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Update on herpes simplex encephalitis

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 DIAGNOSIS AND TREATMENT UPDATE

Update on Herpes
Simplex Encephalitis
Kenneth L. Tyler, MD
Departments of Neurology, Medicine, Microbiology, and Immunology, University of Colorado
Health Sciences Center, and the Neurology Service of the Denver Veterans Affairs Medical Center,
Denver, CO

Herpes simplex encephalitis is the most common identified cause of sporadic viral
encephalitis in the United States. Early diagnosis is critical because treatment with the
antiviral drug acyclovir dramatically decreases morbidity and mortality. The use of
polymerase chain reaction (PCR) techniques to amplify the genome of herpes simplex
virus (HSV) from cerebrospinal fluid (CSF) has become the diagnostic procedure of choice.
False-positive CSF HSV PCR results are rare when testing is performed in experienced
laboratories. Negative CSF HSV PCR results should always be interpreted in the context
of the timing of specimen collection and the likelihood of disease. Negative CSF HSV PCR
tests can occur within the first 72 hours of illness, with subsequent tests becoming posi-
tive. Patients with HSV encephalitis will typically have a negative CSF HSV PCR after 14
days of acyclovir treatment, and a persisting positive PCR should prompt consideration of
additional or revised antiviral therapy. Quantitative PCR testing provides information
about HSV viral load in CSF, but the potential correlation of viral load with prognosis or
other clinical features of disease remains uncertain. Although the neuroimaging abnor-
malities seen in HSV encephalitis are not unique, more than 90% of patients with proven
HSV encephalitis will have magnetic resonance imaging (MRI) abnormalities involving
the temporal lobes. Special MRI techniques, including fluid-attenuated inversion recovery
and diffusion-weighted imaging, might reveal abnormalities not seen with conventional
imaging sequences. Neuroimaging patterns in infants and children differ significantly
from those seen in adults and include a higher frequency of extratemporal lesions.
[Rev Neurol Dis. 2004;1(4):169-178]
© 2004 MedReviews, LLC

Key words: Herpes simplex • Encephalitis • Polymerase chain reaction •

Cerebrospinal fluid • Magnetic resonance imaging • Acyclovir

A
lthough both primary herpes simplex virus (HSV) infection and reacti-
vation are extremely common and affect millions of individuals in the
United States each year, HSV encephalitis remains an extraordinarily
rare event. Encephalitis caused by HSV is the most common cause of sporadic
(nonepidemic) encephalitis in the United States, with an incidence of approxi-
mately 4 cases per million population. In most recent large series, the majority

VOL. 1 NO. 4 2004 REVIEWS IN NEUROLOGICAL DISEASES 169

Herpes Simplex Encephalitis continued
(60%-70%) of cases of suspected viral
encephalitis are of unknown etiology.
Of those cases in which a specific
cause is identified, HSV typically
accounts for 35% to 55%.1,2 HSV iso-
lates are grouped into 2 major
serotypes (HSV-1 and HSV-2). Primary
exposure to HSV-1 outside the neona-
tal period usually results in gingivos-
tomatitis, and by adulthood 60% to
80% of individuals are HSV-1 seropos-
The overwhelming majority of patients with HSV encephalitis do not
have identifiable risk factors predisposing them to disease.
itive. Exposure to HSV-2 is typically
associated with genital herpes, and
acquisition of HSV-2 seropositivity
generally parallels onset of sexual
activity, with 25% to 35% of individ-
uals becoming seropositive by adult-
hood. At least 80% of cases of neona-
tal and infantile herpes encephalitis
or neonatal encephalitis associated
with disseminated herpes infection
are due to HSV-2.3 Neonatal infection
Just over half the patients presented initially with headache, fever, and
alteration of consciousness.
typically results from passage of the
infant through an infected birth
canal during parturition. Conversely,
more than 90% of HSV encephalitis
cases in adults are caused by HSV-1
(see below).
Approximately one third of all
HSV encephalitis cases occur in those
younger than 20 years, and the
majority of these likely reflect pri-
mary infection. By contrast, it is like-
ly that the majority of cases of HSV
encephalitis in older individuals
results from viral reactivation. HSV
infection is an important cause of
encephalitis in the elderly, account-
ing for more than one third of all
170 VOL. 1 NO. 4 2004 REVIEWS IN NEUROLOGICAL DISEASES
cases of encephalitis in those older
than 60 years.4 HSV encephalitis
occurs at all seasons of the year and
in adults affects both sexes equally.
HSV encephalitis in infants and chil-
dren may show a male predomi-
nance.5 The overwhelming majority
of patients with HSV encephalitis do
not have identifiable risk factors pre-
disposing them to disease. However,
isolated cases have occurred after
intracranial surgery. It has also been
suggested that the apolipoprotein ε2
allele is over-represented in patients
with HSV encephalitis compared
with the general population.6
Pathogenesis
The exact pathogenesis of adult HSV
encephalitis remains unknown. It
has been suggested that invasion of
the central nervous system (CNS)
during primary infection might
result from viral entry through the
nose, with subsequent infection of
olfactory bulb neurons and retro-
grade spread to enterorhinal and
parahippocampal and hippocampal
cortex. In the case of encephalitis due
to reactivation of latent virus, virus
reactivating in trigeminal ganglion
may spread to the frontal and tem-
poral lobes via tentorial nerves.
Several recent postmortem studies
have shown that portions of the HSV
genome can be detected in brain and
brainstem tissues from asymptomatic
individuals, although it remains
unknown whether this is indicative
of the presence of fully reactivation-
competent latent virus in CNS neu-
rons that is capable of reactivation to
induce encephalitis.7
Clinical Features
Much of what is currently known
about the clinical and laboratory fea-
tures of HSV encephalitis is the result
of multicenter collaborative studies
coordinated by the Collaborative
Antiviral Study Group (CASG), direct-
ed by Richard Whitley, MD, at the
University of Alabama (Birmingham,
AL). Enrollment in the original CASG
clinical trials required patients to
undergo brain biopsy to unequivo-
cally establish the diagnosis of HSV
encephalitis. Patients with biopsy-
proven HSV encephalitis8 typically
had a history of alteration of con-
sciousness (97%), fever (90%), and
headache (81%). At the time of hos-
pital presentation, fever was present
in 92% and focal neurologic findings
in 85%. Common neurologic abnor-
malities at the time of presentation
included personality change (85%),
aphasia (76%), ataxia (40%), hemi-
paresis (38%), and cranial nerve
deficits (32%). Many patients (38%)
had seizures, which could be focal
(65%), generalized (23%), or both
(12%). Autonomic dysfunction was
also particularly common (80%). In a
Scandinavian study of 53 cases of
HSV encephalitis,9 of which approxi-
mately 40% had diagnosis confirmed
by isolation of virus or detection of
antigen at biopsy or necropsy, the
most common clinical features were
fever (100%), altered consciousness
(100%), personality change (87%),
headache (74%), seizures (62%),
hemiparesis (40%), and aphasia
(36%). These basic features were also
confirmed in a study from Glasgow,10
in which 87% of patients had the
diagnosis established by brain biopsy
either by virus isolation or detection
of viral antigen by immunofluores-

cence. In this study just over half the
patients presented initially with
headache, fever, and alteration of
consciousness. Meningismus was
present in 65%, and 48% had an
influenza-like prodromal illness
preceding the development of
encephalitis. Approximately half the
patients were mute or aphasic, and
one third were in deep coma at the
time of admission.10
In recent years, the use of brain
biopsy as the definitive diagnostic test
for HSV encephalitis has been sup-
planted, except in rare instances, by
the use of polymerase chain reaction
(PCR) techniques to amplify specific
HSV genome fragments from cere-
brospinal fluid (CSF) (reviewed
by DeBiasi and colleagues11 and
Kleinschmidt-DeMasters and col-
leagues12). The clinical features of
PCR-defined HSV encephalitis are
generally similar to those identified in
studies using brain biopsy, although
patients tend to be less severely ill at
time of diagnosis. Fever, CSF pleocy-
tosis, and some degree of alteration in
mental status/level of consciousness
occur in more than 90% of cases.13-15
Other frequent symptoms in PCR-
proven HSV encephalitis include per-
sonality change (40%-60%), seizures
(33%-50%), motor deficits (approxi-
mately 33%), and aphasia (31%). The
severity of mental status changes is
considerably less in PCR-based studies
than in the earlier biopsy-dependent
ones.13-15 In the biopsy era, only
approximately one third of patients
had a Glasgow Coma Scale (GCS)
score greater than 10, whereas this
proportion has increased to approxi-
mately 80% in studies using CSF PCR
for diagnosis.
Data on the clinical presentation
of HSV encephalitis in children are
more limited than those on adults.
Investigators in Israel16 reviewed the
presentation and outcome of 28 chil-
dren aged 9 months to 16 years in
whom the diagnosis of HSV
encephalitis was made by a variety of
means, including CSF antibody stud-
ies and PCR. Symptoms at or before
admission included fever above 38°C
(79%), altered consciousness (68%),
seizures (68%), vomiting (57%),
headache (50%), and personality
change (43%). The lower incidence
of reported headache and personality
change might have reflected in part
the inclusion of young children (21%
in the study were age 1 year or
younger), in whom detection of
these symptoms might have been
more difficult.
Cerebrospinal Fluid
Almost all patients with suspected
HSV encephalitis will have a CSF
examination. The basic CSF profile in
Unfortunately, the basic CSF profile for HSV encephalitis is not specific
and occurs in many CNS viral infections.
HSV encephalitis is a lymphocytic
pleocytosis, a normal or mildly ele-
vated protein level, and normal glu-
cose levels. In 1 series of 93 patients,17
the average cell count was 237 ± 477
leukocytes/mm3 (range, 1-3900
leukocytes/mm3) and the average
protein level 83 ± 56 mg/dL (range,
19-298 mg/dL). In a smaller study,18
investigators found essentially simi-
lar results, with a mean leukocyte
count of 202 leukocytes/mm3 (range,
2-667 leukocytes/mm3) and protein
level of 73 mg/dL (range, 22-146
mg/dL). Unfortunately, this profile is
not specific and occurs in many CNS
viral infections, as well as in acute
disseminated encephalomyelitis and
even in noninfectious conditions. A
normal CSF cell count is seen in less
than 5% of immunocompetent
adults,17 although this number is like-
ly higher in those immunocompro-
mised by human immunodeficiency
VOL. 1 NO. 4 2004
Herpes Simplex Encephalitis
virus infection or other causes. In
infants and children with HSV
encephalitis, approximately 20% of
CSF specimens obtained on the first
day of hospitalization might contain
fewer than 10 cells/mm3.5 A lympho-
cytic pleocytosis is characteristic of
HSV encephalitis, and a predomi-
nance of polymorphonuclear neu-
trophils occurs only in approximate-
ly 2% of cases. A CSF glucose con-
centration of less than 50% of the
serum glucose is seen in less than 5%
of patients. Patients with a normal
CSF cell count, a CSF polymor-
phonuclear pleocytosis, or a
depressed CSF glucose level only
rarely have HSV encephalitis, and
the presence of any of these findings
should prompt a careful search for
alternative diagnostic possibilities.
Cerebrospinal Fluid
Polymerase Chain Reaction
CSF PCR is the diagnostic procedure
of choice in HSV encephalitis, but
care needs to be taken in interpreting
the results obtained. CSF PCR has
been reported to have a sensitivity of
approximately 96% to 98% and a
specificity of approximately 94% to
99% for diagnosis of adult HSV
encephalitis when CSF is obtained in
the appropriate clinical setting and
testing is performed in an experi-
enced laboratory.19,20 The sensitivity
and specificity of PCR for diagnosis
of neonatal and infantile HSV
encephalitis have been more variable,
with reported sensitivities ranging
from 75% to 100% and specificity
approaching 100% if positive results
in patients with herpetic skin-eye-
mouth disease are considered to
reflect occult CNS disease rather than
false-positive studies (see Kimberlin
REVIEWS IN NEUROLOGICAL DISEASES 171
Herpes Simplex Encephalitis continued
and colleagues3). It is important to
recognize that there is no “standard”
protocol for CSF HSV PCR. Different
laboratories use different primer sets
designed to amplify different HSV
genes, different reaction conditions,
and different methods for confirm-
ing the specificity of amplified prod-
ucts. Gene targets for primers include
the viral thymidine kinase and DNA
polymerase genes, as well as the
genes encoding glycoproteins B, C,
Interpretation of PCR results is critically influenced by both the timing
of the test in relation to the onset of clinical illness and the pretest
probability that a patient has HSV encephalitis.
D, or G and a DNA binding protein,21
with the DNA polymerase and glyco-
protein D genes being the most com-
mon targets. Interpretation of PCR
results is critically influenced by both
the timing of the test in relation to
the onset of clinical illness and the
pretest probability that a patient has
HSV encephalitis. In 1 study, 3 of 11
patients tested within 72 hours of
symptom onset had a negative CSF
PCR result that subsequently became
positive when they were retested 4 to
7 days later.22 In a recent retrospec-
tive study in children with HSV
encephalitis,5 investigators found
that 8 of 33 CSF samples (24%)
obtained during the first 3 days of ill-
ness were negative. In 5 cases in
which a second CSF sample was
obtained at 5 to 11 days of illness, 4
were positive.5 The presence of fewer
than 10 leukocytes/mm3 in CSF was
associated with a higher likelihood of
a negative CSF HSV PCR result.
Similarly, approximately 80% of
treated patients will have a negative
CSF PCR result at greater than 14
days of illness (no data are available
for untreated patients).19 Thus, nega-
tive CSF PCR results obtained either
early (< 3 days) or late (> 14 days)
172 VOL. 1 NO. 4 2004 REVIEWS IN NEUROLOGICAL DISEASES
in infection should be interpreted
with caution.
CSF PCR results should also be
interpreted according to the likeli-
hood (prior probability) that the
patient being tested has the disease
being tested for (Bayesian analysis).
For example, in a patient with a high
(eg, 60%) pretest probability of her-
pes encephalitis according to clinical
and laboratory studies, a negative
CSF PCR result dramatically reduces
the likelihood of HSV encephalitis
(post-test probability 6%) but does
not exclude it entirely. Conversely,
in a patient with a low pretest prob-
ability of disease (eg, 5%), a negative
PCR test result reduces the post-test
probability to approximately 0.2%.20
A clinician would likely choose not
to stop therapy in the first instance
but might discontinue therapy in
False-negative CSF PCR results can also occur when CSF contains
components that interfere with PCR reactions.
the second case. In these 2 scenarios,
a positive test would increase the
probability of HSV encephalitis to
99% (high pretest probability) and
83.5% (low pretest probability), and
in both situations treatment would
certainly be continued.
False-Negative Results
In addition to occurring when CSF
specimens are obtained too early or
too late after infection (see above),
false-negative CSF PCR results can
also occur when CSF contains com-
ponents that interfere with PCR
reactions. Fortunately, this situation
seems to be rare for HSV PCR. In a
study comparing PCR with brain
biopsy, 53 of 54 biopsy-positive
specimens were also PCR positive
(98%).19 An additional 164 CSF spec-
imens were tested for inhibitory
activity by spiking them with HSV
DNA (200 copies) and then testing
them by PCR. HSV DNA was success-
fully amplified from 162 specimens
(99%), suggesting that only approxi-
mately 1% of CSF specimens might
contain nonspecific PCR inhibitory
activity.19 Other investigators21 have
suggested that 1% to 5% of CSF spec-
imens might contain inhibitors that
interfere with PCR. High concentra-
tion of porphyrin compounds,
which can be derived from hemoly-
sis of red cells, can interfere with
PCR reactions. These studies suggest
that, although false-negative HSV
PCR results are rarely due to PCR
inhibitory activity in CSF, care
should be taken in interpreting neg-
ative HSV PCR results obtained on
blood-contaminated CSF specimens.
The low rate of apparent false-nega-
tive CSF HSV PCR results is consis-
tent with a retrospective study of
799 CSF HSV PCR-negative patients
with encephalitis, in which it was
suggested (using other tests for diag-
nosis of HSV infection) that 3
patients might have had PCR-nega-
tive HSV encephalitis.23
False-Positive Results
False-positive HSV CSF PCR results
seem to be rare when tests are per-
formed in experienced laboratories
with accepted methods for avoiding
inadvertent contamination of sam-
ples. In the series by Lakeman and
colleagues,19 in which CSF HSV PCR

was compared with brain biopsy, 3 of
47 patients (6%) with negative brain
biopsy results for HSV had positive
CSF HSV PCR results. However, it is
likely that some or even all of these
cases represent examples in which,
owing to sampling error or other
technical issues, the brain biopsy was
falsely negative rather than the CSF
PCR being falsely positive. In another
study that included 116 cases of non-
HSV viral infections of the CNS and
82 nonviral infections of the CNS,
none had a positive CSF HSV PCR. No
positive HSV PCR results were found
in more than 500 other samples from
patients with a variety of noninfec-
tious CNS diseases (eg, stroke) or sys-
temic diseases with CNS symptoms.23
Confirmation of Results
Because HSV PCR testing methodol-
ogy is not standardized, it is impor-
tant to understand the criteria being
used by a specific reporting laborato-
ry in determining whether an HSV
PCR result is considered positive. It
is essential that laboratories confirm
not only that PCR has amplified a
reaction product of the predicted
size for the primers being used, but
also that methods are used to con-
firm that this product actually repre-
sents amplification of the target
gene. This is often done by Southern
blotting and DNA probe hybridiza-
tion, in which the amplification
products are transferred to nitrocel-
lulose paper and then hybridized
with a labeled probe specific for the
target gene. A PCR enzyme-linked
immunosorbent assay (ELISA) sys-
tem has also been developed, in
which PCR amplification products
are mixed with a labeled DNA probe
specific for the target gene of interest
and the probe is then captured onto
a streptavidin-coated ELISA plate
and detected colorimetrically.21
Nucleotide sequence analysis of the
amplification product also confirms
its specificity, but this technique is
used primarily for research rather
than routine clinical applications.
Failure to adequately confirm the
specificity of amplification products
might account for some cases of
false-positive CSF PCR results.
Finally, it is important to recognize
that most studies of the sensitivity
and specificity of CSF PCR testing
have been done in defined clinical
settings (eg, patients with suspected
meningitis or encephalitis). Care
should always be taken when
interpreting a positive test result
obtained in an unexpected or
unusual setting different from that
used to initially validate the test.
Care should also be taken when
extrapolating sensitivity/specificity
There are few studies of the utility of PCR tests in HSV encephalitits.
values obtained in a particular set of
patients to a very different clinical
situation (eg, a CSF specimen sent
for HSV PCR testing obtained in a
patient with no evidence to suggest
an acute CNS infection).
Viral Load
In some CNS viral infections, such as
those caused by human immunode-
ficiency virus, measuring the exact
amount of virus present in CSF
(“viral load”) by quantitative PCR
testing provides valuable prognostic
and therapeutic information. There
are few studies of the utility of quan-
titative PCR tests in HSV encephali-
tis.24-27 It was suggested in 1 study that
patients with higher HSV viral loads
(> 100 copies/mL of CSF) have poor-
er outcomes than those with low
copy numbers.25 However, a study in
children found no correlation
between viral load and outcome.24 In
the study by Domingues and col-
leagues,25 patients with higher copy
numbers were symptomatic longer
VOL. 1 NO. 4 2004
Herpes Simplex Encephalitis
(6.6 ± 3 days vs 3.9 ± 3 days) and
were more likely to have reduced
consciousness (100% vs 43%) and
computed tomography (CT) scan
abnormalities (100% vs 14%) than
those with low copy numbers.
Patients with high copy numbers
also had a higher mortality rate
(63%) compared with those with low
copy numbers (11%). Viral loads do
not seem to differ significantly in
patients with HSV encephalitis due
to primary infection as compared
with reactivation.27
Real-Time PCR
Recently, real-time PCR has been
increasingly used to detect HSV
genome in CSF.28 The advantages of
this technique include reduced han-
dling and manipulation of specimens
with associated reduction in risk of
contamination, and enhanced speed
and ease of use compared with con-
ventional PCR techniques. Real-time
PCR also provides semiquantitative
information about the amount of
viral genome present in the sample
and can be easily configured with use
of appropriate primer sets to identify
the serotype of virus (HSV-1 or HSV-
2). Sensitivity has been reported to be
2000 to 5000 HSV genome equiva-
lents per milliliter of CSF for HSV-1
and 20,000 to 50,000 HSV genome
equivalents per milliliter for HSV-2.
These values were approximately 10-
fold greater than those obtained by
the same laboratory for standard
nested PCR. Other laboratories19,20,22
using conventional PCR techniques
generally report detection levels of 10
to 200 HSV-1 genome copies per mil-
liliter, suggesting that real-time PCR
might be less sensitive than conven-
tional PCR in detecting HSV genome
in CSF.
REVIEWS IN NEUROLOGICAL DISEASES 173
Herpes Simplex Encephalitis continued
CSF Antibody Studies
HSV infections of the CNS are often
associated with increased intrathecal
synthesis of HSV antibodies. In one
study of 53 patients with HSV
encephalitis,9 86% of those who had
virus isolated or antigen detected at
either biopsy or autopsy also had evi-
dence of intrathecal synthesis of HSV
antibody. This percentage dropped to
63% in the subgroup of patients with
No EEG pattern is specific for HSV encephalitis.
positive immunocytochemistry but
no virus isolation.9 CSF HSV anti-
body titers generally increase over
the first week of illness, peaking 2 or
more weeks after onset.29 For this rea-
son, studies of HSV-specific intrathe-
cal antibody responses are generally
insensitive for early diagnosis of HSV
encephalitis and are of limited utility
and are rarely used in this setting.
Both the specificity and sensitivity of
intrathecal antibody tests are consid-
erably less than those of CSF PCR,
and as a result use of these tests is
generally of limited diagnostic value
except under special circumstances.
In the Scandinavian study cited
above,9 24% of encephalitis patients
with negative HSV biopsy results had
evidence of intrathecal synthesis of
HSV antibody—a potential 24%
false-positive rate. As discussed earli-
er, the prevalence of positive HSV
CSF PCR tests declines sharply after
the first week of illness, and less than
20% of specimens obtained after 2 or
more weeks are typically PCR posi-
tive. In this setting, when the only
CSF specimens available are from late
in the course of illness, intrathecal
antibody studies might complement
PCR testing in establishing a diagno-
sis. The specificity of intrathecal anti-
body testing can be enhanced by
obtaining paired CSF and serum sam-
ples, correcting the CSF/serum HSV
174 VOL. 1 NO. 4 2004 REVIEWS IN NEUROLOGICAL DISEASES
antibody ratio with the CSF/serum
albumin ratio (a measure of
blood–brain barrier integrity), and by
performing parallel studies measur-
ing antibodies against another virus.
The demonstration of an increased
CSF/serum HSV antibody ratio sug-
gests that there is intrathecal synthe-
sis of HSV antibody. Under certain
circumstances there might be a gen-
eralized increase in intrathecal syn-
thesis of antibodies against a variety
of viral antigens (eg, in some patients
with multiple sclerosis). Showing
that increased intrathecal antibody
synthesis is limited to HSV-specific
antibodies suggests that HSV was the
cause of disease.
CSF Culture
CSF culture is of extremely low sensi-
tivity for diagnosis of HSV encephali-
tis. Positive cultures have been
reported in less than 5% of cases.30
Electroencephalogram
Electroencephalogram (EEG) abnor-
malities occur in approximately 75%
In one report, 2 of 5 patients were found to have chronic progressive MRI
changes on studies obtained 6 months after hospital discharge, despite
clinical improvement.
of patients with either biopsy- or PCR-
proven HSV encephalitis.31 Common
abnormalities include generalized
slowing with frontotemporal predom-
inance, focal arrhythmic delta activi-
ty, periodic lateralized epileptiform
discharges, and temporal sharp or
spike activity. No EEG pattern is spe-
cific for HSV encephalitis, although
the appearance of abnormalities sug-
gestive of focal dysfunction in the
temporal and/or inferior frontal lobes
in a patient with suspected viral
encephalitis should always raise the
possibility of HSV infection.
Neuroimaging
Virtually all patients with suspected
encephalitis will have neuroimaging
studies done. CT scans are abnormal
in more than 60% of either biopsy-
or PCR-proven cases of HSV
encephalitis.8,13,15,17 However, CT is of
limited utility because abnormalities
typically develop late and are non-
specific. Common findings include
hypodensity in the temporal and
orbital frontal areas often associated
with mass effect and heterogenous
enhancement after contrast admin-
istration. Small areas of hemorrhage
might appear in affected areas and
on rare occasions even frank
hematomas. Magnetic resonance
imaging (MRI) is more sensitive and
specific than CT, and abnormalities
appear earlier. MRI is the neuroimag-
ing procedure of choice in patients
with suspected HSV encephalitis.
More than 90% of PCR-proven HSV
encephalitis cases have abnormal
MRI findings, with increased T2 and
decreased T1 signal in the temporal
lobes.13,15 Associated lesions in the
frontal lobes occur in more than
one third of cases. In adults, lesions
in parietal or occipital lobes are
extremely unusual and occur in less
than 10% of cases.15,17 Extratemporal
lesions are more common in
infants and children (see below).
Enhancement frequently occurs in
T1-weighted images after adminis-
tration of gadolinium. The sensitivi-
ty of MR is enhanced by the use
of specialized imaging techniques,

including fluid-attenuated inversion
recovery (FLAIR) and diffusion-
weighted imaging (DWI) (Figures 1
and 2). The heavily T2-weighted
FLAIR images with long echo times
diminish the intensity of CSF signal,
reduce volume averaging between
CSF and brain parenchyma, and
allow for better visualization of cere-
bral gray matter.32-35 DWI reflects
molecular motion of water within
tissues and might reveal areas of
abnormally increased signal reflect-
ing restricted water diffusion in areas
of cytotoxic or vasogenic edema and
tissue injury that are not seen on
other imaging modalities.36-39 The
corresponding apparent diffusion
Deaths among patients surviving acute infection continue to keep
mortality measured at 1-year postinfection at approximately 28%.
coefficient values are usually
decreased in studies obtained in the
acute phase of illness, when cytoxic
edema predominates. Long-term
neuroimaging studies in patients
surviving HSV encephalitis are limit-
ed. In one report, 2 of 5 patients were
found to have chronic progressive
MRI changes on studies obtained 6
months after hospital discharge,
despite clinical improvement.40
It is important to recognize that the
MR appearance of HSV encephalitis
in young children and infants might
differ significantly from that seen in
adults.41 Neonates with HSV
encephalitis may have prominent
abnormalities in periventricular
white matter. Both infants and
young children may have lesions
that resemble infarcts and that can
occur outside the frontotemporal
area and in the absence of fron-
totemporal lesions (eg, in parietal or
occipital lobes or cerebellum)—fea-
tures that would be almost unheard
of in adults. In a recent study,5 only
Herpes Simplex Encephalitis
60% of infants and children with
HSV encephalitis showed character-
istic temporal lobe lesions, with the
remaining 40% having involvement
of extratemporal areas.
Treatment, Prognosis, and
Sequelae
Data from studies performed before
the advent of effective antiviral
therapy for HSV encephalitis sug-
gest that the mortality in untreated
HSV encephalitis was approximately
70%, with less than 3% of untreated
Figure 1. Fluid-attenuated inversion recovery coronal
individuals returning to normal MRI image from a 61-year-old man with PCR-proven
function. The first drug shown to be HSV encephalitis taken on the fourth day after onset
of neurologic symptoms. There is increased signal in
effective in treatment was vidara- the right temporal lobe. Note the asymmetry between
bine, which reduced mortality to the abnormal right temporal lobe (left side of figure)
and the relatively normal appearing left temporal
lobe (right side of figure). MRI, magnetic resonance
imaging; PCR, polymerase chain reaction; HSV, her-
pes simplex virus.
prognostic factors have been identi-
fied that influence morbidity and
mortality associated with HSV
44% at 6 months postinfection.
encephalitis. In the CASG trial that
Acyclovir was subsequently shown
demonstrated the efficacy of acy-
to be even more effective than
clovir,42 mortality and morbidity were
vidarabine and reduced mortality to
dramatically influenced by both the
19% at 6 months and 28% at 18
months postinfection.42 Essentially
identical results were obtained in a
Scandinavian study.9 More recent
studies, using PCR as the basis for
diagnosis, have typically reported
mortality rates of 6% to 15% at 6
months postinfection,13,17,25 although
late deaths among patients surviv-
ing acute infection continue to keep
mortality measured at 1-year postin-
fection at approximately 28%,17
nearly equivalent to that reported
earlier.42 Studies in children suggest
that mortality rates might be lower
than in adults (7%-8%).43 Figure 2. Diffusion weighted images from a 52-year-
old man with PCR-proven HSV encephalitis taken 2
Moderate or severe sequelae have
days after hospitalization. Note the abnormal increased
been reported in 32% to 56% of adult signal in the left anterior and medial temporal lobes
survivors9,42 and approximately 40% (A, B, right side of figures). Compare to standard T2-
weighted MR images taken at the same time, which
of children surviving HSV encephali- show only subtle and ill-defined areas of increased signal
tis.43 Common sequelae include cog- in the left medial temporal lobe (C, arrow) and in both
insula (D, arrows). PCR, polymerase chain reaction;
nitive deficits, aphasia, seizures, and HSV, herpes simplex virus; MR, magnetic resonance.
focal weakness. In adults, several Reprinted with permission from McCabe K et al.37
VOL. 1 NO. 4 2004 REVIEWS IN NEUROLOGICAL DISEASES 175
Herpes Simplex Encephalitis continued
age of the patients and by their level
of consciousness (as measured by the
GCS) at the time of institution of
treatment. No patient less than age
30 with a GCS score greater than 6
died, and approximately 60% recov-
ered with no or only minor sequelae.
By contrast, in those with a GCS score
of 6 or less, mortality exceeded 30%
and approximately 70% of survivors
Relapse after completion of a minimal 10-day course of acyclovir is
unusual in adults.
had moderate or severe disability.42 In
children, the GCS score was a predic-
tor of both mortality and morbidity,
with patients having a GCS score of
less than 6 dying, between 6 and 10
surviving with moderate sequelae,
and greater than 10 surviving with no
sequelae.43 Both the Acute Physiology
and Chronic Health Evaluation and
Simplified Acute Physiology Score
results have also been shown to cor-
relate with prognosis.17 Several studies
have suggested that time delay
between hospital admission and
institution of acyclovir therapy might
also influence prognosis. In general,
patients treated within 2 days of
admission do better than those treat-
ed later.17,44
Cognitive impairment, and partic-
ularly memory difficulties, remain
major sequelae of HSV encephalitis
and have been reported in up to 65%
of patients.45,46 In a study of neuropsy-
chologic outcome in 22 adult
patients, 6 (27%) were found to be
normal, 13 (59%) had mild impair-
ment, and 3 (14%) had moderate or
severe impairment.47 Findings can
include dense amnesia and severe
anterograde memory impairment.
The severity of amnesia correlates
with severity of damage to limbic
system structures, particularly the
hippocampus, with bilateral injury
176 VOL. 1 NO. 4 2004 REVIEWS IN NEUROLOGICAL DISEASES
typically resulting in more severe
deficits than unilateral impairment.45
Older individuals and those with
lower level of consciousness at start
of treatment tended to have more
severe cognitive deficits.47 Patients
with a delay of fewer than 5 days
between symptom onset and start of
acyclovir therapy did better than
those with longer delay. Cognitive
deficits typically improve after hospi-
tal discharge, and compared with the
level of impairment seen acutely,
recovery can be substantial.46
In initial studies with acyclovir, a
dose of 10 mg/kg every 8 hours given
for a total of 10 days was used.9,42
Although there have been no con-
trolled trials in which the efficacy of
longer treatment regimens was exam-
ined, it is now generally recommend-
ed that treatment be maintained for a
minimum of 10 to 14 days. It has also
been suggested that in immunocom-
promised patients or patients in
whom HSV encephalitis seems to be
the result of primary infection rather
than reactivation (ie, those who are
HSV seronegative at presentation)
treatment be continued for 21 days.48
A consensus report from Europe has
suggested that CSF PCR might be use-
ful for guiding duration of therapy.
This report suggested that patients
whose PCR result is negative after
completion of a standard course (10-
14 days) of intravenous acyclovir can
have treatment stopped. Patients
with a persistently positive PCR
should have a repeat cycle of treat-
ment and their PCR rechecked.49
There are currently no data support-
ing the role of additional oral antivi-
ral therapy after a standard course of
intravenous acyclovir, although in an
ongoing multicenter, randomized,
placebo-controlled, double-blind trial
(CASG 204), investigators are study-
ing the efficacy of treating patients
for an additional 90 days with oral
valacyclovir after completion of stan-
dard intravenous acyclovir. Although
there has been one case report
describing the successful use of oral
valacyclovir in the treatment of HSV
encephalitis, intravenous acyclovir
remains the only treatment of proven
efficacy. Recent studies suggest that a
new class of antiviral drugs that
inhibits the HSV helicase primase
might be more effective than current-
ly available nucleoside analogues in
inhibiting HSV replication in vitro50;
however, these agents have not yet
entered clinical trials.
Relapse after completion of a mini-
mal 10-day course of acyclovir is
unusual in adults. In one series of 53
patients treated for 10 days, there
were 2 relapses (4%), which occurred
8 and 14 days after completion of
treatment.9 In the CASG trial of
vidarabine versus acyclovir, no
relapses were seen in the 28 acyclovir-
treated patients who survived acute
illness.42 Relapses might be a more sig-
nificant problem in pediatric patients,
in whom rates as high as 26% have
been reported in some series.51
Relapses might either be the result of
postinfectious immune-mediated
processes (HSV CSF PCR negative), or
true viral recurrences (HSV CSF PCR
positive).52 Fortunately, the majority
of cases of true viral relapse respond
to a repeat course of acyclovir.51
In addition to specific antiviral
therapy, patients with HSV
encephalitis often need treatment
for associated problems, including
seizures and raised intracranial pres-
sure. In extreme cases, patients with
severe increases in intracranial pres-
sure who do not respond to conven-
tional therapy with steroids and
hyperosmotic agents might require
 Herpes Simplex Encephalitis

surgical decompression and/or
resection of necrotic areas of tempo-
ral lobe.53,54 Although steroids are
used by some physicians in routine
treatment of HSV encephalitis, there
are no controlled trials supporting
their efficacy. However, the mortali-
ty rates in a Scandinavian study of
HSV encephalitis,9 in which 75% of
patients received corticosteroids
(dose and duration not specified) in
addition to acyclovir, were identical
to those in a contemporaneous US
study of acyclovir alone,42 suggest-
ing that the addition of steroids did
not have a positive or negative
impact on mortality in acyclovir-
treated patients.
Dr. Tyler is supported by the Reuler-Lewin
Family Professorship of Neurology and
receives research grants from the Department
of Veterans Affairs (MERIT, REAP), NIH, and
Department of Defense.
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Main Points
• Encephalitis caused by herpes simplex virus (HSV) is a rare event, with an incidence of approximately 4 cases per million
in the United States; HSV encephalitis occurs at all seasons of the year and in adults affects both sexes equally.
• Patients with HSV encephalitis typically have a history of alteration of consciousness, fever, and headache; common
neurologic abnormalities at the time of presentation include personality change, aphasia, ataxia, hemiparesis, and cranial
nerve deficits.
• The basic cerebrospinal fluid (CSF) profile in HSV encephalitis is a lymphocytic pleocytosis, a normal or mildly elevated
protein level, and normal glucose levels; patients with a normal CSF cell count, a CSF polymorphonuclear pleocytosis,
or a depressed CSF glucose level only rarely have HSV encephalitis.
• CSF polymerase chain reaction (PCR) is the diagnostic procedure of choice in HSV encephalitis, with high sensitivity
and specificity; false-positive results seem to be rare when tests are performed in experienced laboratories with accepted
methods for avoiding inadvertent contamination of samples.
• Tests for HSV-specific intrathecal antibody response are generally insensitive for early diagnosis of HSV encephalitis,
and both the specificity and sensitivity of intrathecal antibody tests are considerably less than those of CSF PCR; thus
these tests are generally of limited diagnostic value.
• Magnetic resonance imaging (MRI) is the neuroimaging procedure of choice in patients with suspected HSV
encephalitis; more than 90% of PCR-proven HSV encephalitis cases have abnormal MRI findings, with increased T2
and decreased T1 signal in the temporal lobes.
• Treatment of HSV encephalitis with the antiviral acyclovir has been shown to reduce mortality to 19% at 6 months
and 28% at 18 months postinfection; it is now generally recommended that treatment be maintained for a minimum
of 10 to 14 days.
• Moderate or severe sequelae have been reported in 32% to 56% of adult survivors and approximately 40% of children
surviving HSV encephalitis; common sequelae include cognitive deficits, aphasia, seizures, and focal weakness.

VOL. 1 NO. 4 2004 REVIEWS IN NEUROLOGICAL DISEASES 177

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Copyright © MedReviews, LLC. Reprinted with permission of MedReviews, LLC.
Tyler KL. Update on Herpes Simplex Encephalits. Rev Neurol Dis. 2004.1;4:169-178.
Reviews in Neurological Diseases is a copyrighted publication of MedReviews, LLC. All rights reserved.
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