59NAV24 (40.6%)7 (70%)NAP10 (16.9%)NAPNAPNAVNAV13
      2008GreeceProspective81NAVNAVNAV02 (2.4%)0NAPFavorable03
      2006FinlandProspective14452.7%09 (75%)NAP12 (8.3%)NAPNAVNAVNAV5
      2005AustriaRetrospective3040%4 (13.3%)8 (26.6%)13 (43.3%)17 (56.6%)NAPNAVNAP1 (3.3%)24
      2003TaiwanProspective4142.5%NAVNAV5 (12.1%)NAPNAPNAVNAPNAV23
      2003GermanyRetrospective43NAVNAV1 (50%)NAP2 (4.6%)NAPNAP1 (2.5%) mild to moderate headache or cognitive deficits018
      2001UKRetrospective1526.6%15 (100%)4(44.4%)9 (60%)NAP6 (40%) isolated cranial nerve palsies1 (6.6%) severe neurological sequelaeNAP2 (13.3%)15
      2000FranceProspective34NAP34 (100%)24 (70.5%)13 (38.2%)6 (18%)15 (44%) radiculitis, myelitis4 (33%) severe neurological sequelaeNAV6 (17.6%)14
      ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; NAP, not applicable; NAV, not available; VZV, varicella zoster virus.
      The systemic inflammatory parameters were normal in almost half of our cases with meningitis. This observation was even more striking in the study by Ihekwaba et al.,
      • Ihekwaba U.K.
      • Kudesia G.
      • McKendrick M.W.
      Clinical features of viral meningitis in adults: significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections.
      where the mean level of CRP and the mean leukocyte count were within the normal range in patients with VZV meningitis. In the case series of Pollak et al., the mean leukocyte count was within the normal range in 85% of patients with a diagnosis of CNS VZV infection.
      • Pollak L.
      • Dovrat S.
      • Book M.
      • Mendelson E.
      • Weinberger M.
      Varicella zoster vs. herpes simplex meningoencephalitis in the PCR era. A single center study.
      CSF pleocytosis was absent in half of our small group of patients with encephalitis. This phenomenon is mainly observed in HIV-infected patients with VZV encephalitis (33–40%).
      • De La Blanchardiere A.
      • Rozenberg F.
      • Caumes E.
      • Picard O.
      • Lionnet F.
      • Livartowski J.
      • et al.
      Neurological complications of varicella-zoster virus infection in adults with human immunodeficiency virus infection.
      • Brown M.
      • Scarborough M.
      • Brink N.
      • Manji H.
      • Miller R.
      Varicella zoster virus-associated neurological disease in HIV-infected patients.
      Nevertheless, Persson found 5% of patients without CSF pleocytosis
      • Whitley R.J.
      Varicella-zoster virus.
      in a mixed population of immunocompetent and immunocompromised individuals. In fact, inflammatory parameters were higher in meningitis compared to encephalitis cases in the present study. This suggests that the inflammatory response may be related to immune mechanisms protecting from parenchymal involvement.
      In our series, all the brain images (MRI or CT scan) were deemed normal or to be showing pre-existing abnormalities. Normal neuroimaging was also a common finding in the Pollak case series.
      • Pollak L.
      • Dovrat S.
      • Book M.
      • Mendelson E.
      • Weinberger M.
      Varicella zoster vs. herpes simplex meningoencephalitis in the PCR era. A single center study.
      Radiological imaging provides an inconstant contribution to the diagnosis of VZV encephalitis. Brain CT scans are generally unremarkable and are potentially useful to exclude alternative diagnoses such as hemorrhage or tumor. In contrast, several specific MRI abnormalities have been described in VZV encephalitis. In the case series integrating neuroimaging descriptions, the percentage of abnormal neuroimaging ranged from 20% to 70%.
      • 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.
      • De La Blanchardiere A.
      • Rozenberg F.
      • Caumes E.
      • Picard O.
      • Lionnet F.
      • Livartowski J.
      • et al.
      Neurological complications of varicella-zoster virus infection in adults with human immunodeficiency virus infection.
      • Brown M.
      • Scarborough M.
      • Brink N.
      • Manji H.
      • Miller R.
      Varicella zoster virus-associated neurological disease in HIV-infected patients.
      Brain MRI usually reveals areas of high signal intensity on T2-weighted sequence at the gray–white matter junction and in the deep white matter, or abnormal enhancement.14,154
      Seventy-five percent of our patients were treated with intravenous acyclovir, as recommended by the Infectious Diseases Society of America for patients with VZV encephalitis.
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
      This recommendation is, however, based on small case studies. No clinical trial with a significant number of patients has ever established the efficacy of antiviral therapy for VZV meningitis and encephalitis. Although only occasional reports have shown a clearance of VZV DNA from the CNS with antiviral treatment,
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
      intravenous acyclovir is considered the standard treatment, because of the documented efficacy in other VZV manifestations, the low potential for drug-related adverse events, and the significant morbidity associated with VZV CNS complications.
      • Brown M.
      • Scarborough M.
      • Brink N.
      • Manji H.
      • Miller R.
      Varicella zoster virus-associated neurological disease in HIV-infected patients.
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
      Guidelines for the treatment of VZV meningitis are not available. Nevertheless, the use of acyclovir 5–10 mg/kg intravenous (IV) every 8 h for 10–14 days is common practice.
      • Ihekwaba U.K.
      • Kudesia G.
      • McKendrick M.W.
      Clinical features of viral meningitis in adults: significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections.
      The totality of our cases with meningitis was treated with a similar regimen.
      All our meningitis cases recovered without neurologic sequelae. The outcome of meningitis cases is highly variable. In the few studies available, the outcome has differed from favorable to poor.
      • Iten A.
      • Chatelard P.
      • Vuadens P.
      • Miklossy J.
      • Meuli R.
      • Sahli R.
      • et al.
      Impact of cerebrospinal fluid PCR on the management of HIV-infected patients with varicella-zoster virus infection of the central nervous system.
      • Nowak D.A.
      • Boehmer R.
      • Fuchs H.H.
      A retrospective clinical, laboratory and outcome analysis in 43 cases of acute aseptic meningitis.
      Persson et al. reported neurological sequelae in 50% of their patients with VZV meningitis at 1 month of follow up.
      • Whitley R.J.
      Varicella-zoster virus.
      In contrast, VZV encephalitis is generally considered a severe disease with a poor prognosis, as observed in our series. The mortality of varicella encephalitis ranges from 5% to 15% (Table 3). Long-term sequelae, including seizure disorders and neuropsychological sequelae, are reported in 10–50% of survivors. Among cases of encephalitis in HIV patients, mortality has been high (33%) and sequelae frequent (33%), despite antiviral therapy
      • De La Blanchardiere A.
      • Rozenberg F.
      • Caumes E.
      • Picard O.
      • Lionnet F.
      • Livartowski J.
      • et al.
      Neurological complications of varicella-zoster virus infection in adults with human immunodeficiency virus infection.
      • Brown M.
      • Scarborough M.
      • Brink N.
      • Manji H.
      • Miller R.
      Varicella zoster virus-associated neurological disease in HIV-infected patients.
      (Table 3).
      In studies reporting on follow-up, neurological complications appear to be more frequent in patients who did not develop a characteristic rash.
      • Whitley R.J.
      Varicella-zoster virus.
      The absence of the typical skin manifestation may delay the recognition of VZV CNS infection and hence the initiation of a specific antiviral therapy, thus negatively affecting the outcome.
      • Frantzidou F.
      • Kamaria F.
      • Dumaidi K.
      • Skoura L.
      • Antoniadis A.
      • Papa A.
      Aseptic meningitis and encephalitis because of herpesviruses and enteroviruses in an immunocompetent adult population.
      • Whitley R.J.
      Varicella-zoster virus.
      • Bannister P.
      • Crosse B.
      Severe herpes zoster infection in the United Kingdom: experience in a regional infectious disease unit.
      • Gnann Jr., J.W.
      Varicella-zoster virus: atypical presentations and unusual complications.
      Antiviral treatment might also be prematurely discontinued once the routinely tested herpes simplex virus (HSV) is ruled out.
      As pointed out by Pollak and co-workers,
      • Pollak L.
      • Dovrat S.
      • Book M.
      • Mendelson E.
      • Weinberger M.
      Varicella zoster vs. herpes simplex meningoencephalitis in the PCR era. A single center study.
      differentiation between VZV and HSV CNS infections in the absence of a dermatological rash represents a true challenge. In their study, patients with VZV CNS infections did not differ from patients with HSV CNS infections, neither in demographic characteristics, nor in clinical presentation. These findings highlight the importance of testing CSF for both HSV and VZV if meningitis of viral origin is suspected.
      Until the mid 1990s, infectious complications of the CNS caused by VZV reactivation were regarded as an atypical appearance of low frequency.
      • Frantzidou F.
      • Kamaria F.
      • Dumaidi K.
      • Skoura L.
      • Antoniadis A.
      • Papa A.
      Aseptic meningitis and encephalitis because of herpesviruses and enteroviruses in an immunocompetent adult population.
      • Bannister P.
      • Crosse B.
      Severe herpes zoster infection in the United Kingdom: experience in a regional infectious disease unit.
      The presence of the distinctive skin rash, as well as specific neurological symptoms, were required to diagnose a CNS infection caused by VZV.
      • Frantzidou F.
      • Kamaria F.
      • Dumaidi K.
      • Skoura L.
      • Antoniadis A.
      • Papa A.
      Aseptic meningitis and encephalitis because of herpesviruses and enteroviruses in an immunocompetent adult population.
      • Bannister P.
      • Crosse B.
      Severe herpes zoster infection in the United Kingdom: experience in a regional infectious disease unit.
      The introduction of the PCR technique to detect VZV in the CSF was followed by a significant increase in the number of diagnosed cases.
      • DeBiasi R.L.
      • Tyler K.L.
      Molecular methods for diagnosis of viral encephalitis.
      PCR testing has been instrumental in the identification of VZV as the cause of CNS infections, particularly in the absence of skin manifestations.
      • DeBiasi R.L.
      • Tyler K.L.
      Molecular methods for diagnosis of viral encephalitis.
      Several studies performed in the last decade in countries such as Austria,
      • Aberle S.W.
      • Aberle J.H.
      • Steininger C.
      • Puchhammer-Stöckl E.
      Quantitative real time PCR detection of varicella-zoster virus DNA in cerebrospinal fluid in patients with neurological disease.
      Australia,
      • Huppatz C.
      • Durrheim D.N.
      • Levi C.
      • Dalton C.
      • Williams D.
      • Clements M.S.
      • et al.
      Etiology of encephalitis in Australia, 1990–2007.
      Finland,
      • Koskiniemi M.
      • Rantalaiho T.
      • Piiparinen H.
      • von Bonsdorff C.H.
      • Färkkilä M.
      • Järvinen A.
      • et al.
      Infections of the central nervous system of suspected viral origin: a collaborative study from Finland.
      France,
      • Mailles A.
      • Stahl J.P.
      Infectious encephalitis in France in 2007: a national prospective study.
      Germany,
      • Nowak D.A.
      • Boehmer R.
      • Fuchs H.H.
      A retrospective clinical, laboratory and outcome analysis in 43 cases of acute aseptic meningitis.
      Greece,
      • Frantzidou F.
      • Kamaria F.
      • Dumaidi K.
      • Skoura L.
      • Antoniadis A.
      • Papa A.
      Aseptic meningitis and encephalitis because of herpesviruses and enteroviruses in an immunocompetent adult population.
      Israel,
      • Pollak L.
      • Dovrat S.
      • Book M.
      • Mendelson E.
      • Weinberger M.
      Varicella zoster vs. herpes simplex meningoencephalitis in the PCR era. A single center study.
      Taiwan,
      • Lee T.C.
      • Tsai C.P.
      • Yuan C.L.
      • Wei C.Y.
      • Tsao W.L.
      • Lee R.J.
      • et al.
      Encephalitis in Taiwan: a prospective hospital-based study.
      and the UK
      • Ihekwaba U.K.
      • Kudesia G.
      • McKendrick M.W.
      Clinical features of viral meningitis in adults: significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections.
      have led to the conclusion that VZV is the third most frequent viral agent causing CNS disease in adults. In these studies, samples of suspected cases were tested for the most frequent viral agents. The structure of these studies made it possible to diagnose a large number of cases where the characteristic rash was absent. However, these studies conducted by reference laboratories provided little information on clinical presentation and outcomes of VZV reactivation in the CNS (Table 3).
      Our data show that CNS infections caused by VZV can be observed, in a not negligible frequency, at the emergency department of a community hospital. For our region we estimated an incidence rate of 1.02 cases per 100 000 inhabitants. Given the multiple clinical and laboratory criteria used by different study groups and the limited data available, a comparison with other reports is very difficult. In Sweden, the annual incidence of VZV CNS infections is reported to be 1.8 cases per 100 000 inhabitants.
      • Whitley R.J.
      Varicella-zoster virus.
      Our study is limited by the retrospective design, which may have precluded the inclusion of all CNS infections caused by VZV diagnosed during the period considered for this study. We cannot exclude that patients presenting to the emergency department with meningitis or encephalitis and a typical rash were not more frequently tested for VZV in the CSF than patients without skin manifestations. Nevertheless, the possibility of including information on clinical presentation, laboratory results, and outcomes of patients with VZV reactivation in the CNS represents a clear strength of our study in comparison to previous reports.
      In conclusion, VZV reactivation in the CNS remains a challenge for the emergency physician. The clinical manifestations of VZV CNS complications are variable, non-specific, and indistinguishable from those of other viral CNS infections. Screening for VZV by PCR in the CSF is recommended for all patients with encephalitis and for those with viral meningitis of unknown origin in order to better target antiviral treatment.
      Conflict of interest: No conflict of interest to declare.

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