Acute varicella zoster encephalitis without evidence of primary vasculopathy in a case-series of 20...

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Acute varicella zoster encephalitis without evidence of primary vasculopathy in a case-series of 20 patients T. De Broucker 1 , A. Mailles 2 , S. Chabrier 3 , P. Morand 4 , J.-P. Stahl 5 on behalf of the steering committee and investigators group* 1) Neurology, Hospital Delafontaine, Saint Denis, 2) French Institute for Public Health Surveillance, Saint Maurice, 3) Paediatric Intensive Care Unit, University Hospital, Saint-Etienne, 4) Department of Virology and 5) Department of Infectious Diseases, University Hospital and University Joseph Fourier, Grenoble, France Abstract Varicella zoster virus (VZV) is a leading cause of acute viral encephalitis but little is known about its clinical, biological and imaging fea- tures. Furthermore, the most favourable treatment regimen has not been determined. We studied a prospective cohort of 20 HIV-neg- ative patients presenting with acute VZV encephalitis caused by primary infection or reactivation. VZV was identified in 16 of 20 cases by PCR detection of the DNA in the cerebrospinal fluid. The four remaining cases occurred during or soon after a VZV rash. The med- ian age of the 17 adults was 76 (19–86) years; the three other patients were children (0.5–5 years). Three patients were immunocom- promised. Nine adult patients presented with a rash. Eighteen patients presented with fever and an acute encephalitic syndrome: diffuse brain dysfunction, focal neurological signs, seizures and cranial nerve palsies. Three patients presented with either ventricular or sub- dural haemorrhage, one with myelitis, and one with asymptomatic stenosis of the middle cerebral artery. The imaging was either normal or revealed non-specific abnormalities such as cortical atrophy but no evidence of stroke. All patients were given acyclovir at various dosages and durations but the case fatality rate remained high (15%) and sequelae were frequently observed either at discharge or at follow-up 3 years later. Keywords: Encephalitis, imaging, varicella zoster virus, vasculopathy Original Submission: 16 August 2011; Revised Submission: 13 October 2011; Accepted: 17 October 2011 Editor: L. Kaiser Article published online: 22 October 2011 Clin Microbiol Infect 2012; 18: 808–819 10.1111/j.1469-0691.2011.03705.x Corresponding author: A. Mailles, Institut de veille sanitaire (French Institute for Public Health Surveillance), 12 rue du Val d’Osne, 94415 Saint-Maurice Cedex, France E-mail: [email protected] *Members of the Steering committee and Investigators are listed in Appendix. Introduction Varicella zoster virus (VZV) is a virus of the Alphaherpesviri- nae subfamily, responsible for human infections with various clinical presentations. Primary infection occurs most fre- quently during childhood and presents as varicella; it is fol- lowed by long-lasting viral latency in the spinal and cranial ganglia [1,2]. This infection is common, affecting almost all non-vaccinated children. Infection reactivation occurs mainly in immunocompromised or elderly patients. The most fre- quent presentation in adults is herpes zoster (shingles), with an estimated annual incidence of 1.2–5.2 cases/1000 [2]. Post-herpetic neuralgia is a frequent complication in elderly patients [3]. Neurological complications caused by varicella can involve peripheral or central nervous system. They include cerebelli- tis, meningitis, myelitis, optic neuritis, polyneuropathy, acute encephalitis and vasculopathy [2,4]. Some neurological pre- sentations can also appear with, precede, or follow herpes zoster: sensory or motor peripheral paralysis, isolated and multiple cranial nerve palsies including ophthalmoplegia and the Ramsay Hunt syndrome, myelitis, encephalitis, vasculopa- thy and cerebellar ataxia [5]. Neurological symptoms caused by VZV infection can also occur without any cutaneous rash (zoster sine herpete) and the detection of DNA or specific ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases ORIGINAL ARTICLE VIROLOGY

Transcript of Acute varicella zoster encephalitis without evidence of primary vasculopathy in a case-series of 20...

Acute varicella zoster encephalitis without evidence of primary

vasculopathy in a case-series of 20 patients

T. De Broucker1, A. Mailles2, S. Chabrier3, P. Morand4, J.-P. Stahl5 on behalf of the steering committee and investigators

group*

1) Neurology, Hospital Delafontaine, Saint Denis, 2) French Institute for Public Health Surveillance, Saint Maurice, 3) Paediatric Intensive Care Unit,

University Hospital, Saint-Etienne, 4) Department of Virology and 5) Department of Infectious Diseases, University Hospital and University Joseph Fourier,

Grenoble, France

Abstract

Varicella zoster virus (VZV) is a leading cause of acute viral encephalitis but little is known about its clinical, biological and imaging fea-

tures. Furthermore, the most favourable treatment regimen has not been determined. We studied a prospective cohort of 20 HIV-neg-

ative patients presenting with acute VZV encephalitis caused by primary infection or reactivation. VZV was identified in 16 of 20 cases

by PCR detection of the DNA in the cerebrospinal fluid. The four remaining cases occurred during or soon after a VZV rash. The med-

ian age of the 17 adults was 76 (19–86) years; the three other patients were children (0.5–5 years). Three patients were immunocom-

promised. Nine adult patients presented with a rash. Eighteen patients presented with fever and an acute encephalitic syndrome: diffuse

brain dysfunction, focal neurological signs, seizures and cranial nerve palsies. Three patients presented with either ventricular or sub-

dural haemorrhage, one with myelitis, and one with asymptomatic stenosis of the middle cerebral artery. The imaging was either normal

or revealed non-specific abnormalities such as cortical atrophy but no evidence of stroke. All patients were given acyclovir at various

dosages and durations but the case fatality rate remained high (15%) and sequelae were frequently observed either at discharge or at

follow-up 3 years later.

Keywords: Encephalitis, imaging, varicella zoster virus, vasculopathy

Original Submission: 16 August 2011; Revised Submission: 13 October 2011; Accepted: 17 October 2011

Editor: L. Kaiser

Article published online: 22 October 2011

Clin Microbiol Infect 2012; 18: 808–819

10.1111/j.1469-0691.2011.03705.x

Corresponding author: A. Mailles, Institut de veille sanitaire

(French Institute for Public Health Surveillance), 12 rue du Val

d’Osne, 94415 Saint-Maurice Cedex, France

E-mail: [email protected]

*Members of the Steering committee and Investigators are listed in

Appendix.

Introduction

Varicella zoster virus (VZV) is a virus of the Alphaherpesviri-

nae subfamily, responsible for human infections with various

clinical presentations. Primary infection occurs most fre-

quently during childhood and presents as varicella; it is fol-

lowed by long-lasting viral latency in the spinal and cranial

ganglia [1,2]. This infection is common, affecting almost all

non-vaccinated children. Infection reactivation occurs mainly

in immunocompromised or elderly patients. The most fre-

quent presentation in adults is herpes zoster (shingles), with

an estimated annual incidence of 1.2–5.2 cases/1000 [2].

Post-herpetic neuralgia is a frequent complication in elderly

patients [3].

Neurological complications caused by varicella can involve

peripheral or central nervous system. They include cerebelli-

tis, meningitis, myelitis, optic neuritis, polyneuropathy, acute

encephalitis and vasculopathy [2,4]. Some neurological pre-

sentations can also appear with, precede, or follow herpes

zoster: sensory or motor peripheral paralysis, isolated and

multiple cranial nerve palsies including ophthalmoplegia and

the Ramsay Hunt syndrome, myelitis, encephalitis, vasculopa-

thy and cerebellar ataxia [5]. Neurological symptoms caused

by VZV infection can also occur without any cutaneous rash

(zoster sine herpete) and the detection of DNA or specific

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases

ORIGINAL ARTICLE VIROLOGY

VZV antibodies in the cerebrospinal fluid (CSF) is here the

only proof of VZV involvement [5].

Several mechanisms explain the occurrence of neurological

signs after VZV infection: parenchymatous encephalitis (with

or without demyelination), microglial influx, granulomatous

and large vessel vasculopathy inducing strokes (grossly tran-

sient cerebral arteriopathy in children and delayed contralat-

eral hemiparesis of zoster ophthalmicus in the elderly),

meningitis or necrotizing myelitis [6,7]. Subacute or chronic

VZV encephalitis are encountered in immunocompromised

patients as the result of small vessel vasculopathy and glial

infection inducing leukoencephalitis. Myelitis, large vessel

involvement and ventriculitis have also been reported [7,8].

Acute ataxia in children and vasculopathies in adults are the

most frequently cited neurological complications of VZV

infection [5,9,10]. In contrast, acute encephalitis sensu stricto

has rarely been reported [11–14] and even fewer reports

have been published describing the clinical features and fol-

low-up of these patients [15–18]. The importance of VZV in

the epidemiology of acute encephalitis in the general popula-

tion has been highlighted in multicentre prospective studies

[11–13].

We report the clinical features of patients with VZV

encephalitis enrolled in a prospective multicentre study in

France, in 2007.

Methods

A case-patient with acute encephalitis was a patient 28 days

of age or older hospitalized in mainland France in 2007, with

(i) an acute onset of illness; (ii) at least one abnormality of

CSF (white blood cell count ‡4 cells/mm3 or protein level

‡40 mg/dL); (iii) fever or recent history of fever ‡38�C; and

(iv) decreased consciousness, or seizures, or altered mental

status, or focal neurological signs. HIV infection was an

exclusion criterion. Aetiological investigation of enrolled

patients was described previously [11].

A confirmed case of VZV encephalitis was a case-patient

with VZV DNA detected in the CSF by PCR. A possible

case of VZV encephalitis was a case-patient with encephali-

tis occurring simultaneously or shortly after varicella or

herpes zoster without biological confirmation of VZV infec-

tion, and with other possible aetiologies of encephalitis

excluded by the investigation. Clinical and biological data

were collected using a standardized questionnaire and the

results of electroencephalography examinations were

recorded. A single expert (TdB) reviewed all available mag-

netic resonance and computed tomography images to assess

brain lesions.

The outcome of VZV patients was assessed 3 years after

discharge using the Glasgow outcome scale [19].

Informed written consent was obtained from all patients

or from their parents for children aged <18 years. The study

was approved by the ethics committee of Grenoble (No.

172003).

Results

Demography

Twenty of 253 (8%) case-patients enrolled in the initial study

were VZV patients [11]. Sixteen were confirmed cases and

four were possible cases (Table 1). Two possible cases were

5-year-old boys with negative VZV CSF PCR on admission

and no further CSF testing. They presented with varicella,

respectively, 1 day and 1 week before the onset of neurolog-

ical symptoms. The two other possible cases were adults (76

and 78 years of age) presenting with radicular zoster (one

spinal, one ophthalmicus) 3 days and 3 weeks, respectively,

before the onset of neurological symptoms.

The male to female ratio was 3. Three patients were chil-

dren (the two 5-year-old boys mentioned above and a 6-

month old boy). The distribution of age among adult patients

was bimodal with three young adults (19, 20 and 26 years

old) and 11 people ‡75 years old (median 76 years old,

range 19–86 years). None of the VZV patients had ever been

vaccinated against VZV.

Clinical features

Ten (50%) patients (nine adults and one child) had comorbid-

ities, three of which could be considered immunosuppressive

conditions: osteosarcoma, recent heart–lung transplant and

systemic lupus erythematosus with long-term corticosteroid

treatment (Table 1).

Eleven VZV patients (55%) had a rash before hospitaliza-

tion: zoster in eight adults and varicella in three children, of

whom two (a child and an adult) no longer had cutaneous

signs on admission.

The symptoms of the VZV patients on admission are pre-

sented by frequency in Table 2. Six patients (30%) required

admission to intensive care units, four were mechanically

ventilated. The most frequent neurological symptoms were

disorientation and confusion (70%), meningeal signs (60%),

focal neurological signs (55%) and apathy (50%). Cranial

nerve palsy was present in eight patients (40%), namely cen-

tral facial nerve paralysis in seven cases and oculomotor

nerve paralysis in one case.

Lumbar puncture was performed before day 2 of hospi-

talization in 80% of cases and before day 4 in 95%. The

CMI De Broucker et al. Varicella zoster encephalitis in France in 2007 809

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

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ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

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CMI De Broucker et al. Varicella zoster encephalitis in France in 2007 811

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

median CSF white blood cell count was 150 cells/mm3

(range 0–1240). Lymphocytes were predominant in CSF

(median rate: 81.5% of white blood cells) in all but two

VZV patients. The median protein level in CSF was 0.99 g/L

(0.22–5 g/L). The glucose CSF/serum ratio was >0.40 in 16

patients (80%).

Thirteen of 14 (92%) encephalography recordings showed

abnormalities and all such abnormalities were consistent with

diffuse brain lesions. Focal temporal slow waves were identi-

fied in four cases, and subclinical seizures in two cases.

Imaging

All patients underwent computed tomography scan (n = 10),

magnetic resonance imaging (n = 2), or both (n = 8) on

admission. Eighteen sets of images were available for review-

ing (14 confirmed cases and four possible cases). Four (20%)

patients demonstrated vascular lesions on computed tomog-

raphy of magnetic resonance imaging:

• stenosis of the left middle cerebral artery M1 segment

was observed using magnetic resonance angiography in a

20-year-old patient without stroke (Fig. 1);

• a 6-month-old boy presented with diffuse bleeding and

dilatation of the ventricles on admission and still had a

dilatation of the subarachnoid area with normal ventricu-

lar size on follow-up imaging (Fig. 2);

• thoracic myelitis was observed on admission in a 34-

year-old man with paraplegia, who developed at day 45 a

bilateral subdural haematoma and massive ventricular

bleeding (Fig. 3);

• a 79-year-old patient with cortical atrophy on early

images later demonstrated a haematoma in the thalamic

area with fatal ventricular bleeding at day 23.

Three (15%) other patients had non-vascular lesions: brain-

stem lesions suggesting rhombencephalitis were observed in

two patients; and right-side temporal, parietal and occipital

hypersignals were observed with magnetic resonance imaging

in a 5-year-old boy (possible case).

Four patients (20%), including one possible case, had non-

specific abnormalities (cortical atrophy) and the remaining

FIG. 1. Magnetic resonance image of a 20-year-old man. Narrowing

of the M1 segment of the middle cerebral artery.

TABLE 2. Clinical features of 20 patients presenting with varicella zoster virus encephalitis at day 0 and day 5

Day 0 Day 5

All cases(n = 20)

Confirmed cases(n = 16)

Possible cases(n = 4)

All cases(n = 20)

Confirmed cases(n = 16)

Possible cases(n = 4)

Fever 18 (90%)a 15 (94%)b 3 (75%)b NA NA NAMechanical ventilation 4 (20%) 1 (6%) 3 (75%) 3 (15%) 1 (6%) 2 (50%)Severe sepsis 1 (5%) 1 (6%) 0 0 0 0Meningism 12 (60%) 9 (56%) 3 (75%) 3 (15%) 3 (19%) 0Decreased level of consciousness 5 (25%) 3 (19%) 2 (50%) 2 (10%) 1 (6%) 1 (25%)Disorientation 14 (70%) 11 (69%) 3 (75%) 5 (25%) 5 (31%) 0Confusion 14 (70%) 12 (75%) 2 (50%) 2 (10%) 2 (13%) 0Seizures 4 (20%) 2 (13%) 2 (50%) 0 0 0Focal neurological signs 11 (55%) 7 (44%) 4 (100%) 9 (45%) 7 (44%) 2 (50%)Speech disorders 6 (30%) 5 (31%) 1 (25%) 2 (10%) 1 (6%) 1 (25%)Cranial nerve palsy 8 (40%) 6 (38%) 2 (50%) 8 (40%) 6 (38%) 2 (50%)Cerebellous syndrome 3 (15%) 2 (13%) 1 (25%) 3 (15%) 2 (13%)Sensory disorders 1 (5%) 1 (6%) 0 NA NA NAMyelitis 0 0 0 1 (5%) 1 (6%) 1 (25%)Aggressiveness 1 (5%) 1 (7%) 0 0 0 0Apathy 10 (50%) 7 (44%) 3 (75%) 3 (15%) 3 (19%) 0Agitation 6 (30%) 4 (27%) 2 (50%) 1 (5%) 1 (6%) 0Parkinsonism 0 0 0 NA NA NAMovement disorders 0 0 0 0 0 0Hallucination 0 0 0 0 0 0

NA, not available.aTwo patients were afebrile while taking antipyretic treatment but reported fever before hospitalization.bOne patient was afebrile while taking antipyretic treatment but reported fever before hospitalization.

812 Clinical Microbiology and Infection, Volume 18 Number 8, August 2012 CMI

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

seven (35%) patients, including two possible cases, had nor-

mal imaging results. Ischaemic stroke was ruled out by imag-

ing in all patients.

Treatment

Five of the eight adult patients with zoster rash received acy-

clovir before the onset of neurological symptoms. Acyclovir

was administered intravenously to all 20 patients as encepha-

litis treatment for 3 weeks (n = 8; 40%), 2 weeks (n = 5;

25%) or 1 week (n = 7; 35%). Dosage was reported for 13

of 20 patients: five received 10 mg/kg three times a day, six

received 15 mg/kg three times a day and two children

received 20 mg/kg three times a day.

Outcome

Three male VZV patients (15%) died during hospitalization:

all three were elderly (75, 79 and 82 years old). The mean

duration of hospital stay was 23 days (range 6–80). On dis-

charge, 10 patients (50%) returned home, six patients (30%)

were transferred to a convalescence facility, and one moved

to a nursing home.

Nine patients (45%) were discharged with persistent neu-

rological signs: cognitive impairment (n = 3) and sensory-

motor deficits (n = 6). Three years after discharge, 16 of the

17 surviving patients could be evaluated and one was lost to

follow-up. Among the 16 patients, two had died after being

discharged (with one death being related to the encephalitis),

seven (41%) had moderate to severe sequelae (Glasgow out-

come scale 3 or 4), and the outcome was favourable for

seven (41%) with a Glasgow outcome scale of 5.

Discussion

Varicella zoster virus has been confirmed as a major cause

of encephalitis in France both in the national hospital data-

base and a prospective cohort study [11,20], as well as in

other countries [12,13].

The data described here highlight the main clinical features

of VZV encephalitis. VZV encephalitis is a disease of the

young and elderly immunocompetent patients, as well as a

disease of the immunocompromised of all ages, as illustrated

by four young adults enrolled in our study.

Varicella zoster virus encephalitis has been described dur-

ing the course of or after varicella or zoster with various

time frames. However, the rash was absent in nine of 17

adult patients enrolled in our study with clinical encephalitis

and a positive VZV PCR in CSF. Conversely, no virological

(a) (b)

(c) (d)

FIG. 2. Magnetic resonance image of a 6-

month-old boy. (a, b) Axial T2 gradient echo

sequence: blood in the ventricles and internal

and external hydrocephaly. (c) Axial SET1

sequence after gadolinium infusion: no abnor-

mal enhancement. (d) FLAIR sequence: no

parenchymal abnormality.

CMI De Broucker et al. Varicella zoster encephalitis in France in 2007 813

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

confirmation could be obtained in four patients whose

encephalitis occurred during or shortly after varicella or zos-

ter. In these four patients, the clinical signs, imaging and out-

come strongly suggested a causative link between VZV and

the encephalitis, and the negative result of the PCR might be

related to the early CSF sampling, or to the administration

of acyclovir before CSF sampling [17,21]. The possible lack

of sensitivity of the PCR has been demonstrated for herpes

simplex virus during the first days of neurological signs but

not formally for VZV. In these four patients, it may have

been interesting to have VZV antibodies measured in a con-

valescent sample of CSF to try to confirm the diagnosis [21].

Few studies have been published about patient with VZV

encephalitis (Table 3). In a paediatric study, the case-fatality

rate among encephalitis patients was 34%, which is higher

than in our patients but this study was published before

molecular diagnosis and acyclovir were available [15]. In a

12-patient cohort reported in 1983, ten patients had their

neurological onset a mean of 9 days after a zoster rash and

two patients reported no rash, which is comparable to our

study [16]. Their case fatality rate was 25%, but there again

the study was carried out before acyclovir was widely avail-

able. In a more recent study, CSF samples from encephalitis

patients were screened for VZV and seven patients were

diagnosed with VZV encephalitis during a 5-year period.

Their demographic characteristics (especially the bimodal dis-

tribution of age), and their clinical signs were similar to those

observed in our prospective study [18].

Twenty-six patients with positive CSF VZV DNA were

referred to the California Encephalitis Project, 11 suffering

encephalitis [30]. Some features were similar to those of our

patients (median age 75 years, 73% of imaging was normal or

non-specific), although a zoster rash was more frequent

(64%).

Varicella zoster virus encephalitis is known to be associ-

ated with immunosuppression, especially that caused by HIV.

Because HIV infection was an exclusion criterion, it is likely

that we missed some patients with VZV encephalitis and HIV

infection. However, the case reports published about VZV

encephalitis in patients with AIDS show that their clinical

presentation does not differ from that of immunocompro-

mised patients following cancer or long-term immunosup-

pressive treatment.

No study or clinical trial has yet addressed the best thera-

peutic regimen for VZV encephalitis. The prognosis of her-

pes simplex virus encephalitis has been dramatically

improved by the use of acyclovir and this treatment is rec-

ommended in the guidelines for VZV encephalitis [2]. The

recommended regimen is acyclovir at the same dosage as

herpes simplex virus encephalitis treatment despite the lack

of paediatric data [14,31,32]. Unlike herpes simplex virus,

few studies have been published on VZV encephalitis [33]. In

(a) (b)

(c) (d)

FIG. 3. Magnetic resonance image of a

35-year-old man. (a–c) Cranial magnetic

resonance image, FLAIR sequence showing

punctiform hyperintensities subcortical (right

frontal and left temporal) and in the pons.

(d) Sagittal dorsal spinal cord, T2 sequence:

hypersignal at the T7–T8 level.

814 Clinical Microbiology and Infection, Volume 18 Number 8, August 2012 CMI

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

TA

BL

E3.C

lin

ical,

bio

logic

al

an

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agin

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of

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en

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haliti

sp

ati

en

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ded

inth

em

ain

pu

blish

ed

seri

es

Year

of

dia

gn

osi

sN

um

ber

of

case

sA

ge

of

case

s

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un

est

atu

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om

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1956–1967

53

Mean

5ye

ars

(ran

ge8

month

sto

8.5

year

s)

ND

Neuro

logi

cal

sign

s+

vari

cella

Ras

his

par

tof

the

case

definitio

n

Mean

4day

s(r

ange

1–20)

23

with

ence

phal

itis

,29

with

cere

belli

tis,

one

with

mye

litis

No

imag

ing

2/6

case

sw

ith

necr

opsy

show

ed

sign

sof

peri

vasc

ula

rin

flam

mat

ion

Ence

phal

itis

:eig

ht

deat

hs,

two

dis

char

ged

with

perm

ament

sequela

e.C

ere

belli

tis:

seve

nfu

llre

cove

ries,

no

deat

h.

Mye

litis

:fu

llre

cove

ry

Befo

rebra

inim

agin

g,PC

Ran

dac

yclo

vir

15

1971–1978

12

Media

n71

year

s(r

ange

23–80)

Seve

nim

munosu

ppre

ssed

Ence

phal

itis

or

cere

belli

tis

and

herp

es

zost

er

Herp

es

zost

er

ispar

tof

the

case

definitio

n

Mean

:9

day

s(m

ax28

day

s)H

allu

cinat

ions

10/1

2St

upor

5/1

2C

onfu

sion,head

ache,

cran

ialnerv

epal

sy

1/5

with

abnorm

alre

sults

on

CT

scan

(ventr

icula

renla

rgem

ent)

Thre

edeat

hs,

one

case

with

perm

anent

par

esi

s

Befo

reM

RI,

PC

Ran

dac

yclo

vir

16

1975

2(1

)19

year

sold

(2)

55

year

sold

Both

imm

unodepre

ssed

follo

win

gca

nce

r

Clin

ical

Herp

es

zost

er

inboth

ND

(1)

Cogn

itiv

edecl

ine,

leg

weak

ness

,poor

mem

ory

(2)

Seiz

ure

s,hem

ipar

esi

s,poor

mem

ory

Both

case

s:par

ench

ymal

mas

seffect

,evo

lution

tow

ard

hae

morr

hag

e

Both

case

s:ence

phal

itis

and

seco

ndar

yva

scula

ritis

(1)

Deat

haf

ter

6w

eeks

(2)

deat

haf

ter

6m

onth

s

Befo

reac

yclo

vir

and

MR

Ian

dPC

R

22

1978–1982

2(1

)42

year

sold

(2)

62

year

sold

Both

imm

unoco

mpro

mis

ed(leukae

mia

and

renal

tran

spla

nt)

Neuro

logi

cal

sign

s+

herp

es

zost

er

Herp

es

zost

er

ispar

tof

the

case

definitio

n

(1)

10

weeks

(2)

At

onse

t(1

)A

taxia

,poor

mem

ory

,hem

ipar

esi

s,neura

lgia

(2)

Hem

ipar

esi

s,cr

ania

lnerv

es

alsy

,hem

ianopsi

e

Norm

alin

one

pat

ient,

mas

seffect

for

the

oth

er

No

evi

dence

of

vasc

ula

ritis

Favo

ura

ble

outc

om

ein

both

case

s

Befo

reac

yclo

vir,

MR

Ian

dPC

R6

1985–1995

925–73

year

sold

Imm

unoco

mpete

nt

Sero

logy

on

CSF

or

seru

m,

vira

lcu

lture

of

skin

lesi

ons

5/9

case

s,4–8

day

sbefo

reneuro

logi

cal

onse

t

4–8

day

sFe

ver

3/9

Head

ache

5/7

Speech

dis

ord

ers

5/7

Seiz

ure

s4/7

Moto

rdefici

t3/7

1‘in

farc

t-lik

ele

sion’,

one

non-s

peci

fic

lesi

on,oth

er

norm

al

1‘in

farc

t-lik

ele

sion’

On

dis

char

ge:

Poor

mem

ory

7/9

,dis

inhib

ited

behav

iour

6/9

,poor

conce

ntr

atio

n3/9

23

1990–2004

24

Mean

2ye

ars

and

9m

onth

s(r

ange

2m

onth

sto

6ye

ars)

All im

munoco

mpet

ent

Bra

inin

farc

tion

+va

rice

llaw

ithin

12

month

s

Var

icella

ispar

tof

the

case

definitio

n

Mean

4m

onth

s(r

ange

1w

eek

to1

year

)

Hem

ipar

esi

s23/2

4C

hore

a1/2

4Fa

cial

weak

ness

1/2

4Se

izure

2/2

4

Cau

dat

ean

dle

ntifo

rmnucl

ei

21/2

4In

tern

alca

psu

le13/2

4W

hite

mat

ter

infa

rction

19/2

4C

ort

ical

infa

rction

8/2

4

Infa

rction

ispar

tof

the

case

definitio

n

ND

24

1992–1996

4N

DA

llpat

ients

with

AID

SD

NA

dete

ctio

n+

clin

ical

sign

s+

consi

stent

neuro

imag

ing

2/4

with

herp

es

zost

er

ND

One

ence

phal

itis

,one

menin

goen

cephal

itis

,tw

ofo

cal

ence

phal

itis

One

with

hae

morr

hag

icle

sion,one

with

isch

aem

icle

sion,

one

with

cort

ical

atro

phy,

one

with

bra

inst

em

lesi

ons

Tw

ow

ith

vasc

ula

ritis,

two

with

ence

phal

itis

Tw

odeat

hs

and

two

com

ple

tere

cove

ries

25

CMI De Broucker et al. Varicella zoster encephalitis in France in 2007 815

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

TA

BL

E3.C

on

tin

ued

Year

of

dia

gn

osi

sN

um

ber

of

case

sA

ge

of

case

s

Imm

un

est

atu

so

fcase

s

Dia

gn

osi

s/case

defi

nit

ion

Rash

Dela

yb

etw

een

rash

an

dn

eu

rolo

gic

al

on

set

Clin

ical

patt

ern

sIm

agin

gre

sult

sE

ncep

haliti

s/vasc

ula

riti

sO

utc

om

eC

om

men

tR

ef.

1995–1996

92

All

ages

ND

Clin

ical

sign

s+

sero

logy

or

DN

Adet

ect

ion

Herp

es

zost

er

in37,va

rice

llain

30,none

in25

Max

4w

eeks

for

vari

cella

ND

ND

ND

ND

Nat

ional

study

on

CN

Svi

ral

infe

ctio

ns

17

1995–2006

28

Media

n72

year

s(r

ange

3–86)

ND

Sero

logy

and

RT

-PC

RR

ash

in19/2

8N

DN

D6/2

8w

ith

hae

morr

hag

eor

infa

rction

Six

with

cere

bro

vasc

ula

rle

sions

Tw

odeat

hs,

thre

epat

ients

with

sequela

e

Vas

cula

rle

sions

are

not

deta

iled

26

1998–2009

11

Media

nag

e75

year

s(r

ange

50–85)

5/1

1im

munodepre

ssed

(tw

ow

ith

AID

S),

9/1

1im

munose

nesc

ent

Neuro

logi

cal

sign

s+

DN

Adet

ect

ion

inC

SF

7/1

1(6

4%

)N

DA

taxia

4/1

1C

rania

lnerv

epal

sy4/1

1Fe

ver

5/1

1A

ltere

dm

enta

lst

atus

9/1

1

Vas

culo

pat

hy

2/1

1Par

ench

ymat

ous

lesi

ons

2/1

1N

orm

alIm

agin

gor

non-s

pec

ific

lesi

ons

7/1

1

Tw

oca

ses

with

evi

dence

of

vasc

ulo

pat

hy

ND

21

2000–2001

2(1

)4

year

sold

(2)

16

month

sold

Both

imm

unoco

mpete

nt

Sero

logy

+in

trat

heca

lan

tibody

synth

esi

s+

DN

Adet

ect

ion

(1)

Var

icella

(2)

None

1w

eek

(1)

Foca

lse

izure

,co

nfu

sion

(2)

Feve

r,ir

rita

bili

ty,

confu

sion

(1)

Subco

rtic

alle

sion

inte

mpora

llo

be,no

stro

ke

(2)

Cort

ical

and

subco

rtic

alle

sion

of

par

ieta

llo

be,

White

mat

ter

lesi

ons

No

stro

ke,no

evi

dence

of

vasc

ulo

pat

hy

(1)

Full

reco

very

(2)

Perm

anent

hem

ianopsi

a

27

2004–2009

7M

ean

47

year

s(r

ange

14–79),

bim

odal

dis

trib

ution

2/7 im

munodepre

ssed

Clin

ical

sign

s+

DN

Adet

ect

ion

inC

SF

ND

ND

Most

frequent:

feve

r,head

ache,

neck

stiff

nes

s,photo

phobia

Norm

alim

agin

gin

allpat

ients

No

evi

dence

of

stro

keor

vasc

ulo

pat

hy

One

deat

h(t

erm

inal

renal

failu

re)

18

ND

9M

edia

n72

year

s(r

ange

52–94)

All im

munoco

mpete

nt

Neuro

logi

cal

sign

s+

rash

Herp

es

zost

er

ispar

tof

the

case

defi

nitio

n

ND

Ata

xia

n=

5,cr

ania

lnerv

es

impai

rment

n=

2

CT

scan

in5/9

,norm

alfo

ral

l5

No

evi

dence

of

vasc

ula

ritis

No

deat

h,

sequela

enot

desc

ribed

Appar

ently

befo

rePC

Ran

dM

RI

but

acyc

lovi

rav

aila

ble

28

ND

30

Ran

ge1–88

year

sold

11/3

0im

munoco

mpro

mis

edN

euro

logi

cal

sign

san

dIm

agin

gor

CSF

consi

stent

with

vasc

ulo

pat

hy

and

DN

Adet

ect

ion

or

sero

logy

19/3

0(6

3%

)N

DN

DLar

ge-v

esse

lva

sculo

pat

hy

4/3

0(1

3%

)Sm

all-ve

ssel

vasc

ulo

pat

hy

11/3

0(3

7%

)M

ixed

vasc

ulo

pat

hy

15/3

0(5

0%

)

Vas

culo

pat

hy

ispar

tof

the

case

definitio

n

Favo

ura

ble

outc

om

efo

rfo

ur

case

sw

ith

larg

e-v

ess

el

vasc

ulo

pat

hy

Poor

outc

om

efo

rth

ree

case

sw

ith

smal

l-ve

ssel

and

thre

eca

ses

with

mix

ed

vasc

ulo

pat

hie

s

23

pre

viousl

ypublis

hed

case

s+

seve

nnew

lypublis

hed

case

s

29

816 Clinical Microbiology and Infection, Volume 18 Number 8, August 2012 CMI

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

our study, 3 years after discharge, half of the survivors still

presented with moderate to severe sequelae. Some authors

have suggested that the combination of acyclovir and foscar-

net might improve the prognosis and also prevent a possible

antiviral failure caused by an acyclovir-resistant VZV strain,

but this hypothesis has yet to be confirmed by clinical trial

[34].

Questions and controversies remain on the physiological

mechanisms of the neurological complications of VZV infec-

tion. These complications are different during primary infec-

tion (varicella) and after viral reactivation (zoster). The most

frequent varicella complications are cerebellitis and arterial

ischaemic strokes [15,35,36]. Usually, VZV cerebellitis or

ataxia has a favourable outcome in children and CSF analysis

is generally not performed in this context. Besides ataxia,

arterial ischaemic stroke occurs in up to 1/15 000 cases

[36]. This syndrome, now referred to as post-varicella arteri-

opathy, is defined by focal stenosis of the basal central arter-

ies in children with a history of varicella within the

12 months before the onset of neurological signs.

Varicella acute encephalopathy with fatal outcome has also

been reported following varicella in children with liver and

brain oedema and fatty macrophage infiltration as the result

of Reye’s syndrome, although this does not actually corre-

spond to a direct invasion of the central nervous system

[15].

The physiopathology of VZV encephalitis after reactivation

of the virus is still not clear. The presentations of herpes

zoster encephalitis can be divided into three main categories:

demyelinating disease, vasculopathy and acute infectious

encephalitis of undetermined pathophysiology, as reported in

this case series. The multifocal subacute demyelinating dis-

ease is mostly encountered in immunosuppressed patients,

especially those with AIDS (which was an exclusion criterion

in our study). The direct infection of glial cells and endothe-

lial vascular cells has been demonstrated in these cases [7].

The VZV-induced vasculopathy occurs in immunocompetent

elderly people or in AIDS patients (for instance, zoster oph-

thalmicus contralateral syndrome) [8,29]. Although some

authors claim that most, if not all, cases of herpes zoster

‘encephalitis’ are the result of viral vasculopathy [5,9], imag-

ing failed to demonstrate either vascular lesions or demyelin-

ating areas in 16 of 20 patients enrolled in our study, which

is in favour of direct viral parenchymatous encephalitis.

However, one patient in our series presented with both

myelitis and vasculopathy. He was under immunosuppressive

treatment following heart and lung transplant, and suffered

renal deficiency and diabetes. Myelitis has been described as

a non-vascular clinical presentation, and it has been hypothe-

sized that long-term steroids might be a risk factor for VZV

myelitis [1]. The clinical features and imaging results in this

patient suggest the simultaneous occurrence of two different

clinical presentations: first the myelitis, and second the vas-

culopathy. We can hypothesize that the immunosuppressive

condition of this patient favoured the persistence of a high

viral load in the brain arteries, leading to a massive vasculop-

athy both in subdural and ventricular areas.

Unlike herpes simplex virus, the correlation between the

presence of VZV in CSF and brain infection has not been

demonstrated. However, it has been demonstrated that the

VZV viral load in the CSF was correlated to the severity of

central nervous system symptoms in patients presenting with

encephalitis [37]. Moreover, the acyclovir-induced clearance

of VZV DNA from the CSF was associated with clinical

improvement in four cases of encephalitis [26]. These find-

ings are in favour of a direct viral encephalitis besides vascu-

laritis and demyelinating encephalitis. However, some

crossover between acute VZV encephalitis and VZV-induced

vasculopathy cannot be excluded, and both mechanisms

might exist in the same patients following reactivation of the

virus. This is suggested by the observation of a patient

enrolled in our study with a large vessel vasculopathy on

angiography and normal brain imaging excluding both a

stroke and a demyelinating process.

Conclusion

Varicella zoster virus encephalitis is the second leading cause

of acute infectious encephalitis in France, accounting for

nearly 10% of all cases. According to our results, this diagno-

sis should be considered in any case of central nervous sys-

tem acute febrile disease with lymphocytic aseptic meningitis,

especially in elderly and immunocompromised patients. The

absence of any rash, as in more than half of the cases in our

study, should not be considered as evidence excluding the

diagnosis of VZV encephalitis. Despite the low level of evi-

dence, acyclovir treatment should be prescribed to these

patients, because of its antiviral effectiveness against VZV.

The case fatality rate remains high and sequelae are frequent.

Controversies remain about its pathophysiology and further

research should be undertaken to determine the optimal

therapeutic regimen.

Contribution

TdB, AM, SB, PM and JPS contributed equally in the redac-

tion of the manuscript. AM was responsible for the analysis

of data. The members of the steering committee contributed

CMI De Broucker et al. Varicella zoster encephalitis in France in 2007 817

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

to the critical reviewing of the manuscript. The members of

the investigators group contributed to the investigation and

management of the patients, and to the collection and inter-

pretation of data.

Transparency Declaration

The Institut de veille sanitaire (French institute for public

health surveillance), Saint Maurice, France promoted the

study and funded the salary of two data collection personnel.

Glaxo SmithKline, Roche and Biomerieux funded the setting

up and maintenance of a biobank of samples taken from the

patients. All authors have no conflict of interest to disclose.

Appendix

Steering committee

Cecile Bebear (Bordeaux), Cecile Brouard (Saint-Maurice),

Thomas De Broucker (Saint-Denis), Eric Cua (Nice), Henri

Dabernat (Toulouse), Daniel Floret (Lyon), Benoit Guery

(Lille), Marc Lecuit (Paris), Bruno Lina (Lyon), Olivier Lor-

tholary (Paris), Alexandra Mailles (Saint-Maurice), Christian

Michelet (Rennes), Patrice Morand (Grenoble), Bruno Poz-

zetto (Saint-Etienne), Jean-Paul Stahl (Grenoble), Veronique

Vaillant (Saint-Maurice), Yazdan Yazdanpanah (Tourcoing),

Herve Zeller (Lyon).

Investigators

Philippe Abboud (Rouen), Chakib Alloui (Paris), Christine Ar-

chimbaud (Clermont-Ferrand), Bruno Barroso (Pau), Louis

Bernard (Garches), Pascal Beuret (Roanne), Genevieve Bil-

laud (Lyon), Thierry Blanc (Rouen), Michele Bonnard-Gou-

geon (Clermont-Ferrand), David Boutolleau (Paris), Cedric

Bretonniere (Nantes), Celine Bressollette-Bodin (Nantes),

Fabrice Bruneel (Versailles), Marielle Buisson (Dijon), Anne

Caramella (Nice), Bernard Castan (Auch), Isabelle Cattaneo

(Bry sur Marne), Charles Cazanave (Bordeaux), Stephane

Chabrier (Saint-Etienne), Marie-Laure Chadenat (Versailles),

Martine Chambon (Clermont-Ferrand), Pascal Chavanet (Di-

jon), Mondher Chouchane (Dijon), Pierre Clavelou (Cler-

mont-Ferrand), Pierre Courant (Avignon), Eric Cua (Nice),

Fabienne de Brabant (Montelimar), Arnaud De La Blanch-

ardiere (Caen), Geoffroy De La Gastine (Caen), Henri De

Montclos (Bourg-en-Bresse), Eric Denes (Limoges), Philippe

Desprez (Strasbourg), Anny Dewilde (Lille), Aurelien Dinh

(Garches), Francois Durand (Saint-Etienne), Guillaume Emeri-

aud (Grenoble), Olivier Epaulard (Grenoble), Giovanni Fava-

retto (Avranche), Anna Ferrier (Clermont-Ferrand), Vincent

Foulongne (Montpellier), Francois Fourrier (Lille), Veronique

Gaday (Pontoise), Jacques Gaillat (Annecy), Serge Gallet

(Montlucon), Nicole Gazuy (Clermont-Ferrand), Stephanie

Gouarin (Caen), Pascale Goubin (Caen), Alain Goudeau

(Tours), Joel Gozlan (Paris), Philippe Granier (Bourg-en-

Bresse), Isabelle Gueit (Rouen), Amelie Guihot (Paris), Chris-

tine Guillermet (Besancon), Christelle Guillet-Caruba (Paris),

Yves Guimard (Bourges), Yves Hansmann (Strasbourg),

Cecile Henquell (Clermont-Ferrand), Jean-Louis Herrmann

(Garches), Jerome Honnorat (Lyon), Nadhira Houhou

(Paris), Benoit Jaulhac (Strasbourg), Olivier Join-Lambert

(Paris), Manoelle Kossorotoff (Paris), Emmanuelle Laudrault

(Montelimar), Frederic Laurent (Lyon), Jean-Jacques Lauri-

chesse (Paris), Sylvain Lavoue (Rennes), Leila Lazaro

(Bayonne), Stephane Legriel (Versailles), Olivier Lesens (Cler-

mont-Ferrand), Gerard Level (Verdun), Muriel Mace (Orle-

ans), Benedicte Maisonneuve (Montlucon), Alain Makinson

(Montpellier), Helene Marchandin (Montpellier), Laurent

Martinez-Almoyna (Saint-Denis), Patrick Marthelet (Monteli-

mar), Martin Martinot (Colmar), Bruno Massenavette (Lyon),

Laurence Maulin (Aix-en-Provence), Benoit Misset (Paris),

Catherine Neuwirth (Dijon), Florence Nicot (Toulouse),

Jerome Pacanowski (Paris), Jean-Bernard Palcoux (Clermont-

Ferrand), Patricia Pavese (Grenoble), Thomas Perpoint

(Lyon), Martine Pestel–Caron (Rouen), Robin Pouyau (Lyon),

Thierry Prazuck (Orleans), Virginie Prendki (Paris), Chris-

tophe Rapp (Saint-Mande), Christel Regagnon (Clermont-Fer-

rand), Matthieu Rigal (Auch), Nathalie Roch (Grenoble),

Olivier Rogeaux (Chambery), Sylvie Rogez (Limoges),

Charles Santre (Annecy), Anne Signori-Schmuck (Grenoble),

Fabrice Simon (Marseille), Abdelilah Taimi (Roanne), Jerome

Tayoro (Le Mans), Daniel Terral (Clermont-Ferrand), Audrey

Therby (Versailles), Francis Vuillemet (Colmar).

References

1. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R,

Cohrs RJ. Neurologic complications of the reactivation of varicella-

zoster virus. N Engl J Med 2000; 342: 635–645.

2. Steiner I, Kennedy PGE, Pachner AR. The neurotropic herpes viruses:

herpes simplex and varicella-zoster. Lancet Neurol 2007; 6: 1015–1028.

3. Johnson RW, McElhaney J. Postherpetic neuralgia in the elderly. Int J

Clin Pract 2009; 63: 1386–1391.

4. Gershon AA, Gershon MD, Breuer J, Levin MJ, Oaklander AL, Grif-

fiths PD. Advances in the understanding of the pathogenesis and epi-

demiology of herpes zoster. J Clin Virol 2010; 48 (suppl): S2–S7.

5. Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R, Nagel MA. Vari-

cella-zoster virus infection: clinical features, molecular pathogenesis

of disease, and latency. Neurol Clin 2008; 26: 675–697, viii.

6. Reshef E, Greenberg SB, Jankovic J. Herpes zoster ophthalmicus fol-

lowed by contralateral hemiparesis: report of two cases and review

of literature. J Neurol Neurosurg Psychiatr 1985; 48: 122–127.

818 Clinical Microbiology and Infection, Volume 18 Number 8, August 2012 CMI

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819

7. Kleinschmidt-DeMasters BK, Gilden DH. Varicella-Zoster virus infec-

tions of the nervous system: clinical and pathologic correlates. Arch

Pathol Lab Med 2001; 125: 770–780.

8. de Broucker T, Verollet D, Schoindre Y et al. [Cerebral vasculitis

with aneurysms caused by varicella-zoster virus infection during

AIDS: a new clinicoangiographical syndrome]. Rev Neurol (Paris) 2008;

164: 61–71.

9. Gilden D, Cohrs RJ, Mahalingam R, Nagel MA. Varicella-zoster virus

vasculopathies: diverse clinical manifestations, laboratory features,

pathogenesis, and treatment. Lancet Neurol 2009; 8: 731–740.

10. Gilden D. Varicella-zoster virus and central nervous system syn-

dromes. Herpes 2004; 11 (suppl 2): 89A–94A.

11. Mailles A, Stahl J-P. Infectious encephalitis in France in 2007: a

national prospective study. Clin Infect Dis 2009; 49: 1838–1847.

12. Granerod J, Ambrose HE, Davies NW et al. Causes of encephalitis

and differences in their clinical presentations in England: a multicen-

tre, population-based prospective study. Lancet Infect Dis 2010; 10:

835–844.

13. Glaser CA, Honarmand S, Anderson LJ et al. Beyond viruses: clinical

profiles and etiologies associated with encephalitis. Clin Infect Dis

2006; 43: 1565–1577.

14. Tunkel AR, Glaser CA, Bloch KC et al. The management of encepha-

litis: clinical practice guidelines by the Infectious Diseases Society of

America. Clin Infect Dis 2008; 47: 303–327.

15. Johnson R, Milbourn PE. Central nervous system manifestations of

chickenpox. Can Med Assoc J 1970; 102: 831–834.

16. Jemsek J, Greenberg SB, Taber L, Harvey D, Gershon A, Couch RB.

Herpes zoster-associated encephalitis: clinicopathologic report of 12

cases and review of the literature. Medicine (Baltimore) 1983; 62: 81–97.

17. Koskiniemi M, Piiparinen H, Rantalaiho T et al. Acute central nervous

system complications in Varicella-zoster virus infections. J Clin Virol

2002; 25: 293–301.

18. Douglas A, Harris P, Francis F, Norton R. Herpes zoster meningoen-

cephalitis: not only a disease of the immunocompromised? Infection

2010; 38: 73–75.

19. Jennett B, Bond M. Assessment of outcome after severe brain dam-

age. Lancet 1975; 1: 480–484.

20. Mailles A, Vaillant V, Stahl J-P. [Infectious encephalitis in France from

2000 to 2002: the hospital database is a valuable but limited source

of information for epidemiological studies]. Med Mal Infect 2007; 37:

95–102.

21. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz

C. Detection of varicella-zoster virus DNA by polymerase chain

reaction in the cerebrospinal fluid of patients suffering from neuro-

logical complications associated with chicken pox or herpes zoster. J

Clin Microbiol 1991; 29: 1513–1516.

22. Horten B, Price RW, Jimenez D. Multifocal varicella-zoster virus leu-

koencephalitis temporally remote from herpes zoster. Ann Neurol

1981; 9: 251–266.

23. Hokkanen L, Launes J, Poutiainen E et al. Subcortical type cognitive

impairment in herpes zoster encephalitis. J Neurol 1997; 244: 239–

245.

24. Miravet E, Danchaivijitr N, Basu H, Saunders DE, Ganesan V. Clinical

and radiological features of childhood cerebral infarction following

varicella zoster virus infection. Dev Med Child Neurol 2007; 49: 417–

422.

25. Cinque P, Bossolasco S, Vago L et al. Varicella-zoster virus (VZV)

DNA in cerebrospinal fluid of patients infected with human

immunodeficiency virus: VZV disease of the central nervous system

or subclinical reactivation of VZV infection? Clin Infect Dis 1997; 25:

634–639.

26. Persson A, Bergstrom T, Lindh M, Namvar L, Studahl M. Varicella-

zoster virus CNS disease—viral load, clinical manifestations and

sequels. J Clin Virol 2009; 46: 249–253.

27. Hausler M, Schaade L, Kemeny S, Schweizer K, Schoenmackers C,

Ramaekers VT. Encephalitis related to primary varicella-zoster virus

infection in immunocompetent children. J Neurol Sci 2002; 2: 111–

116.

28. Peterslund NA. Herpes zoster associated encephalitis: clinical findings

and acyclovir treatment. Scand J Infect Dis 1988; 20: 583–592.

29. Nagel MA, Cohrs RJ, Mahalingam R et al. The Varicella-zoster virus

vasculopathies: clinical, CSF, imaging, and virologic features. Neurology

2008; 70: 853–860.

30. Pahud BA, Glaser CA, Dekker CL, Arvin AM, Schmid DS. Varicella-

zoster disease of the central nervous system: epidemiological, clinical,

and laboratory features 10 years after the introduction of the vari-

cella vaccine. J Infect Dis 2011; 203: 316–323.

31. Arvin AM. Antiviral therapy for varicella and herpes zoster. Semin

Pediatr Infect Dis 2002; 13: 12–21.

32. Dworkin RH, Johnson RW, Breuer J et al. Recommendations for the

management of herpes zoster. Clin Infect Dis 2007; 44 (suppl 1): S1–

S26.

33. Raschilas F, Wolff M, Delatour F et al. Outcome of and prognostic

factors for herpes simplex encephalitis in adult patients: results of a

multicenter study. Clin Infect Dis 2002; 35: 254–260.

34. Schmidt-Hieber M, Zweigner J, Uharek L, Blau IW, Thiel E. Central

nervous system infections in immunocompromised patients: update

on diagnostics and therapy. Leuk Lymphoma 2009; 50: 24–36.

35. Sawaishi Y, Takada G. Acute cerebellitis. Cerebellum 2002; 1: 223–

228.

36. Askalan R, Laughlin S, Mayank S et al. Chickenpox and stroke in

childhood: a study of frequency and causation. Stroke 2001; 32: 1257–

1262.

37. Aberle SW, Aberle JH, Steininger C, Puchhammer-Stockl E. Quantita-

tive real time PCR detection of Varicella-zoster virus DNA in

cerebrospinal fluid in patients with neurological disease. Med Microbiol

Immunol 2005; 194: 7–12.

CMI De Broucker et al. Varicella zoster encephalitis in France in 2007 819

ª2011 The Authors

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 808–819