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

ORIGINAL ARTICLE

10.1111/j.1469-0691.2011.03705.x

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 features. Furthermore, the most favourable treatment regimen has not been determined. We studied a prospective cohort of 20 HIV-negative 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 median age of the 17 adults was 76 (19–86) years; the three other patients were children (0.5–5 years). Three patients were immunocompromised. 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 subdural 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 Clin Microbiol Infect 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 Alphaherpesvirinae subfamily, responsible for human infections with various clinical presentations. Primary infection occurs most frequently during childhood and presents as varicella; it is followed 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 frequent 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 cerebellitis, meningitis, myelitis, optic neuritis, polyneuropathy, acute encephalitis and vasculopathy [2,4]. Some neurological presentations 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, vasculopathy 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

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Clinical Microbiology and Infection

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 transient cerebral arteriopathy in children and delayed contralateral 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 follow-up of these patients [15–18]. The importance of VZV in the epidemiology of acute encephalitis in the general population 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 ‡38C; 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 encephalitis occurring simultaneously or shortly after varicella or herpes zoster without biological confirmation of VZV infection, 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 magnetic resonance and computed tomography images to assess brain lesions.

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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 neurological 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 children (the two 5-year-old boys mentioned above and a 6month 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 comorbidities, 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 hospitalization: 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 presented 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 central facial nerve paralysis in seven cases and oculomotor nerve paralysis in one case. Lumbar puncture was performed before day 2 of hospitalization in 80% of cases and before day 4 in 95%. The

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI

Age (years)

Sex

M

M

M

Lungs and heart transplant, Renal insufficiency, Diabetes mellitus Steroids

Cardiac insufficiency

None

None

Comorbidities

5

P

M

M

Adrenal insufficiency Steroids, Failure to thrive

None

77

85

C

C

M

F

Respiratory insufficiency, Osteosarcoma, bilateral nephrectomy Cardiac insufficiency, Paraparesis following discal herniation

Patients with non-specific lesions on imaging C 86 F Cardiac insufficiency Dementia

55

None

Shingles

Shingles

Varicellab

None

None

None

Shingles

None

Varicella

VZV rash

Fever, disorientation, apathy, incoherent speech

Fever, more disorientated and incoherent, decreased consciousness, deficit of right leg Fever, agitation, incoherent speech, facial paralysis, ataxia, radiculitis

Fever, disorientation, agitation, seizures, facial paralysis, hemiparesis, hemianopia

Fever, aggressiveness, ideo-motor apraxia, repetitive speech, disorientation, seizures Fever, brainstem deficits, tinnitus, ataxia

Fever, found unconscious at home, seizures, decreased consciousness, brainstem deficits, tetraparesis

Fever, headache, incoherent speech, aphasia, facial paralysis, hemiparesis, Disorientation, incoherent speech, meningeal syndrome, facial paralysis, severe sepsis

Fever, vomiting, fontanelle bulging, downward gaze deviation, apathy

Clinical signs

14

15

8

7

15

–

3

14

–

10

GCSa on admission

200

16

30

930

48

40

100

66

350

400

WBC count (/mm3)

1.9

0.4

1

0.2

0.8

0.8

5

1.1

0.8

0.8

CSF proteins (g/L)

–

–

Cortical atrophy

–

–

D0: bilateral temporal hypodensities

D4 and D22: normal J27: ventricular bleeding, thalamic and temporal haematoma, brain herniation Normal

D0: Ventricular hydrocephaly, ventricular bleeding D8: external hydrocephaly

CT scan

Leukoaraiosis, bilateral basal ganglia lacunar sequelae

Cortical atrophy

–

Hypersignals in brainstem and upper medulla Hypersignal in temporal, parietal, and occipital lobes on T2 weighted MRI

–

D0: bilateral millimetric high signal T2 lesions of internal capsules, pons and spinal cord at T7–T8 level D12 : bilateral subdural hydromas D16 : normal D45 :ventricular bleeding and hydro cephaly

D0: focal stenosis of the left middle cerebral artery D1: left external capsule lacunar sequelae

D1: external hydrocephaly

MRI

Considered cured on discharged, deaf and bedridden 3 years later

Died of cancer 2 years after discharge

Died with acute coma 2 months after discharge

Still suffers from tinnitus, ataxia and aphasia 3 years later Back to previous medical condition

Full recovery

Discharged to rehabilitation facility, still paraplegic 3 years later

Died on D34 of hospital stay

Full recovery

Recovery, CSF derivation still in place 3 years later

Outcome

De Broucker et al.

C

Patients with parenchymal non vascular lesions C 75 M History of renal carcinoma

34

79

C

C

20

C

Patients with brain vasculopathy C 0.5 M

Confirmed/ Possible

TABLE 1. Characteristics of 20 patients with varicella zoster virus encephalitis, France 2007

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ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI

78

Age (years)

M

Sex

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI

20

76

82

84

63

C

P

C

C

C

M

F

M

F

F

M

Depression

None

Systemic Lupus erythematous Hemiplegia (spinal compression) depression Steroids None

None

None

None

None

Comorbidities

Shingles

None

None

Shingles

Shingles

Shingles

None

None

Varicella

Ophthalmic shingles

VZV rash

Fever, cough, incoherent speech, disorientation, drowsiness Fever, cough, vomiting, disorientation, incoherent speech, nystagmus, facial palsy, radiculitis, laryngeal paralysis

Fever, incoherent speech, hyperaesthesia Flu-like syndrome, incoherent speech, disorientation, agitation

Fever, disorientation, incoherent speech

Fever, Cough, decreased consciousness, disorientation, seizures, tetraparesis, gaze deviation Fever, deafness, ataxia, brainstem deficit, meningeal syndrome Incoherent speech, headache, disorientation, meningeal syndrome Diarrhoea, incoherent speech, pyramidal pathways deficit, decreased consciousness

Vomiting, disorientation, incoherent speech, diplopia, aphasia, non-reflexive mydriasis, cerebellous syndrome

Clinical signs

b

a

GOS, Glasgow outcome scale. Maximum value = 10 before 6 months of age, 12 before 1 year of age, 15 afterwards. This patient did not present with any more rash on admission.

Patients with no set of images available for review C 83 M Renal, cardiac and lung insufficiency C 75 M None

26

C

Patients with normal imaging results P 5 M

P

Confirmed/ Possible

TABLE 1. Continued

–

14

14

15

15

9

320

300

1240

70

20

92

600

321

–

–

0

330

WBC count (/mm3)

10

–

GCSa on admission

1.8

3

3.9

1

0.8

1

1

1.6

0.7

1.2

CSF proteins (g/L)

Not available

Not available

J5: normal

–

Normal

Normal

–

Normal

–

–

CT scan

D7: normal D18: normal

Normal

–

–

Normal

–

Normal

Cortical atrophy

MRI

Persistent memory disorders and cognitive impairment Died at D23 of hospitalization from aspiration pneumonia

Full recovery

Improved under treatment then suddenly died at D18 of hospitalization GOS = 3

Back to previous medical condition (impaired)

Discharged with partial deafness and facial palsy, total recovery 3 years later Discharged with memory and attention impairment

Full recovery

Discharged with ataxia and disorientation, full recovery 3 years later

Outcome

4 Clinical Microbiology and Infection

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De Broucker et al.

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Varicella zoster encephalitis in France in 2007

5

TABLE 2. Clinical features of 20 patients presenting with varicella zoster virus encephalitis at day 0 and day 5 Day 0 All cases (n = 20) Fever Mechanical ventilation Severe sepsis Meningism Decreased level of consciousness Disorientation Confusion Seizures Focal neurological signs Speech disorders Cranial nerve palsy Cerebellous syndrome Sensory disorders Myelitis Aggressiveness Apathy Agitation Parkinsonism Movement disorders Hallucination

18 4 1 12 5 14 14 4 11 6 8 3 1 0 1 10 6 0 0 0

(90%)a (20%) (5%) (60%) (25%) (70%) (70%) (20%) (55%) (30%) (40%) (15%) (5%) (5%) (50%) (30%)

Day 5 Confirmed cases (n = 16) 15 1 1 9 3 11 12 2 7 5 6 2 1 0 1 7 4 0 0 0

(94%)b (6%) (6%) (56%) (19%) (69%) (75%) (13%) (44%) (31%) (38%) (13%) (6%) (7%) (44%) (27%)

Possible cases (n = 4) 3 3 0 3 2 3 2 2 4 1 2 1 0 0 0 3 2 0 0 0

(75%)b (75%) (75%) (50%) (75%) (50%) (50%) (100%) (25%) (50%) (25%)

(75%) (50%)

All cases (n = 20)

Confirmed cases (n = 16)

Possible cases (n = 4)

NA 3 (15%) 0 3 (15%) 2 (10%) 5 (25%) 2 (10%) 0 9 (45%) 2 (10%) 8 (40%) 3 (15%) NA 1 (5%) 0 3 (15%) 1 (5%) NA 0 0

NA 1 (6%) 0 3 (19%) 1 (6%) 5 (31%) 2 (13%) 0 7 (44%) 1 (6%) 6 (38%) 2 (13%) NA 1 (6%) 0 3 (19%) 1 (6%) NA 0 0

NA 2 (50%) 0 0 1 (25%) 0 0 0 2 (50%) 1 (25%) 2 (50%) NA 1 (25%) 0 0 0 NA 0 0

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

a

b

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 identified 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 reviewing (14 confirmed cases and four possible cases). Four (20%) patients demonstrated vascular lesions on computed tomography 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 ventricular size on follow-up imaging (Fig. 2); • thoracic myelitis was observed on admission in a 34year-old man with paraplegia, who developed at day 45 a bilateral subdural haematoma and massive ventricular bleeding (Fig. 3);

FIG. 1. Magnetic resonance image of a 20-year-old man. Narrowing of the M1 segment of the middle cerebral artery.

• 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: brainstem 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 nonspecific abnormalities (cortical atrophy) and the remaining

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Clinical Microbiology and Infection

(a)

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(b)

FIG. 2. Magnetic resonance image of a 6month-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 abnormal enhancement. (d) FLAIR sequence: no

(c)

(d)

seven (35%) patients, including two possible cases, had normal imaging results. Ischaemic stroke was ruled out by imaging in all patients. Treatment

Five of the eight adult patients with zoster rash received acyclovir before the onset of neurological symptoms. Acyclovir was administered intravenously to all 20 patients as encephalitis 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 discharge, 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 neurological signs: cognitive impairment (n = 3) and sensorymotor deficits (n = 6). Three years after discharge, 16 of the

parenchymal abnormality.

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 outcome 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 database 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 during 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

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De Broucker et al.

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(a)

FIG. 3. Magnetic 35-year-old

man.

resonance (a–c)

image

Cranial

of

Varicella zoster encephalitis in France in 2007

7

(b)

a

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.

(c)

confirmation could be obtained in four patients whose encephalitis occurred during or shortly after varicella or zoster. In these four patients, the clinical signs, imaging and outcome 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 convalescent 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 available. 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-

(d)

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 associated 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 immunocompromised patients following cancer or long-term immunosuppressive treatment. No study or clinical trial has yet addressed the best therapeutic regimen for VZV encephalitis. The prognosis of herpes simplex virus encephalitis has been dramatically improved by the use of acyclovir and this treatment is recommended 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

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI

Number of cases

53

12

2

2

9

24

4

Year of diagnosis

1956–1967

1971–1978

1975

1978–1982

1985–1995

1990–2004

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI

1992–1996

ND

Mean 2 years and 9 months (range 2 months to 6 years)

25–73 years old

(1) 42 years old (2) 62 years old

(1) 19 years old (2) 55 years old

Median 71 years (range 23–80)

Mean 5 years (range 8 months to 8.5 years)

Age of cases

All patients with AIDS

All immunocompetent

Immunocompetent

Both immunocompromised (leukaemia and renal transplant)

Both immunodepressed following cancer

Seven immunosuppressed

ND

Immune status of cases

DNA detection + clinical signs + consistent neuroimaging

Brain infarction + varicella within 12 months

Serology on CSF or serum, viral culture of skin lesions

Neurological signs + herpes zoster

Encephalitis or cerebellitis and herpes zoster Clinical

Neurological signs + varicella

Diagnosis/ case definition

2/4 with herpes zoster

Varicella is part of the case definition

5/9 cases, 4–8 days before neurological onset

Herpes zoster is part of the case definition

Herpes zoster in both

Herpes zoster is part of the case definition

Rash is part of the case definition

Rash

ND

Mean 4 months (range 1 week to 1 year)

4–8 days

(1) 10 weeks (2) At onset

ND

Mean: 9 days (max 28 days)

Mean 4 days (range 1–20)

Delay between rash and neurological onset

One encephalitis, one meningoen cephalitis, two focal encephalitis

Hemiparesis 23/24 Chorea 1/24 Facial weakness 1/24 Seizure 2/24

Hallucinations 10/12 Stupor 5/12 Confusion, headache, cranial nerve palsy (1) Cognitive decline, leg weakness, poor memory (2) Seizures, hemiparesis, poor memory (1) Ataxia, poor memory, hemiparesis, neuralgia (2) Hemiparesis, cranial nerves alsy, hemianopsie Fever 3/9 Headache 5/7 Speech disorders 5/7 Seizures 4/7 Motor deficit 3/7

23 with encephalitis, 29 with cerebellitis, one with myelitis

Clinical patterns

Two with vascularitis, two with encephalitis

Infarction is part of the case definition

Two deaths and two complete recoveries

On discharge: Poor memory 7/9, disinhibited behaviour 6/9, poor concentration 3/9 ND

1 ‘infarct-like lesion’ 1 ‘infarct-like lesion’, one non-specific lesion, other normal

Caudate and lentiform nuclei 21/24 Internal capsule 13/24 White matter infarction 19/24 Cortical infarction 8/24 One with haemorrhagic lesion, one with ischaemic lesion, one with cortical atrophy, one with brainstem lesions

Favourable outcome in both cases

Encephalitis: eight deaths, two discharged with permament sequelae. Cerebellitis: seven full recoveries, no death. Myelitis: full recovery Three deaths, one case with permanent paresis (1) Death after 6 weeks (2) death after 6 months

Outcome

No evidence of vascularitis

Both cases: encephalitis and secondary vascularitis

2/6 cases with necropsy showed signs of perivascular inflammation

Encephalitis/ vascularitis

Normal in one patient, mass effect for the other

1/5 with abnormal results on CT scan (ventricular enlargement) Both cases: parenchymal mass effect, evolution toward haemorrhage

No imaging

Imaging results

TABLE 3. Clinical, biological and imaging features of varicella zoster encephalitis patients included in the main published series

Before acyclovir, MRI and PCR

Before acyclovir and MRI and PCR

Before MRI, PCR and acyclovir

Before brain imaging, PCR and acyclovir

Comment

25

24

23

6

22

16

15

Ref.

8 Clinical Microbiology and Infection

CMI

7

9

30

ND

ND

11

1998–2009

2004–2009

28

1995–2006

2

92

1995–1996

2000–2001

Number of cases

Year of diagnosis

11/30 immunocompromised

All immunocompetent

2/7 immunodepressed

Both immunocompetent

5/11 immunodepressed (two with AIDS), 9/11 immunosenescent

ND

ND

Immune status of cases

Neurological signs and Imaging or CSF consistent with vasculopathy and DNA detection or serology

Clinical signs + DNA detection in CSF Neurological signs + rash

Serology + intrathecal antibody synthesis + DNA detection

Neurological signs + DNA detection in CSF

Clinical signs + serology or DNA detection Serology and RT-PCR

Diagnosis/ case definition

19/30 (63%)

Herpes zoster is part of the case definition

ND

(1) Varicella (2) None

7/11 (64%)

Herpes zoster in 37, varicella in 30, none in 25 Rash in 19/28

Rash

ND

ND

ND

1 week

ND

ND

Max 4 weeks for varicella

Delay between rash and neurological onset

ND

Most frequent: fever, headache, neck stiffness, photophobia Ataxia n = 5, cranial nerves impairment n=2

Ataxia 4/11 Cranial nerve palsy 4/11 Fever 5/11 Altered mental status 9/11 (1) Focal seizure, confusion (2) Fever, irritability, confusion

ND

ND

Clinical patterns

Large-vessel vasculopathy 4/30 (13%) Small-vessel vasculopathy 11/30 (37%) Mixed vasculopathy 15/30 (50%)

CT scan in 5/9, normal for all 5

6/28 with haemorrhage or infarction Vasculopathy 2/11 Parenchymatous lesions 2/11 Normal Imaging or non-specific lesions 7/11 (1) Subcortical lesion in temporal lobe, no stroke (2) Cortical and subcortical lesion of parietal lobe, White matter lesions Normal imaging in all patients

ND

Imaging results

Vasculopathy is part of the case definition

No evidence of vascularitis

No evidence of stroke or vasculopathy

No stroke, no evidence of vasculopathy

Six with cerebrovascular lesions Two cases with evidence of vasculopathy

ND

Encephalitis/ vascularitis

Favourable outcome for four cases with large-vessel vasculopathy Poor outcome for three cases with small-vessel and three cases with mixed vasculopathies

No death, sequelae not described

One death (terminal renal failure)

(1) Full recovery (2) Permanent hemianopsia

Two deaths, three patients with sequelae ND

ND

Outcome

Apparently before PCR and MRI but acyclovir available 23 previously published cases + seven newly published cases

Vascular lesions are not detailed

National study on CNS viral infections

Comment

29

28

18

27

21

26

17

Ref.

De Broucker et al.

Range 1–88 years old

Mean 47 years (range 14–79), bimodal distribution Median 72 years (range 52–94)

(1) 4 years old (2) 16 months old

Median 72 years (range 3–86) Median age 75 years (range 50–85)

All ages

Age of cases

TABLE 3. Continued

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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 foscarnet 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 infection. These complications are different during primary infection (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 arteriopathy, is defined by focal stenosis of the basal central arteries 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 correspond 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 disease 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 endothelial 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 ophthalmicus 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], imaging failed to demonstrate either vascular lesions or demyelinating 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 hypothesized that long-term steroids might be a risk factor for VZV

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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 vasculopathy. 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 vasculopathy 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 findings are in favour of a direct viral encephalitis besides vascularitis 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 diagnosis should be considered in any case of central nervous system 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 evidence, 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 redaction of the manuscript. AM was responsible for the analysis of data. The members of the steering committee contributed

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI

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De Broucker et al.

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 interpretation 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 Biome´rieux 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 Be´be´ar (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 Lortholary (Paris), Alexandra Mailles (Saint-Maurice), Christian Michelet (Rennes), Patrice Morand (Grenoble), Bruno Pozzetto (Saint-Etienne), Jean-Paul Stahl (Grenoble), Veronique Vaillant (Saint-Maurice), Yazdan Yazdanpanah (Tourcoing), Herve Zeller (Lyon). Investigators

Philippe Abboud (Rouen), Chakib Alloui (Paris), Christine Archimbaud (Clermont-Ferrand), Bruno Barroso (Pau), Louis Bernard (Garches), Pascal Beuret (Roanne), Genevie`ve Billaud (Lyon), Thierry Blanc (Rouen), Miche`le Bonnard-Gougeon (Clermont-Ferrand), David Boutolleau (Paris), Ce´dric Bretonnie`re (Nantes), Ce´line Bressollette-Bodin (Nantes), Fabrice Bruneel (Versailles), Marielle Buisson (Dijon), Anne Caramella (Nice), Bernard Castan (Auch), Isabelle Cattaneo (Bry sur Marne), Charles Cazanave (Bordeaux), Ste´phane Chabrier (Saint-Etienne), Marie-Laure Chadenat (Versailles), Martine Chambon (Clermont-Ferrand), Pascal Chavanet (Dijon), Mondher Chouchane (Dijon), Pierre Clavelou (Clermont-Ferrand), Pierre Courant (Avignon), Eric Cua (Nice), Fabienne de Brabant (Monte´limar), Arnaud De La Blanchardie`re (Caen), Geoffroy De La Gastine (Caen), Henri De Montclos (Bourg-en-Bresse), Eric Denes (Limoges), Philippe Desprez (Strasbourg), Anny Dewilde (Lille), Aurelien Dinh (Garches), Franc¸ois Durand (Saint-Etienne), Guillaume Emeriaud (Grenoble), Olivier Epaulard (Grenoble), Giovanni Favaretto (Avranche), Anna Ferrier (Clermont-Ferrand), Vincent

Varicella zoster encephalitis in France in 2007

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Foulongne (Montpellier), Franc¸ois Fourrier (Lille), Ve´ronique Gaday (Pontoise), Jacques Gaillat (Annecy), Serge Gallet (Montluc¸on), Nicole Gazuy (Clermont-Ferrand), Ste´phanie Gouarin (Caen), Pascale Goubin (Caen), Alain Goudeau (Tours), Joel Gozlan (Paris), Philippe Granier (Bourg-enBresse), Isabelle Gueit (Rouen), Ame´lie Guihot (Paris), Christine Guillermet (Besanc¸on), Christelle Guillet-Caruba (Paris), Yves Guimard (Bourges), Yves Hansmann (Strasbourg), Ce´cile Henquell (Clermont-Ferrand), Jean-Louis Herrmann (Garches), Je´rome Honnorat (Lyon), Nadhira Houhou (Paris), Benoit Jaulhac (Strasbourg), Olivier Join-Lambert (Paris), Manoelle Kossorotoff (Paris), Emmanuelle Laudrault (Monte´limar), Fre´de´ric Laurent (Lyon), Jean-Jacques Laurichesse (Paris), Sylvain Lavoue (Rennes), Leila Lazaro (Bayonne), Stephane Legriel (Versailles), Olivier Lesens (Clermont-Ferrand), Ge´rard Level (Verdun), Muriel Mace (Orle´ans), Be´ne´dicte Maisonneuve (Montluc¸on), Alain Makinson (Montpellier), He´le`ne Marchandin (Montpellier), Laurent Martinez-Almoyna (Saint-Denis), Patrick Marthelet (Monte´limar), Martin Martinot (Colmar), Bruno Massenavette (Lyon), Laurence Maulin (Aix-en-Provence), Benoit Misset (Paris), Catherine Neuwirth (Dijon), Florence Nicot (Toulouse), Je´rome Pacanowski (Paris), Jean-Bernard Palcoux (ClermontFerrand), Patricia Pavese (Grenoble), Thomas Perpoint (Lyon), Martine Pestel–Caron (Rouen), Robin Pouyau (Lyon), Thierry Prazuck (Orle´ans), Virginie Prendki (Paris), Christophe Rapp (Saint-Mande´), Christel Regagnon (Clermont-Ferrand), Matthieu Rigal (Auch), Nathalie Roch (Grenoble), Olivier Rogeaux (Chambe´ry), Sylvie Rogez (Limoges), Charles Santre (Annecy), Anne Signori-Schmuck (Grenoble), Fabrice Simon (Marseille), Abdelilah Taimi (Roanne), Je´rome 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 varicellazoster 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, Griffiths PD. Advances in the understanding of the pathogenesis and epidemiology of herpes zoster. J Clin Virol 2010; 48 (suppl): S2–S7. 5. Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R, Nagel MA. Varicella-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 followed by contralateral hemiparesis: report of two cases and review of literature. J Neurol Neurosurg Psychiatr 1985; 48: 122–127.

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI

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7. Kleinschmidt-DeMasters BK, Gilden DH. Varicella-Zoster virus infections 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 syndromes. 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 multicentre, 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 encephalitis: 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 meningoencephalitis: not only a disease of the immunocompromised? Infection 2010; 38: 73–75. 19. Jennett B, Bond M. Assessment of outcome after severe brain damage. 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-Sto¨ckl 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 neurological 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 leukoencephalitis temporally remote from herpes zoster. Ann Neurol 1981; 9: 251–266.

CMI

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, Bergstro¨m T, Lindh M, Namvar L, Studahl M. Varicellazoster 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. Varicellazoster 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. 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-Sto¨ckl E. Quantitative real time PCR detection of Varicella-zoster virus DNA in cerebrospinal fluid in patients with neurological disease. Med Microbiol Immunol 2005; 194: 7–12.

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