REVIEW

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Herpesvirus infections of the nervous system

Donald H Gilden*, Ravi Mahalingam, Randall J Cohrs and Kenneth L Tyler

S U M M A RY
There are eight human herpesviruses (HHVs). Primary infection by any of
the eight viruses, usually occurring in childhood, is either asymptomatic or
produces fever and rash of skin or mucous membranes; other organs might
be involved on rare occasions. After primary infection, the virus becomes
latent in ganglia or lymphoid tissue. With the exception of HHV-8, which
causes Kaposis sarcoma in patients with AIDS, reactivation of HHVs
can produce one or more of the following complications: meningitis,
encephalitis, myelitis, vasculopathy, ganglioneuritis, retinal necrosis and
optic neuritis. Disease can be monophasic, recurrent or chronic. Infection
with each herpesvirus produces distinctive clinical features and imaging
abnormalities. This Review highlights the patterns of neurological
symptoms and signs, along with the typical imaging abnormalities,
produced by each of the HHVs. Optimal virological studies of blood,
cerebrospinal fluid and affected tissue for confirmation of diagnosis are
discussed; this is particularly important because some HHV infections of
the nervous system can be treated successfully with antiviral agents.
KEYWORDS herpesviruses, infection, latency, neurological complications,
treatment

REVIEW CRITERIA
PubMed was searched using Entrez for articles published up to 30 June 2006,
including electronic early release publications. Search terms included herpes
simplex virus, herpes simplex virus 1, HSV-1 and Bells palsy, herpes
simplex virus 2, HSV neuropathy, zosteriform eruption, HSV meningitis,
HSV myelitis, brainstem encephalitis, varicella zoster virus, VZV
vasculopathy, virus latency, radiculoneuritis, postherpetic neuralgia,
EpsteinBarr virus, cytomegalovirus, human herpesvirus 6, human
herpesvirus 7, human herpesvirus 8 and Kaposis sarcoma-associated
herpesvirus. The abstracts of retrieved citations were reviewed and prioritized
by relevant content. Full articles were obtained and references were checked for
additional material where appropriate.

DH Gilden is the Louise Baum Professor and Chairman of the Department

of Neurology, and Professor of Microbiology; R Mahalingam is a Research
Professor in the Department of Neurology; RJ Cohrs is a Research Professor
in the Department of Neurology; and KL Tyler is the Reuler-Lewin Family
Professor of Neurology and Professor of Medicine, Microbiology and
Immunology; all are at the University of Colorado Health Sciences Center,
Denver, CO, USA.
Correspondence
*Department of Neurology, University of Colorado at Denver and Health Sciences Center,
4200 East 9th Avenue, Mail Stop B182, Denver, CO 80262, USA
don.gilden@uchsc.edu
Received 18 October 2006 Accepted 30 November 2006
www.nature.com/clinicalpractice
doi:10.1038/ncpneuro0401

82 NATURE CLINICAL PRACTICE NEUROLOGY

INTRODUCTION

Herpesviruses are large double-stranded

DNA viruses. Approximately 130 different
herpesviruses have been identified, not only in
mammals, but also in frogs, lizards, birds, fish
and mosquitoes. There are eight human herpesviruses (HHVs): herpes simplex virus (HSV-) 1,
HSV-2, varicella zoster virus (VZV or HHV-3),
EpsteinBarr virus (EBV or HHV-4), cytomegalovirus (CMV or HHV-5), HHV-6, HHV-7,
and HHV-8. A characteristic feature of all herpesviruses is their ability to become latent, primarily
in ganglia of the nervous system and lymphoid
tissue. For example, HSV and VZV become latent
in neurons of ganglia, whereas EBV is latent in
B lymphocytes. Most of the HHVs are neurotropic and infrequently cause serious acute and
chronic neurological disease of the PNS and CNS
that might be monophasic, recurrent or chronic.
Infection with each herpesvirus produces different
clinical features and imaging abnormalities, and
many HHV infections can now be treated. This
Review focuses on the neurological complications
of the HHVs, and discusses optimal virological
tests to identify the etiological agent, along with
state-of-the-art treatments for these disorders.
HERPES SIMPLEX VIRUS 1
Clinical features

Encephalitis is the most serious neurological

complication caused by HSV-1. Symptoms and
signs of encephalitis can include fever, headache,
lethargy, irritability, confusion, focal deficit,
aphasia and seizures, and they reflect virus
replication with accompanying inflammation in
the medial temporal lobe and orbital surface of
the frontal lobe. Progressive temporal lobe edema
can lead to uncal herniation, with tachycardia,
hyperventilation, flexor (and later extensor)
posturing, and a dilated pupil (usually on the side
of the herniated temporal lobe). Survivors can
be left with a permanent seizure disorder, mental
status changes, aphasia or motor deficit. Before
the advent of aciclovir treatment, most patients
with HSV-1 encephalitis died.

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The cerebrospinal fluid (CSF) is usually

abnormal in patients with HSV-1 encephalitis.
The opening pressure is often elevated, and
a CSF pleocytosis is observed in over 90% of
patients, although its initial absence does not
rule out HSV-1 encephalitis. Patients typically
have a mononuclear pleocytosis, with a mean
of 200 cells/mm3 (0.2 109 cells/l). CSF protein
levels are usually elevated, but CSF glucose levels
are usually normal. Increased CSF antibody to
HSV-1, and a reduced serum:CSF antibody
ratio, might help to diagnose HSV-1 encephalitis. Antibody titers are not usually detected
until 2 weeks or more after disease onset,
however, and their practical value lies in retrospective presumptive diagnosis. HSV-1 can be
isolated from cerebral biopsy or autopsy material, but isolation of the virus from CSF is rare.
Polymerase chain reaction (PCR) detection of
HSV-1 DNA in CSF is sensitive and specific, and
has become the diagnostic procedure of choice,1
although PCR results can be negative during the
early stages of disease.2 Pathological changes in
HSV-1 encephalitis include localized inflammation, hemorrhagic necrosis and formation
of inclusion bodies.
Electroencephalography in patients with HSV-1
encephalitis shows background disorganization
with generalized or focal slowing, predominantly
over the involved temporal region.3 In some
patients, widespread, periodic and stereotyped
sharp-wave and slow-wave complexes develop
at intervals of 23 seconds.4 Bilateral periodic
complexes appear if both hemispheres are involved
and, although they are seen in other CNS disorders,
the presence of such complexes in the setting of
fever and rapidly progressive neurological disease
is strongly indicative of HSV-1 encephalitis. CT
scanning reveals hypodense lesions involving the
medial temporal regions, with a sharp transition
from the hypodense temporal lesion to normal
basal ganglia.5 Edema and mass effect occur in
80% of cases, and lesions enhance with contrast.
MRI reveals a decrease in T1 signal and an
increase in T2 signal in the orbitofrontal and
medial temporal lobes and insulae, with abnormalities appearing earlier and more frequently
than with CT.6 With modern neuroimaging techniques, HSV-1 encephalitis is only rarely confused
with cerebritis, abscess, tumor or infarction.
Figure 1 shows typical CT and MRI changes in
patients with HSV-1 encephalitis compared with
imaging abnormalities in VZV vasculopathy (see
below) and other viral encephalitides.

FEBRUARY 2007 VOL 3 NO 2 GILDEN ET AL.

Figure 1 Typical changes seen on CT and MRI in patients with herpesvirus

infections. (A) Herpes simplex virus 1 (HSV-1) encephalitis: T2-weighted
MRI brain scan demonstrates bilateral involvement of temporal lobes. The
exaggerated signal does not extend beyond the insular cortex (thin arrow),
but does involve the cingulate gyrus (thick arrow). (B) Varicella zoster virus
(VZV) vasculopathy: proton-density brain MRI scan shows multiple areas of
infarction in both hemispheres, particularly involving white matter (thin arrow)
and extending to graywhite-matter junctions (thick arrow). (C,D) CT and MRI
changes in a patient with probable enterovirus encephalitis. Other viruses can
produce the same changes. In contrast to A and B, panel C demonstrates
relative effacement of sulci posteriorly in both hemispheres (thin arrow),
compared with normal sulcal spaces anteriorly (thick arrow). Panel D is a
T2-weighted inversion recovery (fluid-attenuated inversion recovery [FLAIR])
MRI brain scan of the same patient, demonstrating areas of increased signal
in both hemispheres, greater on the right and even more marked posteriorly
(arrow), reflecting increased water content in this mildly swollen brain.

Pathogenesis and latency

Primary HSV-1 infection often results in painful

skin or mucosal lesions, but can also be asymptomatic. Virus replicates at the portal of entry,
usually oral or genital mucosal tissue, leading to
infection of sensory nerve endings. Virus is then
transported to regional ganglia where it establishes latency. Recurrence is directly related to
the severity of primary infection, as reflected

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by the size, number and spread of lesions. The

mechanism by which HSV-1 infects the CNS
to cause encephalitis has not been definitively
established. The predilection of HSV-1 for the
orbital surface of the frontal lobe and medial
surface of the temporal lobe indicates that virus
might spread from olfactory mucosa through
the cribiform plate of the ethmoid bone into
the anterior fossa. Latent virus in the trigeminal
ganglia might also reactivate and spread via
tentorial nerves that innervate the meninges of
the anterior and middle cranial fossa.
HSV-1 latency is restricted to cranial nerve
ganglia, as indicated by spontaneous, recurrent outbreaks of vesicles on the mouth, or by
isolation of HSV-1 from postmortem explants
of human trigeminal,7,8 nodose, vagal9 and
ciliary10 ganglia. HSV-1 DNA sequences have
been detected in human thoracic ganglia11
and brain,12 but virus has never been recovered from these sites. Most humans harbor
latent HSV-1.11
Neurons are the exclusive site of HSV-1
latency in human ganglia, and also in mouse
and rabbit models. Studies of latently infected
mouse ganglia have revealed HSV-1 DNA in
130% of neurons.13 In humans, the latent
HSV-1 DNA copy number ranges from less than
300 copies/105 cells to over 10,000 copies/105
cells in trigeminal ganglia,14 and has a mean of
176,705 255,916 copies/105 cells in vestibular
ganglia, 9,948 22,066 copies/105 cells in geniculate ganglia, and 3,527 9,360 copies/105 cells
in cochlear ganglia.15 During latency, HSV-1
DNA is endlessthat is, circular or concatameric16and does not integrate into the
host genome.
In ganglia latently infected with HSV-1, only
one region of the viral genome is abundantly
transcribed. This region encodes the latencyassociated transcripts (LATs). The LAT domain
is transcriptionally complex, and although
the predominant species that accumulates in
the neuronal nucleus during latency is a 2.0 kb
stable intron,17 other RNA species are also transcribed, including a number of lytic or acutephase transcripts. No LAT protein has ever
been detected. LAT-deficient HSV-1 mutants
become latent,18 and splicing of the primary
LAT transcript appears to be important in
promoting latency.19 The function of LATs
is unknown, but they might protect neurons
from apoptosis,20 perhaps by acting through
microsomal RNA.21

84 NATURE CLINICAL PRACTICE NEUROLOGY

HSV-1 reactivates after ultraviolet (UV)

light stimulation, epinephrine iontophoresis,
hyperthermia, or even social stress. Variables
include duration of stimuli and latent virus
DNA burden. Accumulating evidence from
rodent models indicates that HSV-1 infection
suppresses the hypothalamicpituitaryadrenal
axis during primary infection, and that this
stress-induced suppression has a role in virus
reactivation. The relevance of animal models to
humans must, however, always be questioned.
For example, guinea pigs vaccinated with HSV-2
glycoprotein D were protected from reactivation,
whereas subunit vaccines were only marginally
effective in human trials.22
Treatment

Intravenous aciclovir (10 mg/kg body weight

three times a day for 1421 days) is the standard treatment for HSV-1 encephalitis in adults
(Table 1). Steroids are sometimes given as well,
although data regarding the efficacy of this
approach remain anecdotal. Cognitive impairment and seizures are significant neurological
sequelae in treated patients.
Herpes simplex virus 1 and Bells palsy

Virologic analysis of endoneurial fluid obtained

during decompression surgery revealed HSV-1
DNA in 11 out of 14 patients with Bells palsy.23
As seropositivity to HSV-1 is well established by
adult life, when Bells palsy is most common,
the palsy probably reflects virus reactivation from latency in the geniculate ganglion24
rather than primary infection. The mechanism
through which the virus damages the facial
nerve is unknown.
HERPES SIMPLEX VIRUS 2
Clinical features

HSV-2 causes genital herpes, and neurological

complications include aseptic meningitis and
recurrent radiculopathy. HSV-2 also causes
myelitis in immunocompromised individuals.
Typical features of HSV-2 meningitis are headache,
fever, stiff neck, and lymphocytic pleocytosis in
the CSF. HSV-2 meningitis might be preceded
by pelvic inflammatory disease, genital pain or
both, and clinical examination should include
a search for vesicular lesions over the external
genitalia, and also for lesions in the vagina or on
the cervix. It is important to recognize, however,
that many patients with HSV-2 meningitis do
not have active genital lesions at the time of

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Table 1 Antiviral treatment of human herpesvirus infection of the nervous system.

Viral infection

Clinical diagnosis

Drug

Dose

Comments

Herpes simplex virus

(HSV)

Encephalitis

Aciclovir

10 mg/kg i.v. every 8 h

for 1421 days

Monitor renal function

HSV

Meningitis

Aciclovir

10 mg/kg i.v. every 8 h

for 57 days

HSV-2, not HSV-1, usually causes

meningitis;
no controlled trials have established
optimal treatment of single or recurrent
episodes of HSV meningitis

Prophylaxis
against meningitis
required

Valaciclovir

1,000 mg peroral daily

Only anecdotal evidence that antiviral

prophylaxis is effective

HSV

Myelitis

Aciclovir

10 mg/kg i.v. every 8 h

for 1421 days

None

Varicella zoster virus

(VZV)

Herpes zoster
(shingles);
herpes zoster
ophthalmicus

Valaciclovir

1,000 mg peroral thrice

daily for 1 week

None

VZV

VZV vasculopathy
or myelitis, or
zoster sine herpete
(dermatomal pain
without rash)

Aciclovir

1015 mg/kg i.v. every

8 h for 14 days

Test CSF for anti-VZV antibody and

VZV DNA

EpsteinBarr virus

NA

No antiviral treatment

NA

NA

Cytomegalovirus
(CMV) in
immunocompromised
patients

CNS infection,
polyradiculopathy

Induction therapy:
ganciclovir
Maintenance therapy:
valganciclovir
or ganciclovir
Induction therapy:
ganciclovir
and/or foscarnet
Maintenance therapy:
ganciclovir
or foscarnet

Human herpesvirus 6
(HHV-6): B variant

Encephalitis

Induction therapy:
foscarnet
Maintenance therapy:
foscarnet
Induction therapy:
ganciclovir
Maintenance therapy:
valganciclovir
or ganciclovir

5 mg/kg i.v. every 12 h

for 1421 days;
900 mg peroral daily
5 mg/kg i.v. daily
6 mg/kg i.v. daily
5 days/week

Polyradiculitis most likely in patients

with AIDS
Consider combination ganciclovir and
foscarnet if neurological disease develops
despite prior anti-CMV therapy
Consider serial CSF PCR for CMV DNA to
monitor response to anti-CMV therapy

5 mg/kg i.v. every 12 h

for 1421 days
60 mg/kg i.v. every 8 h
for 1421 days

Long-term maintenance therapy might

be necessary in patients who remain
profoundly immunosuppressed

5 mg/kg i.v. once daily

or 6 mg/kg i.v. once
daily 5 days/week
90120 mg/kg i.v. daily

Consider combined therapy in HIV-infected

patients with CD4+ counts <100 cells/mm3
or immunocompromised patients with poor
response to monotherapy

60 mg/kg i.v. every 8 h

for 14 days
90 mg/kg i.v. daily for
14 weeks

HHV-6 encephalitis usually occurs in the

setting of severe immunosuppression
Several reports of successful treatment, but
no clinical trial data are available

5 mg/kg i.v. every 12 h

for 1421 days
900 mg peroral daily
5 mg/kg i.v. daily

Abbreviations: CSF, cerebrospinal fluid; i.v., intravenously; NA, not applicable; PCR, polymerase chain reaction.

meningitis, and often have no known history

of genital herpes. HSV-2 was shown to cause
aseptic meningitis in one patient with recurrent
dermatomal distribution skin lesions.25 PCR has
shown that HSV-2,26 and less often HSV-1,27

FEBRUARY 2007 VOL 3 NO 2 GILDEN ET AL.

causes benign recurrent lymphocytic meningitis,

which is usually self-limited.
HSV-2 encephalitis occurs most often in
newborn babies and, more rarely, in immunocompromised adults. Approximately 5% of HSV

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encephalitis cases in immunocompetent adults

are also attributable to HSV-2. In infants and
immunocompromised adults, HSV-2 encephalitis is diffuse, unlike the focal lesions produced
by HSV-1 infection. Nevertheless, seizures, alterations in the state of consciousness, and focal
neurological deficits also characterize HSV-2
encephalitis. HSV-2 and CMV encephalitis can
coexist in patients with AIDS. The clinical features
of HSV-2 encephalitis in immunocompetent
adults are generally similar to those seen with
HSV-1 encephalitis, although some immunocompetent patients with HSV-2 encephalitis have
less-aggressive forms of encephalitis.
Pathogenesis and latency

HSV-2 has been isolated from normal human

sacral ganglia,28 but the physical state of HSV-2
DNA and HSV-2 gene expression in latently
infected human ganglia have not been studied
nearly as extensively as the characteristics of
HSV-1 in trigeminal ganglia. Latent lumbosacral ganglionic infection can be established
in mice and guinea pigs by intravaginal infection, and virus can be reactivated after sciatic
nerve section (mice) or UV irradiation (guinea
pigs). Whereas HSV-1 latency is found only in
cranial nerve ganglia, HSV-2 becomes latent
in lumbrosacral ganglia.
Treatment

The treatment for HSV-2 encephalitis is the same

as for HSV-1 (see above).
HSV neuropathy (zosteriform eruption)

HSV-2 can produce pain and dermatomal distribution rash (zosteriform eruption). Herpes
lesions above the neck typically result from
reactivation of HSV-1, whereas lesions below
the waist result from reactivation of HSV-2,
although exceptions to this rule occur. There is
usually a prodrome of diffuse neuralgia, often
with malaise and fever, followed within days
by the appearance of vesicles.29 Most reports
describe lesions in one or more of the facial
areas served by the trigeminal nerve, and also on
the trunk, extremities and genitalia. Recurrent
sciatica has been associated with HSV.30 A first
episode can be confused with herpes zoster, but
recurrent episodes of dermatomal neuralgic pain
and zosteriform eruptions are usually caused by
HSV-2.25 Although HSV neuropathy is now well
documented, the exact type of HSV responsible
for each form of neuropathy is still unknown.

86 NATURE CLINICAL PRACTICE NEUROLOGY

Future DNA analysis of herpesvirus isolates, by

PCR with virus-specific primers, should clarify
whether neuropathy is caused primarily by
HSV-1 or HSV-2.
HSV meningitis, myelitis and brainstem
encephalitis

HSV meningitis is usually caused by HSV-2. There

have been no controlled trials of antiviral therapy
for either isolated or recurrent HSV meningitis,
although noncontrolled experience indicates
that treatment with aciclovir or related antiviral
drugs might reduce the duration and severity of
attacks. Prophylactic antiviral treatment might
also reduce the frequency and severity of recurrent meningitis, although its therapeutic efficacy
has not been clearly established.
HSV-2 can also cause monophasic or recurrent
brainstem encephalitis and myelitis. As almost
all published studies are single-case reports, it
is not possible to evaluate the efficacy of antiviral therapy for these conditions. The severity
of these infections has, however, highlighted the
need for treatments, usually the same as those
for HSV encephalitis. In patients with recurrent
disease, valaciclovir or aciclovir have been used
to reduce the likelihood of recurrences.
VARICELLA ZOSTER VIRUS
Clinical features

VZV causes chickenpox (varicella), after which

the virus becomes latent in cranial nerve,
dorsal root and autonomic nervous system
ganglia along the entire neuraxis. Decades
later, a declining VZV-specific host immunity31
leads to virus reactivation, usually resulting in
herpes zoster (also known as shingles), which
is characterized by pain and rash restricted to
13 dermatomes. The NIH Shingles Prevention
Study estimates that herpes zoster affects
between 600,000 and 1,000,000 Americans each
year.32 The incidence and severity of herpes
zoster in immunodeficient individuals can be
viewed as a continuum, ranging from a natural
decline in VZV-specific immunity with age,
to more serious host immune deficits such as
those encountered in transplant recipients, or
in patients with cancer or AIDS.
Because VZV is latent in most ganglia, herpes
zoster can occur anywhere on the body. The
most common sites are thoracic, and in the cutaneous distribution of the ophthalmic branch of
the trigeminal nerve. VZV reactivation from the
geniculate (seventh cranial nerve) ganglion can

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cause the Ramsay Hunt syndrome, features of

which include peripheral facial weakness and
rash around the ear (zoster oticus).
In many herpes zoster patients over the
age of 60 years, painso-called postherpetic
neuralgia (PHN)continues for months or
years. Although the cause of PHN is uncertain, analyses of blood, CSF and postmortem
ganglia indicate that it is related to persistent or
low-grade productive infection in ganglia.33
After herpes zoster, VZV can also spread to
blood vessels of the brain, producing a unifocal
or multifocal vasculopathy, particularly in
immunocompromised individuals. Virological
analyses of patients who died from VZV vasculopathy have revealed both VZV DNA and VZV
antigen in cerebral arteries,34 indicating active
virus infection. Unifocal vasculopathy, formerly
called granulomatous arteritis, is the predominant form in elderly immunocompetent adults,
and is characterized by an acute focal deficit
that develops weeks to months after contralateral trigeminal distribution herpes zoster.
Multifocal vasculopathy develops in immunocompromised individuals, and is associated
with headache, fever, mental status changes and
focal deficit. CSF mononuclear pleocytosis is
usually present in both vasculopathies. Brain
MRI scanning reveals a single large infarct in
unifocal vasculopathy; in multifocal vasculopathy, ischemic and hemorrhagic infarcts are
seen in both cortical and subcortical areas
(Figure 1). Cerebral angiography reveals
focal arterial stenosis. Pathological changes
in affected arteries include the presence of
multinucleated giant cells, Cowdry A inclusion
bodies and herpesvirus particles. Virological
analysis reveals VZV DNA and antigen in
affected vessels. Vasculopathy occurs without
rash, can recur, and presents with transient
ischemic attacks, including posterior ischemic
optic neuropathy, remote from, and months
after, acute herpes zoster.35 Detection of VZV
DNA or antibody in CSF confirms a diagnosis
of VZV vasculopathy. As infection is active and
often protracted, anti-VZV IgM or IgG antibody is found in CSF, with reduced serum:CSF
ratios of VZV antibody compared with total IgG
or albumin.36 Detection of antibody to VZV in
CSF, even without amplifiable VZV DNA, can
be diagnostic. Recognition of the wide spectrum of VZV vasculopathy and its proclivity to
recur is essential, as effective antiviral therapy
can be curative.

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Pathogenesis and latency

The dermatomal distribution of herpes zoster

lesions, combined with peak VZV titers in varicella or herpes zoster vesicles, indicate that virus
that has reactivated from latency in PNS ganglia
spreads to the skin by intra-axonal transportation,
although the presence of VZV in multiple organs
in disseminated zoster is most consistent with
hematogenous dissemination. VZV-associated
viremia and lymphotropism have been documented during varicella, herpes zoster, PHN and
zoster sine herpete, and even in normal healthy
adults. During varicella, T cells are productively
infected, probably contributing to the spread of
the virus. VZV DNA, transcripts and protein have
been detected in mononuclear cells (MNCs) of
herpes zoster and PHN patients. With one exception,37 attempts to recover infectious VZV from
MNCs of immunocompetent herpes zoster
patients have failed.38,39 In herpes zoster and
PHN patients, lack of detectable infectious virus
might be attributable to the cell-associated nature
of the virus, low-level or abortive infection of
MNCs, or a decrease in the frequency of MNCs
that support productive infection, as compared
with primary infection.
The detection of VZV DNA40,41 and VZVspecific proteins42 in blood MNCs of some
patients with PHN and zoster sine herpete,4345
as well as in tissue of patients with chronic VZV
ganglionitis,46 might reflect low-level productive infection in gangliaa hypothesis that is
supported by favorable clinical responses in some
PHN patients treated with antiviral agents.47,48
MNCs, and in particular antigen-presenting
cells, might acquire virus while trafficking
through ganglia. Ultimately, digestion of virus
would account for the detection of some, but
not all, regions of the VZV genome in circulating
MNCs,49 compared with the presence of the
entire virus genome in latently infected ganglia.
Digestion of viral DNA by MNCs also helps to
explain why VZV DNA is found in MNCs from
only 20% of patients with PHN; there would only
be a limited probability that any given fragment
of viral DNA would be amplified by PCR.
Unlike HSV-1, VZV cannot be isolated from
latently infected human ganglia, although nucleic
acid hybridization and PCR have detected VZV
DNA in ganglia during latency.11,50 Whereas
HSV-1 latency is mostly restricted to cranial
nerve ganglia, VZV is latent in cranial nerve,
dorsal root and autonomic nervous system
ganglia in over 90% of healthy adults. As in the

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Table 2 Clinical features of virus reactivation.

Feature

Herpes simplex virus

Varicella zoster virus

Reactivation

Multiple times

Usually once

Age

Young

Elderly

Rash

Localized

Dermatomal

Cause

Sunlight; trauma

Immunosuppression

case of HSV-1, neurons are the exclusive site of

latent VZV.51,52 Analysis of trigeminal ganglia
revealed no difference in VZV copy number
between the left and right trigeminal ganglia of
the same individual, but showed a wide variation of 193,145 copies per latently infected
ganglion between individuals,14 probably
reflecting the uneven amount of VZV encountered during primary infection. Like HSV-1,
VZV DNA exists as an endless (either circular
or concatameric) episome.53 Five VZV genes
corresponding to open reading frames 21, 29,
62, 63 and 66 are transcribed, and proteins from
three of these (62, 63 and 66) have been found in
latently infected ganglionic neurons. Important
differences between the clinical features of HSV
and VZV reactivation are cited in Table 2.
Treatment

As the neurological complications of VZV infection are generally caused by replication of VZV
in the nervous system, inhibition of replication
is an obvious target for treatment.
Herpes zoster
Antiviral therapy is recommended for immunocompetent adults over 50 years of age with
herpes zoster, particularly if it can be initiated
within 72 hours of lesion onset. The improved
pharmacokinetic profiles and simpler dosing
regimens of oral valaciclovir (1,000 mg three
times daily for 7 days) or famciclovir (250 mg
or 500 mg three times daily) have led to their
use instead of aciclovir (800 mg five times daily)
as the preferred treatment. Steroids might
reduce the inflammation that contributes to
acute pain, provided that there are no contraindications and the potential risk of excessive
adverse effects is explained. Although they do
not prevent PHN, steroids reduce acute symptoms and might facilitate a return to normal
quality of life. There is no indication for the
use of topical antiviral agents to treat cutaneous
herpes zoster.

88 NATURE CLINICAL PRACTICE NEUROLOGY

The premise that the pain experienced

by people with herpes zoster is primarily
attributable to inflammation and necrosis of
neurons led to the suggestion that, by reducing
inflammation, corticosteroids would reduce
pain. The debate on the role of corticosteroid
therapy in herpes zoster has largely been
resolved by two large prospective clinical trials,
which demonstrated the benefit of corticosteroids in reducing the duration of acute pain,
although neither study showed any reduction
in the incidence or duration of PHN among
corticosteroid recipients.54,55
Postherpetic neuralgia
PHN is operationally defined as pain that
persists for more than 3 months after herpes
zoster. Tricyclic antidepressants, such as
amitriptyline or nortriptyline (initiated at 10
25 mg and increasing weekly by 25 mg [10 mg if
the patient is >65 years old or frail]), relieve pain
in some patients. Gabapentin, 300900 mg/day
up to 3,600 mg/day (provided that there is
unimpaired renal function), is also recommended. Pregabalin is another FDA-approved
drug that is being used increasingly to treat
PHN. A topical local anesthetic (e.g. lidocaine
patch 5%) might also help.
Vasculopathy and myelitis
Vasculopathy and myelitis are treated with intravenous aciclovir (1015 mg/kg every 8 hours
for 1014 days [Table 1]). The role of antiviral
therapy in individuals presenting with rarer
complications of varicella, such as cerebellar
ataxia, has not been studied in a prospective
or controlled fashion; however, administration of intravenous aciclovir to such patients is
likely to be appropriate. Immunocompromised
patients might require longer periods of treatment. Treatment should be discontinued
if both VZV DNA and anti-VZV antibody
are absent from CSF collected at the time of
treatment initiation.

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EPSTEINBARR VIRUS
Clinical features

EBV causes aseptic meningitis, encephalomyeloneuritis and neuritis. The EBV neuropathies present with ophthalmoplegia,
lumbosacral plexopathy, and sensory or autonomic neuropathy. Historically, the association
of virus with neurological disease was suggested
by a positive serum heterophile antibody titer,
and later by the presence of EBV DNA, antibody
or both in CSF.56 EBV is latent in B cells, and
caution should be used in attributing neurological disease to EBV purely on the basis of a
positive CSF PCR; in previously EBV-infected
individuals, PCR might detect EBV DNA latent in
B cells that are part of the inflammatory response
induced by another agent. The presence of antiEBV IgM or IgG antibody in CSF is more likely
to be significant, particularly if there is evidence
of intrathecal synthesis of EBV antibody (see
below). In a comprehensive clinical, radiological
and virological analysis of four patients with
EBV myeloradiculitis, encephalomyeloradiculitis
and meningoencephalomyeloradiculitis,57 the
CSF contained a mononuclear pleocytosis with
elevated protein and normal glucose; in two
patients, MRI scans revealed an increased signal
in the spinal cord and lumbosacral roots, but
no brain swelling or focal changes. In all four
patients, EBV DNA was found in the CSF and
there were reduced serum:CSF ratios of antibody to EBV, but not to total IgG or albumin,
consistent with intrathecal antibody synthesis.
Residual neurological deficits were evident.
Disappearance of viral DNA from CSF at the time
of improvement of neurological disease, particularly before a decline in CSF white blood cells,
supports the theory that CNS disease results from
direct invasion of the CNS by virus. EBV DNA
has been found in brain biopsies from affected
patients.58 CSF from patients with EBV infection of the nervous system contains mainly EBVspecific CD8+ T cells, a few CD4+ T cells, and
no CD19+ B cells.59 CD8+ cells from one patient
with EBV infection were shown to contain EBV
DNA, and had unrestricted cytotoxic activity.60
Patients with postinfectious complications of
EBV infection have a low EBV load and a high
CSF leukocyte count. Encephalitis is characterized by intense viral replication and vigorous
inflammation, whereas CNS lymphoma is associated
with a limited inflammatory response.
EBV-associated CNS lymphomas are rare in
immunocompetent individuals. EBV triggers

FEBRUARY 2007 VOL 3 NO 2 GILDEN ET AL.

AIDS-associated primary CNS lymphoma

(PCNSL) and post-transplantation lymphoproliferative disorder (PTLD). EBV DNA
can be found in tumor tissue in both of these
conditions61 and in CSF of patients with AIDSassociated PCNSL. Deficiency in cytotoxic
T lymphocytes seems to permit the outgrowth
of EBV-transformed B cells, resulting in PTLD.
Administration of autologous EBV-specific
cytotoxic T cells has been shown to produce
specific killing of EBV-transformed B cells in
patients with PTLD.62
Pathogenesis and latency

EBV infects B and T lymphocytes of more than

90% of the general population before adulthood.
Primary infection results in transient viremia,
followed by a rapid immune response. EBV
replicates in the oropharynx and is transmitted
through oral secretions. Primary EBV infection
frequently results in infectious mononucleosis.
EBV is also associated with nasopharyngeal carcinoma, Burkitts lymphoma, Hodgkins disease,
and lymphoproliferative disease in immunocompromised individuals.63 It is estimated
that neurological complications occur in 15%
of individuals with infectious mononucleosis.
Given the widespread prevalence of EBV infection, the burden of neurological disease is probably underestimated; for example, virtually
all CNS lymphomas in AIDS patients contain
EBV DNA.61
EBV establishes latency in B lymphocytes,
which adopt restricted patterns of EBV gene
expression. EBV latency has been classified
into three types: type I (Burkitts lymphoma),
in which only the EBV-encoded nuclear antigen
(EBNA-1) is expressed; type II (nasopharyngeal
carcinoma), in which EBNA-1 is coexpressed
along with the latent membrane proteins LMP-1,
LMP-2A and LMP-2B; and type III (lymphoproliferative diseases in immunosuppressed
individuals), in which five EBNAs and the
three LMPs are expressed. Autoactivation of
gene expression by LMP-1 might be important in type II latency, and EBNA-2-dependent
regulation of LMP-1 expression appears to be
important in type III latency.64 The precise
mechanism by which EBV reactivates remains
unknown, however.
Treatment

There is no known effective antiviral or other

accepted treatment for EBV.

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CYTOMEGALOVIRUS
Clinical features

CMV produces neurological disease predominantly in infants with congenital infection.

Although most congenital CMV infections
are asymptomatic, many carriers develop
sensorineural hearing loss and intellectual
handicaps. Other neurological complications
include microcephaly, seizures, hypotonia and
spasticity. In immunocompetent adults, the
most common neurological complication of
CMV infection is GuillainBarr syndrome,
and CMV has also been associated with acute
brachial plexopathy.65
The natural history of CMV infection of the
CNS in immunocompetent adults is unknown.
CMV encephalitis was first described in renal66
and bone marrow transplant recipients, and
CMV infections in patients with AIDS can
cause encephalitis, myelitis, retinitis and polyradiculitis. The CSF might show neutrophilic or
mononuclear pleocytosis, or an elevated protein
and depressed glucose content, and MRI can reveal
enhancement in the ventricular ependyma. Focal
disease has been attributed to CMV vasculitis or
demyelination. Characteristic owl-eyed cytomegalic inclusions and CMV-specific antigens have
been found in brain tissue and blood vessels of
AIDS patients with subacute encephalopathy.
Complicating the picture, however, is the additional presence of HSV-2. It is difficult, therefore, to attribute specific symptoms and signs
to CMV.
CMV polyradiculopathy in patients with
AIDS begins insidiously as a cauda equina
syndrome with paresthesias and distal weakness
(usually asymmetric), incontinence, and sacraldistribution sensory loss. CSF pleocytosis is
usually present, often with a predominance of
polymorphonuclear leukocytes. Most cases have
elevated CSF protein and hypoglycorrhachia.
CMV can be isolated from CSF, and CMV DNA
can be amplified by CSF PCR. Postmortem
examination reveals inflammation, necrosis and
focal vasculitis of nerve roots, along with typical
CMV inclusions.67
Pathogenesis and latency

CMV has a genome nearly twice as large as those

of other HHVs, one which encodes more than
200 genes. During primary infection, CMV
replicates in leukocytes and vascular endothelial
cells, after which virus becomes latent principally
in bone marrow progenitor cells and myeloid

90 NATURE CLINICAL PRACTICE NEUROLOGY

cells.68 Human CMVs show DNA sequence variability69 and, when adapted to in vitro growth,
acquire extensive DNA deletions.70 Reactivation
and shedding of infectious human CMV follows
immunosuppression, differentiation of latently
infected progenitor cells, or allogeneic organ
transplant.71 After reactivation, CMV eludes
immunological clearance by suppressing MHC
class I and class II responses, inhibiting apoptotic
cell death, and sequestering chemokines.72
Treatment

There have been no randomized controlled

studies of antiviral therapy in adults with CMV
infection of the nervous system. An international
panel that developed guidelines for treatment
of CMV diseases in adults with AIDS receiving
highly active antiretroviral therapy73 recommended treatment with intravenous ganciclovir,
intravenous foscarnet, or a combination of the
two drugs. Patients who develop CMV polyradiculopathy while on ganciclovir or foscarnet
therapy should receive combination therapy with
both drugs (Table 1). Patients not on treatment
at the time of disease onset could be treated with
either drug as monotherapy, and switched to
combination therapy if they progressed clinically
and/or had persisting CSF pleocytosis (a potential marker of drug failure). Reports of antiviral
therapy for CMV-associated mononeuritis
multiplex or painful symmetrical neuropathy are
too limited to permit conclusions about efficacy
of antiviral therapy.
HUMAN HERPESVIRUS 6
Clinical features

HHV-6 causes roseola, a common childhood

exanthematous disease. Neurological complications can result from direct invasion of the
CNS. HHV-6 DNA has been detected in the CSF
of patients with febrile seizures74 and in the
brains of patients with fulminant hepatitis.75
HHV-6 antigen was found in brain tissue from
a fatal case of roseola.76 HHV-6 causes encephalitis primarily after bone marrow or stem cell
transplantation,77 and might present as limbic
encephalitis.78 Diagnosis is confirmed by detection of HHV-6 DNA in the CSF. On the basis
of the presence of HHV-6 DNA and increased
levels of antibody to HHV-6 in blood and CSF
of patients with multiple sclerosis (MS), HHV-6
has been implicated in the pathogenesis of the
disease. HHV-6 is, however, found in only a
minority of MS patients, and HHV-6 DNA and

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elevated HHV-6 antibody levels are also seen in

patients with other neurological diseases.
Pathogenesis and latency

As HHV-6 becomes latent in cells of the monocytemacrophage lineage,79 the detection of

HHV-6 DNA and antigen in brain tissue is
likely to reflect HHV-6 reactivation from latency
in blood MNCs trafficking through the brain in
patients with inflammatory CNS disease. CD46
is an HHV-6 receptor that is expressed mostly
in macrophages and cells lining blood vessels,
and less often in cells of neuronal origin. HHV-6
expresses proinflammatory cytokines that
are cytotoxic to oligodendrocytes and induce
caspase-independent apoptosis.80 HHV-6 has
also been shown to inhibit G1S-phase transition in glial precursor cells, which are important
in remyelination.81 Reactivation of latent HHV-6
is frequently associated with drug-induced
hypersensitivity syndrome, possibly because of
the acute decrease in serum IgG levels observed
in these patients.
Treatment

There have been no randomized controlled trials

of antiviral therapies in either immunocompetent
or immunocompromised patients. Ganciclovir
and foscarnet have been used (Table 1),
but their efficacy is unknown. The outcome in
immunocompetent patients does not appear
to be substantially better than that in immunocompromised individuals. Real-time fluorescent probe CSF PCR has been used to follow
the effects of antiviral therapy on HHV-6
DNA levels in the CSF of 11 hematopoietic
stem cell recipients with HHV-6 infection (8 of
whom had HHV-6 encephalitis).82 All patients
were treated with ganciclovir, foscarnet or
both. Within 3 weeks of commencing antiviral
therapy, median CSF viral load had decreased
from 25,000 copies/ml to 100 copies/ml,
although the difference was not statistically
significant (P = 0.13). Four of the eight patients
with HHV-6 encephalitis improved clinically,
with viral load declining concurrently with
antiviral therapy.
HUMAN HERPESVIRUS 7

HHV-7 is closely related to HHV-6, and can

induce reactivation of the latter in vitro. HHV-7
was first isolated from CD4+ T cells of a healthy
26-year-old under conditions that promote T-cell
activation.83 HHV-7 is ubiquitous and is acquired

FEBRUARY 2007 VOL 3 NO 2 GILDEN ET AL.

in childhood. There is a single report of primary

HHV-7 encephalitis in an immunocompetent
adult, in whom HHV-7 DNA was found in the
CSF,84 and another report of meningitis and
optic neuritis resulting from reactivation of
HHV-7 in a stem cell transplant recipient.85
HHV-7 infection in children has been linked
with seizures and encephalitis through the detection of intrathecal synthesis of antibody against
the virus.86
KAPOSIS SARCOMA-ASSOCIATED
HERPESVIRUS

Kaposis sarcoma-associated herpesvirus (KSHV

or HHV-8) is the most recently discovered HHV.
Using PCR-based subtractive analysis, Chang
et al.87 detected segments of the KSHV genome
in tumor cells of Kaposis sarcomas, the most
common tumors seen in patients with AIDS.
KSHV is also associated with primary effusion
lymphoma and specific forms of multicentric
Castleman disease, both of which are B-cell
lymphoproliferative disorders. KSHV becomes
latent in B cells. The viral genome is episomal,
and its complete sequence (137 kilobase pairs)
has been determined. Like EBV, KSHV encodes a
latency-associated nuclear antigen, which tethers
the virus episome to the host chromosome. This
tethering not only ensures that virus DNA replication is synchronous with host chromosome
replication, but also represses activation of virus
genes associated with replication. Expression
of a lytic HHV-8 gene that encodes a viral
G-protein-coupled receptor can lead to the
formation of Kaposis sarcoma-like lesions in
mice.88 To date, no neurological disease has been
associated with KSHV infection.
CONCLUSIONS

Most HHVs can cause serious neurological

disease of the PNS and CNS through primary
infection or following virus reactivation from
latently infected human ganglia or lymphoid
tissue. The neurological complications include
meningitis, encephalitis, myelitis, vasculopathy,
acute and chronic radiculoneuritis, and various
inflammatory diseases of the eye. Disease can be
monophasic, recurrent or chronic. Recognition
of the clinical patterns and imaging characteristics of disease produced by different herpesviruses is important, because infection by many
of the herpesviruses can be treated successfully. Early diagnosis and proper treatment are
essential to a favorable outcome.

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KEY POINTS

Herpes simplex virus 1 (HSV-1) encephalitis

predominantly involves the orbital surface of
the frontal lobes and medial surface of the
temporal lobes, resulting in areas of increased
T2 signal on MRI
Herpes simplex virus 2 (HSV-2) is the primary
cause of recurrent meningitis
After varicella, the varicella zoster virus (VZV)
becomes latent in ganglia along the entire
neuraxis; its reactivation can lead to herpes
zoster, vasculopathy, myelitis, necrotizing
retinitis or zoster sine herpete
The neurological complications of EpsteinBarr
virus are diverse, and include meningitis,
encephalitis, myelitis, radiculoneuropathy, and
even autonomic neuropathy
The most common neurological complication
of cytomegalovirus (CMV) is polyradiculoneuropathy in immunocompromised
individuals
Virological confirmation of neurological disease
relies on the detection of herpesvirus-specific
DNA in bodily fluids or tissues, herpesvirusspecific IgM in blood, or herpesvirus-specific
IgM or IgG antibody in cerebrospinal fluid
HSV-1, HSV-2, VZV and CMV are the most
treatable herpesviruses

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Acknowledgments
This work was supported
in part by Public Health
Service grants NS32623
and AG06127 from the
National Institutes of Health.
We thank Marina Hoffman
for editorial assistance and
Cathy Allen for manuscript
preparation.

Competing interests
The authors declared
they have no competing
interests.

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