viral encephalitis, 2007
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doi:10.1136/jnnp.2007.1290982007;7;288-305Practical Neurology
Tom Solomon, Ian J Hart and Nicholas J Beeching
Viral encephalitis: a clinicians guide
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REVIEWPract Neurol 2007; 7: 288305
Viralencephalitis: aclinicians guideTom Solomon, Ian J Hart, Nicholas J Beeching
T SolomonProfessor of Neurology and MRC
Senior Clinical Fellow, University ofLiverpool Divisions of Neurological
Science and Medical Microbiology,
and The Walton Centre for
Neurology and Neurosurgery,
Liverpool, UK
I J HartConsultant Clinical Microbiologist,
Division of Medical Microbiology
and Genitourinary Medicine, Royal
Liverpool University Hospital,
Liverpool, UK
N J BeechingSenior 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, LiverpoolL69 3GA, UK; [email protected] Virions of herpes simplex virus within the neuron, from a patient who died of herpes simplex encephalitis. FromOppenheimers Diagnostic Neuropathology, Third Edition, Hodder Arnold 2006 EMargaret Esiri and Daniel Perl
288 Practical Neurology
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The management of patients with suspected viral encephalitis has beenrevolutionised 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 notuncommon. While some patients are attacked with all known antimicrobialswith 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 suspectedcentralnervous system (CNS) infections, whomighthave viral encephalitis, are not. Inaddition, the increasing number of immunocompromised patients who mayhave viral CNS infections, plus the spread of encephalitis caused byarthropod-borne viruses, present new challenges to clinicians. This articlediscusses the Liverpool approach to the investigation and treatment of adultswith suspected viral encephalitis, and introduces the Liverpool algorithm forinvestigation and treatment of immunocompetent adults with suspected viralencephalitis (available at www.liv.ac.uk/braininfections).
There 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
eath within a few days, despite the best
reatment efforts. Even when treatment is
uccessful and patients survive apparently
ntact, in many cases the family say that the
erson they took home with them is not the
ame as the one they brought to hospital, with
hanges in personality, irritability, and poorhort-term memory. The management of
atients with suspected encephalitis has been
evolutionised in recent years with improved
maging and viral diagnostics, better antiviral
nd immunomodulatory therapies, and
nhanced neurointensive care settings. Despite
his, disasters in patient management are sadly
ot uncommon. Although viral encephalitis is
elatively rare, patients with suspected central
ervous system (CNS) infections, who might
ave viral encephalitis, are not. In addition, the
ncreasing number of immunocompromised
atients, who may have viral CNS infections,
lus the spread of encephalitis caused by
rthropod-borne viruses, present new chal-
enges to clinicians. This review aims to provide
rational approach to the investigation and
reatment of a patient with suspected viral
ncephalitis.
WHAT IS ENCEPHALITIS?ncephalitis means inflammation of the brain
arenchyma, 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 monocytogenesand
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 mostpatients 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.
PATHOGENESISDepending 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). Fo
most viruses, the brain parenchyma and
neuronal cells are primarily infected, but fo
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 causean 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 zoste
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 trigemina
nerve to give latent infection in the trigemina
ganglion, in most if not all those infectedAbout 30% of infected people have clinically
apparent herpes labialis, but even asympto-
matic individuals have episodes or vira
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 younge
TABLE 1 Causes of acute viral encephalitis (modified from Solomon andWhitley58)
Sporadic causes of viral encephalitis (not geographically restricted) listed bygroupl Herpes viruses
Herpes simplex virus types 1 & 2, varicella zoster virus, Epstein-Barrvirus, cytomegalovirus, human herpes virus types 6 & 7
l Enteroviruses Coxsackie viruses, echoviruses, enteroviruses 70 & 71, parechovirus,
poliovirusl Paramyxoviruses
Measles virus, mumps virus,l Others (rarer causes)
Influenza viruses, adenovirus, parvovirus, lymphocytic choreomeningitisvirus, 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 tickfever 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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atients, particularly children, HSV-1 ence-
halitis occurs during primary infection.
HSV type 2 (HSV-2) is usually transmitted
ia the genital mucosa, causing genital herpes
n adults. In the USA approximately 20% of
ndividuals are sero-positive for HSV-2. The
eurological 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 fromSolomon and Whiteley58)
Central nervous system infections Para/post-infectious causesBacteria Guillain-Barresyndrome*
Bacterial meninigitis Viral illnesses with febrile convulsions
Tuberculosis ShigellaBrain abscessTyphoid feverParameningeal infectionLyme disease
Systemic viral illnesses with febrile convulsionsSystemic viral illnesses associated with swollenfontanelle
Syphilis Non-infectious diseasesRelapsing fever VascularLeptospirosis VasculitisMycoplasma pneumoniaeListeriosisBrucellosis
Systemic lupus erythematosusSubarachnoid and subdural haemorrhageIschaemic stroke
Subacute bacterial endocarditis Behcets disease
Whipples disease NeoplasticNocardia Primary brain tumourActinomycosis
FungiCandidiasisCryptococcus
MetastasesParaneoplastic limbic encephalitisMetabolicHepatic encephalopathyRenal encephalopathy
Coccidiomycosis HypoglycaemiaHistoplasmosis Reyes syndromeNorth American blastomycosis Toxic encephalopathy (alcohol, drugs)
OtherParasites Drug reactions
Cerebral malaria EpilepsyToxoplasmosis HysteriaCysticercosis Voltage gated K channel limbic encephalitisTrypanosomiasisEchinococcusTrichinosisAmoebiasis
RickettsiaeRocky Mountain spotted feverTyphusQ feverErlichiosis (anaplasma)
Cat-scratch fever
*Guillain-Barre syndrome and acute disseminated encephalomyelitis may follow viral orbacterial 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 VIRALENCEPHALITISChanging epidemiologyWhile HSV-1 encephalitis occurs with
dependable regularity across the globe, therehave been notable changes in the epidemiol-
ogy of other viral causes:
N Cytomegalovirus (CMV) and Epstein-Barrvirus (EBV), and to some extent humanherpes virus (HHV)-6, are being seen moreoften because they occur in patientsimmunocompromised by HIV, transplantor cancer chemotherapy.
N Arboviruses such as West Nile virus andJapanese encephalitis virus are spreadingto new areas.5 West Nile virus has caused
outbreaks in the Americas and southernEurope, and there is evidence suggestingthe virus has reached the UK,6 although ithas not yet caused human disease there.The contribution of climate change to thespread of these viruses is not clear. Otherviruses that have caused large unex-pected outbreaks in Asia and are spread-ing include enterovirus 71, and Nipahvirus. Enterovirus 71 has caused massiveoutbreaks of hand foot and mouthdisease 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 asmeasles) that was recognised for the firsttime in 1998 when it caused encephalitisin humans in Malaysia.8 This virus hasalso caused disease in Bangladesh andappears to be spreading.
N Encephalitis caused by vaccine preventa-ble viruses such as measles and mumps isless common in industrialised nationshowever, in the UK reduced vaccineuptake in recent years has been asso-ciated with a resurgence of these viruses.
Incidence of viral encephalitisIt is difficult to determine the incidence of
encephalitis because the various studies have
used different case definitions and vira
diagnostic capabilities. However, most studiesreport an annual incidence of 510 pe
100 000,10, 11 highest in the young and elderly
Higher incidences are found in areas with
arthropod-borne viruses. A lower annua
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 mos
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 ENCEPHALITISBE 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 microgliaand dead neurons with nuclear
dissolution (karyolysis) and
hypereosinophilia within the cytoplasm
retaining the original pyramidal contour
(H&E640). (Pictures courtesy of Dr
Daniel Crooks.)
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ltered consciousness, often associated with
eizures and focal neurological signs (fig 2).
ighty five (91%) of 93 adults with HSV-1
ncephalitis in one recent study were febrile
n admission.14 Disorientation (76%), speech
isturbances (59%) and behavioural changes
41%) were the most common features, and
ne 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 symptomsproperly 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 drugs15 (table 4).
IMPORTANT FEATURES IN THEHISTORYAs 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 doesnot 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 lungwormAngiostrongylus 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 ba
TABLE 3 Why encephalitis may be missed
l Wrongly attributing a patients fever and confusion to a urinary tractinfection (based on a urine dipstick) or a chest infection (based on a fewcrackles in the chest) without strong evidence
l Failure to realise that a patient has a febrile illness, just because they are
not febrile on admissionl 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 avery 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 nocontraindications
TABLE 4 Causes of subacute and chronic viral encephalitis
In immunocompromised patients (HIV, organ transplant recipients, cancerpatients, those on immunosuppressive therapy, including steroids)l Measles (inclusion body encephalitis)l
Varicella zoster virus (causes a multifocal leukoencephalopathy)l Cytomegalovirusl Herpes simplex virus (especially HSV-2)l Human herpes virus 6l Enterovirusl JC/BK* virus (causes progressive multifocal leukoencephalopathy)In immunocompetent patientsl 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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yssaviruses).20 Other risk factors are related to
ccupation and recreational activities:
leptospirosis can be acquired from raturine during fresh water activities
lymphocytic choreomeningitis virus(LCMV) is transmitted in rodent faeces;
humans are exposed when cleaning outbarns, etc
hikers in the forests of Austria, Germany,and Eastern Europe are at risk of tick-borne encephalitis virus (TBEV)
a related virus, Louping ill virus, causesoccasional encephalitis in sheep in theScottish Highlands, and very rarely inhumans
hikers in the New Forest in the UK are atrisk of Lyme disease.
Ask about risk factors for HIV, including
revious blood transfusions, and high-risk
ehaviours such as intravenous drug use, sex
etween men, and multiple sexual partners,
specially with people from high-risk areas of
he world such as sub-Saharan Africa and
hailand.
MPORTANT EXAMINATIONFINDINGSOn examination the first priorities are to
heck that the airway is protected, assess and
ocument the level of consciousness, using a
uantitative scale such as the Glasgow Coma
cale (GCS), and treat any immediate com-
lications of infection such as generalised
eizures. For patients with mild behavioural
bnormalities or disorientation, document the
dd behaviour, and record the mini-mental
est score. The general medical examination
hould include a search for other possible
xplanations of the coma.
Look for a purpuric (meningococcal) rash
nd other exanthema, bites and stigmata thatmay suggest an aetiology; is there the rash of
hingles? Are there injection sites that might
ndicate intravenous drug use? Look for
eborrhoeic dermatitis, oral candida or oral
airy leukoplakia in the mouth, or Kaposis
arcoma on the skin indicative of undiag-
osed HIV infection. In patients with HIV look
or mouth ulcers or umbilicated skin papules
uggestive of disseminated histoplasmosis or
ryptococcosis. Look at the genitals for the
lcers of HSV and chancres of syphilis.
xamine 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 anabscess, 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 inmumps 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 aleukocytosis or leukopenia. Atypical lym-
phocytes are seen in EBV infection, andeosinophilia in eosinophilic meningitis.
TABLE 5 Brainstem encephalitis (rhombencephalitis): clues and causes
Suggestive clinical featuresl Lower cranial nerve involvementl Myoclonusl Autonomic dysfunctionl Locked-in syndromel MRI changes in the brainstem, with gadolinium enhancement of basal
meningesCausesviral and otherl Enteroviruses (especially EV71)l Flaviviruses, eg West Nile virus, Japanese encephalitis virusl Listerial Tuberculosisl Brucellal Borrelial Paraneoplastic syndromes
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N Hyponatraemia due to the syndrome ofinappropriate antidiuretic hormone(SIADH) is common in encephalitis.
N A raised serum amylase is common inmumps virus infection.
N If there has been a respiratory componentto the presentation check for cold agglu-tinins, which occur in mycoplasma infec-tion, and order appropriate serologicalinvestigations for mycoplasma and chla-mydia (atypical respiratory infections).
N Blood cultures should be taken as part of
the investigation of possible bacterialcauses, and PCR of the blood formeningococcus considered.
N Bacterial antigen testing of CSF and urinemay be helpful.
N A chest x ray is essential to look forpulmonary 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 isuncertain. Our practice is to perform the
test in all patients with undiagnosed CNSinfection because if positive it makessuch a difference to the differential andmanagement.
THE LUMBAR PUNCTURECONTROVERSYFew 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 antimicrobia
therapy. Subsequent studies such as culture
and PCR confirm precisely what the organism
is, which allows the therapy to be tailored andappropriate 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 lumba
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
whichmightindicate 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 alsorecommended 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 lumba
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 nofocal 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 severa
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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atients have a purpuric rash suggestive of
meningococcal septicaemia, or are deteriorat-
ng rapidly, antibiotics should be started
mmediately.26 In HSV-1 encephalitis, a bad
utcome is associated with a delay of two days
r more between hospitalisation and starting
reatment.14 In practice, HSV encephalitis is
are, and most suspected cases turn out to
ave something different.27 While one would
ot advocate unnecessary delays, together
hese data suggest that for patients withuspected encephalitis the emphasis should be
n investigating promptly where possible
efore starting treatment. For most patients
with no contraindication, it should be possible
o perform a lumbar puncture, and get the
esult back within a few hours to then guide
he management. If there are delays or a
atient appears to be deteriorating, then
resumptive treatment with aciclovir is appro-
riate, 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 requirealternative 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 FLUIDFINDINGSIn 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 bacterialmeningitis
Tuberculousmeningitis Fungal Normal
Opening pressure Normal/high High High Highvery high 1020 cm*
Colour Gin clear Cloudy Cloudy/yellow Clear/cloudy ClearCells/mm3 Slightly increased Highvery high Slightly increased Normalhigh
51000 10050000 25500 01000 ,5{Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes LymphocytesCSF/plasma glucoseratio
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, Neurology2006;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 forevery 700 red blood cells/mm3 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:NIn viral CNS infections, an early lumbar puncture may give predominantly neutrophils, or there may be no cells in early or late
lumbar punctures.NIn 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.NCSF 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/mm3, with predominant lymphocytes
(table 6). However, early in the infection theCSF 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 VIROLOGYThe definitive diagnosis of a viral CNS infection
is based on demonstrating the virus in the CNS
either from culture 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 thebody of a patient with a CNS syndrome (for
example, from throat, rectal or vesicle swabs), o
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 CSFThe 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, 3
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, especiallyin 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 alsooccasionally associated with CNS disease
especially in children.36, 37 PCR can also be used
to detectChlamydia pneumoniaein 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 clinica
utility of this test, and are becoming available
for herpes viruses and enteroviruses.38
TABLE 7 Staged approach to microbiological investigation of viralencephalitis
CSF PCRl 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), forantibodies 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 recentdepending on the type of antibodies) but does not necessarily mean thisvirus 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 notnecessarily 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
ome of the recent PCR assays for herpes
iruses, such as EBV and CMV, can make
ositive results difficult to interpret. Most of
he adult population have been infected with
hese viruses and carry them in their
ymphocytes. Therefore, there is debate aboutwhether detection of the viruses by PCR of
he CSF represents true pathogenic infection,
ather than just the presence of infected
ymphocytes.39 Where there is uncertainty
bout the significance of a result, the amount
f virus in the CSF compared with the blood
determined by quantitative PCR) usually
elps resolve it. For example, in a patient
with HIV, a CSF CMV PCR titre that is higher
han that in the serum is usually significant.
Antibody testingAntibody testing continues to play an impor-
ant role in the diagnosis of many viral CNS
nfections. Traditional techniques required the
emonstration of a fourfold rise in antibody
etween acute and convalescent serum
amples collected 24 weeks apart, and thus
re not helpful in making an early diagnosis.
And in practice convalescent samples are
ften forgotten.
Newer enzyme immunoassays can detect
mmunoglobulin (Ig)-M and IgG antibodies in
he serum and CSF against most of the
mportant viruses, as well as Mycoplasma
pneumoniae. Specific anti-viral IgM is often
roduced within a few days of a primary
nfection and can be measured by IgM
nzyme immunoassays. The detection of virus
pecific IgM antibodies in the CSF in higher
itres than in serum indicates local production
f antibody in the CNS in response to
nfection. IgM does not normally cross the
lood-brain barrier because of its size.However, if there is inflammation the barrier
s leaky to IgM, and other immunoglobulins.
n this circumstance, the ratio of CSF to
erum for the specific IgM antibody can be
ompared to the ratio for immunoglobulin as
whole, to decide if this is local production
ather than leak across an inflamed blood-
rain barrier. IgM detection is especially
seful for flavivirus infections, but less so
or herpes virus infections, which are often
eactivations. In contrast to IgM, IgG is
ormally 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 indicatorthat 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 HSVinfections, 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 OTHERSAMPLESOther investigations include:
N PCR and/or culture of throat and rectalswabs for enteroviruses, mumps virus or
measles virus.
N PCR or antigen detection and culture ofnasopharyngeal aspirates for respiratoryviruses such as adenoviruses, RSV, para-influenza viruses or influenza viruses.
N Urine culture for mumps virus.
N Chlamydia pneumoniaeand Mycoplasmapneumoniacan also be detected in throatswabs using PCR.
N Vesicles, for example in hand foot and
mouth disease, should be aspirated forculture or PCR, for enteroviruses.
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N VZV or HSV can be detected in herpeticrashes by cell culture, antigen detectionby immunofluorescence or PCR. Electronmicroscopy of vesicle fluids may alsodemonstrate 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 vesicleswabs 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 ofpatients 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 o
patients with suspected HSV-1 encephalitis
who had a brain biopsy had an alternative
diagnosis, of which 40% were treatable.27
IMAGING AND EEGAs 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 inthe brain areas affected (fig 4),buteven MR
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 sincebeen seen in other conditions.43
MANAGEMENTThere are three elements to the management
of patients with encephalitis:
N the first is to consider whether there isany antiviral or immunomodulatory treat-ment to halt or reverse the diseaseprocess;
N
the second is to control the immediatecomplications 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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the third is to prevent some of thesecondary and late complications.
Standard intensive care for patients with
ncephalitis include oxygen via a mask,
aying attention to fluid and hydration,
asogastric or parenteral feeding, and treat-
ng the complications of infection such as
neumonia. Patients with a reduced coma
core or impaired gag reflex, should be
ssessed by an intensive care unit outreach
eam, with a view to early transfer.
When to start aciclovir
n most immunocompetent patients in devel-ped countries aciclovir should be given as
oon as there is a strong suspicion of viral
ncephalitis, based on the clinical presenta-
ion and initial CSF and/or imaging findings. If
erforming these investigations is likely to
ead to long delays and the clinical suspicion
s strong, then treatment should be started at
nce, for both viral encephalitis and possible
acterial meningitis. The situation may be
ifferent in developing countries, where the
ost of aciclovir may be an issue, and other
auses 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-associatedCNS 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 riskof renal failure. Other rare adverse effects
include local inflammation at the site of the
intravenous canula, hepatitis, and bone
marrow failure.
When to stop aciclovirAlthough 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 encephalitisHerpes simplex virus 1 and 2 AciclovirVaricella zoster virus (incluing cerebellitis) Aciclovir plus corticosteroidsHuman herpes virus-6 Ganciclovir, foscarnet
Rabies Ketamine*, amantidine, ribavirinSubacute/chronic encephalitisIn the immunocompromised
Varicella-zoster virus AciclovirCytomegalovirus Ganciclovir, foscarnet, cidofovirMeasles inclusion body encephalitis RibavirinEnterovirus Pleconaril, specific immunoglobulinProgressive multifocal leukoencephalophy in HIV patients Highly active antiretroviral therapy (HAART), cidofovir
In the immunocompetent
Subacute sclerosing panencephalitis Interferon alpha (intraventricular), ribavirin inosiplexProgressive multifocal leukoencephalopathy Consider cytosine arabinoside (ARA-C)Progressive rubella panencephalitis Plasma exchange
Rasmussens encephalitis IVIgImmune-mediated encephalitis
Acute disseminated encephalomyelitis{ Coricoteroids/IVIg/plasma exchangeParaneoplastic Treatment of underlying tumour, consider immunosuppressionVoltage 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 prolongedhigh 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 notbe
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 thepatient 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 treatmentsIn patients with brain swelling, corticosteroids
and mannitol are often used to control raised
intracranial pressure. A recent trial suggestssteroids 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 andimmunomodulatory treatmentsThere 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 understandingof the pathogenesis, in vitro data, anecdota
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 initia
treatment, followed by intravenous immuno-
globulin, plasma exchange, or further treatmen
with steroids, depending on the response to the
initial treatment.
In some circumstances, both antiviral and
immunosuppressive drugs are given. Fo
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 aretreated 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 othe
flavivirus infections, but a randomised con-
trolled trial in Japanese encephalitis showed it
was not effective.55
Management of seizures, raisedintracranial pressure and othercomplicationsSeizures 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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yes, particularly in children. An EEG should
e performed if there is any uncertainty.
Uncontrolled seizures lead to raised intra-
ranial pressure, increased metabolic activity,
cidosis and vasodilatation, which in turn
eads to further raised pressure. The resulting
ositive feedback cycle can ultimately pre-ipitate brain shift and herniation. If seizures
re not easily controlled with phenytoin and
ow doses of benzodiazepines, patients should
e intubated and ventilated mechanically, so
hat higher doses of sedating anticonvulsive
rugs, including benzodiazepines and pheno-
arbital, can be used. Electroencephalographic
monitoring, with or without continuous
unction and analysing monitoring (CFAM),
hould be used to detect ongoing epileptic
ctivity.
Standard measures to control raised intra-
ranial pressure include nursing the patient at
0 head up, keeping the head straight tonsure there is no obstruction to venous
eturn, and ventilating to maintain a low
rterial pCO2. Although there are no good
ata for viral encephalitis, data from other
nfectious encephalopathies suggest that
smotic diuretics produce a short-term
eduction in pressure.56 The role of anti-
nflammatory drugs in viral encephalitis is
ncertain.51
To reduce the risk of deep venoushrombosis and pulmonary embolism,
atients with reduced mobility should be
itted with compression stockings, and once it
s clear that there is no major haemorrhagic
omponent to the encephalitis, they should
e given prophylactic heparin. Bed sores are a
isk in immobile patients, and appropriate
mattresses and regular turning are needed.
Patients with encephalitis are also at risk of
econdary pneumonia, due to aspiration, and
rinary tract infections. Passive and active
mb movements will reduce the risk of limb
ontractures, which can occur in patients
with limb weakness, and splints and braces
may be needed to facilitate mobilisation.
Management in the recoveryperioddeally, a full neuropsychological assessment
hould be organised at hospital discharge, or
oon after. This should include cognitive
unction, intelligence, memory and speech
ssessment, 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 particularlyprominent 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 ANDOUTCOMEAlthough 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 consciousnessshould be investigated for a central nervous system (CNS) infection, unlessthere 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 punctureshould 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.
ACKNOWLEDGEMENTSWe 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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