Atypical presentation of varicella-zoster virus
encephalitis in an immunocompetent adult
Maria Mpaka, MD,a Apostolos H. Karantanas, MD,b and Epaminondas Zakynthinos, MDa

BACKGROUND: Varicella-zoster virus encephalitis is uncommon, but not rare, in immunocompetent
adults. Typically, patients develop stroke with hemiplegia caused by large vessel vasculopathy days to
weeks after herpes zoster ophthalmicus.
METHOD: A previously healthy 66-year-old man developed obtundation deteriorating to coma within
24 hours. He had lymphocytic meningitis and multiple bilateral edematous and hemorrhagic lesions
predominantly in the white matter, and intraventricular and subarachnoid hemorrhage. Treatment with
acyclovir and dexamethasone was readily administered. The diagnosis of varicella-zoster virus encephalitis was confirmed by polymerase chain reaction analysis of the cerebrospinal fluid. No zosteriform rash
preceded or followed encephalitis. Two years later, the patient is in good health, and no relapse or sign
of immunosuppression has been reported.
CONCLUSION: This is a case of varicella-zoster virus encephalitis in an immunocompetent patient
presenting without typical rash and with clinicoradiologic features of multifocal encephalitis, which
characterize immunosuppression. (Heart Lung® 2008;37:61– 66.)

T

he typical clinical presentations of varicella
and herpes zoster are distinctive and readily
recognized by most experienced clinicians.
However, atypical clinical presentations of these
diseases can pose diagnostic and therapeutic challenges.
Varicella-zoster virus (VZV) is an alpha herpesvirus found exclusively in humans. Typically, it causes
an acute infantile exanthematous illness (varicella
or chickenpox). After chickenpox resolves, VZV becomes latent in the neurons of cranial and spinal
ganglia of nearly all individuals with no morphologic or functional consequences.1-4 In elderly and
in immunocompromised individuals, VZV may reactivate to produce a dermatomal rash with radicular
pain (zoster or shingles). Less commonly, viral reactivation may be followed by central nervous system (CNS) involvement, usually by affecting adjacent vessels.3,4 Two distinctive patterns of brain
involvement have been described, depending on the

From the aIntensive Care Unit, University of Thessaly, Larissa,
Greece; and bDepartment of Radiology, Faculty of Medicine, University of Crete, Crete, Greece.
Reprint requests: Epaminondas Zakynthinos, MD, Intensive Care
Unit, University Hospital of Larissa, Mezourlo, 41110 Larissa,
Greece.
0147-9563/$ – see front matter
Copyright © 2008 by Mosby, Inc.
doi:10.1016/j.hrtlng.2007.02.009

HEART & LUNG VOL. 37, NO. 1

immunologic status of the host.4-6 In immunocompetent adults, VZV may spread to the large cerebral
arteries of the base of the skull to produce unifocal
large-vessel vascular damage, usually presenting
with stroke.6,7 In immunocompromised patients,
VZV tends to spread to the brain structures with a
much deeper tissue penetration, producing a wide
variety of syndromes ranging from diffuse smallvessel vasculopathy (multifocal leukoencephalopathy) to meningitis and ventriculitis.4-7 Immunodeficient patients often present with more severe
clinical picture and recurrent disease.8-10
The typical zosteriform rash affecting one to three
dermatomes of cranial or peripheral nerves usually
precedes CNS involvement in both patient
groups.4-7 The diagnosis may be missed in cases
without typical rash, and therefore treatment might
be delayed even in severe VZV infections.7,11-13

CASE REPORT
A 66-year-old man was admitted to our tertiary
care hospital with mental obtundation. Four days
before admission, headache with nausea, vomiting,
agitation, and disorientation had rapidly developed
in the patient. He was not receiving any medication
regularly because he had no known disease. He did
not have any recent exanthematous disease and
had not been exposed to chickenpox or VZV vacci-

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Varicella-zoster encephalitis

nees. He had not received a varicella vaccine in
adulthood, but records of contagious diseases in his
childhood were not available. The computed tomography (CT) scan performed at his district hospital
demonstrated a single nonenhancing hypodense lesion in the periphery of the right lobe of the cerebellum and no sign of hemisphere involvement. The
cerebrospinal fluid (CSF) was limpid containing 35
nucleated cells/␮L with lymphocytic predominance.
CSF glucose was 64 mg/dL (serum glucose of 102
mg/dL), and CSF protein was 380 mg/dL. Intravenous acyclovir (10 mg/kg every 8 hours), dexamethasone (4 mg every 8 hours), and broad-spectrum
antibiotics (ceftriaxone, ampicillin/sulbactam) were
immediately initiated. In the next 24 hours, his neurologic status continued to deteriorate, and he was
transferred to our hospital. In the emergency department, a body temperature of 36.8°C was recorded, along with neck stiffness and coma, with a
score of 7 on the Glasgow Coma Scale. No papilledema or gross focal neurologic deficit was observed. No skin lesion or mucosal lesion was
present in the oral cavity, external ear canal, and
cornea. The patient was intubated and transferred
to the intensive care unit. His white blood cell count
was 14,000 cells/␮L (79% neutrophils), and serum
biochemistry, urinalysis, and chest radiography all
showed normal results. At that time, CSF analysis
revealed lymphocytic pleocytosis (360 cells/␮L, 93%
lymphocytes) with numerous erythrocytes (900
cells/␮L), a glucose level of 68 mg/dL (serum glucose of 112 mg/dL), and a protein level of 560
mg/dL. An urgent CT scan of the brain demonstrated
multiple bilateral parenchymal hemorrhagic foci in
the frontotemporal regions in addition to the preexisting lesion on the right cerebellar lobe, and
intraventricular and subarachnoid hemorrhage
(Fig 1).
On admission, CSF polymerase chain reaction
(PCR) was positive for the VZV genome (Table I), but
negative for herpes simplex virus (HSV) 1 and 2,
cytomegalovirus (CMV), Epstein-Barr virus (EBV),
and mycobacterium tuberculosis DNA. At that time,
the serum was positive for immunoglobulin (Ig)G
antibodies against VZV (Table I), EBV (61 IU; normal
values ⬍ 9), and HSV-1 (110 IU; normal values ⬍ 9).
Serum anti-VZV IgM antibodies were slightly positive on admission but decreased to normal range
levels 2 weeks later, whereas serum anti-VZV IgG
increased (Table I). CSF IgG antibodies against VZV
remained positive throughout the patient’s intensive care unit stay (Table I). All antibodies were
measured using the enzyme-linked immunosorbent
assay method. In regard to the CSF, a nested PCR

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Mpaka et al

Fig 1 Unenhanced CT in the acute setting, at the level of
the lateral ventricles, reveals subarachnoid (small arrows) and intraventricular hemorrhage (arrows), and
edema in the right frontotemporal area.

assay was performed using oligonucleotide primer
pairs specific for the Xbal M region of VZV, the
glycoprotein D sequence of HSV-1, the glycoprotein
G sequence of HSV-2, the immediate early gene of
CMV, the BamHI-W region of EBV, and the gene
coding for protein MBP 64 of Mycobacterium tuberculosis.
Antibodies against Borrelia burgdorferi, Coxiella burnetii, Mycoplasma pneumoniae, and adenovirus, influenza A and B, parainfluenza 1-3, Coxsackie, ECHO,
and CMV viruses were negative. Antinuclear antibodies and thrombophilia screen (protein C and S,
partial thromboplastin time, antithrombin III, anticardiolipin antibodies, and lupus anticoagulant)
were also negative. CSF cultures for common bacteria were negative. Similarly, acid-fast bacillus
stains and mycobacterial cultures of CSF, sputum,
and urine were negative.
Electroencephalogram showed generalized slow
wave activity with “theta” and “delta” basal activity,
consistent with diffuse encephalitis.
Magnetic resonance imaging (MRI) examination
was performed on the 15th day with a Tesla scanner
(Philips Intera, Best, The Netherlands) and a head
coil applying T1-weighted spin echo, T2-weighted
GraSe, FLAIR, and contrast-enhanced T1-weighted
spin echo sequences. MRI findings indicated multifocal edematous and hemorrhagic lesions predom-

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Varicella-zoster encephalitis

Table I
Virologic and serologic findings
Day after first
symptom

VZV PCR in CSF

Titers of VZV antibodiesCSF (IU)

Titers of VZV antibodiesserum† (IU)

4*

Positive

IgG 105
IgM 5.2

IgG 85
IgM 13.5

7

Positive

IgG 152
IgM 4.7

IgG 135
IgM 11.7

16

Negative

IgG 145
IgM 2.47

IgG 132
IgM 6.96

VZV, Varicella-zoster virus; PCR, polymerase chain reaction; CSF, cerebrospinal fluid; Ig, Immunoglobin.
*Commencement of treatment with acyclovir on day 3. Overall treatment for 3 wk.
†Normal values ⬍ 9 IU.

inately in the white matter and deep-seated areas
both supra- and infratentorially (Fig 2A-C). Evidence
of hemosiderin deposition was obvious on T2weighted images. In addition, enhancement indicated active encephalitis.
Antibacterial agents were discontinued as soon
as VZV genome was isolated in the patient’s CSF.
Acyclovir administration was continued for 3 weeks
in total, and dexamethasone was tapered off after
the first week of treatment.14
The patient’s neurologic status further deteriorated during the first days despite treatment (acyclovir), which was commenced 24 hours before admission to our unit. However, it gradually improved,
and he was transferred to the medical ward after 30
days of intensive care unit treatment. By that time,
he had no movement deficit but presented aphasia
and disorientation in time and space. The patient
was discharged from the hospital 2 weeks later; his
ability to nominate objects and recognize persons
was improved, but he was still disoriented. He fully
recovered 6 months later. No zosteriform exanthema, enanthema, or radicular pain was reported
on admission with encephalitis, and they were not
observed during the 2-year follow-up. Human immunodeficiency virus test was negative in two separate examinations. No immunodeficiency or neoplastic syndrome was made evident in the 2-year
period.

DISCUSSION
The diagnosis of acute encephalitis is suspected
in febrile patients who present with altered con-

HEART & LUNG VOL. 37, NO. 1

sciousness and signs of diffuse cerebral dysfunction.15 Nevertheless, in any patient who presents
with altered mental status or personality change,
one should consider the possibility of an infectious
cause regardless of the absence of fever,15,16 as was
the case of our patient on admission in our hospital.
HSV, enteroviruses, EBV, mumps, measles, and VZV
are responsible for most cases of acute viral encephalitis in the Western world.15,17,18
HSV encephalitis, considered the commonest viral encephalitis, may have an abrupt onset and may
occur in immunocompetent patients with or without mucocutaneous lesions.15-19 HSV CNS infection
has a high mortality rate if untreated, whereas early
therapy with acyclovir significantly improves the
outcome.15 In our patient, lymphocytic meningitis
with intracranial hemorrhagic and edematous lesions dictated the need for immediate acyclovir
treatment, because “herpetic meningoencephalitis”
was the most probable diagnosis. VZV encephalitis
was confirmed by detection of the viral genome in
the CSF by PCR and presence of intrathecal anti-VZV
antibodies.
The patient we describe is a rare case of severe
VZV encephalitis presenting significant deviation
from the expected clinical and laboratory presentation: (1) Brain involvement by VZV usually occurs in
immunosuppressed, mainly those with acquired immune deficiency syndrome,20 and is uncommon in
immunocompetent patients.4,8,21,22 (2) Encephalitis
from VZV is now recognized to be a vasculopathy
affecting large or small vessels. However, large-vessel arterial disease (granulomatous arteritis) occurs

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Mpaka et al

Fig 2 MRI performed 2 weeks after onset of clinical symptoms. A: Axial T2-weighted GraSe MRI
shows edematous lesions in both temporal lobes (white arrows), old hemorrhage with hemosiderin
deposition in the anterior left temporal lobe (black arrow), and peripheral hemosiderin deposition
at the site of previous parenchymal hemorrhage (small black arrows). B: T1-weighted turbo-spin echo
MRI shows a high-intensity area corresponding to parenchymal hemorrhage (arrow). C: Enhanced
T1-weighted turbo-spin echo MRI shows abnormal enhancement in the left temporal lobe (arrows).

predominantly in immunocompetent patients, and
encephalitis mediated by small vessels multifocal
leukoencephalopathy is found virtually exclusively
in immunodeficient patients. Typically, large-vessel
encephalitis is characterized by acute focal deficit
(stroke) that develops days to months after zoster of
contralateral trigeminal distribution with predominant ocular involvement (herpes zoster ophthalmicus);4-6,23 the internal carotid artery or its branches
ipsilateral to the zoster are usually affected with
resultant vessel thrombosis and large brain infarctions.4,5 In our case, the progression of the disease to coma without gross focal neurologic deficit and the radiologic findings of multiple
bilateral edematous and hemorrhagic lesions (Figs
1 and 2) are compatible with small vessel, or mixed
small and large vessel, arteriopathy characteristic of
immunodeficiency.3-6 (3) In our case, no rash indicative of zoster was reported before or after CNS
involvement on the follow-up of 2 years. The typical
rash has been reported to precede encephalitis by
up to 10 months or occur after encephalitis for up to
6 months.3-5 Encephalitis related to VZV without

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skin manifestations has been described mainly in
patients with HIV and other immunocompromised
patients,3,12,24 but rare cases have also been reported in previously healthy patients.3,7,13,25 (4) In
our case, specific antibodies were detected in the
CSF with the onset of symptoms (Table I), probably
referring to early subclinical CNS involvement. Typically, the immune response in the CSF is expected
10 to 12 days from the onset of the CNS disease.26,27
(5) Subarachnoid and intraventricular hemorrhages
are rare findings in VZV encephalitis. To our knowledge, only four cases of subarachnoid hemorrhage have been published, and no cases of intraventricular hemorrhage have been published.28-31
These hemorrhagic complications have probably
contributed to the initial worsening of the patient’s status, which continued to deteriorate despite treatment.
On admission, the severity of the clinical image
indicated a bacterial origin of the disease rather
than a viral one.32 Thus, broad-spectrum antibiotics
were discontinued only when CSF PCR results were
available.

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Mpaka et al

PCR for viral DNA amplification has significantly
facilitated the diagnosis of infective encephalitis.
CSF PCR is diagnostic for encephalitis because of
HSV 1 and 2, VZV, CMV, and EBV. PCR for the HSV
and VZV genomes in experienced laboratories is
virtually 100% specific, and the sensitivity of this
test exceeds 90%.33,34 The results of PCR assays of
the CSF must be cautiously interpreted: They may
be negative if the CSF is collected after the emergence of intrathecal antibodies or after acyclovir
therapy.34 False-negative results may also occur if
hemoglobin or heparin is present in the CSF, if the
sample is processed too late, or if it was inappropriately stored.34 CSF PCR analysis for VZV DNA has
been critical in identifying VZV as a causative factor
in cases of CNS infections that may be clinically
confusing as cases without skin manifestations.11,20,24,34,35
In viral encephalitis, intrathecal IgG antibodies
are measured in the post-acute stage from day 7 to
day 12 of the disease, reach maximum values on day
20, and then persist for several years.17 Intrathecal
immune response may be further delayed or even
absent when antiviral treatment is started early.36
Therefore, the measurement of intrathecal antibodies does not serve as a primary diagnostic tool for
the diagnosis of viral encephalitis; yet, it allows
confirming the clinical diagnosis in an acceptable
percentage of prolonged and chronic cases or when
antiviral therapy has been initiated several days
earlier.26,37 Occasionally, IgG antibodies against
VZV in the CSF may be detected early in the course
of the encephalitis (Table I), because VZV infection
of the nervous system is often protracted, especially
in immunocompromised patients.4 CSF anti-VZV
IgM antibodies are positive in a minority of patients,
reaching up to 15% of patients with proved CNS VZV
infection.27
The analysis of serum anti-VZV IgG antibodies is
of no value because VZV antibodies persist in the
serum of nearly all adults.4,38
The elevated level of IgM antibodies in the serum, especially the progressive decrease over the
course of the disease (Table I), strongly supports a
VZV cause.27
MRI is the imaging of choice in acute encephalitis, although it may be easier to obtain a CT on an
urgent basis. Characteristic neuroimaging changes
may offer clues as to the specific infective cause, for
example, frontotemporal changes in HSV and thalamic hemorrhage in Japanese encephalitis.17 The
bilateral edematous and hemorrhagic lesions, as
well as the enhanced lesions, in our patient are

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Varicella-zoster encephalitis

characteristic of VZV multifocal leukoencephalitis
consistent with small vessel viral angiopathy.4,8

CONCLUSION
This is a rare case of VZV encephalitis in an
immunocompetent patient who presented with severe complications and a clinicoradiologic presentation typical of immunosuppression. Clinicians
must bear in mind that multifocal leukoencephalitis
even without zosteriform rash should prompt the
investigation for CNS VZV disease in both immunocompetent and immunocompromised patients.38

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