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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.
INTRODUCTION
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Clinical diagnosis
Drug
Dose
Comments
Encephalitis
Aciclovir
HSV
Meningitis
Aciclovir
Prophylaxis
against meningitis
required
Valaciclovir
HSV
Myelitis
Aciclovir
None
Herpes zoster
(shingles);
herpes zoster
ophthalmicus
Valaciclovir
None
VZV
VZV vasculopathy
or myelitis, or
zoster sine herpete
(dermatomal pain
without rash)
Aciclovir
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
Abbreviations: CSF, cerebrospinal fluid; i.v., intravenously; NA, not applicable; PCR, polymerase chain reaction.
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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.
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Reactivation
Multiple times
Usually once
Age
Young
Elderly
Rash
Localized
Dermatomal
Cause
Sunlight; trauma
Immunosuppression
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.
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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
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CYTOMEGALOVIRUS
Clinical features
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
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KEY POINTS
References
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herpes simplex encephalitis: application of polymerase
chain reaction to cerebrospinal fluid from brainbiopsied patients and correlation with disease.
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857863
2 Weil AA et al. (2002) Patients with suspected herpes
simplex encephalitis: rethinking an initial negative
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3 Westmoreland BF (1987) The EEG in cerebral
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4 Smith JB et al. (1975) A distinctive clinical EEG profile
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7 Bastian FO et al. (1972) Herpesvirus hominis: isolation
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8 Baringer JR and Swoveland P (1973) Recovery of
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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.