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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

10.1136/jnnp.2007.129098

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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

289Solomon, Hart, Beeching

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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.)


10.1136/jnnp.2007.129098



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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





8/19

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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