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Notes
Viral
encephalitis: a
clinicians guide
Tom Solomon, Ian J Hart, Nicholas J Beeching
T Solomon
Professor of Neurology and MRC
Senior Clinical Fellow, University of
Liverpool Divisions of Neurological
Science and Medical Microbiology,
and The Walton Centre for
Neurology and Neurosurgery,
Liverpool, UK
I J Hart
Consultant Clinical Microbiologist,
Division of Medical Microbiology
and Genitourinary Medicine, Royal
Liverpool University Hospital,
Liverpool, UK
N J Beeching
Senior Lecturer and Clinical Lead,
Tropical and Infectious Diseases
Unit, Royal Liverpool University
Hospital, Liverpool, UK
Correspondence to:
Professor T Solomon
University of Liverpool Divisions of
Neurological Science and Medical
Microbiology, 8th Floor Duncan
Building, Daulby Street, Liverpool Virions of herpes simplex virus within the neuron, from a patient who died of herpes simplex encephalitis. From
L69 3GA, UK; tsolomon@liv.ac.uk Oppenheimers Diagnostic Neuropathology, Third Edition, Hodder Arnold 2006 E Margaret Esiri and Daniel Perl
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here can be few things more frightening enkephalon, brain. Encephalitis can be caused
Rickettsiae
Rocky Mountain spotted fever
Typhus
Q fever
Erlichiosis (anaplasma)
Cat-scratch fever
Figure 1
Histopathological picture of the
temporal cortex of a man who died
from herpes simplex virus encephalitis.
(A) Intense perivascular inflammatory
infiltrate consisting of activated
microglia, macrophages and
lymphocytes (H&E staining, 620). (B)
High power view showing microglia
and dead neurons with nuclear
dissolution (karyolysis) and
hypereosinophilia within the cytoplasm
retaining the original pyramidal contour
(H&E 640). (Pictures courtesy of Dr
Daniel Crooks.)
with recurrent meningitis in whom the cause morbillivirus (in the same family as
is still not known. Neonates can also be measles) that was recognised for the first
infected with HSV-2 during delivery to cause time in 1998 when it caused encephalitis
neonatal herpes, a disseminated infection in humans in Malaysia.8 This virus has
also caused disease in Bangladesh and
often with CNS involvement.
appears to be spreading.
The other major route by which viruses
enter the nervous system is during a viraemia N Encephalitis caused by vaccine preventa-
ble viruses such as measles and mumps is
and subsequent spread across the blood brain
less common in industrialised nations;
barrier. This occurs with enteroviruses such as
however, in the UK reduced vaccine
poliovirus and arboviruses such as West Nile uptake in recent years has been asso-
virus. ciated with a resurgence of these viruses.9
Figure 2
altered consciousness, often associated with Alterations in higher mental function include
seizures and focal neurological signs (fig 2). lethargy, drowsiness, confusion, disorienta-
Eighty five (91%) of 93 adults with HSV-1 tion and coma. With the advent of CSF PCR
encephalitis in one recent study were febrile more subtle presentations of HSV encephalitis
on admission.14 Disorientation (76%), speech have been recognised;15 low grade pyrexia
disturbances (59%) and behavioural changes rather than a high fever, speech disturbances
(41%) were the most common features, and (dysphasia and aphasia), and behavioural
one third of patients had seizures.14 changes which can mistaken for psychiatric
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patients have a purpuric rash suggestive of antimicrobial treatment has been started, it
meningococcal septicaemia, or are deteriorat- is still essential to perform a lumbar puncture,
ing rapidly, antibiotics should be started because this informs the diagnosis and guides
immediately.26 In HSV-1 encephalitis, a bad subsequent management.28 Giving blind anti-
outcome is associated with a delay of two days bacterial and antiviral treatment to all
or more between hospitalisation and starting patients with suspected CNS infection, and
treatment.14 In practice, HSV encephalitis is then not investigating with lumbar puncture
rare, and most suspected cases turn out to because it makes no difference to the
have something different.27 While one would management is unacceptable practice and
not advocate unnecessary delays, together should be discouraged.21 This approach risks
these data suggest that for patients with missing other diagnoses that may require
suspected encephalitis the emphasis should be alternative treatments,29 and increases the
on investigating promptly where possible risk of adverse effects of the unwarranted
before starting treatment. For most patients and unnecessary drugs. For HSV-1 encepha-
with no contraindication, it should be possible litis, PCR of the CSF remains positive in about
to perform a lumbar puncture, and get the 80% of patients even a week after starting
result back within a few hours to then guide antiviral therapy.13
the management. If there are delays or a
patient appears to be deteriorating, then CEREBROSPINAL FLUID
presumptive treatment with aciclovir is appro- FINDINGS
priate, at least while investigations proceed. In encephalitis, the CSF opening pressure is
For patients with suspected bacterial often slightly raised, and there is usually a
meningitis or viral encephalitis, even if mild to moderate CSF pleocytosis of 51000
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DIAGNOSTIC VIROLOGY
TABLE 7 Staged approach to microbiological investigation of viral The definitive diagnosis of a viral CNS infection
encephalitis is based on demonstrating the virus in the CNS,
either from culture or PCR of brain tissue or CSF,
CSF PCR or by demonstrating a specific antibody
l All patients
response in the CSF. Less strong evidence
HSV-1, HSV-2, VZV
comes from detecting virus elsewhere in the
Enterovirus, parechovirus,
l If indicated body of a patient with a CNS syndrome (for
EBV/CMV (especially if immunocompromised) example, from throat, rectal or vesicle swabs), or
HHV 6,7 (especially if immunocompromised, or children) showing an antibody response to the virus in
Adenovirus, influenza A & B, rotavirus (children) the serum (the organism is then presumed to be
Measles, mumps (if clinically indicated) responsible for the clinical presentation,
Parvovirus B19 although there is always the possibility that it
Chlamydia (if clinically indicated) is a coincidental infection).
l Special circumstance
Rabies, West Nile virus, tick-borne encephalitis virus (if appropriate
exposure) PCR of CSF
Antibody testing (where indicatedsee text) *
The diagnosis of viral encephalitis used to rely
l Viruses: IgM and IgG in CSF and serum (acute and convalescent), for
antibodies against HSV 1 & 2, VZV, CMV, HHV6, HHV7, enteroviruses, RSV, on brain biopsy,27 but many important viruses
parvovirus B19, adenovirus, influenza A & B;* can now be detected with PCR.32, 33 PCR tests
l Antibody detection in the serum identifies infection (past or recent for HSV have overall sensitivity and specificity
depending on the type of antibodies) but does not necessarily mean this .95%, but may be negative in the first few
virus has caused the CNS disease days of the illness, or after about 10 days.34, 35
l If associated with atypical pneumonia, test serum for Initial investigation of immunocompetent
Mycoplasma serology and cold agglutinins patients with encephalitis should include
Chlamydia serology PCR for both HSV and VZV because these
Ancillary investigations (these establish systemic infection, but not
are potentially treatable with aciclovir (see
necessarily the cause of the CNS disease)
below) (table 7). Enterovirus PCR is often
l Throat swab, nasopharyngeal aspirate, rectal swab
PCR/culture of throat swab, rectal swab for enteroviruses included at this stage, because it is a relatively
PCR of throat swab for mycoplasma, chlamydia common cause of viral meningitis, especially
PCR/antigen detection of nasopharyngeal aspirate for respiratory in the summer/autumn. In immunocompro-
viruses, adenovirus, influenza virus (especially children) mised patients, EBV and CMV PCR should also
l Vesicle electron microscopy, PCR and culture be performed, and HHV-6 and HHV-7 con-
Patients with herpetic lesions (for HSV, VZV) sidered. Measles and mumps should be looked
Children with hand foot and mouth disease (for enteroviruses) for if there is a suggestive clinical indication,
l Brain biopsy although they can occasionally cause ence-
For culture, electron microscopy, PCR and immunohistochemistry
phalitis in patients with no other features.
Other viruses to consider, especially in children,
include adenoviruses, HHV-6, respiratory
cells/mm3, with predominant lymphocytes syncitial virus (RSV), and influenza virus A and
(table 6). However, early in the infection the B; rotaviruses and parvovirus B19 are also
CSF white cell count may be normal, or occasionally associated with CNS disease,
neutrophils may predominate, as they do in especially in children.36, 37 PCR can also be used
viral meningitis.30 The CSF red cell count is to detect Chlamydia pneumoniae in the CSF.
usually normal, or slightly raised, but it may CSF viral culture is now rarely performed,
be markedly raised in HSV-1 encephalitis, although it has the potential advantage over
which can be haemorrhagic, or in acute PCR of being able to detect any virus, whereas
necrotising haemorrhagic leukoencephalitis. PCR only detects the viruses being targeted by
The glucose ratio is usually normal in viral the panel of PCR assays used. Newer more
CNS infections, though it may be a little sensitive PCR methods, such as real-time and
reducedfor example, in mumps or enter- quantitative PCR have improved the clinical
ovirus infection.31 The CSF protein is often utility of this test, and are becoming available
slightly raised, between 0.5 and 1.0 g/l. for herpes viruses and enteroviruses.38
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One problem is that the high sensitivity of 1/200th of the serum concentration; hence in a
some of the recent PCR assays for herpes primary acute CNS infection, IgG rises later than
viruses, such as EBV and CMV, can make IgM both in CSF and serum. In reactivations and
positive results difficult to interpret. Most of secondary infections, IgG tends to rise earlier
the adult population have been infected with and to a greater extent than IgM.
these viruses and carry them in their The detection of oligoclonal bands is
lymphocytes. Therefore, there is debate about sometimes a useful non-specific indicator
whether detection of the viruses by PCR of that a patient has an inflammatory process in
the CSF represents true pathogenic infection, the CNS, rather than a non-inflammatory
rather than just the presence of infected cause of encephalopathy. Immunoblotting of
lymphocytes.39 Where there is uncertainty the bands against viral proteins has been
about the significance of a result, the amount used, but mostly as a research tool to help
of virus in the CSF compared with the blood determine the cause of the inflammationfor
(determined by quantitative PCR) usually example, HSV-1 or HSV-2.29, 34 However, the
helps resolve it. For example, in a patient detection of intrathecal anti-HSV antibody
with HIV, a CSF CMV PCR titre that is higher has a sensitivity of 50% by 10 days after
than that in the serum is usually significant. clinical presentation, and is thus only con-
sidered useful for retrospective diagnosis.
Our practice, at least for diagnosing HSV
Antibody testing infections, is to ask for PCR on CSF acutely. If
Antibody testing continues to play an impor- this is negative, but suspicion remains high,
tant role in the diagnosis of many viral CNS PCR of the CSF is repeated after a few days
infections. Traditional techniques required the (as indicated above PCR can sometimes be
demonstration of a fourfold rise in antibody negative if the sample is taken early in the
between acute and convalescent serum illness). If two CSFs are negative for HSV by
samples collected 24 weeks apart, and thus PCR then it is unlikely that the patient has
are not helpful in making an early diagnosis. HSV infection. If for logistic reasons CSFs
And in practice convalescent samples are were not taken at this time, or were not sent
often forgotten. for HSV PCR, then testing a late CSF (for
Newer enzyme immunoassays can detect example, later than 10 days of hospitalisa-
immunoglobulin (Ig)-M and IgG antibodies in tion) for the production of intrathecal anti-
the serum and CSF against most of the bodies against HSV, by IgM, IgG or antibody-
important viruses, as well as Mycoplasma mediated immunoblotting of oligoclonal
pneumoniae. Specific anti-viral IgM is often bands, can be useful.
produced within a few days of a primary
infection and can be measured by IgM
enzyme immunoassays. The detection of virus INVESTIGATION OF OTHER
specific IgM antibodies in the CSF in higher SAMPLES
titres than in serum indicates local production Other investigations include:
of antibody in the CNS in response to
infection. IgM does not normally cross the
N PCR and/or culture of throat and rectal
swabs for enteroviruses, mumps virus or
blood-brain barrier because of its size. measles virus.
However, if there is inflammation the barrier
is leaky to IgM, and other immunoglobulins. N PCR or antigen detection and culture of
nasopharyngeal aspirates for respiratory
In this circumstance, the ratio of CSF to
viruses such as adenoviruses, RSV, para-
serum for the specific IgM antibody can be influenza viruses or influenza viruses.
compared to the ratio for immunoglobulin as
a whole, to decide if this is local production N Urine culture for mumps virus.
rather than leak across an inflamed blood- N Chlamydia pneumoniae and Mycoplasma
brain barrier. IgM detection is especially pneumonia can also be detected in throat
useful for flavivirus infections, but less so swabs using PCR.
for herpes virus infections, which are often N Vesicles, for example in hand foot and
reactivations. In contrast to IgM, IgG is mouth disease, should be aspirated for
normally found in the CSF at a ratio of culture or PCR, for enteroviruses.
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TABLE 8 Treatment options to consider in encephalitis (modified from Boos and Esiri)52
*Considered experimental.
{Acute disseminated encephalomyelitis presents acutely; the others typically present with a subacute encephalitis.
N the third is to prevent some of the For example in much of Asia large outbreaks
secondary and late complications. of Japanese encephalitis occur; in parts of
Standard intensive care for patients with Asia and sub-Saharan Africa, HIV-associated
encephalitis include oxygen via a mask, CNS infections and cerebral malaria are
paying attention to fluid and hydration, common.
nasogastric or parenteral feeding, and treat- Aciclovir is a nucleoside analogue that is
ing the complications of infection such as highly effective against HSV and some of the
pneumonia. Patients with a reduced coma other herpes viruses, such as VZV and herpes
score or impaired gag reflex, should be B virus. Intravenous administration of aciclo-
assessed by an intensive care unit outreach vir at 10 mg/kg three times daily reduces the
team, with a view to early transfer. risk of a fatal outcome from approximately
70% to less than 20%.44, 45 Renal function
When to start aciclovir should be monitored closely and adequate
In most immunocompetent patients in devel- hydration maintained, because of the rare risk
oped countries aciclovir should be given as of renal failure. Other rare adverse effects
soon as there is a strong suspicion of viral include local inflammation at the site of the
encephalitis, based on the clinical presenta- intravenous canula, hepatitis, and bone
tion and initial CSF and/or imaging findings. If marrow failure.
performing these investigations is likely to
lead to long delays and the clinical suspicion When to stop aciclovir
is strong, then treatment should be started at Although the original aciclovir trials were for
once, for both viral encephalitis and possible 10 days treatment, most physicians continue
bacterial meningitis. The situation may be for 14 or 21 days, especially in patients with
different in developing countries, where the proven herpes encephalitis, because of the
cost of aciclovir may be an issue, and other risk of relapse after 10 days.46 Some advocate
causes of CNS infection are more common. repeating the CSF examination at the end of
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reduced coma score on admission,44 especially 9. Bloom S, Wharton M. Mumps outbreak among
young adults in UK. BMJ 2005;331:E3634.
if (6,45 and delays between hospitalisation 10. Rantala H, Uhari M. Occurrence of childhood
and starting aciclovir treatment (especially encephalitis: a population-based study. Pediatr
delays of more than two days).14, 16 Two thirds Infect Dis J 1989;8:42630.
of survivors have significant neuropsychiatric 11. Koskiniemi M, Korppi M, Mustonen K, et al.
Epidemiology of encephalitis in children. A
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(69%), personality and behavioural change 1997;156:5415.
(45%), dysphasia (41%) and epilepsy in up to 12. Davison KL, Crowcroft NS, Ramsay ME, et al. Viral
encephalitis in England, 19891998: what did we
25%.16 This means that in addition to the high miss? Emerg Infect Dis 2003;9:23440.
hospitalisation costs estimated in the USA at 13. Whitley RJ. Herpes simplex encephalitis:
$500 million for 1983 alone, there are adolescents and adults. Antiviral Res
considerable additional costs of long-term 2006;71:1418.
14. Raschilas F, Wolff M, Delatour F, et al. Outcome of
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ACKNOWLEDGEMENTS 16. McGrath N, Anderson NE, Croxson MC, et al. Herpes
simplex encephalitis treated with acyclovir:
We thank our clinical and laboratory colleagues diagnosis and long term outcome. J Neurol
at the Walton Centre for Neurology and Neurosurg Psychiatry 1997;63:3216.
Neurosurgery and the Royal Liverpool University 17. Whitty CJ, Lalloo D, Ustianowski A. Malaria: an
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the Early Management of Suspected Viral 18. Julian KG, Eidson M, Kipp AM, et al. Early season
Encephalitis in Adults, which is available from crow mortality as a sentinel for West Nile virus
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Vector Borne Zoonotic Dis 2002;2:14555.
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the Encephalitis Society for sharing with us their rabies after a two week holiday in India. BMJ
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20. Nathwani D, McIntyre PG, White K, et al. Fatal
This article was reviewed by Neil Scolding,
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2003;37:598601.
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