Report

Herpes zoster with progression to acute varicella zoster

virus-meningoencephalitis
Markus Braun-Falco, MD, and Marco Hoffmann, MD

From the Department of Dermatology,

University Medical Center Freiburg,
Freiburg, Germany
Correspondence
Markus Braun-Falco, MD
Department of Dermatology
University Medical Center Freiburg
Hauptstrae 7
79104 Freiburg
Germany
E-mail: markus.braun-falco@uniklinikfreiburg.de

Abstract
Background Acute meningoencephalitis (ME) from varicella zoster virus (VZV) reactivation is
a rare and serious complication of herpes zoster (HZ).
Objectives and methods As early diagnostic detection is mandatory to prevent long-term
sequelae, any clinical indication is helpful to identify patients that are at higher risk of the
development of VZV-ME. In order to find such risk factors, the clinical data of 38 patients
consecutively hospitalized for the treatment of HZ over a 1-year period were analyzed.
Results Four of the 38 patients with HZ developed ME. Of these, three had involvement of
the trigeminal nerve branch, one including an ophthalmic affection, and one presented with
disseminated HZ. All were women with an average age of 83.5 years, in comparison with
patients with HZ but without ME who had an average age of 69.3 years and a female
preponderance of 60%. The first clinical signs of ME were rapidly progressing somnolence and
meningism. Patients with HZ-ME were treated with intravenous acyclovir, oral
glucocorticosteroids, and antiseizure therapy, and recovered almost completely without major
residual symptoms.
Conclusion Progression of HZ to ME seems to occur more often than normally believed.
Female patients above 80 years of age with either ophthalmic involvement or disseminated HZ
are at a potentially high risk of the development of ME. The general recommendation of starting
oral glucocorticosteroids from day 1 of antiviral treatment in older patients must be questioned,
as it may stimulate VZV replication and dissemination.

Introduction

834

Herpes zoster (HZ), also known as shingles, usually occurs as

a self-limiting vesicular eruption caused by the reactivation of
latent varicella zoster virus (VZV) that is maintained in the
spinal dorsal root ganglia and sensory ganglia of the cranial
nerves throughout life during primary infection (varicella/
chickenpox).1,2 Infection with VZV takes place in more than
90% of the population before adolescence, and approximately 2030% will develop HZ later in life in an age-related
manner. The incidence in the general population is approximately 2.93.3 per 1000 person-years, and increases to 10.2
11.6 in patients 80 years of age and older.3 In the majority of
cases, the clinical course of the eruption is uniform and
restricted unilaterally to a dermatome corresponding to the
neuronal segment of the affected ganglion. Following a prodromal phase of several days (414 days) with burning sensations and shooting pain in the affected dermatome and
malaise, several slightly elevated erythematous lesions containing groups of clear vesicles evolve over a 37-day period.
International Journal of Dermatology 2009, 48, 834839

Within a week, the vesicles become turbid, ulcerated, and

crusted. They heal with pigmentary changes and slight scarring. Neuralgic pain accompanies the skin lesions and fades
slowly over a few weeks. Usually, HZ does not incur any lasting morbidity. In contrast with this uneventful normal course,
HZ can be aggravated, giving rise to several serious complications that can cause long-term sequelae, such as necrotization
and generalization of cutaneous lesions, postherpetic neuralgia, myelitis, ophthalmic and ear involvement, and cranial
and peripheral nerve palsies, such as RamsayHunt syndrome, Bells palsy, and delayed contralateral hemiparesis,
among others.47 One serious neurologic complication of HZ
is acute VZV-meningoencephalitis (ME). As VZV-ME can
have a fatal outcome, it requires early diagnostic detection
and intensive treatment. In this study, four of the 38 patients
treated in our institution for HZ over a 1-year period demonstrated progression to acute ME. In order to determine clinical
factors that point to an increased risk for progression to ME,
we compared the clinical data of the four patients with ME
with those of the patients without progression.
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Braun-Falco and Hoffmann

Patients and Methods

The files of the Department of Dermatology, University Medical
Center Freiburg, Freiburg, Germany, were retrieved for patients
treated for HZ at the inpatient service over a 1-year period from
May 2007 to May 2008. The files found were evaluated for the
patients past medical history, clinical data, treatment, and course
of disease.

Results
Within a 1-year period, a total of 38 patients were hospitalized
for intravenous antiviral treatment of HZ according to
general guidelines and recommendations for the management
of HZ.1,8 All patients exhibited clinical lesions primarily
suggestive for HZ, such as unilateral dermatome-oriented
groups of small blisters or pustules on edematous reddish
skin. In 28 cases, the diagnosis was additionally proven by either
positive Tzanck smear (10) or polymerase chain reaction
(PCR) analyses (18). The reasons for hospitalization were
cranial involvement, severe clinical presentation, underlying
illnesses, and overall reduced health condition. Of the 38
patients with HZ, 27 cases involved the face with a distribution
of neuronal dermatomes as follows: 19 ophthalmic nerve
(ophthalmic HZ; trigeminal branch 1; V1), six of which had
ophthalmic involvement (two with aberrant lesions and four
without) and two had aberrant lesions (without ophthalmic
involvement); three maxillary nerve (V2); one mandibular
nerve (V3); one cranial nerve VII/VIII (HZ oticus); and three
cervical nerves. The remaining 11 manifested at lower spinal
nerve segments with five thoracic, four lumbar, and two sacral.
All patients were started on intravenous antiviral therapy
with acyclovir at a dose of 510 mg/kg body weight three
times daily for at least 7 days. In the case of a cranial location,
the dosage was at least 7.5 mg/kg body weight three times
daily. Four patients left the hospital before the recommended
minimal treatment recommendation of 7 days, and were put
on 1000 mg valacyclovir orally three times daily. In all patients,
anti-pain treatment was usually started with metamizole
sodium and tramadol hydrochloride. In cases with severe
pain and/or cranial location, patients (29) received, in
addition, 4050 mg prednisone orally (21), pregabalin at
75 mg/day (four), or both (four). The clinical data of the
patients are summarized in Table 1. The average age was
69.3 years, ranging from 32 to 93 years; there were 24 women
and 14 men.
Four of the 38 patients with HZ developed a sudden onset
of rapidly progressing somnolence or signs of meningism, and
were immediately transferred to the Department of Neurology
for evaluation of the neurologic status. A diagnosis of ME
was made according to the clinical presentation in conjunction
with positive PCR for VZV in the cerebrospinal fluid (CSF)
(three), elevated cell number (four) and protein (four) in CSF,
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Progression of HZ to ME

Report

and deceleration of wave frequency (47 Hz theta waves;

< 3 Hz delta waves) in electroencephalogram (two). In two
patients, magnetic resonance imaging (MRI) of the brain was
performed to exclude focal lesions caused by cerebral infarcts
and intracerebral hemorrhage. In the four patients, the
affected dermatomes were trigeminal nerve 1 with ocular
involvement in three patients, and cervical nerve 34 with
aberrant lesions in thoracic segments 24 in one. All four
were women with an average age of 83.5 years (7990 years;
standard deviation, 4.65 years), which was significantly older
than the median age of all of our patients with HZ. In the group
of patients with HZ-ME, intravenous antiviral treatment was
started within 3.5 days (25 days) after the first symptoms
had occurred, in comparison with an average of 5.7 days
before treatment was initiated in the other patients with HZ.
All patients with HZ-ME received 4050 mg prednisone
orally from day 1 of antiviral treatment. The time from
hospitalization (first day of treatment) to the beginning of
neurologic symptoms other than zoster-associated neuralgia
varied considerably in the four patients at 1, 3, 6, and 9 days,
respectively. The neurologic symptoms are summarized in
Table 2. The first neurologic symptoms experienced by the
patients were rapidly progressing somnolence within a few
hours or meningism with frontal headache, photophobia,
and neck stiffness. After a diagnosis of VZV-ME had been
made, intravenous acyclovir and glucocorticosteroid therapy
were continued for another 1421 days, in combination with
anticonvulsive or neuroleptic drugs. All four patients recovered
almost completely with only minor sequelae.
Discussion
ME is thought to be a relatively rare neurologic complication
of HZ.9 So far, reliable epidemiologic data from larger
surveys are scarce. Since the introduction of PCR has aided in
the detection of VZV DNA within CSF, the incidence of
HZ-associated ME has shown an increase. Several PCR
studies have found VZV DNA within CSF at a frequency of
0.10.2% of patients with VZV infection.6,10 A clinically
oriented study from Spain demonstrated that, of 100 patients
with neurologic complications of HZ, 88 developed postherpetic neuralgia, two meningitis, and only one encephalitis.11
In our 1-year retrospective study comprising 38 patients with
severe HZ requiring systemic antiviral treatment, four
patients developed ME, indicating that progression of HZ to
ME occurs fairly frequently among stationary treated HZ
patients. These four patients with HZ-ME were women with
an average age of 83.5 years. Since the average age of all of
our HZ patients was 69.3 years and the female to male ratio
was 3 : 2, statistical numbers comparable with larger HZ
studies,3 it can be assumed that women aged above 80 years
are at a particularly high risk of showing HZ progression to
ME. Old age is an important aggravating factor associated
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Progression of HZ to ME

Braun-Falco and Hoffmann

Table 1 Clinical data of patients with herpes zoster

No.

Dermatome

Herpes zoster with

1
V1
2
V1
3
V1
4
C34, T24
Trigeminal nerve 1
5
V1
6
V1
7
V1
8
V1
9
V1
10
V1
11
V1
12
V12
13
V1
14
V1
15
V1
16
V1
17
V1
18
V12, C23
19
V1
20
V1
Trigeminal nerve 2
21
V2
22
V2
23
V2
Trigeminal nerve 3
24
V3
25
VII/VIII
Cervical nerves
26
C2
27
C56
Thoracic nerves
28
T23
29
T24
30
T1012
31
T12L1
32
T12L2
Lumbar nerves
33
L12
34
L15
35
L2
36
L23
Sacral nerves
37
S1
38
S2

Age
(years)

Sex

Meningoencephalitis

meningoencephalitis
90
f
+
83
f
+
82
f
+
79
f
+
ophthalmic
89
f

87
f

84
f

82
f

81
f

81
m

78
f

78
m

77
m

70
m

65
m

60
f

58
m

57
m

54
f

32
m

maxillary
81
f

62
f

57
f

mandibular/oticus
36
f

77
m

Ocular
inv.

Aberrant
lesion

Necrotizing

Start of
i.v. treatment

+
+
+

5
3
4
2

+
+

3
3
14
3
10
5
14
3
5
5
4
2
5
3
5
5

4
10
7

Thyroid adenoma
Breast cancer
Cervical cancer

Otitis

2
n.d.

AML, PBSCT

77
84

m
f

7
8

48
36
93
83
50

f
m
f
f
m

2
n.d.
n.d.
10
11

74
50
74
78

f
m
f
f

69
36

f
m

Underlying disease

Stroke
Dementia
Diabetes mellitus, kidney insufficiency

Breast cancer
Diabetes mellitus, heart insufficiency
CAD

ALL, PBSCT
HIV

CLL
CAD
Alport syndrome, kidney transplant
Rheumatoid arthritis
Stroke, anemia

4
7
7
5

Diabetes mellitus
NK-L

3
3

Cervical cancer

CAD

ALL, acute lymphatic leukemia; AML, acute myeloid leukemia; CAD, coronary artery disease; CLL, chronic lymphatic leukemia;
HIV, human immunodeficiency virus; i.v., intravenous; NK-L, natural killer T-cell lymphoma; PBSCT, peripheral blood stem cell
transplantation.

with an increasing incidence and severity of HZ, increasing

incidence and intensity of postherpetic neuralgia,12 and an
overall higher rate of complications.5 Protection from reactivation of VZV from latency seems to depend on VZV-specific
International Journal of Dermatology 2009, 48, 834839

T-cell-mediated immunity that is elicited during primary

infection. This response declines with advancing age below a
crucial level that can be measured by the ability of T cells to
produce interferon-c after VZV-specific stimulation.13 This
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Braun-Falco and Hoffmann

Progression of HZ to ME

Report

Table 2 Neurologic pathologies in patients with varicella zoster virus (VZV)-meningoencephalitis

First clinical symptoms

Days after initiation of
antiviral treatment
Additional neurologic
symptoms
CSF cell number/lL
Protein (mg/L) in CSF
CSF VZV-PCR
EEG

MRI
Persisting symptoms

Patient 1

Patient 2

Patient 3

Patient 4

Loss of vigilance,
dysarthria
1

Severe frontal headache,

photophobia, neck stiffness
9

Loss of vigilance,
disorientation, confusion
6

Repeated loss of consciousness,

retrograde amnesia
3

Ipsilateral abducens
nerve palsy, papillary
rigidity, diplopia
224
7500
+
Descending theta and
delta rhythms

Seizure

Slight anomia

No focal lesions
Ipsilateral mydriasis,
inadequate light reaction

No focal lesions

Ipsilateral papillary rigidity,

slight Bells palsy, disorientation
to time and location
85
873
n.d.
Theta waves at 67 Hz;
intermittent, descending,
shooting delta waves
n.d.

235
1420
+
n.d.

60
382
+
Alpha rhythm at 9 Hz

n.d.
Slight anomia and attention deficit

CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging; n.d., not determined; PCR, polymerase
chain reaction.

so-called immunosenescence correlates with a striking

increase in frequency and severity of HZ in older age.14 In
addition, there exist certain temporary or permanent comorbidities that may accelerate the decline of T-cell-mediated
VZV immunity and may provoke HZ and intensify its course,
such as trauma, spinal anesthesia, psychologic stress, diabetes
mellitus, consuming malignancies, human immunodeficiency
virus (HIV), and iatrogenic immunosuppression for the
treatment of autoimmune diseases, prevention of organ
transplant rejection, and as a consequence of chemotherapy.4
Because of the increasing age of the population, the increased
number of organ transplantations, and more effective treatments for malignancies and autoimmune diseases, a future
increase in the incidence of HZ and its complications can be
expected. It should be noted that only one of the four patients
with HZ-ME had diabetes mellitus, whereas 14 of the 34
patients with a normal course of HZ suffered from diabetes
mellitus, malignancies, HIV, or iatrogenic immunosuppression
(Table 1). As the high risk of VZV dissemination in immunocompromised patients is well known, the need to start
intravenous antiviral treatment early and at high doses may
be much greater in immunocompromised patients than in
older people in general.
Location seems to be another potential risk factor for
progression of HZ to VZV-ME. Three of our patients with
HZ-ME had preceding HZ of the first trigeminal branch with
proven ophthalmic affection. Ocular involvement seems to be
a particular predisposing factor, as 50% of HZ with ocular
involvement progressed to ME, in comparison with none of
the 13 HZ cases with an affected trigeminal 1 dermatome
without ocular involvement.
2009 The International Society of Dermatology

Another factor, even less pronounced, was the presence of

aberrant lesions: these were seen in eight of the 38 HZ cases,
one of which progressed to ME.
The time between the appearance of the first symptoms of
HZ and of ME was highly variable, ranging from 1 to 9 days
after the initiation of antiviral treatment. The initial symptoms
of ME were acute to subacute delirium accompanied by a few
focal neurologic signs, and meningism with severe frontal
headache, photophobia, and neck stiffness.
In general, this acute form of ME must be separated from
chronic ME that presents clinically several weeks to months
after the skin lesions have resolved.1,4,6 The latter is almost
exclusively seen in severely immunocompromised patients
with marked depletion in CD4+ T cells, especially in patients
with acquired immunodeficiency syndrome (AIDS) and
allogeneic peripheral blood stem cell transplantation. The
clinical features may be very similar to those of the acute form
with subacute headache, fever, mental status changes, and
seizures. Differentiation can be made easily on MRI, which
shows no focal changes in the acute form, but plaque-like
lesions in the deep white matter, ischemic or hemorrhagic
infarcts of the cortical and subcortical gray and white matter,
and signs of demyelination and small-vessel vasculitis in the
chronic form. Although acute ME has a mortality rate of
approximately 10%, the chronic form very often undergoes a
clinical course of progressive deterioration and death despite
high-dose antiviral therapy. In cases of HZ with ocular
involvement, another form of chronic encephalitis must be
discriminated, termed HZ ophthalmicus, with delayed
contralateral hemiparesis. It is not restricted to immunocompromised patients and has a mortality rate of 2025%.
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Progression of HZ to ME

Usually 7 weeks, occasionally up to 6 months, after the

resolution of HZ, patients with HZ ophthalmicus present
with headache and hemiplegia at the contralateral side of the
originally affected dermatome. The stroke-like symptoms
result from necrotizing granulomatous large-vessel arteritis of
unknown pathophysiology.
What additional factors may influence the development
of ME? Newer guidelines for the management of HZ recommend, in addition to antiviral therapy, the administration
of corticosteroids at tapering dosages over a 3-week course.
Originally given to prevent postherpetic neuralgia, it is now
known that corticosteroids are beneficial to decrease acute
pain, resolve edema, and shorten the time period until
patients experience uninterrupted sleep, return to normal
daily activity, and stop analgesic therapy.1,15 According to this
recommendation, all of our patients with HZ-ME received
corticosteroids. One overlooked drawback of this immunosuppressive therapy, given at the very acute phase of active
viral replication, is that it may further depress the already
decreased immune system and thus may promote a higher
rate and wider dissemination of newly amplified VZV virions.
The application of gabapentin or pregabalin for the prevention
and therapy of postherpetic neuralgia can cause sedation and
dizziness that may be mistaken for the early symptoms of
acute ME.
A diagnosis of VZV-ME can always be made with confidence when PCR analyses reveal VZV DNA in the CSF, and
when anti-VZV antibodies are detectable in the CSF. MRI
should always be performed to exclude any type of vasculitis
and infarction. With regard to the therapy of the neurologic
complications of HZ, no controlled studies have yet been conducted to demonstrate the benefit of high-dose intravenous
antiviral agents, but they are usually given without much
reluctance, as the potential impact outweighs most risk
factors. The dosage of intravenous acyclovir is recommended
at 10 mg/kg body weight three times daily for at least 10
14 days. Alternatively, intravenous foscarnet can be given at
40 mg/kg two to three times daily for 23 weeks. Both antiviral
regimens need adjustment in case of impaired renal function;
12 mg/kg body weight prednisolone-equivalent is often
added to decrease inflammation and acute pain, and anticonvulsive or neuroleptic drugs to prevent seizures. For the
prevention of severe HZ in older adults, the benefit of VZV
vaccination has been well demonstrated.16,17 In a large, doubleblind, placebo-controlled trial, the vaccination of adults,
60 years of age or older, with live attenuated Oka/Merck
VZV resulted in a decrease in the incidence of HZ by more
than 50%, of postherpetic neuralgia by 66.5%, and of burden
of illness by 61.1%, without causing any systemic adverse
events. Although the primary neurologic endpoint was
postherpetic neuralgia, it can be speculated that vaccination
of older people will also reduce the incidence and severity
of serious VZV complications, including ME. Thus, the
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Braun-Falco and Hoffmann

appropriateness of VZV vaccination is not only recommended for young children; it may also be helpful in the
elderly.
Conclusion
Acute ME is a remarkable complication of HZ that, according
to our series of patients, predominantly affects older women
who develop HZ of the first trigeminal branch with ophthalmic
involvement or disseminated HZ. In order to ensure early
diagnosis and accurate treatment, each patient with HZ who
becomes drowsy within a few hours should undergo CSF
aspiration for PCR and anti-VZV antibody analyses and MRI
to exclude any vascular insults.
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