Clin Microbiol Infect
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.
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 . Post-herpetic neuralgia is a frequent complication in elderly patients .
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 . Neurological symptoms caused by VZV infection can also occur without any cutaneous rash (zoster sine herpete) and the detection of DNA or specific VZV antibodies in the cerebrospinal fluid (CSF) is here the only proof of VZV involvement .
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.
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 .
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.
The outcome of VZV patients was assessed 3 years after discharge using the Glasgow outcome scale .
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).
Twenty of 253 (8%) case-patients enrolled in the initial study were VZV patients . 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.
|Confirmed/Possible||Age (years)||Sex||Comorbidities||VZV rash||Clinical signs||GCSa on admission||WBC count (/mm3)||CSF proteins (g/L)||CT scan||MRI||Outcome|
|Patients with brain vasculopathy|
|C||0.5||M||None||Varicella||Fever, vomiting, fontanelle bulging, downward gaze deviation, apathy||10||400||0.8||D0: Ventricular hydrocephaly, ventricular bleeding |
D8: external hydrocephaly
|D1: external hydrocephaly||Recovery, CSF derivation still in place 3 years later|
|C||20||M||None||None||Fever, headache, incoherent speech, aphasia, facial paralysis, hemiparesis,||–||350||0.8||D0: focal stenosis of the left middle cerebral artery||Full recovery|
|C||79||M||Cardiac insufficiency||Shingles||Disorientation, incoherent speech, meningeal syndrome, facial paralysis, severe sepsis||14||66||1.1||D4 and D22: normal |
J27: ventricular bleeding, thalamic and temporal haematoma, brain herniation
|D1: left external capsule lacunar sequelae||Died on D34 of hospital stay|
|C||34||M||Lungs and heart transplant, |
Renal insufficiency, Diabetes mellitus
|None||Fever, found unconscious at home, seizures, decreased consciousness, brainstem deficits, tetraparesis||3||100||5||Normal||D0: bilateral millimetric high signal T2 lesions of internal capsules, pons and spinal cord at T7–T8 |
D12 : bilateral subdural hydromas
D16 : normal
D45 :ventricular bleeding and hydrocephaly
|Discharged to rehabilitation facility, still paraplegic 3 years later|
|Patients with parenchymal non vascular lesions|
|C||75||M||History of renal carcinoma||None||Fever, aggressiveness, ideo-motor apraxia, repetitive speech, disorientation, seizures||–||40||0.8||D0: bilateral temporal hypodensities||–||Full recovery|
|C||55||M||None||None||Fever, brainstem deficits, tinnitus, ataxia||15||48||0.8||–||Hypersignals in brainstem and upper medulla||Still suffers from tinnitus, ataxia and aphasia 3 years later|
|P||5||M||Adrenal insufficiency |
Steroids, Failure to thrive
|Varicellab||Fever, disorientation, agitation, seizures, facial paralysis, hemiparesis, hemianopia||7||930||0.2||–||Hypersignal in temporal, parietal, and occipital lobes on T2 weighted MRI||Back to previous medical condition|
|Patients with non-specific lesions on imaging|
|C||86||F||Cardiac insufficiency |
|Shingles||Fever, more disorientated and incoherent, decreased consciousness, deficit of right leg||8||30||1||Cortical atrophy||–||Died with acute coma 2 months after discharge|
|C||77||F||Respiratory insufficiency, Osteosarcoma, bilateral nephrectomy||Shingles||Fever, agitation, incoherent speech, facial paralysis, ataxia, radiculitis||15||16||0.4||–||Cortical atrophy||Died of cancer 2 years after discharge|
|C||85||M||Cardiac insufficiency, |
Paraparesis following discal herniation
|None||Fever, disorientation, apathy, incoherent speech||14||200||1.9||–||Leukoaraiosis, bilateral basal ganglia lacunar sequelae||Considered cured on discharged, deaf and bedridden 3 years later|
|P||78||M||None||Ophthalmic shingles||Vomiting, disorientation, incoherent speech, diplopia, aphasia, non-reflexive mydriasis, cerebellous syndrome||–||330||1.2||–||Cortical atrophy||Discharged with ataxia and disorientation, full recovery 3 years later|
|Patients with normal imaging results|
|P||5||M||None||Varicella||Fever, Cough, decreased consciousness, disorientation, seizures, tetraparesis, gaze deviation||10||0||0.7||–||Normal||Full recovery|
|C||26||M||None||None||Fever, deafness, ataxia, brainstem deficit, meningeal syndrome||–||321||1.6||Normal||–||Discharged with partial deafness and facial palsy, total recovery 3 years later|
|C||20||F||None||None||Incoherent speech, headache, disorientation, meningeal syndrome||–||600||1||–||Normal||Discharged with memory and attention impairment|
|P||76||F||Systemic Lupus erythematous |
Hemiplegia (spinal compression) depression
|Shingles||Diarrhoea, incoherent speech, pyramidal pathways deficit, decreased consciousness||9||92||1||Normal||–||Back to previous medical condition (impaired)|
|C||82||M||None||Shingles||Fever, disorientation, incoherent speech||15||20||0.8||Normal||–||Improved under treatment then suddenly died at D18 of hospitalization|
|C||84||F||None||Shingles||Fever, incoherent speech, hyperaesthesia||15||70||1||–||Normal||GOS = 3|
|C||63||M||Depression||None||Flu-like syndrome, incoherent speech, disorientation, agitation||14||1240||3.9||J5: normal||D7: normal |
|Patients with no set of images available for review|
|C||83||M||Renal, cardiac and lung insufficiency||None||Fever, cough, incoherent speech, disorientation, drowsiness||14||300||3||Not available||Persistent memory disorders and cognitive impairment|
|C||75||M||None||Shingles||Fever, cough, vomiting, disorientation, incoherent speech, nystagmus, facial palsy, radiculitis, laryngeal paralysis||–||320||1.8||Not available||Died at D23 of hospitalization from aspiration pneumonia|
The male to female ratio was 3. Three patients were children (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.
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.
|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||NA|
|Mechanical ventilation||4 (20%)||1 (6%)||3 (75%)||3 (15%)||1 (6%)||2 (50%)|
|Severe sepsis||1 (5%)||1 (6%)||0||0||0||0|
|Meningism||12 (60%)||9 (56%)||3 (75%)||3 (15%)||3 (19%)||0|
|Decreased 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%)||0|
|Confusion||14 (70%)||12 (75%)||2 (50%)||2 (10%)||2 (13%)||0|
|Seizures||4 (20%)||2 (13%)||2 (50%)||0||0||0|
|Focal 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||NA|
|Myelitis||0||0||0||1 (5%)||1 (6%)||1 (25%)|
|Aggressiveness||1 (5%)||1 (7%)||0||0||0||0|
|Apathy||10 (50%)||7 (44%)||3 (75%)||3 (15%)||3 (19%)||0|
|Agitation||6 (30%)||4 (27%)||2 (50%)||1 (5%)||1 (6%)||0|
Lumbar puncture was performed before day 2 of hospitalization in 80% of cases and before day 4 in 95%. The 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.
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 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: 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 non-specific abnormalities (cortical atrophy) and the remaining seven (35%) patients, including two possible cases, had normal imaging results. Ischaemic stroke was ruled out by imaging in all patients.
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.
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 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 outcome scale 3 or 4), and the outcome was favourable for seven (41%) with a Glasgow outcome scale of 5.
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 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 .
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 . 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 . 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 distribution of age), and their clinical signs were similar to those observed in our prospective study .
|Year of diagnosis||Number of cases||Age of cases||Immune status of cases||Diagnosis/case definition||Rash||Delay between rash and neurological onset||Clinical patterns||Imaging results||Encephalitis/|
|1956–1967||53||Mean 5 years (range 8 months to 8.5 years)||ND||Neurological signs + varicella||Rash is part of the case definition||Mean 4 days (range 1–20)||23 with encephalitis, 29 with cerebellitis, one with myelitis||No imaging||2/6 cases with necropsy showed signs of perivascular inflammation||Encephalitis: eight deaths, two discharged with permament sequelae. |
Cerebellitis: seven full recoveries, no death.
Myelitis: full recovery
|Before brain imaging, PCR and acyclovir||15|
|1971–1978||12||Median 71 years (range 23–80)||Seven immunosuppressed||Encephalitis or cerebellitis and herpes zoster||Herpes zoster is part of the case definition||Mean: 9 days (max 28 days)||Hallucinations 10/12 |
Confusion, headache, cranial nerve palsy
|1/5 with abnormal results on CT scan (ventricular enlargement)||Three deaths, one case with permanent paresis||Before MRI, PCR and acyclovir||16|
|1975||2||(1) 19 years old |
(2) 55 years old
|Both immunodepressed following cancer||Clinical||Herpes zoster in both||ND||(1) Cognitive decline, leg weakness, poor memory |
(2) Seizures, hemiparesis, poor memory
|Both cases: parenchymal mass effect, evolution toward haemorrhage||Both cases: encephalitis and secondary vascularitis||(1) Death after 6 weeks |
(2) death after 6 months
|Before acyclovir and MRI and PCR||22|
|1978–1982||2||(1) 42 years old |
(2) 62 years old
|Both immunocompromised (leukaemia and renal transplant)||Neurological signs + herpes zoster||Herpes zoster is part of the case definition||(1) 10 weeks |
(2) At onset
|(1) Ataxia, poor memory, hemiparesis, neuralgia |
(2) Hemiparesis, cranial nerves alsy, hemianopsie
|Normal in one patient, mass effect for the other||No evidence of vascularitis||Favourable outcome in both cases||Before acyclovir, MRI and PCR||6|
|1985–1995||9||25–73 years old||Immunocompetent||Serology on CSF or serum, viral culture of skin lesions||5/9 cases, 4–8 days before neurological onset||4–8 days||Fever 3/9 |
Speech disorders 5/7
Motor deficit 3/7
|1 ‘infarct-like lesion’, one non-specific lesion, other normal||1 ‘infarct-like lesion’||On discharge: Poor memory 7/9, disinhibited behaviour 6/9, poor concentration 3/9||23|
|1990–2004||24||Mean 2 years and 9 months (range 2 months to 6 years)||All immunocompetent||Brain infarction + varicella within 12 months||Varicella is part of the case definition||Mean 4 months (range 1 week to 1 year)||Hemiparesis 23/24 |
Facial weakness 1/24
|Caudate and lentiform nuclei 21/24 |
Internal capsule 13/24
White matter infarction 19/24
Cortical infarction 8/24
|Infarction is part of the case definition||ND||24|
|1992–1996||4||ND||All patients with AIDS||DNA detection + clinical signs + consistent neuroimaging||2/4 with herpes zoster||ND||One encephalitis, one meningoencephalitis, two focal encephalitis||One with haemorrhagic lesion, one with ischaemic lesion, one with cortical atrophy, one with brainstem lesions||Two with vascularitis, two with encephalitis||Two deaths and two complete recoveries||25|
|1995–1996||92||All ages||ND||Clinical signs + serology or DNA detection||Herpes zoster in 37, varicella in 30, none in 25||Max 4 weeks for varicella||ND||ND||ND||ND||National study on CNS viral infections||17|
|1995–2006||28||Median 72 years (range 3–86)||ND||Serology and RT-PCR||Rash in 19/28||ND||ND||6/28 with haemorrhage or infarction||Six with cerebrovascular lesions||Two deaths, three patients with sequelae||Vascular lesions are not detailed||26|
|1998–2009||11||Median age 75 years (range 50–85)||5/11 immunodepressed (two with AIDS), 9/11 immunosenescent||Neurological signs + DNA detection in CSF||7/11 (64%)||ND||Ataxia 4/11 |
Cranial nerve palsy 4/11
Altered mental status 9/11
|Vasculopathy 2/11 |
Parenchymatous lesions 2/11
Normal Imaging or non-specific lesions 7/11
|Two cases with evidence of vasculopathy||ND||21|
|2000–2001||2||(1) 4 years old |
(2) 16 months old
|Both immunocompetent||Serology + intrathecal antibody synthesis + DNA detection||(1) Varicella |
|1 week||(1) Focal seizure, confusion |
(2) Fever, irritability, confusion
|(1) Subcortical lesion in temporal lobe, no stroke |
(2) Cortical and subcortical lesion of parietal lobe, White matter lesions
|No stroke, no evidence of vasculopathy||(1) Full recovery |
(2) Permanent hemianopsia
|2004–2009||7||Mean 47 years (range 14–79), bimodal distribution||2/7 immunodepressed||Clinical signs + DNA detection in CSF||ND||ND||Most frequent: fever, headache, neck stiffness, photophobia||Normal imaging in all patients||No evidence of stroke or vasculopathy||One death (terminal renal failure)||18|
|ND||9||Median 72 years (range 52–94)||All immunocompetent||Neurological signs + rash||Herpes zoster is part of the case definition||ND||Ataxia n = 5, cranial nerves impairment n = 2||CT scan in 5/9, normal for all 5||No evidence of vascularitis||No death, sequelae not described||Apparently before PCR and MRI but acyclovir available||28|
|ND||30||Range 1–88 years old||11/30 immunocompromised||Neurological signs and Imaging or CSF consistent with vasculopathy and DNA detection or serology||19/30 (63%)||ND||ND||Large-vessel vasculopathy 4/30 (13%) |
Small-vessel vasculopathy 11/30 (37%)
Mixed vasculopathy 15/30 (50%)
|Vasculopathy is part of the case definition||Favourable outcome for four cases with large-vessel vasculopathy |
Poor outcome for three cases with small-vessel and three cases with mixed vasculopathies
|23 previously published cases + seven newly published cases||29|
Twenty-six patients with positive CSF VZV DNA were referred to the California Encephalitis Project, 11 suffering encephalitis . 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 . 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 . In 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 .
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 . 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 .
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 . 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 myelitis . 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 . Moreover, the acyclovir-induced clearance of VZV DNA from the CSF was associated with clinical improvement in four cases of encephalitis . 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.
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.
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 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.
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 Biomérieux funded the setting up and maintenance of a biobank of samples taken from the patients. All authors have no conflict of interest to disclose.
Cecile Bébéar (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).
Philippe Abboud (Rouen), Chakib Alloui (Paris), Christine Archimbaud (Clermont-Ferrand), Bruno Barroso (Pau), Louis Bernard (Garches), Pascal Beuret (Roanne), Geneviève Billaud (Lyon), Thierry Blanc (Rouen), Michèle Bonnard-Gougeon (Clermont-Ferrand), David Boutolleau (Paris), Cédric Bretonnière (Nantes), Céline Bressollette-Bodin (Nantes), Fabrice Bruneel (Versailles), Marielle Buisson (Dijon), Anne Caramella (Nice), Bernard Castan (Auch), Isabelle Cattaneo (Bry sur Marne), Charles Cazanave (Bordeaux), Stéphane 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 (Montélimar), Arnaud De La Blanchardière (Caen), Geoffroy De La Gastine (Caen), Henri De Montclos (Bourg-en-Bresse), Eric Denes (Limoges), Philippe Desprez (Strasbourg), Anny Dewilde (Lille), Aurelien Dinh (Garches), François Durand (Saint-Etienne), Guillaume Emeriaud (Grenoble), Olivier Epaulard (Grenoble), Giovanni Favaretto (Avranche), Anna Ferrier (Clermont-Ferrand), Vincent Foulongne (Montpellier), François Fourrier (Lille), Véronique Gaday (Pontoise), Jacques Gaillat (Annecy), Serge Gallet (Montluçon), Nicole Gazuy (Clermont-Ferrand), Stéphanie Gouarin (Caen), Pascale Goubin (Caen), Alain Goudeau (Tours), Joel Gozlan (Paris), Philippe Granier (Bourg-en-Bresse), Isabelle Gueit (Rouen), Amélie Guihot (Paris), Christine Guillermet (Besançon), Christelle Guillet-Caruba (Paris), Yves Guimard (Bourges), Yves Hansmann (Strasbourg), Cécile Henquell (Clermont-Ferrand), Jean-Louis Herrmann (Garches), Jérome Honnorat (Lyon), Nadhira Houhou (Paris), Benoit Jaulhac (Strasbourg), Olivier Join-Lambert (Paris), Manoelle Kossorotoff (Paris), Emmanuelle Laudrault (Montélimar), Frédéric Laurent (Lyon), Jean-Jacques Laurichesse (Paris), Sylvain Lavoue (Rennes), Leila Lazaro (Bayonne), Stephane Legriel (Versailles), Olivier Lesens (Clermont-Ferrand), Gérard Level (Verdun), Muriel Mace (Orléans), Bénédicte Maisonneuve (Montluçon), Alain Makinson (Montpellier), Hélène Marchandin (Montpellier), Laurent Martinez-Almoyna (Saint-Denis), Patrick Marthelet (Montélimar), Martin Martinot (Colmar), Bruno Massenavette (Lyon), Laurence Maulin (Aix-en-Provence), Benoit Misset (Paris), Catherine Neuwirth (Dijon), Florence Nicot (Toulouse), Jérome Pacanowski (Paris), Jean-Bernard Palcoux (Clermont-Ferrand), Patricia Pavese (Grenoble), Thomas Perpoint (Lyon), Martine Pestel–Caron (Rouen), Robin Pouyau (Lyon), Thierry Prazuck (Orléans), Virginie Prendki (Paris), Christophe Rapp (Saint-Mandé), Christel Regagnon (Clermont-Ferrand), Matthieu Rigal (Auch), Nathalie Roch (Grenoble), Olivier Rogeaux (Chambéry), Sylvie Rogez (Limoges), Charles Santre (Annecy), Anne Signori-Schmuck (Grenoble), Fabrice Simon (Marseille), Abdelilah Taimi (Roanne), Jérome Tayoro (Le Mans), Daniel Terral (Clermont-Ferrand), Audrey Therby (Versailles), Francis Vuillemet (Colmar).