REVIEWPract Neurol 2007; 7: 285–302

Viralencephalitis: aclinician’s guideTom Solomon, Ian J Hart, Nicholas J Beeching

T SolomonProfessor of Neurology and MRC

Senior Clinical Fellow, University of

Liverpool Divisions of Neurological

Science and Medical Microbiology,

and The Walton Centre for

Neurology and Neurosurgery,

Liverpool, UK

I J 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, Liverpool

L69 3GA, UK; tsolomon@liv.ac.uk

285Solomon, Hart, Beeching

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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 othersthere are prolonged and inappropriate delays before treatment is started.Although viral encephalitis is relatively rare, patients with suspected centralnervous system (CNS) infections, who might have 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

death within a few days, despite the best

treatment efforts. Even when treatment is

successful and patients survive apparently

intact, in many cases the family say that the

person they took home with them is not the

same as the one they brought to hospital, with

changes in personality, irritability, and poor

short-term memory. The management of

patients with suspected encephalitis has been

revolutionised in recent years with improved

imaging and viral diagnostics, better antiviral

and immunomodulatory therapies, and

enhanced neurointensive care settings. Despite

this, disasters in patient management are sadly

not uncommon. Although viral encephalitis is

relatively rare, patients with suspected central

nervous system (CNS) infections, who might

have viral encephalitis, are not. In addition, the

increasing number of immunocompromised

patients, who may have viral CNS infections,

plus the spread of encephalitis caused by

arthropod-borne viruses, present new chal-

lenges to clinicians. This review aims to provide

a rational approach to the investigation and

treatment of a patient with suspected viral

encephalitis.

WHAT IS ENCEPHALITIS?Encephalitis means inflammation of the brain

parenchyma, and comes from the Greek

enkephalon, brain. Encephalitis can be caused

directly by a range of viruses, the herpes

viruses and some arboviruses being especially

important (table 1). Other microorganisms

can also cause encephalitis, particularly

protozoa such as Toxoplasma gondii, and

bacteria such as Listeria monocytogenes and

Mycobacterium tuberculosis (table 2). For

viruses such as HIV that infect the brain but

without causing inflammation, the term

‘‘encephalitis’’ is not usually used.

Encephalitis can also occur as an immune-

mediated phenomenon—for example, acute

disseminated encephalomyelitis (ADEM,

which follows infections or vaccinations),

paraneoplastic limbic encephalitis, and vol-

tage gated potassium channel limbic ence-

phalitis.1

Strictly speaking, encephalitis is a patho-

logical diagnosis that should only be made if

there is tissue confirmation, either at autopsy

or on brain biopsy. However, in practice most

patients are diagnosed with encephalitis if

they have the appropriate clinical presenta-

tion (febrile illness, severe headache reduced

consciousness (see below)) and surrogate

markers of brain inflammation, such as

inflammatory cells in the cerebrospinal fluid

(CSF), or inflammation shown on imaging,

especially if an appropriate organism is

detected. Encephalitis must be distinguished

from encephalopathy, the clinical syndrome

of reduced consciousness, which can be

caused by viral encephalitis, other infectious

286 Practical Neurology

10.1136/jnnp.2007.129098

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 affected—for

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). For

most viruses, the brain parenchyma and

neuronal cells are primarily infected, but for

some the blood vessels can be attacked giving

a strong vasculitic component. Demyelination

following infection can also contribute.

Herpes simplex virus (HSV) for example,

primarily targets the brain parenchyma in

the temporal lobes, sometimes with frontal or

parietal involvement. Mumps virus can cause

an acute viral encephalitis, or a delayed

immune mediated encephalitis. Measles virus

causes a post-infectious encephalitis, which

can sometimes have a severe haemorrhagic

component (acute haemorrhagic leukoence-

phalitis). With influenza A virus, diffuse

cerebral oedema is a major component in

the pathogenesis, while for varicella zoster

virus (VZV), vasculitis is a major pathogenic

process.

How and when the virus crosses the blood

brain barrier is a key issue in the pathogenesis

of any viral encephalitis.

For example, primary infection with HSV

type 1 (HSV-1) occurs in the oral mucosa, and

may cause herpes labialis (vesicles and ulcers

around the mouth) or be asymptomatic

(serological studies show that up to 90% of

healthy adults have been infected with HSV-

1). Following primary infection the virus

travels centripetally along the trigeminal

nerve to give latent infection in the trigeminal

ganglion, in most if not all those infected.

About 30% of infected people have clinically

apparent herpes labialis, but even asympto-

matic individuals have episodes or viral

shedding. About 70% of cases of HSV-1

encephalitis already have antibody present,

indicating that reactivation of virus must be

the most common mechanism;3 however, it is

not clear whether this is due to reactivation

of virus in the trigeminal ganglion, or virus

that had already established latency in the

brain itself.4 Why HSV sometimes reactivates

is not known. In contrast to adults, in younger

TABLE 1 Causes of acute viral encephalitis (modified from Solomon 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 encephalitis—mostly 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.

287Solomon, Hart, Beeching

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patients, particularly children, HSV-1 ence-

phalitis occurs during primary infection.

HSV type 2 (HSV-2) is usually transmitted

via the genital mucosa, causing genital herpes

in adults. In the USA approximately 20% of

individuals are sero-positive for HSV-2. The

neurological syndromes it causes include

meningitis, especially recurrent meningitis,

encephalitis, particularly in neonates, and

lumbosacral radiculitis. Most cases of recur-

rent meningitis that were previously called

Mollaret’s meningitis are now thought to be

due to HSV-2, although some feel the term

Mollaret’s 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-Barre syndrome*

–Bacterial meninigitis–Tuberculosis Viral illnesses with febrile convulsions–Brain abscess Shigella–Typhoid fever–Parameningeal infection–Lyme disease

Systemic viral illnesses with febrile convulsionsSystemic viral illnesses associated with swollenfontanelle

–Syphilis Non-infectious diseases–Relapsing fever Vascular–Leptospirosis –Vasculitis–Mycoplasma pneumoniae –Systemic lupus erythematosus–Listeriosis –Behcet’s disease–Brucellosis Neoplastic–Subacute bacterial endocarditis –Primary brain tumour–Whipple’s disease –Metastases–Nocardia –Paraneoplastic limbic encephalitis–Actinomycosis Metabolic

–Hepatic encephalopathyFungi –Renal encephalopathy

–Candidiasis –Hypoglycaemia–Cryptococcus –Reye’s syndrome–Coccidiomycosis –Toxic encephalopathy (alcohol, drugs)–Histoplasmosis Other–North American blastomycosis –Drug reactions

–Subarachnoid and subdural haemorrhageParasites Ischaemic stroke

–Cerebral malaria –Epilepsy–Toxoplasmosis –Hysteria–Cysticercosis –Voltage gated K channel limbic encephalitis–Trypanosomiasis–Echinococcus–Trichinosis–Amoebiasis

Rickettsiae–Rocky Mountain spotted fever–Typhus–Q fever–Erlichiosis (anaplasma)–Cat-scratch fever

*Guillain-Barre syndrome and acute disseminated encephalomyelitis may follow viral orbacterial infections or vaccinations.

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10.1136/jnnp.2007.129098

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, there

have 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 causedoutbreaks 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 isoften 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 nations;however, in the UK reduced vaccineuptake in recent years has been asso-ciated with a resurgence of these viruses.9

Incidence of viral encephalitisIt is difficult to determine the incidence of

encephalitis because the various studies have

used different case definitions and viral

diagnostic capabilities. However, most studies

report an annual incidence of 5–10 per

100 000,10, 11 highest in the young and elderly.

Higher incidences are found in areas with

arthropod-borne viruses. A lower annual

incidence of 1.5 per 100 000 has been

reported in England, based on hospitalisation

data,12 although this was probably an under-

estimate. HSV encephalitis is the most

commonly diagnosed viral encephalitis in

industrialised nations, with an annual inci-

dence of 1 in 250 000 to 500 000.13 Most HSV

encephalitis is due to HSV-1, but about 10%

are HSV-2. The latter typically occurs in

immunocompromised individuals, and neo-

nates, in whom it causes a disseminated

infection.

WHEN SHOULD 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 1Histopathological picture of the

temporal cortex of a man who died

from herpes simplex virus encephalitis.

(A) Intense perivascular inflammatory

infiltrate consisting of activated

microglia, macrophages and

lymphocytes (H&E staining, 620). (B)

High power view showing microglia

and dead neurons with nuclear

dissolution (karyolysis) and

hypereosinophilia within the cytoplasm

retaining the original pyramidal contour

(H&E 640). (Pictures courtesy of Dr

Daniel Crooks.)

289Solomon, Hart, Beeching

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altered consciousness, often associated with

seizures and focal neurological signs (fig 2).

Eighty five (91%) of 93 adults with HSV-1

encephalitis in one recent study were febrile

on admission.14 Disorientation (76%), speech

disturbances (59%) and behavioural changes

(41%) were the most common features, and

one third of patients had seizures.14

Alterations in higher mental function include

lethargy, drowsiness, confusion, disorienta-

tion and coma. With the advent of CSF PCR

more subtle presentations of HSV encephalitis

have been recognised;15 low grade pyrexia

rather than a high fever, speech disturbances

(dysphasia and aphasia), and behavioural

changes which can mistaken for psychiatric

illness, or the consequences of drugs or

alcohol, occasionally with tragic consequences.

Figure 2Liverpool algorithm for investigation

and treatment of immunocompetent

adults with suspected viral encephalitis.

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Seizures can sometimes be the initial presenting

feature of a patient with encephalitis. Any adult

with a seizure in the context of a febrile illness,

or a seizure from which they do not recover,

must be investigated for possible CNS infection.

There are several reasons why one may not

think of encephalitis, particularly a failure to

appreciate the importance of altered con-

sciousness in the context of a febrile illness,

or failure to investigate these symptoms

properly when they are recognised (table 3).

One of the commonest failings is delay in

performing a lumbar puncture in patients

with an acute confusional state, which has

been incorrectly attributed to a systemic

infection.16 Although most viral encephalitis

presents acutely, subacute and chronic pre-

sentations can be caused by CMV, VZV and

HSV, especially in patients immunocompro-

mised as a result of HIV, or immunosuppres-

sive 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 ‘‘does

not seem right’’, should not be ignored, even

if the Glasgow Coma Score is 15; remember

this is a very crude tool that was devised for

assessing patients with head injuries.

Ask about recent rashes such as measles.

Even if there is no such history in the patient,

ask whether others in the family or in the

community have been affected (these viruses

occasionally cause encephalitis without the

obvious stigmata). In children, a recent rash

may suggest chickenpox, parvovirus or HHV-6.

Parotitis, testicular pain or abdominal pain due

to pancreatitis may suggest mumps virus as the

causative organism. If the patient is conscious,

ask about any strange smells, which may be

olfactory hallucinations reflecting frontotem-

poral involvement in HSV-1 encephalitis.

A travel history is essential, as are vaccination

details. Travellers from Asia with fever and

reduced consciousness may be infected with

dengue or Japanese encephalitis viruses; they

may also have acquired meningoencephalitis

from eating snails carrying the rat lungworm

Angiostrongylus cantonensis. Cerebral malaria

should also be considered in returning travellers,

especially from Africa.17

Ask if there has been any contact with

animals, or whether there are sick animals in

the neighbourhood. In the USA some out-

breaks of West Nile virus were heralded by

sick birds falling from the sky.18 The history of

a dog bite in a rabies endemic area may be

important,19 as may a bite or scratch from a

bat; in the UK and Europe, Daubenton’s bats

carry rabies-like viruses (European bat lyssa-

viruses).20 Other risk factors are related to

occupation and recreational activities:

TABLE 3 Why encephalitis may be missed

l Wrongly attributing a patient’s 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 arenot febrile on admission

l Ignoring a relative’s complaint that a patient is ‘‘not quite right’’, sleepy orlethargic, 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 whomthey were first isolated.

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N leptospirosis can be acquired from raturine during fresh water activities

N lymphocytic choreomeningitis virus(LCMV) is transmitted in rodent faeces;humans are exposed when cleaning outbarns, etc

N hikers in the forests of Austria, Germany,and Eastern Europe are at risk of tick-borne encephalitis virus (TBEV)

N a related virus, Louping ill virus, causesoccasional encephalitis in sheep in theScottish Highlands, and very rarely inhumans

N hikers in the New Forest in the UK are atrisk of Lyme disease.

Ask about risk factors for HIV, including

previous blood transfusions, and high-risk

behaviours such as intravenous drug use, sex

between men, and multiple sexual partners,

especially with people from high-risk areas of

the world such as sub-Saharan Africa and

Thailand.

IMPORTANT EXAMINATIONFINDINGSOn examination the first priorities are to

check that the airway is protected, assess and

document the level of consciousness, using a

quantitative scale such as the Glasgow Coma

Scale (GCS), and treat any immediate com-

plications of infection such as generalised

seizures. For patients with mild behavioural

abnormalities or disorientation, document the

odd behaviour, and record the mini-mental

test score. The general medical examination

should include a search for other possible

explanations of the coma.

Look for a purpuric (meningococcal) rash

and other exanthema, bites and stigmata that

may suggest an aetiology; is there the rash of

shingles? Are there injection sites that might

indicate intravenous drug use? Look for

seborrhoeic dermatitis, oral candida or oral

hairy leukoplakia in the mouth, or Kaposi’s

sarcoma on the skin indicative of undiag-

nosed HIV infection. In patients with HIV look

for mouth ulcers or umbilicated skin papules

suggestive of disseminated histoplasmosis or

cryptococcosis. Look at the genitals for the

ulcers of HSV and chancres of syphilis.

Examine also the chest, ears and urine for

infection. However, beware ascribing reduced

consciousness to a urinary or chest infection,

especially in someone who is otherwise fit

and well. Such patients need a lumbar

puncture to rule out a CNS infection.

Look for seizures including subtle motor

seizures, and examine the side of the tongue

or inside cheek for bites indicating that a

seizure has occurred. Test for meningism, and

look for focal neurological signs, including

hemispheric signs that could indicate an

abscess, or flaccid paralysis suggestive of

spinal cord involvement. Tremors and abnor-

mal movements are seen in some forms of

encephalitis, particularly those that involve

the basal ganglia, such as West Nile virus and

other flaviviruses, or toxoplasmosis. An acute

febrile encephalopathy with lower cranial

neuropathies and myoclonus suggests a

rhomboencephalitis or basal meningoence-

phalitis, as seen with some enteroviruses, or

listeria (table 5). Deafness is quite common in

mumps and some rickettsial infections. Upper

limb weakness and fasciculation suggest a

cervical myelitis, for example in tick-borne

encephalitis. Encephalitis associated with

radiculitis is seen in CMV and EBV.

INITIAL INVESTIGATIONS

N A peripheral blood count may show aleukocytosis or leukopenia. Atypical lym-phocytes are seen in EBV infection, andeosinophilia in eosinophilic meningitis.

N Hyponatraemia due to the syndrome ofinappropriate antidiuretic hormone(SIADH) is common in encephalitis.

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

meningesCauses—viral 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 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 ofthe 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 thetest in all such patients, because ifpositive it makes such a difference tothe differential and management.

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 antimicrobial

therapy. Subsequent studies such as culture

and PCR confirm precisely what the organism

is, which allows the therapy to be tailored and

appropriate public health measures, including

disease notification, to be organised.

However, if patients have a space-occupy-

ing 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 problem—indeed

patients with idiopathic intracranial hyper-

tension are treated by lumbar punctures, and

in most patients with CNS infection the CSF

opening pressure is raised to some degree.22, 23

The problem is the swelling or shift which is

sometimes associated with the raised pres-

sure, so the pressure is not the same in all the

CSF compartments. For this reason patients

should be assessed for clinical features which

might indicate a space-occupying lesion,

brain swelling or shift, and who should then

have computed tomography (CT) before

lumbar puncture (fig 3); focal neurological

signs (for example a hemiparesis), new onset

seizures, papilloedema and deep coma. CT is

also recommended for immunocompromised

patients, who may lack the clinical signs of an

inflammatory mass lesion.24 Opinions vary as

to what level of ‘‘deep coma’’ necessitates a

CT scan before lumbar puncture. To some

extent it depends on how quickly imaging can

be organised. If a CT scan can be performed

promptly, so that it will not delay lumbar

puncture for more than an hour or two, then

it is reasonable to do this first. However, in a

patient who is only mildly confused with no

focal neurological signs, than a lumbar

puncture should be done straight away,

without the unnecessary delay of a CT.24

If a CT is going to cause a delay of several

hours, then presumptive treatment for both

bacterial and/or viral pathogens should be

started. There are no hard and fast rules

about how long a delay is acceptable before

treatment 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 out-

come.25 If patients have a purpuric rash

suggestive of meningococcal septicaemia, or

Figure 3CT 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.

293Solomon, Hart, Beeching

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are deteriorating rapidly, antibiotics should be

started immediately.26 In HSV-1 encephalitis, a

bad outcome is associated with a delay of two

days or more between hospitalisation and

starting treatment.14 In practice, HSV ence-

phalitis is rare, and most suspected cases turn

out to have something different.27 While one

would not advocate unnecessary delays,

together these data suggest that for patients

with suspected encephalitis the emphasis

should be on investigating promptly where

possible before starting treatment. For most

patients with no contraindication, it should be

possible to perform a lumbar puncture, and

get the result back within a few hours to then

guide the management. If there are delays or

a patient appears to be deteriorating, then

presumptive treatment with aciclovir is

appropriate, at least while investigations

proceed.

For patients with suspected bacterial menin-

gitis 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 antibacterial and

antiviral treatment to all patients with sus-

pected CNS infection, and then not investigat-

ing with lumbar puncture because it ‘‘makes no

difference to the management’’ is unacceptable

practice and should be discouraged.21 This

approach risks missing other diagnoses that

may require alternative treatments,29 and

increases the risk of adverse effects of the

unwarranted and unnecessary drugs. For HSV-1

encephalitis, 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 5–1000

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 High–very high 10–20 cm*Colour ‘‘Gin’’ clear Cloudy Cloudy/yellow Clear/cloudy ClearCells/mm3 Slightly increased High–very high Slightly increased Normal–high

5–1000 100–50000 25–500 0–1000 ,5{Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes LymphocytesCSF/plasma glucoseratio

Normal Low Low–very low(,30%)

Normal–low 66%{

Protein (g/l) Normal–high High High–very high Normal–high ,0.45{0.5–1 .1 1.0–5.0 0.2–5.0

*Normal CSF opening pressure is generally ,20 cm for adults, ,10 cm for children below age 8, but may be as high as 25 cm(Whiteley et al, Neurology 2006;67:1690–1).{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:N In viral CNS infections, an early lumbar puncture may give predominantly neutrophils, or there may be no cells in early or late

lumbar punctures.N In patients with acute bacterial meningitis that has been partially pre-treated with antibiotics (or patients ,1 year old) the

CSF cell count may not be very high and may be mostly lymphocytic.N Tuberculous meningitis may have predominant CSF polymorphs early on.N Listeria can give a similar CSF picture to tuberculous meningitis, but the history is shorter.N CSF findings in bacterial abscesses range from near normal to purulent, depending on location of the abscess, and whether

there is associated meningitis, or rupture.N A cryptococcal antigen test and India ink stain should be performed on the CSF of all patients in whom cryptococcus is

possible.

294 Practical Neurology

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cells/mm3, with predominant lymphocytes

(table 6). However, early in the infection the

CSF white cell count may be normal, or

neutrophils may predominate, as they do in

viral meningitis.30 The CSF red cell count is

usually normal, or slightly raised, but it may

be markedly raised in HSV-1 encephalitis,

which can be haemorrhagic, or in acute

necrotising haemorrhagic leukoencephalitis.

The glucose ratio is usually normal in viral

CNS infections, though it may be a little

reduced—for 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 the

body of a patient with a CNS syndrome (for

example, from throat, rectal or vesicle swabs), or

showing an antibody response to the virus in

the serum (the organism is then presumed to be

responsible for the clinical presentation,

although there is always the possibility that it

is a coincidental infection).

PCR of 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, 35

Initial investigation of immunocompetent

patients with encephalitis should include

PCR for both HSV and VZV because these

are potentially treatable with aciclovir (see

below) (table 7). Enterovirus PCR is often

included at this stage, because it is a relatively

common cause of viral meningitis, especially

in the summer/autumn. In immunocompro-

mised patients, EBV and CMV PCR should also

be performed, and HHV-6 and HHV-7 con-

sidered. Measles and mumps should be looked

for if there is a suggestive clinical indication,

although they can occasionally cause ence-

phalitis in patients with no other features.

Other viruses to consider, especially in children,

include adenoviruses, HHV-6, respiratory

syncitial virus (RSV), and influenza virus A and

B; rotaviruses and parvovirus B19 are also

occasionally associated with CNS disease,

especially in children.36, 37 PCR can also be used

to detect Chlamydia pneumoniae in the CSF.

CSF viral culture is now rarely performed,

although it has the potential advantage over

PCR of being able to detect any virus, whereas

PCR only detects the viruses being targeted by

the panel of PCR assays used. Newer more

sensitive PCR methods, such as ‘‘real-time’’ and

quantitative PCR have improved the clinical

utility of this test, and are becoming available

for herpes viruses and enteroviruses.38

TABLE 7 Staged approach to microbiological investigation of 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 indicated—see 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

some of the recent PCR assays for herpes

viruses, such as EBV and CMV, can make

positive results difficult to interpret. Most of

the adult population have been infected with

these viruses and carry them in their

lymphocytes. Therefore, there is debate about

whether detection of the viruses by PCR of

the CSF represents true pathogenic infection,

rather than just the presence of infected

lymphocytes.39 Where there is uncertainty

about the significance of a result, the amount

of virus in the CSF compared with the blood

(determined by quantitative PCR) usually

helps resolve it. For example, in a patient

with HIV, a CSF CMV PCR titre that is higher

than that in the serum is usually significant.

Antibody testingAntibody testing continues to play an impor-

tant role in the diagnosis of many viral CNS

infections. Traditional techniques required the

demonstration of a fourfold rise in antibody

between acute and convalescent serum

samples collected 2–4 weeks apart, and thus

are not helpful in making an early diagnosis.

And in practice convalescent samples are

often forgotten.

Newer enzyme immunoassays can detect

immunoglobulin (Ig)-M and IgG antibodies in

the serum and CSF against most of the

important viruses, as well as Mycoplasma

pneumoniae. Specific anti-viral IgM is often

produced within a few days of a primary

infection and can be measured by IgM

enzyme immunoassays. The detection of virus

specific IgM antibodies in the CSF in higher

titres than in serum indicates local production

of antibody in the CNS in response to

infection. IgM does not normally cross the

blood-brain barrier because of its size.

However, if there is inflammation the barrier

is leaky to IgM, and other immunoglobulins.

In this circumstance, the ratio of CSF to

serum for the specific IgM antibody can be

compared to the ratio for immunoglobulin as

a whole, to decide if this is local production

rather than leak across an inflamed blood-

brain barrier. IgM detection is especially

useful for flavivirus infections, but less so

for herpes virus infections, which are often

reactivations. In contrast to IgM, IgG is

normally found in the CSF at a ratio of

1/200th of the serum concentration; hence in a

primary acute CNS infection, IgG rises later than

IgM both in CSF and serum. In reactivations and

secondary infections, IgG tends to rise earlier

and to a greater extent than IgM.

The detection of oligoclonal bands is

sometimes a useful non-specific indicator

that a patient has an inflammatory process in

the CNS, rather than a non-inflammatory

cause of encephalopathy. Immunoblotting of

the bands against viral proteins has been

used, but mostly as a research tool to help

determine the cause of the inflammation—for

example, HSV-1 or HSV-2.29, 34 However, the

detection of intrathecal anti-HSV antibody

has a sensitivity of 50% by 10 days after

clinical presentation, and is thus only con-

sidered useful for retrospective diagnosis.

Our practice, at least for diagnosing HSV

infections, is to ask for PCR on CSF acutely. If

this is negative, but suspicion remains high,

PCR of the CSF is repeated after a few days

(as indicated above PCR can sometimes be

negative if the sample is taken early in the

illness). If two CSFs are negative for HSV by

PCR then it is unlikely that the patient has

HSV infection. If for logistic reasons CSFs

were not taken at this time, or were not sent

for HSV PCR, then testing a late CSF (for

example, later than 10 days of hospitalisa-

tion) for the production of intrathecal anti-

bodies against HSV, by IgM, IgG or antibody-

mediated immunoblotting of oligoclonal

bands, can be useful.

INVESTIGATION OF OTHERSAMPLESOther investigations include:

N PCR and/or culture of throat and rectalswabs for enteroviruses, mumps virus ormeasles 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 pneumoniae and Mycoplasmapneumonia can also be detected in throatswabs using PCR.

N Vesicles, for example in hand foot andmouth disease, should be aspirated forculture or PCR, for enteroviruses.

296 Practical Neurology

10.1136/jnnp.2007.129098

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 vesicle

swabs indicate that they are temporally

associated with the acute infection, whereas

shedding from the rectum occurs for several

weeks after an acute infection.40

The list of all possible investigations for

causes of viral CNS disease is clearly very

long. Our practice is to do the initial CSF PCR

for HSV and VZV as soon as the samples are

received, because of their importance for

early management. PCR for enteroviruses and

parechoviruses is also usually done at this

stage. In addition, patients that are immuno-

compromised are investigated with CMV and

EBV PCR. Further investigations are guided by

the clinical picture, especially the patient’s

immune competence and the initial CSF

findings. The opinion of a clinical virologist

in assessing such patients is invaluable.

With the advent of PCR, brain biopsy of

patients with suspected encephalitis has

become less common. Previously it was

considered the gold standard for diagnosis

of HSV-1 encephalitis. It may still have a role

in undiagnosed patients that are deteriorat-

ing. In one study approximately half of

patients with suspected HSV-1 encephalitis

who had a brain biopsy had an alternative

diagnosis, of which 40% were treatable.27

IMAGING AND 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 in

the brain areas affected (fig 4), but even MRI

scans can look normal if performed very

early.41 Diffusion-weighted MRI may be

especially useful for demonstrating early

changes.42

An EEG usually shows non-specific diffuse

high amplitude slow waves of encephalo-

pathy, but can be useful to look for subtle

epileptic seizures. Periodic lateralised epilepti-

form discharges were once thought to be

diagnostic of HSV encephalitis, but have since

been seen in other conditions.43

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 4T2-weighted MRI brain scan showing

right temporal lobe hyperintensity in a

patient with herpes encephalitis.

297Solomon, Hart, Beeching

www.practical-neurology.com

N the third is to prevent some of thesecondary and late complications.

Standard intensive care for patients with

encephalitis include oxygen via a mask,

paying attention to fluid and hydration,

nasogastric or parenteral feeding, and treat-

ing the complications of infection such as

pneumonia. Patients with a reduced coma

score or impaired gag reflex, should be

assessed by an intensive care unit outreach

team, with a view to early transfer.

When to start aciclovirIn most immunocompetent patients in devel-

oped countries aciclovir should be given as

soon as there is a strong suspicion of viral

encephalitis, based on the clinical presenta-

tion and initial CSF and/or imaging findings. If

performing these investigations is likely to

lead to long delays and the clinical suspicion

is strong, then treatment should be started at

once, for both viral encephalitis and possible

bacterial meningitis. The situation may be

different in developing countries, where the

cost of aciclovir may be an issue, and other

causes of CNS infection are more common.

For example in much of Asia large outbreaks

of Japanese encephalitis occur; in parts of

Asia and sub-Saharan Africa, HIV-associated

CNS infections and cerebral malaria are

common.

Aciclovir is a nucleoside analogue that is

highly effective against HSV and some of the

other herpes viruses, such as VZV and herpes

B virus. Intravenous administration of aciclo-

vir at 10 mg/kg three times daily reduces the

risk of a fatal outcome from approximately

70% to less than 20%.44, 45 Renal function

should be monitored closely and adequate

hydration maintained, because of the rare risk

of renal failure. Other rare adverse effects

include local inflammation at the site of the

intravenous canula, hepatitis, and bone

marrow failure.

When to stop 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, foscarnetRabies Ketamine*, amantidine, ribavirin

Subacute/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 immunocompetentSubacute sclerosing panencephalitis Interferon alpha (intraventricular), ribavirin inosiplexProgressive multifocal leukoencephalopathy Consider cytosine arabinoside (ARA-C)Progressive rubella panencephalitis Plasma exchangeRasmussen’s encephalitis IVIg

Immune-mediated encephalitisAcute 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.

298 Practical Neurology

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treatment and continuing with aciclovir if

HSV is still detected by PCR. This approach is

being evaluated by the American

Collaborative Antiviral Study Group, which is

assessing the prognostic value of quantitative

PCR detection of viral DNA in the CSF at the

end of three weeks’ treatment and prolonged

high dose oral valaciclovir for three months.

If the initial CSF PCR is negative for HSV

but other features are consistent with HSV

encephalitis, then the aciclovir should not be

stopped, because false negative PCR results

can occur, particularly early on.47, 48 In such

patients the lumbar puncture should be

repeated because it may be positive 24–48 h

later and, even if negative again, treatment

continued for at least 10 days. However, if a

definitive alternative diagnosis has become

apparent, or it seems very unlikely that the

patient has viral encephalitis, then it is

reasonable to stop the acyclovir earlier.

A role for oral valaciclovir?In circumstances where ongoing intravenous

treatment is proving difficult (for example, in

a child who is now fully conscious), oral

valaciclovir may be reasonable,49 although we

would only consider this after the first

10 days of intravenous treatment.

Valaciclovir is the valene ester of aciclovir,

which is converted to aciclovir after absorp-

tion, and has good oral bioavailability.

Although oral valaciclovir may have a role,

oral aciclovir should not be used in HSV

encephalitis, because the levels achieved in

the CSF are inadequate.

Ancillary treatmentsIn patients with brain swelling, corticosteroids

and mannitol are often used to control raised

intracranial pressure. A recent trial suggests

steroids may be beneficial even in patients

without marked swelling.50 Their role in HSV

encephalitis merits further study.51 In patients

with severe brain swelling, decompressive

hemicraniectomy is sometimes performed.

Antibiotic treatment with a cephalosporin is

often also given, especially if the initial CSF

findings could be consistent with bacterial

disease (for algorithm see http://www.

britishinfectionsociety.org). If listeria is sus-

pected, ampicillin and gentamicin, or high

dose cotrimoxazole, should be given.

Other antiviral 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 understanding

of the pathogenesis, in vitro data, anecdotal

reports, or small clinical series, although these

sometimes provide conflicting data (table 8).

If the clinical presentation and imaging

findings suggest a post- or para-infectious

encephalitis such as ADEM, acute haemorrhagic

leukoencephalitis or diffuse encephalopathy

associated with systemic viral infection, immu-

nosuppressive drugs are given.52 High dose

corticosteroid treatment is often the initial

treatment, followed by intravenous immuno-

globulin, plasma exchange, or further treatment

with steroids, depending on the response to the

initial treatment.

In some circumstances, both antiviral and

immunosuppressive drugs are given. For

example, in HSV encephalitis corticosteroids

are sometimes used in addition to aciclovir as

described above. In VZV encephalitis cortico-

steroids are used alongside aciclovir because

of the strong vasculitic component of the

disease.

Severe CMV and HHV-6 infections are

treated with ganciclovir, foscarnet or cidofo-

vir, severe adenovirus infections have been

treated with cidofovir or ribavirin and

Pleconaril has been used for severe enter-

ovirus infections, particularly in the immuno-

compromised, although its overall role

remains unclear.53, 54 Interferon alpha has

been used in West Nile virus and other

flavivirus infections, but a randomised con-

trolled trial in Japanese encephalitis showed it

was not effective.55

Management of seizures, 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

299Solomon, Hart, Beeching

www.practical-neurology.com

eyes, particularly in children. An EEG should

be performed if there is any uncertainty.

Uncontrolled seizures lead to raised intra-

cranial pressure, increased metabolic activity,

acidosis and vasodilatation, which in turn

leads to further raised pressure. The resulting

positive feedback cycle can ultimately pre-

cipitate brain shift and herniation. If seizures

are not easily controlled with phenytoin and

low doses of benzodiazepines, patients should

be intubated and ventilated mechanically, so

that higher doses of sedating anticonvulsive

drugs, including benzodiazepines and pheno-

barbital, can be used. Electroencephalographic

monitoring, with or without continuous

function and analysing monitoring (CFAM),

should be used to detect ongoing epileptic

activity.

Standard measures to control raised intra-

cranial pressure include nursing the patient at

30˚ head up, keeping the head straight to

ensure there is no obstruction to venous

return, and ventilating to maintain a low

arterial pCO2. Although there are no good

data for viral encephalitis, data from other

infectious encephalopathies suggest that

osmotic diuretics produce a short-term

reduction in pressure.56 The role of anti-

inflammatory drugs in viral encephalitis is

uncertain.51 To reduce the risk of deep venous

thrombosis and pulmonary embolism,

patients with reduced mobility should be

fitted with compression stockings, and once it

is clear that there is no major haemorrhagic

component to the encephalitis, they should

be given prophylactic heparin. Bed sores are a

risk in immobile patients, and appropriate

mattresses and regular turning are needed.

Patients with encephalitis are also at risk of

secondary pneumonia, due to aspiration, and

urinary tract infections. Passive and active

limb movements will reduce the risk of limb

contractures, which can occur in patients

with limb weakness, and splints and braces

may be needed to facilitate mobilisation.

Management in the recoveryperiodIdeally, a full neuropsychological assessment

should be organised at hospital discharge, or

soon after. This should include cognitive

function, intelligence, memory and speech

assessment, because these help determine the

extent of any damage, and the help that

might be needed. Regular out-patient assess-

ment following encephalitis is especially

important in children. Behavioural and psy-

chiatric disturbances are common and may

include depression or disinhibition.

Antidepressants and mild night-time seda-

tives may be necessary. Other disabilities in

the recovery period or afterwards include

seizures, post-encephalitic parkinsonism seen

after encephalitis lethargica, and encephalitis

caused by flaviviruses. The risk of seizures is

greatest in those who had seizures during the

acute period; in one study the cumulative risk

of seizures at 5 years was 10% for patients

with no acute seizures, which increased to

20% for those with acute seizures.57

Memory difficulties can be particularly

prominent after HSV encephalitis. A range of

practical approaches can help to overcome

these difficulties such as the patient keeping

a notebook and diary, labelling items around

the house, and leaving messages as remin-

ders. More sophisticated aids being developed

include a neuropage system (http://www.

neuropage.nhs.uk), which sends pager remin-

der messages throughout the day, and a

camera, worn around the neck, which auto-

matically takes pictures throughout the day

as a reminder of what the patient has been

doing (SenseCam – http://reseach.microsoft.

com.sendev/). 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

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 aspossible, unless there is an indication for a brain CT first.

l Patients with a meningococcal rash and/or sepsis should receive immediateantibiotics, but for most other patients investigation with lumbar punctureshould be possible before starting treatment.

300 Practical Neurology

10.1136/jnnp.2007.129098

HSV encephalitis include age above 60,

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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