doi:10.1136/jnnp.2007.

129098
2007;7;288-305 Practical Neurology

Tom Solomon, Ian J Hart and Nicholas J Beeching

Viral encephalitis: a clinicians guide
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REVIEW
Pract Neurol 2007; 7: 288305
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
L69 3GA, UK; tsolomon@liv.ac.uk
Virions of herpes simplex virus within the neuron, from a patient who died of herpes simplex encephalitis. From
Oppenheimers Diagnostic Neuropathology, Third Edition, Hodder Arnold 2006
E
Margaret Esiri and Daniel Perl
288 Practical Neurology
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The management of patients with suspected viral encephalitis has been
revolutionised in recent years with improved imaging and viral diagnostics,
better antiviral and immunomodulatory therapies, and enhanced neuro-
intensive care. Despite this, disasters in patient management are sadly not
uncommon. While some patients are attacked with all known antimicrobials
with little thought to investigation of the cause of their illness, for others
there are prolonged and inappropriate delays before treatment is started.
Although viral encephalitis is relatively rare, patients with suspected central
nervous system (CNS) infections, who might have viral encephalitis, are not. In
addition, the increasing number of immunocompromised patients who may
have viral CNS infections, plus the spread of encephalitis caused by
arthropod-borne viruses, present new challenges to clinicians. This article
discusses the Liverpool approach to the investigation and treatment of adults
with suspected viral encephalitis, and introduces the Liverpool algorithm for
investigation and treatment of immunocompetent adults with suspected viral
encephalitis (available at www.liv.ac.uk/braininfections).
T
here can be few things more frightening
than seeing an adult or child who was
perfectly fit and well, progress from a
flu-like illness to confusion, coma and
death within a few days, despite the best
treatment efforts. Even when treatment is
successful and patients survive apparently
intact, in many cases the family say that the
person they took home with them is not the
same as the one they brought to hospital, with
changes in personality, irritability, and poor
short-term memory. The management of
patients with suspected encephalitis has been
revolutionised in recent years with improved
imaging and viral diagnostics, better antiviral
and immunomodulatory therapies, and
enhanced neurointensive care settings. Despite
this, disasters in patient management are sadly
not uncommon. Although viral encephalitis is
relatively rare, patients with suspected central
nervous system (CNS) infections, who might
have viral encephalitis, are not. In addition, the
increasing number of immunocompromised
patients, who may have viral CNS infections,
plus the spread of encephalitis caused by
arthropod-borne viruses, present new chal-
lenges to clinicians. This review aims to provide
a rational approach to the investigation and
treatment of a patient with suspected viral
encephalitis.
WHAT IS ENCEPHALITIS?
Encephalitis means inflammation of the brain
parenchyma, and comes from the Greek
enkephalon, brain. Encephalitis can be caused
directly by a range of viruses, the herpes
viruses and some arboviruses being especially
important (table 1). Other microorganisms
can also cause encephalitis, particularly
protozoa such as Toxoplasma gondii, and
bacteria such as Listeria monocytogenes and
Mycobacterium tuberculosis (table 2). For
viruses such as HIV that infect the brain but
without causing inflammation, the term
encephalitis is not usually used.
Encephalitis can also occur as an immune-
mediated phenomenonfor example, acute
disseminated encephalomyelitis (ADEM,
which follows infections or vaccinations),
paraneoplastic limbic encephalitis, and vol-
tage gated potassium channel limbic ence-
phalitis.
1
Strictly speaking, encephalitis is a patho-
logical diagnosis that should only be made if
there is tissue confirmation, either at autopsy
or on brain biopsy. However, in practice most
patients are diagnosed with encephalitis if
they have the appropriate clinical presenta-
tion (febrile illness, severe headache reduced
consciousness (see below)) and surrogate
markers of brain inflammation, such as
inflammatory cells in the cerebrospinal fluid
(CSF), or inflammation shown on imaging,
especially if an appropriate organism is
detected. Encephalitis must be distinguished
from encephalopathy, the clinical syndrome
of reduced consciousness, which can be
caused by viral encephalitis, other infectious
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diseases, metabolic disorders, drugs and
alcohol. Metabolic and toxic causes of
encephalopathy can usually be distinguished
from viral encephalitis by the lack of any
acute febrile illness, more gradual onset, lack
of a CSF pleocytosis and absence of focal
changes on brain MRI.
2
Some of the organisms that cause ence-
phalitis often also cause an associated
meningeal reaction (meningitis), spinal cord
inflammation (myelitis), or nerve root invol-
vement (radiculitis); these terms are some-
times used in various combinations to reflect
whichever part of the neuraxis is affectedfor
example. meningoencephalitis, encephalo-
myelitis, meningoencephalomyelitis, myelora-
diculitis, meningoencephaloradiculitis. The
term limbic encephalitis refers to encepha-
litis of the temporal lobes (and often of other
limbic structures), while rhombencephalitis
means hindbrain, or brainstem encephalitis.
PATHOGENESIS
Depending on the virus, the pathogenesis
consists of a mixture of direct viral cyto-
pathology (that is, viral destruction of cells)
and/or a para- or post-infectious inflamma-
tory or immune-mediated response (fig 1). For
most viruses, the brain parenchyma and
neuronal cells are primarily infected, but for
some the blood vessels can be attacked giving
a strong vasculitic component. Demyelination
following infection can also contribute.
Herpes simplex virus (HSV) for example,
primarily targets the brain parenchyma in
the temporal lobes, sometimes with frontal or
parietal involvement. Mumps virus can cause
an acute viral encephalitis, or a delayed
immune mediated encephalitis. Measles virus
causes a post-infectious encephalitis, which
can sometimes have a severe haemorrhagic
component (acute haemorrhagic leukoence-
phalitis). With influenza A virus, diffuse
cerebral oedema is a major component in
the pathogenesis, while for varicella zoster
virus (VZV), vasculitis is a major pathogenic
process.
How and when the virus crosses the blood
brain barrier is a key issue in the pathogenesis
of any viral encephalitis.
For example, primary infection with HSV
type 1 (HSV-1) occurs in the oral mucosa, and
may cause herpes labialis (vesicles and ulcers
around the mouth) or be asymptomatic
(serological studies show that up to 90% of
healthy adults have been infected with HSV-
1). Following primary infection the virus
travels centripetally along the trigeminal
nerve to give latent infection in the trigeminal
ganglion, in most if not all those infected.
About 30% of infected people have clinically
apparent herpes labialis, but even asympto-
matic individuals have episodes or viral
shedding. About 70% of cases of HSV-1
encephalitis already have antibody present,
indicating that reactivation of virus must be
the most common mechanism;
3
however, it is
not clear whether this is due to reactivation
of virus in the trigeminal ganglion, or virus
that had already established latency in the
brain itself.
4
Why HSV sometimes reactivates
is not known. In contrast to adults, in younger
TABLE 1 Causes of acute viral encephalitis (modified from Solomon and
Whitley
58
)
Sporadic causes of viral encephalitis (not geographically restricted) listed by
group
l
Herpes viruses
Herpes simplex virus types 1 & 2, varicella zoster virus, Epstein-Barr
virus, cytomegalovirus, human herpes virus types 6 & 7
l
Enteroviruses
Coxsackie viruses, echoviruses, enteroviruses 70 & 71, parechovirus,
poliovirus
l
Paramyxoviruses
Measles virus, mumps virus,
l
Others (rarer causes)
Influenza viruses, adenovirus, parvovirus, lymphocytic choreomeningitis
virus, rubella virus
Geographically restricted causes of encephalitismostly arthropod-borne*
l
The Americas
West Nile, La Cross, St Louis, Rocio, Powassan encephalitis,
Venezuelan, eastern & western equine encephalitis, Colorado tick
fever virus, dengue, rabies
l
Europe/Middle East
Tick-borne encephalitis, West Nile, Tosana, rabies, (dengue virus,
louping ill virus)
l
Africa
West Nile, (Rift Valley fever virus, Crimean-Congo haemorrhagic fever,
dengue, chikungunya), rabies
l
Asia
Japanese encephalitis, West Nile, dengue, Murray Valley encephalitis,
rabies, (chikungunya virus, Nipah)
l
Australasia
Murray Valley encephalitis, Japanese encephalitis (kunjin, dengue)
Rarer or suspected arboviral causes are shown in brackets.
*All viruses are arthropod-borne, except for rabies and Nipah.
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patients, particularly children, HSV-1 ence-
phalitis occurs during primary infection.
HSV type 2 (HSV-2) is usually transmitted
via the genital mucosa, causing genital herpes
in adults. In the USA approximately 20% of
individuals are sero-positive for HSV-2. The
neurological syndromes it causes include
meningitis, especially recurrent meningitis,
encephalitis, particularly in neonates, and
lumbosacral radiculitis. Most cases of recur-
rent meningitis that were previously called
Mollarets meningitis are now thought to be
due to HSV-2, although some feel the term
Mollarets should still be reserved for those
TABLE 2 Diseases that may mimic viral meningoencephalitis (modified from
Solomon and Whiteley
58
)
Central nervous system infections Para/post-infectious causes
Bacteria Guillain-Barre syndrome*
Bacterial meninigitis Viral illnesses with febrile convulsions
Tuberculosis Shigella
Brain abscess
Typhoid fever
Parameningeal infection
Lyme disease
Systemic viral illnesses with febrile convulsions
Systemic viral illnesses associated with swollen
fontanelle
Syphilis Non-infectious diseases
Relapsing fever Vascular
Leptospirosis Vasculitis
Mycoplasma pneumoniae
Listeriosis
Brucellosis
Systemic lupus erythematosus
Subarachnoid and subdural haemorrhage
Ischaemic stroke
Subacute bacterial endocarditis Behcets disease
Whipples disease Neoplastic
Nocardia Primary brain tumour
Actinomycosis
Fungi
Candidiasis
Cryptococcus
Metastases
Paraneoplastic limbic encephalitis
Metabolic
Hepatic encephalopathy
Renal encephalopathy
Coccidiomycosis Hypoglycaemia
Histoplasmosis Reyes syndrome
North American blastomycosis Toxic encephalopathy (alcohol, drugs)
Other
Parasites Drug reactions
Cerebral malaria Epilepsy
Toxoplasmosis Hysteria
Cysticercosis Voltage gated K channel limbic encephalitis
Trypanosomiasis
Echinococcus
Trichinosis
Amoebiasis
Rickettsiae
Rocky Mountain spotted fever
Typhus
Q fever
Erlichiosis (anaplasma)
Cat-scratch fever
*Guillain-Barre syndrome and acute disseminated encephalomyelitis may follow viral or
bacterial infections or vaccinations.
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with recurrent meningitis in whom the cause
is still not known. Neonates can also be
infected with HSV-2 during delivery to cause
neonatal herpes, a disseminated infection
often with CNS involvement.
The other major route by which viruses
enter the nervous system is during a viraemia
and subsequent spread across the blood brain
barrier. This occurs with enteroviruses such as
poliovirus and arboviruses such as West Nile
virus.
EPIDEMIOLOGY OF VIRAL
ENCEPHALITIS
Changing epidemiology
While HSV-1 encephalitis occurs with
dependable regularity across the globe, there
have been notable changes in the epidemiol-
ogy of other viral causes:
N Cytomegalovirus (CMV) and Epstein-Barr
virus (EBV), and to some extent human
herpes virus (HHV)-6, are being seen more
often because they occur in patients
immunocompromised by HIV, transplant
or cancer chemotherapy.
N Arboviruses such as West Nile virus and
Japanese encephalitis virus are spreading
to new areas.
5
West Nile virus has caused
outbreaks in the Americas and southern
Europe, and there is evidence suggesting
the virus has reached the UK,
6
although it
has not yet caused human disease there.
The contribution of climate change to the
spread of these viruses is not clear. Other
viruses that have caused large unex-
pected outbreaks in Asia and are spread-
ing include enterovirus 71, and Nipah
virus. Enterovirus 71 has caused massive
outbreaks of hand foot and mouth
disease in Asia in recent years, which is
often associated with aseptic meningitis,
encephalitis or myelitis.
7
Nipah virus is a
morbillivirus (in the same family as
measles) that was recognised for the first
time in 1998 when it caused encephalitis
in humans in Malaysia.
8
This virus has
also caused disease in Bangladesh and
appears to be spreading.
N Encephalitis caused by vaccine preventa-
ble viruses such as measles and mumps is
less common in industrialised nations;
however, in the UK reduced vaccine
uptake in recent years has been asso-
ciated with a resurgence of these viruses.
9
Incidence of viral encephalitis
It is difficult to determine the incidence of
encephalitis because the various studies have
used different case definitions and viral
diagnostic capabilities. However, most studies
report an annual incidence of 510 per
100 000,
10, 11
highest in the young and elderly.
Higher incidences are found in areas with
arthropod-borne viruses. A lower annual
incidence of 1.5 per 100 000 has been
reported in England, based on hospitalisation
data,
12
although this was probably an under-
estimate. HSV encephalitis is the most
commonly diagnosed viral encephalitis in
industrialised nations, with an annual inci-
dence of 1 in 250 000 to 500 000.
13
Most HSV
encephalitis is due to HSV-1, but about 10%
are HSV-2. The latter typically occurs in
immunocompromised individuals, and neo-
nates, in whom it causes a disseminated
infection.
WHEN SHOULD ENCEPHALITIS
BE SUSPECTED?
The classical presentation of viral encephalitis
is generally as an acute flu-like prodrome,
developing into an illness with high fever,
severe headache, nausea, vomiting and
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.)
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altered consciousness, often associated with
seizures and focal neurological signs (fig 2).
Eighty five (91%) of 93 adults with HSV-1
encephalitis in one recent study were febrile
on admission.
14
Disorientation (76%), speech
disturbances (59%) and behavioural changes
(41%) were the most common features, and
one third of patients had seizures.
14
Alterations in higher mental function include
lethargy, drowsiness, confusion, disorienta-
tion and coma. With the advent of CSF PCR
more subtle presentations of HSV encephalitis
have been recognised;
15
low grade pyrexia
rather than a high fever, speech disturbances
(dysphasia and aphasia), and behavioural
changes which can mistaken for psychiatric
Figure 2
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illness, or the consequences of drugs or
alcohol, occasionally with tragic consequences.
Seizures can sometimes be the initial presenting
feature of a patient with encephalitis. Any adult
with a seizure in the context of a febrile illness,
or a seizure from which they do not recover,
must be investigated for possible CNS infection.
There are several reasons why one may not
think of encephalitis, particularly a failure to
appreciate the importance of altered con-
sciousness in the context of a febrile illness,
or failure to investigate these symptoms
properly when they are recognised (table 3).
One of the commonest failings is delay in
performing a lumbar puncture in patients
with an acute confusional state, which has
been incorrectly attributed to a systemic
infection.
16
Although most viral encephalitis
presents acutely, subacute and chronic pre-
sentations can be caused by CMV, VZV and
HSV, especially in patients immunocompro-
mised as a result of HIV, or immunosuppres-
sive drugs
15
(table 4).
IMPORTANT FEATURES IN THE
HISTORY
As well as being crucial in determining who
needs investigation for encephalitis, the
history can provide useful clues to aetiology.
Never accept that the history is not avail-
able for a confused patient; track down a
relative or neighbour on the phone.
Comments from relatives that a patient does
not seem right, should not be ignored, even
if the Glasgow Coma Score is 15; remember
this is a very crude tool that was devised for
assessing patients with head injuries.
Ask about recent rashes such as measles.
Even if there is no such history in the patient,
ask whether others in the family or in the
community have been affected (these viruses
occasionally cause encephalitis without the
obvious stigmata). In children, a recent rash
may suggest chickenpox, parvovirus or HHV-6.
Parotitis, testicular pain or abdominal pain due
to pancreatitis may suggest mumps virus as the
causative organism. If the patient is conscious,
ask about any strange smells, which may be
olfactory hallucinations reflecting frontotem-
poral involvement in HSV-1 encephalitis.
A travel history is essential, as are vaccination
details. Travellers from Asia with fever and
reduced consciousness may be infected with
dengue or Japanese encephalitis viruses; they
may also have acquired meningoencephalitis
from eating snails carrying the rat lungworm
Angiostrongylus cantonensis. Cerebral malaria
should also be considered in returning travellers,
especially from Africa.
17
Ask if there has been any contact with
animals, or whether there are sick animals in
the neighbourhood. In the USA some out-
breaks of West Nile virus were heralded by
sick birds falling from the sky.
18
The history of
a dog bite in a rabies endemic area may be
important,
19
as may a bite or scratch from a
bat; in the UK and Europe, Daubentons
bats carry rabies-like viruses (European bat
TABLE 3 Why encephalitis may be missed
l
Wrongly attributing a patients fever and confusion to a urinary tract
infection (based on a urine dipstick) or a chest infection (based on a few
crackles in the chest) without strong evidence
l
Failure to realise that a patient has a febrile illness, just because they are
not febrile on admission
l
Ignoring a relatives complaint that a patient is not quite right, sleepy or
lethargic, just because the Glasgow coma score is 15 (the coma score is a
very crude tool)
l
Wrongly attributing clouding of consciousness to drugs or alcohol,
without good evidence to do so
l
Failure to properly investigate a patient with a fever and seizure,
following which they do not recover consciousness
l
Failure to do a lumbar puncture, even though there are no
contraindications
TABLE 4 Causes of subacute and chronic viral encephalitis
In immunocompromised patients (HIV, organ transplant recipients, cancer
patients, those on immunosuppressive therapy, including steroids)
l
Measles (inclusion body encephalitis)
l
Varicella zoster virus (causes a multifocal leukoencephalopathy)
l
Cytomegalovirus
l
Herpes simplex virus (especially HSV-2)
l
Human herpes virus 6
l
Enterovirus
l
JC/BK* virus (causes progressive multifocal leukoencephalopathy)
In immunocompetent patients
l
JC/BK* virus (causes progressive multifocal leukoencephalopathy)
l
Measles virus (subacute sclerosing panencephalitis, years after primary
infection)
l
Rubella virus (causes progressive rubella panencephalitis, very rare)
*JE and BK viruses are named after the initials of the patients from whom
they were first isolated.
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lyssaviruses).
20
Other risk factors are related to
occupation and recreational activities:
N leptospirosis can be acquired from rat
urine during fresh water activities
N lymphocytic choreomeningitis virus
(LCMV) is transmitted in rodent faeces;
humans are exposed when cleaning out
barns, etc
N hikers in the forests of Austria, Germany,
and Eastern Europe are at risk of tick-
borne encephalitis virus (TBEV)
N a related virus, Louping ill virus, causes
occasional encephalitis in sheep in the
Scottish Highlands, and very rarely in
humans
N hikers in the New Forest in the UK are at
risk of Lyme disease.
Ask about risk factors for HIV, including
previous blood transfusions, and high-risk
behaviours such as intravenous drug use, sex
between men, and multiple sexual partners,
especially with people from high-risk areas of
the world such as sub-Saharan Africa and
Thailand.
IMPORTANT EXAMINATION
FINDINGS
On examination the first priorities are to
check that the airway is protected, assess and
document the level of consciousness, using a
quantitative scale such as the Glasgow Coma
Scale (GCS), and treat any immediate com-
plications of infection such as generalised
seizures. For patients with mild behavioural
abnormalities or disorientation, document the
odd behaviour, and record the mini-mental
test score. The general medical examination
should include a search for other possible
explanations of the coma.
Look for a purpuric (meningococcal) rash
and other exanthema, bites and stigmata that
may suggest an aetiology; is there the rash of
shingles? Are there injection sites that might
indicate intravenous drug use? Look for
seborrhoeic dermatitis, oral candida or oral
hairy leukoplakia in the mouth, or Kaposis
sarcoma on the skin indicative of undiag-
nosed HIV infection. In patients with HIV look
for mouth ulcers or umbilicated skin papules
suggestive of disseminated histoplasmosis or
cryptococcosis. Look at the genitals for the
ulcers of HSV and chancres of syphilis.
Examine also the chest, ears and urine for
infection. However, beware ascribing reduced
consciousness to a urinary or chest infection,
especially in someone who is otherwise fit
and well. Such patients need a lumbar
puncture to rule out a CNS infection.
Look for seizures including subtle motor
seizures, and examine the side of the tongue
or inside cheek for bites indicating that a
seizure has occurred. Test for meningism, and
look for focal neurological signs, including
hemispheric signs that could indicate an
abscess, or flaccid paralysis suggestive of
spinal cord involvement. Tremors and abnor-
mal movements are seen in some forms of
encephalitis, particularly those that involve
the basal ganglia, such as West Nile virus and
other flaviviruses, or toxoplasmosis. An acute
febrile encephalopathy with lower cranial
neuropathies and myoclonus suggests a
rhomboencephalitis or basal meningoence-
phalitis, as seen with some enteroviruses, or
listeria (table 5). Deafness is quite common in
mumps and some rickettsial infections. Upper
limb weakness and fasciculation suggest a
cervical myelitis, for example in tick-borne
encephalitis. Encephalitis associated with
radiculitis is seen in CMV and EBV.
INITIAL INVESTIGATIONS
N A peripheral blood count may show a
leukocytosis or leukopenia. Atypical lym-
phocytes are seen in EBV infection, and
eosinophilia in eosinophilic meningitis.
TABLE 5 Brainstem encephalitis (rhombencephalitis): clues and causes
Suggestive clinical features
l
Lower cranial nerve involvement
l
Myoclonus
l
Autonomic dysfunction
l
Locked-in syndrome
l
MRI changes in the brainstem, with gadolinium enhancement of basal
meninges
Causesviral and other
l
Enteroviruses (especially EV71)
l
Flaviviruses, eg West Nile virus, Japanese encephalitis virus
l
Listeria
l
Tuberculosis
l
Brucella
l
Borrelia
l
Paraneoplastic syndromes
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N Hyponatraemia due to the syndrome of
inappropriate antidiuretic hormone
(SIADH) is common in encephalitis.
N A raised serum amylase is common in
mumps virus infection.
N If there has been a respiratory component
to the presentation check for cold agglu-
tinins, which occur in mycoplasma infec-
tion, and order appropriate serological
investigations for mycoplasma and chla-
mydia (atypical respiratory infections).
N Blood cultures should be taken as part of
the investigation of possible bacterial
causes, and PCR of the blood for
meningococcus considered.
N Bacterial antigen testing of CSF and urine
may be helpful.
N A chest x ray is essential to look for
pulmonary infiltrates in atypical pneu-
monia, for example in mycoplasma pneu-
monia, legionella or LCMV.
N HIV testing should also be considered,
especially if the cause of CNS infection is
uncertain. Our practice is to perform the
test in all patients with undiagnosed CNS
infection because if positive it makes
such a difference to the differential and
management.
THE LUMBAR PUNCTURE
CONTROVERSY
Few topics have led to as much confusion,
contradiction and controversy as the role of
lumbar punctures in patients with suspected
CNS infection.
21
A lumbar puncture is an
essential investigation because the initial CSF
findings (especially the cell count, differential
and glucose ratio) reveal firstly whether or
not there is infection, and secondly whether it
is likely to be bacterial or viral infection,
which thus informs the initial antimicrobial
therapy. Subsequent studies such as culture
and PCR confirm precisely what the organism
is, which allows the therapy to be tailored and
appropriate public health measures, including
disease notification, to be organised.
However, if patients have a space-occupying
lesion, marked brain swelling, or brain shift (for
example herniation across the midline, the
tentorium or the foramen magnum), then a
lumbar puncture may of course make things
worse. Raised intracranial pressure itself is not a
problemindeed patients with idiopathic intra-
cranial hypertension are treated by lumbar
punctures, and in most patients with CNS
infection the CSF opening pressure is raised to
some degree.
22, 23
The problem is the swelling or
shift which is sometimes associated with the
raised pressure, so the pressure is not the same
in all the CSF compartments. For this reason
patients should be assessed for clinical features
which might indicate a space-occupying lesion,
brain swelling or shift, and who should then
have computed tomography (CT) before lumbar
puncture (fig 3); focal neurological signs (for
example a hemiparesis), new onset seizures,
papilloedema and deep coma. CT is also
recommended for immunocompromised
patients, who may lack the clinical signs of an
inflammatory mass lesion.
24
Opinions vary as to
what level of deep coma necessitates a CT
scan before lumbar puncture. To some extent it
depends on how quickly imaging can be
organised. If a CT scan can be performed
promptly, so that it will not delay lumbar
puncture for more than an hour or two, then it
is reasonable to do this first. However, in a
patient who is only mildly confused with no
focal neurological signs, than a lumbar punc-
ture should be done straight away, without the
unnecessary delay of a CT.
24
If a CT is going to cause a delay of several
hours, then presumptive treatment for both
bacterial and/or viral pathogens should be
started. There are no hard and fast rules about
how long a delay is acceptable before treat-
ment is initiated. For bacterial meningitis a
delay of more than six hours between arrival in
hospital and initiation of antibiotic treatment
is associated with a worse outcome.
25
If
Figure 3
CT scan with contrast of a middle-aged
man with a one-week history of a flu-
like illness, severe headache and
increasing confusion, who had HSV
encephalitis confirmed by CSF PCR. (A)
A low density area in the left temporal
lobe, with swelling and some contrast
enhancement. (B) The same patient four
days later with more marked changes
(Photos: T Solomon).
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patients have a purpuric rash suggestive of
meningococcal septicaemia, or are deteriorat-
ing rapidly, antibiotics should be started
immediately.
26
In HSV-1 encephalitis, a bad
outcome is associated with a delay of two days
or more between hospitalisation and starting
treatment.
14
In practice, HSV encephalitis is
rare, and most suspected cases turn out to
have something different.
27
While one would
not advocate unnecessary delays, together
these data suggest that for patients with
suspected encephalitis the emphasis should be
on investigating promptly where possible
before starting treatment. For most patients
with no contraindication, it should be possible
to perform a lumbar puncture, and get the
result back within a few hours to then guide
the management. If there are delays or a
patient appears to be deteriorating, then
presumptive treatment with aciclovir is appro-
priate, at least while investigations proceed.
For patients with suspected bacterial
meningitis or viral encephalitis, even if
antimicrobial treatment has been started, it
is still essential to perform a lumbar puncture,
because this informs the diagnosis and guides
subsequent management.
28
Giving blind anti-
bacterial and antiviral treatment to all
patients with suspected CNS infection, and
then not investigating with lumbar puncture
because it makes no difference to the
management is unacceptable practice and
should be discouraged.
21
This approach risks
missing other diagnoses that may require
alternative treatments,
29
and increases the
risk of adverse effects of the unwarranted
and unnecessary drugs. For HSV-1 encepha-
litis, PCR of the CSF remains positive in about
80% of patients even a week after starting
antiviral therapy.
13
CEREBROSPINAL FLUID
FINDINGS
In encephalitis, the CSF opening pressure is
often slightly raised, and there is usually a
mild to moderate CSF pleocytosis of 51000
TABLE 6 Typical cerebrospinal fluid findings in central nervous system infections
Viral meningo-
encephalitis
Acute bacterial
meningitis
Tuberculous
meningitis Fungal Normal
Opening pressure Normal/high High High Highvery high 1020 cm*
Colour Gin clear Cloudy Cloudy/yellow Clear/cloudy Clear
Cells/mm
3
Slightly increased Highvery high Slightly increased Normalhigh
51000 10050000 25500 01000 ,5{
Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes Lymphocytes
CSF/plasma glucose
ratio
Normal Low Lowvery low
(,30%)
Normallow 66%{
Protein (g/l) Normalhigh High Highvery high Normalhigh ,0.45{
0.51 .1 1.05.0 0.25.0
*Normal CSF opening pressure is generally ,20 cm for adults, ,10 cm for children below age 8, but may be as high as 25 cm
(Whiteley et al, Neurology 2006;67:16901).
{A bloody tap will falsely elevate the CSF white cell count and protein. To correct for a bloody tap, subtract 1 white cell for
every 700 red blood cells/mm
3
in the CSF, and 0.1 g/dl of protein for every 1000 red blood cells.
{A normal glucose ratio is usually quoted as 66%, though only values below 50% are likely to be significant.
Some important exceptions:
N In viral CNS infections, an early lumbar puncture may give predominantly neutrophils, or there may be no cells in early or late
lumbar punctures.
N In patients with acute bacterial meningitis that has been partially pre-treated with antibiotics (or patients ,1 year old) the
CSF cell count may not be very high and may be mostly lymphocytic.
N Tuberculous meningitis may have predominant CSF polymorphs early on.
N Listeria can give a similar CSF picture to tuberculous meningitis, but the history is shorter.
N CSF findings in bacterial abscesses range from near normal to purulent, depending on location of the abscess, and whether
there is associated meningitis, or rupture.
N A cryptococcal antigen test and India ink stain should be performed on the CSF of all patients in whom cryptococcus is
possible.
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cells/mm
3
, with predominant lymphocytes
(table 6). However, early in the infection the
CSF white cell count may be normal, or
neutrophils may predominate, as they do in
viral meningitis.
30
The CSF red cell count is
usually normal, or slightly raised, but it may
be markedly raised in HSV-1 encephalitis,
which can be haemorrhagic, or in acute
necrotising haemorrhagic leukoencephalitis.
The glucose ratio is usually normal in viral
CNS infections, though it may be a little
reducedfor example, in mumps or enter-
ovirus infection.
31
The CSF protein is often
slightly raised, between 0.5 and 1.0 g/l.
DIAGNOSTIC VIROLOGY
The definitive diagnosis of a viral CNS infection
is based on demonstrating the virus in the CNS,
either fromculture or PCR of brain tissue or CSF,
or by demonstrating a specific antibody
response in the CSF. Less strong evidence
comes from detecting virus elsewhere in the
body of a patient with a CNS syndrome (for
example, from throat, rectal or vesicle swabs), or
showing an antibody response to the virus in
the serum(the organism is then presumed to be
responsible for the clinical presentation,
although there is always the possibility that it
is a coincidental infection).
PCR of CSF
The diagnosis of viral encephalitis used to rely
on brain biopsy,
27
but many important viruses
can now be detected with PCR.
32, 33
PCR tests
for HSV have overall sensitivity and specificity
.95%, but may be negative in the first few
days of the illness, or after about 10 days.
34, 35
Initial investigation of immunocompetent
patients with encephalitis should include
PCR for both HSV and VZV because these
are potentially treatable with aciclovir (see
below) (table 7). Enterovirus PCR is often
included at this stage, because it is a relatively
common cause of viral meningitis, especially
in the summer/autumn. In immunocompro-
mised patients, EBV and CMV PCR should also
be performed, and HHV-6 and HHV-7 con-
sidered. Measles and mumps should be looked
for if there is a suggestive clinical indication,
although they can occasionally cause ence-
phalitis in patients with no other features.
Other viruses to consider, especially in children,
include adenoviruses, HHV-6, respiratory
syncitial virus (RSV), and influenza virus A and
B; rotaviruses and parvovirus B19 are also
occasionally associated with CNS disease,
especially in children.
36, 37
PCR can also be used
to detect Chlamydia pneumoniae in the CSF.
CSF viral culture is now rarely performed,
although it has the potential advantage over
PCR of being able to detect any virus, whereas
PCR only detects the viruses being targeted by
the panel of PCR assays used. Newer more
sensitive PCR methods, such as real-time and
quantitative PCR have improved the clinical
utility of this test, and are becoming available
for herpes viruses and enteroviruses.
38
TABLE 7 Staged approach to microbiological investigation of viral
encephalitis
CSF PCR
l
All patients
HSV-1, HSV-2, VZV
Enterovirus, parechovirus,
l
If indicated
EBV/CMV (especially if immunocompromised)
HHV 6,7 (especially if immunocompromised, or children)
Adenovirus, influenza A & B, rotavirus (children)
Measles, mumps (if clinically indicated)
Parvovirus B19
Chlamydia (if clinically indicated)
l
Special circumstance
Rabies, West Nile virus, tick-borne encephalitis virus (if appropriate
exposure)
Antibody testing (where indicatedsee text) *
l
Viruses: IgM and IgG in CSF and serum (acute and convalescent), for
antibodies against HSV 1 & 2, VZV, CMV, HHV6, HHV7, enteroviruses, RSV,
parvovirus B19, adenovirus, influenza A & B;*
l
Antibody detection in the serum identifies infection (past or recent
depending on the type of antibodies) but does not necessarily mean this
virus has caused the CNS disease
l
If associated with atypical pneumonia, test serum for
Mycoplasma serology and cold agglutinins
Chlamydia serology
Ancillary investigations (these establish systemic infection, but not
necessarily the cause of the CNS disease)
l
Throat swab, nasopharyngeal aspirate, rectal swab
PCR/culture of throat swab, rectal swab for enteroviruses
PCR of throat swab for mycoplasma, chlamydia
PCR/antigen detection of nasopharyngeal aspirate for respiratory
viruses, adenovirus, influenza virus (especially children)
l
Vesicle electron microscopy, PCR and culture
Patients with herpetic lesions (for HSV, VZV)
Children with hand foot and mouth disease (for enteroviruses)
l
Brain biopsy
For culture, electron microscopy, PCR and immunohistochemistry
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One problem is that the high sensitivity of
some of the recent PCR assays for herpes
viruses, such as EBV and CMV, can make
positive results difficult to interpret. Most of
the adult population have been infected with
these viruses and carry them in their
lymphocytes. Therefore, there is debate about
whether detection of the viruses by PCR of
the CSF represents true pathogenic infection,
rather than just the presence of infected
lymphocytes.
39
Where there is uncertainty
about the significance of a result, the amount
of virus in the CSF compared with the blood
(determined by quantitative PCR) usually
helps resolve it. For example, in a patient
with HIV, a CSF CMV PCR titre that is higher
than that in the serum is usually significant.
Antibody testing
Antibody testing continues to play an impor-
tant role in the diagnosis of many viral CNS
infections. Traditional techniques required the
demonstration of a fourfold rise in antibody
between acute and convalescent serum
samples collected 24 weeks apart, and thus
are not helpful in making an early diagnosis.
And in practice convalescent samples are
often forgotten.
Newer enzyme immunoassays can detect
immunoglobulin (Ig)-M and IgG antibodies in
the serum and CSF against most of the
important viruses, as well as Mycoplasma
pneumoniae. Specific anti-viral IgM is often
produced within a few days of a primary
infection and can be measured by IgM
enzyme immunoassays. The detection of virus
specific IgM antibodies in the CSF in higher
titres than in serum indicates local production
of antibody in the CNS in response to
infection. IgM does not normally cross the
blood-brain barrier because of its size.
However, if there is inflammation the barrier
is leaky to IgM, and other immunoglobulins.
In this circumstance, the ratio of CSF to
serum for the specific IgM antibody can be
compared to the ratio for immunoglobulin as
a whole, to decide if this is local production
rather than leak across an inflamed blood-
brain barrier. IgM detection is especially
useful for flavivirus infections, but less so
for herpes virus infections, which are often
reactivations. In contrast to IgM, IgG is
normally found in the CSF at a ratio of
1/200th of the serum concentration; hence in a
primary acute CNS infection, IgG rises later than
IgM both in CSF and serum. In reactivations and
secondary infections, IgG tends to rise earlier
and to a greater extent than IgM.
The detection of oligoclonal bands is
sometimes a useful non-specific indicator
that a patient has an inflammatory process in
the CNS, rather than a non-inflammatory
cause of encephalopathy. Immunoblotting of
the bands against viral proteins has been
used, but mostly as a research tool to help
determine the cause of the inflammationfor
example, HSV-1 or HSV-2.
29, 34
However, the
detection of intrathecal anti-HSV antibody
has a sensitivity of 50% by 10 days after
clinical presentation, and is thus only con-
sidered useful for retrospective diagnosis.
Our practice, at least for diagnosing HSV
infections, is to ask for PCR on CSF acutely. If
this is negative, but suspicion remains high,
PCR of the CSF is repeated after a few days
(as indicated above PCR can sometimes be
negative if the sample is taken early in the
illness). If two CSFs are negative for HSV by
PCR then it is unlikely that the patient has
HSV infection. If for logistic reasons CSFs
were not taken at this time, or were not sent
for HSV PCR, then testing a late CSF (for
example, later than 10 days of hospitalisa-
tion) for the production of intrathecal anti-
bodies against HSV, by IgM, IgG or antibody-
mediated immunoblotting of oligoclonal
bands, can be useful.
INVESTIGATION OF OTHER
SAMPLES
Other investigations include:
N PCR and/or culture of throat and rectal
swabs for enteroviruses, mumps virus or
measles virus.
N PCR or antigen detection and culture of
nasopharyngeal aspirates for respiratory
viruses such as adenoviruses, RSV, para-
influenza viruses or influenza viruses.
N Urine culture for mumps virus.
N Chlamydia pneumoniae and Mycoplasma
pneumonia can also be detected in throat
swabs using PCR.
N Vesicles, for example in hand foot and
mouth disease, should be aspirated for
culture or PCR, for enteroviruses.
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N VZV or HSV can be detected in herpetic
rashes by cell culture, antigen detection
by immunofluorescence or PCR. Electron
microscopy of vesicle fluids may also
demonstrate herpes viruses.
In general, a virus detected in sterile sites,
such as vesicles, is more likely to be causal
than a virus from non-sterile sites. For
example, enteroviruses detected in vesicle
swabs indicate that they are temporally
associated with the acute infection, whereas
shedding from the rectum occurs for several
weeks after an acute infection.
40
The list of all possible investigations for
causes of viral CNS disease is clearly very long.
Our practice is to do the initial CSF PCR for HSV
and VZV as soon as the samples are received,
because of their importance for early manage-
ment. PCR for enteroviruses and parechoviruses
is also usually done at this stage. In addition,
patients that are immunocompromised are
investigated with CMV and EBV PCR. Further
investigations are guided by the clinical picture,
especially the patients immune competence
and the initial CSF findings. The opinion of a
clinical virologist in assessing such patients is
invaluable.
With the advent of PCR, brain biopsy of
patients with suspected encephalitis has
become less common. Previously it was
considered the gold standard for diagnosis
of HSV-1 encephalitis. It may still have a role
in undiagnosed patients that are deteriorat-
ing. In one study approximately half of
patients with suspected HSV-1 encephalitis
who had a brain biopsy had an alternative
diagnosis, of which 40% were treatable.
27
IMAGING AND EEG
As described above, in patients with ence-
phalopathy and fever, a CT scan is generally
done before the lumbar puncture if there are
clinical features of brain shift or a space-
occupying lesion. In HSV the scan may be
normal initially, or there may be subtle
swelling of the frontotemporal region with
loss of the normal gyral pattern (fig 1).
Subsequently there is hypodensity, or there
may be high signal change if haemorrhagic
transformation occurs. MRI is generally more
sensitive, showing high signal intensities in
the brain areas affected (fig 4), but even MRI
scans can look normal if performed very
early.
41
Diffusion-weighted MRI may be
especially useful for demonstrating early
changes.
42
An EEG usually shows non-specific diffuse
high amplitude slow waves of encephalo-
pathy, but can be useful to look for subtle
epileptic seizures. Periodic lateralised epilepti-
form discharges were once thought to be
diagnostic of HSV encephalitis, but have since
been seen in other conditions.
43
MANAGEMENT
There are three elements to the management
of patients with encephalitis:
N the first is to consider whether there is
any antiviral or immunomodulatory treat-
ment to halt or reverse the disease
process;
N the second is to control the immediate
complications of the encephalitis;
Figure 4
T2-weighted MRI brain scan showing
right temporal lobe hyperintensity in a
patient with herpes encephalitis
(Photos: T Solomon).
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N the third is to prevent some of the
secondary and late complications.
Standard intensive care for patients with
encephalitis include oxygen via a mask,
paying attention to fluid and hydration,
nasogastric or parenteral feeding, and treat-
ing the complications of infection such as
pneumonia. Patients with a reduced coma
score or impaired gag reflex, should be
assessed by an intensive care unit outreach
team, with a view to early transfer.
When to start aciclovir
In most immunocompetent patients in devel-
oped countries aciclovir should be given as
soon as there is a strong suspicion of viral
encephalitis, based on the clinical presenta-
tion and initial CSF and/or imaging findings. If
performing these investigations is likely to
lead to long delays and the clinical suspicion
is strong, then treatment should be started at
once, for both viral encephalitis and possible
bacterial meningitis. The situation may be
different in developing countries, where the
cost of aciclovir may be an issue, and other
causes of CNS infection are more common.
For example in much of Asia large outbreaks
of Japanese encephalitis occur; in parts of
Asia and sub-Saharan Africa, HIV-associated
CNS infections and cerebral malaria are
common.
Aciclovir is a nucleoside analogue that is
highly effective against HSV and some of the
other herpes viruses, such as VZV and herpes
B virus. Intravenous administration of aciclo-
vir at 10 mg/kg three times daily reduces the
risk of a fatal outcome from approximately
70% to less than 20%.
44, 45
Renal function
should be monitored closely and adequate
hydration maintained, because of the rare risk
of renal failure. Other rare adverse effects
include local inflammation at the site of the
intravenous canula, hepatitis, and bone
marrow failure.
When to stop aciclovir
Although the original aciclovir trials were for
10 days treatment, most physicians continue
for 14 or 21 days, especially in patients with
proven herpes encephalitis, because of the
risk of relapse after 10 days.
46
Some advocate
repeating the CSF examination at the end of
TABLE 8 Treatment options to consider in encephalitis (modified from Boos and Esiri)
52
Acute viral encephalitis
Herpes simplex virus 1 and 2 Aciclovir
Varicella zoster virus (incluing cerebellitis) Aciclovir plus corticosteroids
Human herpes virus-6 Ganciclovir, foscarnet
Rabies Ketamine*, amantidine, ribavirin
Subacute/chronic encephalitis
In the immunocompromised
Varicella-zoster virus Aciclovir
Cytomegalovirus Ganciclovir, foscarnet, cidofovir
Measles inclusion body encephalitis Ribavirin
Enterovirus Pleconaril, specific immunoglobulin
Progressive multifocal leukoencephalophy in HIV patients Highly active antiretroviral therapy (HAART), cidofovir
In the immunocompetent
Subacute sclerosing panencephalitis Interferon alpha (intraventricular), ribavirin inosiplex
Progressive multifocal leukoencephalopathy Consider cytosine arabinoside (ARA-C)
Progressive rubella panencephalitis Plasma exchange
Rasmussens encephalitis IVIg
Immune-mediated encephalitis
Acute disseminated encephalomyelitis{ Coricoteroids/IVIg/plasma exchange
Paraneoplastic Treatment of underlying tumour, consider immunosuppression
Voltage gated K channel limbic encephalitis IVIg/plasma exchange plus corticosteroids
*Considered experimental.
{Acute disseminated encephalomyelitis presents acutely; the others typically present with a subacute encephalitis.
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treatment and continuing with aciclovir if
HSV is still detected by PCR. This approach is
being evaluated by the American
Collaborative Antiviral Study Group, which is
assessing the prognostic value of quantitative
PCR detection of viral DNA in the CSF at the
end of three weeks treatment and prolonged
high dose oral valaciclovir for three months.
If the initial CSF PCR is negative for HSV
but other features are consistent with HSV
encephalitis, then the aciclovir should not be
stopped, because false negative PCR results
can occur, particularly early on.
47, 48
In such
patients the lumbar puncture should be
repeated because it may be positive 2448 h
later and, even if negative again, treatment
continued for at least 10 days. However, if a
definitive alternative diagnosis has become
apparent, or it seems very unlikely that the
patient has viral encephalitis, then it is
reasonable to stop the acyclovir earlier.
A role for oral valaciclovir?
In circumstances where ongoing intravenous
treatment is proving difficult (for example, in
a child who is now fully conscious), oral
valaciclovir may be reasonable,
49
although we
would only consider this after the first
10 days of intravenous treatment.
Valaciclovir is the valene ester of aciclovir,
which is converted to aciclovir after absorp-
tion, and has good oral bioavailability.
Although oral valaciclovir may have a role,
oral aciclovir should not be used in HSV
encephalitis, because the levels achieved in
the CSF are inadequate.
Ancillary treatments
In patients with brain swelling, corticosteroids
and mannitol are often used to control raised
intracranial pressure. A recent trial suggests
steroids may be beneficial even in patients
without marked swelling.
50
Their role in HSV
encephalitis merits further study.
51
In patients
with severe brain swelling, decompressive
hemicraniectomy is sometimes performed.
Antibiotic treatment with a cephalosporin is
often also given, especially if the initial CSF
findings could be consistent with bacterial
disease (for algorithm see http://www.
britishinfectionsociety.org). If listeria is sus-
pected, ampicillin and gentamicin, or high
dose cotrimoxazole, should be given.
Other antiviral and
immunomodulatory treatments
There are few large, randomised controlled trials
assessing the efficacy of antiviral treatments in
viral CNS infections, other than for HSV
encephalitis. Nonetheless treatments for other
conditions are given based on an understanding
of the pathogenesis, in vitro data, anecdotal
reports, or small clinical series, although these
sometimes provide conflicting data (table 8).
If the clinical presentation and imaging
findings suggest a post- or para-infectious
encephalitis such as ADEM, acute haemorrhagic
leukoencephalitis or diffuse encephalopathy
associated with systemic viral infection, immu-
nosuppressive drugs are given.
52
High dose
corticosteroid treatment is often the initial
treatment, followed by intravenous immuno-
globulin, plasma exchange, or further treatment
with steroids, depending on the response to the
initial treatment.
In some circumstances, both antiviral and
immunosuppressive drugs are given. For
example, in HSV encephalitis corticosteroids
are sometimes used in addition to aciclovir as
described above. In VZV encephalitis cortico-
steroids are used alongside aciclovir because
of the strong vasculitic component of the
disease.
Severe CMV and HHV-6 infections are
treated with ganciclovir, foscarnet or cidofo-
vir, severe adenovirus infections have been
treated with cidofovir or ribavirin and
Pleconaril has been used for severe enter-
ovirus infections, particularly in the immuno-
compromised, although its overall role
remains unclear.
53, 54
Interferon alpha has
been used in West Nile virus and other
flavivirus infections, but a randomised con-
trolled trial in Japanese encephalitis showed it
was not effective.
55
Management of seizures, raised
intracranial pressure and other
complications
Seizures are common in encephalitis, parti-
cularly in children. In adults, seizures can be
useful in distinguishing acute viral encepha-
litis from para-infectious inflammatory ence-
phalopathies. There may be obvious
generalised tonic clonic seizures or subtle
motor seizures, which may manifest as
twitching of a digit, or around the mouth or
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eyes, particularly in children. An EEG should
be performed if there is any uncertainty.
Uncontrolled seizures lead to raised intra-
cranial pressure, increased metabolic activity,
acidosis and vasodilatation, which in turn
leads to further raised pressure. The resulting
positive feedback cycle can ultimately pre-
cipitate brain shift and herniation. If seizures
are not easily controlled with phenytoin and
low doses of benzodiazepines, patients should
be intubated and ventilated mechanically, so
that higher doses of sedating anticonvulsive
drugs, including benzodiazepines and pheno-
barbital, can be used. Electroencephalographic
monitoring, with or without continuous
function and analysing monitoring (CFAM),
should be used to detect ongoing epileptic
activity.
Standard measures to control raised intra-
cranial pressure include nursing the patient at
30

head up, keeping the head straight to

ensure there is no obstruction to venous
return, and ventilating to maintain a low
arterial pCO
2
. Although there are no good
data for viral encephalitis, data from other
infectious encephalopathies suggest that
osmotic diuretics produce a short-term
reduction in pressure.
56
The role of anti-
inflammatory drugs in viral encephalitis is
uncertain.
51
To reduce the risk of deep venous
thrombosis and pulmonary embolism,
patients with reduced mobility should be
fitted with compression stockings, and once it
is clear that there is no major haemorrhagic
component to the encephalitis, they should
be given prophylactic heparin. Bed sores are a
risk in immobile patients, and appropriate
mattresses and regular turning are needed.
Patients with encephalitis are also at risk of
secondary pneumonia, due to aspiration, and
urinary tract infections. Passive and active
limb movements will reduce the risk of limb
contractures, which can occur in patients
with limb weakness, and splints and braces
may be needed to facilitate mobilisation.
Management in the recovery
period
Ideally, a full neuropsychological assessment
should be organised at hospital discharge, or
soon after. This should include cognitive
function, intelligence, memory and speech
assessment, because these help determine the
extent of any damage, and the help that
might be needed. Regular out-patient assess-
ment following encephalitis is especially
important in children. Behavioural and psy-
chiatric disturbances are common and may
include depression or disinhibition.
Antidepressants and mild night-time seda-
tives may be necessary. Other disabilities in
the recovery period or afterwards include
seizures, post-encephalitic parkinsonism seen
after encephalitis lethargica, and encephalitis
caused by flaviviruses. The risk of seizures is
greatest in those who had seizures during the
acute period; in one study the cumulative risk
of seizures at 5 years was 10% for patients
with no acute seizures, which increased to
20% for those with acute seizures.
57
Memory difficulties can be particularly
prominent after HSV encephalitis. A range of
practical approaches can help to overcome
these difficulties such as the patient keeping
a notebook and diary, labelling items around
the house, and leaving messages as remin-
ders. More sophisticated aids being developed
include a neuropage system (http://www.
neuropage.nhs.uk), which sends pager remin-
der messages throughout the day, and a
camera, worn around the neck, which auto-
matically takes pictures throughout the day
as a reminder of what the patient has been
doing (SenseCam). Excellent help and advice
can be obtained from patient support groups,
such as the encephalitis society (http://www.
encephalitis.info)
PROGNOSTIC FACTORS AND
OUTCOME
Although treatment with aciclovir has
reduced the mortality of HSV, the morbidity
remains high.
13
Poor prognostic factors after
HSV encephalitis include age above 60,
PRACTICE POINTS
l
All patients with a febrile illness and altered behaviour or consciousness
should be investigated for a central nervous system (CNS) infection, unless
there is very clear evidence of another diagnosis.
l
Patients with a suspected CNS infection need a lumbar puncture as soon as
possible, unless there is an indication for a brain CT first.
l
Patients with a meningococcal rash and/or sepsis should receive immediate
antibiotics, but for most other patients investigation with lumbar puncture
should be possible before starting treatment.
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reduced coma score on admission,
44
especially
if (6,
45
and delays between hospitalisation
and starting aciclovir treatment (especially
delays of more than two days).
14, 16
Two thirds
of survivors have significant neuropsychiatric
sequelae, including memory impairment
(69%), personality and behavioural change
(45%), dysphasia (41%) and epilepsy in up to
25%.
16
This means that in addition to the high
hospitalisation costs estimated in the USA at
$500 million for 1983 alone, there are
considerable additional costs of long-term
care and support. If the personal tragedies
themselves were not impetus enough, this
major financial burden emphasises the need
for a rational approach to investigation and
treatment of this devastating condition.
ACKNOWLEDGEMENTS
We thank our clinical and laboratory colleagues
at the Walton Centre for Neurology and
Neurosurgery and the Royal Liverpool University
Hospital for help in developing the Algorithm for
the Early Management of Suspected Viral
Encephalitis in Adults, which is available from
http://www.liv.ac.uk/braininfections (under
Education). We are also grateful to members of
the Encephalitis Society for sharing with us their
experiences.
This article was reviewed by Neil Scolding,
Bristol, UK.
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