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Viral encephalitis: a clinicians guide


Tom Solomon, Ian J Hart and Nicholas J Beeching

Practical Neurology 2007;7;288-305


doi:10.1136/jnnp.2007.129098

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288 Practical Neurology

REVIEW Pract Neurol 2007; 7: 288305

Viral
encephalitis: a
clinicians guide
Tom Solomon, Ian J Hart, Nicholas J Beeching

T Solomon
Professor of Neurology and MRC
Senior Clinical Fellow, University of
Liverpool Divisions of Neurological
Science and Medical Microbiology,
and The Walton Centre for
Neurology and Neurosurgery,
Liverpool, UK

I J Hart
Consultant Clinical Microbiologist,
Division of Medical Microbiology
and Genitourinary Medicine, Royal
Liverpool University Hospital,
Liverpool, UK

N J Beeching
Senior Lecturer and Clinical Lead,
Tropical and Infectious Diseases
Unit, Royal Liverpool University
Hospital, Liverpool, UK

Correspondence to:
Professor T Solomon
University of Liverpool Divisions of
Neurological Science and Medical
Microbiology, 8th Floor Duncan
Building, Daulby Street, Liverpool Virions of herpes simplex virus within the neuron, from a patient who died of herpes simplex encephalitis. From
L69 3GA, UK; tsolomon@liv.ac.uk Oppenheimers Diagnostic Neuropathology, Third Edition, Hodder Arnold 2006 E Margaret Esiri and Daniel Perl

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Solomon, Hart, Beeching 289

The management of patients with suspected viral encephalitis has been


revolutionised in recent years with improved imaging and viral diagnostics,
better antiviral and immunomodulatory therapies, and enhanced neuro-
intensive care. Despite this, disasters in patient management are sadly not
uncommon. While some patients are attacked with all known antimicrobials
with little thought to investigation of the cause of their illness, for others
there are prolonged and inappropriate delays before treatment is started.
Although viral encephalitis is relatively rare, patients with suspected central
nervous system (CNS) infections, who might have viral encephalitis, are not. In
addition, the increasing number of immunocompromised patients who may
have viral CNS infections, plus the spread of encephalitis caused by
arthropod-borne viruses, present new challenges to clinicians. This article
discusses the Liverpool approach to the investigation and treatment of adults
with suspected viral encephalitis, and introduces the Liverpool algorithm for
investigation and treatment of immunocompetent adults with suspected viral
encephalitis (available at www.liv.ac.uk/braininfections).

here can be few things more frightening enkephalon, brain. Encephalitis can be caused

T 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
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
successful and patients survive apparently bacteria such as Listeria monocytogenes and
intact, in many cases the family say that the Mycobacterium tuberculosis (table 2). For
person they took home with them is not the viruses such as HIV that infect the brain but
same as the one they brought to hospital, with without causing inflammation, the term
changes in personality, irritability, and poor encephalitis is not usually used.
short-term memory. The management of Encephalitis can also occur as an immune-
patients with suspected encephalitis has been mediated phenomenonfor example, acute
revolutionised in recent years with improved disseminated encephalomyelitis (ADEM,
imaging and viral diagnostics, better antiviral which follows infections or vaccinations),
and immunomodulatory therapies, and paraneoplastic limbic encephalitis, and vol-
enhanced neurointensive care settings. Despite tage gated potassium channel limbic ence-
this, disasters in patient management are sadly phalitis.1
not uncommon. Although viral encephalitis is Strictly speaking, encephalitis is a patho-
relatively rare, patients with suspected central logical diagnosis that should only be made if
nervous system (CNS) infections, who might there is tissue confirmation, either at autopsy
have viral encephalitis, are not. In addition, the
or on brain biopsy. However, in practice most
increasing number of immunocompromised
patients are diagnosed with encephalitis if
patients, who may have viral CNS infections,
they have the appropriate clinical presenta-
plus the spread of encephalitis caused by
tion (febrile illness, severe headache reduced
arthropod-borne viruses, present new chal-
consciousness (see below)) and surrogate
lenges to clinicians. This review aims to provide
markers of brain inflammation, such as
a rational approach to the investigation and
inflammatory cells in the cerebrospinal fluid
treatment of a patient with suspected viral
(CSF), or inflammation shown on imaging,
encephalitis.
especially if an appropriate organism is
detected. Encephalitis must be distinguished
WHAT IS ENCEPHALITIS? from encephalopathy, the clinical syndrome
Encephalitis means inflammation of the brain of reduced consciousness, which can be
parenchyma, and comes from the Greek caused by viral encephalitis, other infectious
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290 Practical Neurology

limbic structures), while rhombencephalitis


TABLE 1 Causes of acute viral encephalitis (modified from Solomon and means hindbrain, or brainstem encephalitis.
Whitley58)

Sporadic causes of viral encephalitis (not geographically restricted) listed by PATHOGENESIS


group Depending on the virus, the pathogenesis
l Herpes viruses consists of a mixture of direct viral cyto-
Herpes simplex virus types 1 & 2, varicella zoster virus, Epstein-Barr pathology (that is, viral destruction of cells)
virus, cytomegalovirus, human herpes virus types 6 & 7 and/or a para- or post-infectious inflamma-
l Enteroviruses tory or immune-mediated response (fig 1). For
Coxsackie viruses, echoviruses, enteroviruses 70 & 71, parechovirus, most viruses, the brain parenchyma and
poliovirus neuronal cells are primarily infected, but for
l Paramyxoviruses
some the blood vessels can be attacked giving
Measles virus, mumps virus,
l Others (rarer causes) a strong vasculitic component. Demyelination
Influenza viruses, adenovirus, parvovirus, lymphocytic choreomeningitis following infection can also contribute.
virus, rubella virus Herpes simplex virus (HSV) for example,
Geographically restricted causes of encephalitismostly arthropod-borne* primarily targets the brain parenchyma in
l The Americas the temporal lobes, sometimes with frontal or
West Nile, La Cross, St Louis, Rocio, Powassan encephalitis, parietal involvement. Mumps virus can cause
Venezuelan, eastern & western equine encephalitis, Colorado tick an acute viral encephalitis, or a delayed
fever virus, dengue, rabies immune mediated encephalitis. Measles virus
l Europe/Middle East causes a post-infectious encephalitis, which
Tick-borne encephalitis, West Nile, Tosana, rabies, (dengue virus, can sometimes have a severe haemorrhagic
louping ill virus)
component (acute haemorrhagic leukoence-
l Africa
phalitis). With influenza A virus, diffuse
West Nile, (Rift Valley fever virus, Crimean-Congo haemorrhagic fever,
dengue, chikungunya), rabies cerebral oedema is a major component in
l Asia the pathogenesis, while for varicella zoster
Japanese encephalitis, West Nile, dengue, Murray Valley encephalitis, virus (VZV), vasculitis is a major pathogenic
rabies, (chikungunya virus, Nipah) process.
l Australasia How and when the virus crosses the blood
Murray Valley encephalitis, Japanese encephalitis (kunjin, dengue) brain barrier is a key issue in the pathogenesis
of any viral encephalitis.
Rarer or suspected arboviral causes are shown in brackets.
For example, primary infection with HSV
*All viruses are arthropod-borne, except for rabies and Nipah.
type 1 (HSV-1) occurs in the oral mucosa, and
may cause herpes labialis (vesicles and ulcers
diseases, metabolic disorders, drugs and around the mouth) or be asymptomatic
alcohol. Metabolic and toxic causes of (serological studies show that up to 90% of
encephalopathy can usually be distinguished healthy adults have been infected with HSV-
from viral encephalitis by the lack of any 1). Following primary infection the virus
acute febrile illness, more gradual onset, lack travels centripetally along the trigeminal
of a CSF pleocytosis and absence of focal nerve to give latent infection in the trigeminal
changes on brain MRI.2 ganglion, in most if not all those infected.
Some of the organisms that cause ence- About 30% of infected people have clinically
phalitis often also cause an associated apparent herpes labialis, but even asympto-
meningeal reaction (meningitis), spinal cord matic individuals have episodes or viral
inflammation (myelitis), or nerve root invol- shedding. About 70% of cases of HSV-1
vement (radiculitis); these terms are some- encephalitis already have antibody present,
times used in various combinations to reflect indicating that reactivation of virus must be
whichever part of the neuraxis is affectedfor the most common mechanism;3 however, it is
example. meningoencephalitis, encephalo- not clear whether this is due to reactivation
myelitis, meningoencephalomyelitis, myelora- of virus in the trigeminal ganglion, or virus
diculitis, meningoencephaloradiculitis. The that had already established latency in the
term limbic encephalitis refers to encepha- brain itself.4 Why HSV sometimes reactivates
litis of the temporal lobes (and often of other is not known. In contrast to adults, in younger
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Solomon, Hart, Beeching 291

TABLE 2 Diseases that may mimic viral meningoencephalitis (modified from


Solomon and Whiteley58)

Central nervous system infections Para/post-infectious causes


Bacteria Guillain-Barre syndrome*
Bacterial meninigitis Viral illnesses with febrile convulsions
Tuberculosis Shigella
Brain abscess Systemic viral illnesses with febrile convulsions
Typhoid fever Systemic viral illnesses associated with swollen
Parameningeal infection fontanelle
Lyme disease
Syphilis Non-infectious diseases
Relapsing fever Vascular
Leptospirosis Vasculitis
Mycoplasma pneumoniae Systemic lupus erythematosus
Listeriosis Subarachnoid and subdural haemorrhage
Brucellosis Ischaemic stroke
Subacute bacterial endocarditis Behcets disease
Whipples disease Neoplastic
Nocardia Primary brain tumour
Actinomycosis Metastases
Paraneoplastic limbic encephalitis
Fungi Metabolic
Candidiasis Hepatic encephalopathy
Cryptococcus Renal encephalopathy
Coccidiomycosis Hypoglycaemia
Histoplasmosis Reyes syndrome
North American blastomycosis Toxic encephalopathy (alcohol, drugs)
Other
Parasites Drug reactions
Cerebral malaria Epilepsy
Toxoplasmosis Hysteria
Cysticercosis Voltage gated K channel limbic encephalitis
Trypanosomiasis
Echinococcus
Trichinosis
Amoebiasis

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

*Guillain-Barre syndrome and acute disseminated encephalomyelitis may follow viral or


bacterial infections or vaccinations.

patients, particularly children, HSV-1 ence- meningitis, especially recurrent meningitis,


phalitis occurs during primary infection. encephalitis, particularly in neonates, and
HSV type 2 (HSV-2) is usually transmitted lumbosacral radiculitis. Most cases of recur-
via the genital mucosa, causing genital herpes rent meningitis that were previously called
in adults. In the USA approximately 20% of Mollarets meningitis are now thought to be
individuals are sero-positive for HSV-2. The due to HSV-2, although some feel the term
neurological syndromes it causes include Mollarets should still be reserved for those
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292 Practical Neurology

Figure 1
Histopathological picture of the
temporal cortex of a man who died
from herpes simplex virus encephalitis.
(A) Intense perivascular inflammatory
infiltrate consisting of activated
microglia, macrophages and
lymphocytes (H&E staining, 620). (B)
High power view showing microglia
and dead neurons with nuclear
dissolution (karyolysis) and
hypereosinophilia within the cytoplasm
retaining the original pyramidal contour
(H&E 640). (Pictures courtesy of Dr
Daniel Crooks.)

with recurrent meningitis in whom the cause morbillivirus (in the same family as
is still not known. Neonates can also be measles) that was recognised for the first
infected with HSV-2 during delivery to cause time in 1998 when it caused encephalitis
neonatal herpes, a disseminated infection in humans in Malaysia.8 This virus has
also caused disease in Bangladesh and
often with CNS involvement.
appears to be spreading.
The other major route by which viruses
enter the nervous system is during a viraemia N Encephalitis caused by vaccine preventa-
ble viruses such as measles and mumps is
and subsequent spread across the blood brain
less common in industrialised nations;
barrier. This occurs with enteroviruses such as
however, in the UK reduced vaccine
poliovirus and arboviruses such as West Nile uptake in recent years has been asso-
virus. ciated with a resurgence of these viruses.9

EPIDEMIOLOGY OF VIRAL Incidence of viral encephalitis


ENCEPHALITIS It is difficult to determine the incidence of
Changing epidemiology encephalitis because the various studies have
While HSV-1 encephalitis occurs with used different case definitions and viral
dependable regularity across the globe, there diagnostic capabilities. However, most studies
have been notable changes in the epidemiol- report an annual incidence of 510 per
ogy of other viral causes: 100 000,10, 11 highest in the young and elderly.
N Cytomegalovirus (CMV) and Epstein-Barr Higher incidences are found in areas with
virus (EBV), and to some extent human arthropod-borne viruses. A lower annual
herpes virus (HHV)-6, are being seen more incidence of 1.5 per 100 000 has been
often because they occur in patients reported in England, based on hospitalisation
immunocompromised by HIV, transplant data,12 although this was probably an under-
or cancer chemotherapy. estimate. HSV encephalitis is the most
N Arboviruses such as West Nile virus and commonly diagnosed viral encephalitis in
Japanese encephalitis virus are spreading industrialised nations, with an annual inci-
to new areas.5 West Nile virus has caused dence of 1 in 250 000 to 500 000.13 Most HSV
outbreaks in the Americas and southern encephalitis is due to HSV-1, but about 10%
Europe, and there is evidence suggesting
are HSV-2. The latter typically occurs in
the virus has reached the UK,6 although it
immunocompromised individuals, and neo-
has not yet caused human disease there.
The contribution of climate change to the nates, in whom it causes a disseminated
spread of these viruses is not clear. Other infection.
viruses that have caused large unex-
pected outbreaks in Asia and are spread-
ing include enterovirus 71, and Nipah
WHEN SHOULD ENCEPHALITIS
virus. Enterovirus 71 has caused massive
BE SUSPECTED?
outbreaks of hand foot and mouth The classical presentation of viral encephalitis
disease in Asia in recent years, which is is generally as an acute flu-like prodrome,
often associated with aseptic meningitis, developing into an illness with high fever,
encephalitis or myelitis.7 Nipah virus is a severe headache, nausea, vomiting and
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Solomon, Hart, Beeching 293

Figure 2

altered consciousness, often associated with Alterations in higher mental function include
seizures and focal neurological signs (fig 2). lethargy, drowsiness, confusion, disorienta-
Eighty five (91%) of 93 adults with HSV-1 tion and coma. With the advent of CSF PCR
encephalitis in one recent study were febrile more subtle presentations of HSV encephalitis
on admission.14 Disorientation (76%), speech have been recognised;15 low grade pyrexia
disturbances (59%) and behavioural changes rather than a high fever, speech disturbances
(41%) were the most common features, and (dysphasia and aphasia), and behavioural
one third of patients had seizures.14 changes which can mistaken for psychiatric
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294 Practical Neurology

with an acute confusional state, which has


TABLE 3 Why encephalitis may be missed been incorrectly attributed to a systemic
infection.16 Although most viral encephalitis
l Wrongly attributing a patients fever and confusion to a urinary tract presents acutely, subacute and chronic pre-
infection (based on a urine dipstick) or a chest infection (based on a few sentations can be caused by CMV, VZV and
crackles in the chest) without strong evidence HSV, especially in patients immunocompro-
l Failure to realise that a patient has a febrile illness, just because they are mised as a result of HIV, or immunosuppres-
not febrile on admission
sive drugs15 (table 4).
l Ignoring a relatives complaint that a patient is not quite right, sleepy or
lethargic, just because the Glasgow coma score is 15 (the coma score is a
very crude tool) IMPORTANT FEATURES IN THE
l Wrongly attributing clouding of consciousness to drugs or alcohol, HISTORY
without good evidence to do so
As well as being crucial in determining who
l Failure to properly investigate a patient with a fever and seizure,
needs investigation for encephalitis, the
following which they do not recover consciousness
l Failure to do a lumbar puncture, even though there are no history can provide useful clues to aetiology.
contraindications 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
illness, or the consequences of drugs or not seem right, should not be ignored, even
alcohol, occasionally with tragic consequences. if the Glasgow Coma Score is 15; remember
Seizures can sometimes be the initial presenting this is a very crude tool that was devised for
feature of a patient with encephalitis. Any adult assessing patients with head injuries.
with a seizure in the context of a febrile illness, Ask about recent rashes such as measles.
or a seizure from which they do not recover, Even if there is no such history in the patient,
must be investigated for possible CNS infection. ask whether others in the family or in the
There are several reasons why one may not community have been affected (these viruses
think of encephalitis, particularly a failure to occasionally cause encephalitis without the
appreciate the importance of altered con- obvious stigmata). In children, a recent rash
sciousness in the context of a febrile illness, may suggest chickenpox, parvovirus or HHV-6.
or failure to investigate these symptoms Parotitis, testicular pain or abdominal pain due
properly when they are recognised (table 3). to pancreatitis may suggest mumps virus as the
One of the commonest failings is delay in causative organism. If the patient is conscious,
performing a lumbar puncture in patients ask about any strange smells, which may be
olfactory hallucinations reflecting frontotem-
poral involvement in HSV-1 encephalitis.
TABLE 4 Causes of subacute and chronic viral encephalitis A travel history is essential, as are vaccination
details. Travellers from Asia with fever and
In immunocompromised patients (HIV, organ transplant recipients, cancer reduced consciousness may be infected with
patients, those on immunosuppressive therapy, including steroids) dengue or Japanese encephalitis viruses; they
l Measles (inclusion body encephalitis) may also have acquired meningoencephalitis
l Varicella zoster virus (causes a multifocal leukoencephalopathy)
from eating snails carrying the rat lungworm
l Cytomegalovirus
Angiostrongylus cantonensis. Cerebral malaria
l Herpes simplex virus (especially HSV-2)
l Human herpes virus 6 should also be considered in returning travellers,
l Enterovirus especially from Africa.17
l JC/BK* virus (causes progressive multifocal leukoencephalopathy) Ask if there has been any contact with
In immunocompetent patients animals, or whether there are sick animals in
l JC/BK* virus (causes progressive multifocal leukoencephalopathy) the neighbourhood. In the USA some out-
l Measles virus (subacute sclerosing panencephalitis, years after primary breaks of West Nile virus were heralded by
infection) sick birds falling from the sky.18 The history of
l Rubella virus (causes progressive rubella panencephalitis, very rare) a dog bite in a rabies endemic area may be
important,19 as may a bite or scratch from a
*JE and BK viruses are named after the initials of the patients from whom
bat; in the UK and Europe, Daubentons
they were first isolated.
bats carry rabies-like viruses (European bat
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Solomon, Hart, Beeching 295

lyssaviruses).20 Other risk factors are related to


occupation and recreational activities: TABLE 5 Brainstem encephalitis (rhombencephalitis): clues and causes
N leptospirosis can be acquired from rat
Suggestive clinical features
urine during fresh water activities
l Lower cranial nerve involvement
N lymphocytic choreomeningitis virus l Myoclonus
(LCMV) is transmitted in rodent faeces; l Autonomic dysfunction
humans are exposed when cleaning out l Locked-in syndrome
barns, etc l MRI changes in the brainstem, with gadolinium enhancement of basal
N hikers in the forests of Austria, Germany, meninges
and Eastern Europe are at risk of tick- Causesviral and other
borne encephalitis virus (TBEV) l Enteroviruses (especially EV71)
N a related virus, Louping ill virus, causes l Flaviviruses, eg West Nile virus, Japanese encephalitis virus
occasional encephalitis in sheep in the l Listeria
Scottish Highlands, and very rarely in l Tuberculosis
humans l Brucella
N hikers in the New Forest in the UK are at l Borrelia
risk of Lyme disease. l Paraneoplastic syndromes
Ask about risk factors for HIV, including
previous blood transfusions, and high-risk
behaviours such as intravenous drug use, sex infection. However, beware ascribing reduced
between men, and multiple sexual partners, consciousness to a urinary or chest infection,
especially with people from high-risk areas of especially in someone who is otherwise fit
the world such as sub-Saharan Africa and and well. Such patients need a lumbar
Thailand. puncture to rule out a CNS infection.
Look for seizures including subtle motor
seizures, and examine the side of the tongue
IMPORTANT EXAMINATION
FINDINGS or inside cheek for bites indicating that a
seizure has occurred. Test for meningism, and
On examination the first priorities are to
look for focal neurological signs, including
check that the airway is protected, assess and
hemispheric signs that could indicate an
document the level of consciousness, using a
abscess, or flaccid paralysis suggestive of
quantitative scale such as the Glasgow Coma
spinal cord involvement. Tremors and abnor-
Scale (GCS), and treat any immediate com-
mal movements are seen in some forms of
plications of infection such as generalised
encephalitis, particularly those that involve
seizures. For patients with mild behavioural
abnormalities or disorientation, document the the basal ganglia, such as West Nile virus and
odd behaviour, and record the mini-mental other flaviviruses, or toxoplasmosis. An acute
test score. The general medical examination febrile encephalopathy with lower cranial
should include a search for other possible neuropathies and myoclonus suggests a
explanations of the coma. rhomboencephalitis or basal meningoence-
Look for a purpuric (meningococcal) rash phalitis, as seen with some enteroviruses, or
and other exanthema, bites and stigmata that listeria (table 5). Deafness is quite common in
may suggest an aetiology; is there the rash of mumps and some rickettsial infections. Upper
shingles? Are there injection sites that might limb weakness and fasciculation suggest a
indicate intravenous drug use? Look for cervical myelitis, for example in tick-borne
seborrhoeic dermatitis, oral candida or oral encephalitis. Encephalitis associated with
hairy leukoplakia in the mouth, or Kaposis radiculitis is seen in CMV and EBV.
sarcoma on the skin indicative of undiag-
nosed HIV infection. In patients with HIV look INITIAL INVESTIGATIONS
for mouth ulcers or umbilicated skin papules
suggestive of disseminated histoplasmosis or N A peripheral blood count may show a
cryptococcosis. Look at the genitals for the leukocytosis or leukopenia. Atypical lym-
ulcers of HSV and chancres of syphilis. phocytes are seen in EBV infection, and
Examine also the chest, ears and urine for eosinophilia in eosinophilic meningitis.
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296 Practical Neurology

and glucose ratio) reveal firstly whether or


not there is infection, and secondly whether it
is likely to be bacterial or viral infection,
which thus informs the initial antimicrobial
therapy. Subsequent studies such as culture
and PCR confirm precisely what the organism
is, which allows the therapy to be tailored and
appropriate public health measures, including
disease notification, to be organised.
However, if patients have a space-occupying
lesion, marked brain swelling, or brain shift (for
example herniation across the midline, the
tentorium or the foramen magnum), then a
lumbar puncture may of course make things
worse. Raised intracranial pressure itself is not a
problemindeed patients with idiopathic intra-
cranial hypertension are treated by lumbar
Figure 3 N Hyponatraemia due to the syndrome of punctures, and in most patients with CNS
CT scan with contrast of a middle-aged inappropriate antidiuretic hormone infection the CSF opening pressure is raised to
man with a one-week history of a flu- (SIADH) is common in encephalitis. some degree.22, 23 The problem is the swelling or
like illness, severe headache and
increasing confusion, who had HSV N A raised serum amylase is common in shift which is sometimes associated with the
encephalitis confirmed by CSF PCR. (A) mumps virus infection. raised pressure, so the pressure is not the same
A low density area in the left temporal
lobe, with swelling and some contrast
N If there has been a respiratory component in all the CSF compartments. For this reason
enhancement. (B) The same patient four
to the presentation check for cold agglu- patients should be assessed for clinical features
days later with more marked changes tinins, which occur in mycoplasma infec- which might indicate a space-occupying lesion,
(Photos: T Solomon). tion, and order appropriate serological brain swelling or shift, and who should then
investigations for mycoplasma and chla-
have computed tomography (CT) before lumbar
mydia (atypical respiratory infections).
puncture (fig 3); focal neurological signs (for
N Blood cultures should be taken as part of
example a hemiparesis), new onset seizures,
the investigation of possible bacterial
causes, and PCR of the blood for papilloedema and deep coma. CT is also
meningococcus considered. recommended for immunocompromised
patients, who may lack the clinical signs of an
N Bacterial antigen testing of CSF and urine
may be helpful. inflammatory mass lesion.24 Opinions vary as to
what level of deep coma necessitates a CT
N A chest x ray is essential to look for
pulmonary infiltrates in atypical pneu- scan before lumbar puncture. To some extent it
monia, for example in mycoplasma pneu- depends on how quickly imaging can be
monia, legionella or LCMV. organised. If a CT scan can be performed
N HIV testing should also be considered, promptly, so that it will not delay lumbar
especially if the cause of CNS infection is puncture for more than an hour or two, then it
uncertain. Our practice is to perform the is reasonable to do this first. However, in a
test in all patients with undiagnosed CNS patient who is only mildly confused with no
infection because if positive it makes focal neurological signs, than a lumbar punc-
such a difference to the differential and ture should be done straight away, without the
management.
unnecessary delay of a CT.24
If a CT is going to cause a delay of several
THE LUMBAR PUNCTURE hours, then presumptive treatment for both
CONTROVERSY bacterial and/or viral pathogens should be
Few topics have led to as much confusion, started. There are no hard and fast rules about
contradiction and controversy as the role of how long a delay is acceptable before treat-
lumbar punctures in patients with suspected ment is initiated. For bacterial meningitis a
CNS infection.21 A lumbar puncture is an delay of more than six hours between arrival in
essential investigation because the initial CSF hospital and initiation of antibiotic treatment
findings (especially the cell count, differential is associated with a worse outcome.25 If
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Solomon, Hart, Beeching 297

TABLE 6 Typical cerebrospinal fluid findings in central nervous system infections

Viral meningo- Acute bacterial Tuberculous


encephalitis meningitis meningitis Fungal Normal
Opening pressure Normal/high High High Highvery high 1020 cm*
Colour Gin clear Cloudy Cloudy/yellow Clear/cloudy Clear
Cells/mm3 Slightly increased Highvery high Slightly increased Normalhigh
51000 10050000 25500 01000 ,5{
Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes Lymphocytes
CSF/plasma glucose Normal Low Lowvery low Normallow 66%{
ratio (,30%)
Protein (g/l) Normalhigh High Highvery high Normalhigh ,0.45{
0.51 .1 1.05.0 0.25.0
*Normal CSF opening pressure is generally ,20 cm for adults, ,10 cm for children below age 8, but may be as high as 25 cm
(Whiteley et al, Neurology 2006;67:16901).
{A bloody tap will falsely elevate the CSF white cell count and protein. To correct for a bloody tap, subtract 1 white cell for
every 700 red blood cells/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.

patients have a purpuric rash suggestive of antimicrobial treatment has been started, it
meningococcal septicaemia, or are deteriorat- is still essential to perform a lumbar puncture,
ing rapidly, antibiotics should be started because this informs the diagnosis and guides
immediately.26 In HSV-1 encephalitis, a bad subsequent management.28 Giving blind anti-
outcome is associated with a delay of two days bacterial and antiviral treatment to all
or more between hospitalisation and starting patients with suspected CNS infection, and
treatment.14 In practice, HSV encephalitis is then not investigating with lumbar puncture
rare, and most suspected cases turn out to because it makes no difference to the
have something different.27 While one would management is unacceptable practice and
not advocate unnecessary delays, together should be discouraged.21 This approach risks
these data suggest that for patients with missing other diagnoses that may require
suspected encephalitis the emphasis should be alternative treatments,29 and increases the
on investigating promptly where possible risk of adverse effects of the unwarranted
before starting treatment. For most patients and unnecessary drugs. For HSV-1 encepha-
with no contraindication, it should be possible litis, PCR of the CSF remains positive in about
to perform a lumbar puncture, and get the 80% of patients even a week after starting
result back within a few hours to then guide antiviral therapy.13
the management. If there are delays or a
patient appears to be deteriorating, then CEREBROSPINAL FLUID
presumptive treatment with aciclovir is appro- FINDINGS
priate, at least while investigations proceed. In encephalitis, the CSF opening pressure is
For patients with suspected bacterial often slightly raised, and there is usually a
meningitis or viral encephalitis, even if mild to moderate CSF pleocytosis of 51000
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298 Practical Neurology

DIAGNOSTIC VIROLOGY
TABLE 7 Staged approach to microbiological investigation of viral The definitive diagnosis of a viral CNS infection
encephalitis is based on demonstrating the virus in the CNS,
either from culture or PCR of brain tissue or CSF,
CSF PCR or by demonstrating a specific antibody
l All patients
response in the CSF. Less strong evidence
HSV-1, HSV-2, VZV
comes from detecting virus elsewhere in the
Enterovirus, parechovirus,
l If indicated body of a patient with a CNS syndrome (for
EBV/CMV (especially if immunocompromised) example, from throat, rectal or vesicle swabs), or
HHV 6,7 (especially if immunocompromised, or children) showing an antibody response to the virus in
Adenovirus, influenza A & B, rotavirus (children) the serum (the organism is then presumed to be
Measles, mumps (if clinically indicated) responsible for the clinical presentation,
Parvovirus B19 although there is always the possibility that it
Chlamydia (if clinically indicated) is a coincidental infection).
l Special circumstance
Rabies, West Nile virus, tick-borne encephalitis virus (if appropriate
exposure) PCR of CSF
Antibody testing (where indicatedsee text) *
The diagnosis of viral encephalitis used to rely
l Viruses: IgM and IgG in CSF and serum (acute and convalescent), for
antibodies against HSV 1 & 2, VZV, CMV, HHV6, HHV7, enteroviruses, RSV, on brain biopsy,27 but many important viruses
parvovirus B19, adenovirus, influenza A & B;* can now be detected with PCR.32, 33 PCR tests
l Antibody detection in the serum identifies infection (past or recent for HSV have overall sensitivity and specificity
depending on the type of antibodies) but does not necessarily mean this .95%, but may be negative in the first few
virus has caused the CNS disease days of the illness, or after about 10 days.34, 35
l If associated with atypical pneumonia, test serum for Initial investigation of immunocompetent
Mycoplasma serology and cold agglutinins patients with encephalitis should include
Chlamydia serology PCR for both HSV and VZV because these
Ancillary investigations (these establish systemic infection, but not
are potentially treatable with aciclovir (see
necessarily the cause of the CNS disease)
below) (table 7). Enterovirus PCR is often
l Throat swab, nasopharyngeal aspirate, rectal swab
PCR/culture of throat swab, rectal swab for enteroviruses included at this stage, because it is a relatively
PCR of throat swab for mycoplasma, chlamydia common cause of viral meningitis, especially
PCR/antigen detection of nasopharyngeal aspirate for respiratory in the summer/autumn. In immunocompro-
viruses, adenovirus, influenza virus (especially children) mised patients, EBV and CMV PCR should also
l Vesicle electron microscopy, PCR and culture be performed, and HHV-6 and HHV-7 con-
Patients with herpetic lesions (for HSV, VZV) sidered. Measles and mumps should be looked
Children with hand foot and mouth disease (for enteroviruses) for if there is a suggestive clinical indication,
l Brain biopsy although they can occasionally cause ence-
For culture, electron microscopy, PCR and immunohistochemistry
phalitis in patients with no other features.
Other viruses to consider, especially in children,
include adenoviruses, HHV-6, respiratory
cells/mm3, with predominant lymphocytes syncitial virus (RSV), and influenza virus A and
(table 6). However, early in the infection the B; rotaviruses and parvovirus B19 are also
CSF white cell count may be normal, or occasionally associated with CNS disease,
neutrophils may predominate, as they do in especially in children.36, 37 PCR can also be used
viral meningitis.30 The CSF red cell count is to detect Chlamydia pneumoniae in the CSF.
usually normal, or slightly raised, but it may CSF viral culture is now rarely performed,
be markedly raised in HSV-1 encephalitis, although it has the potential advantage over
which can be haemorrhagic, or in acute PCR of being able to detect any virus, whereas
necrotising haemorrhagic leukoencephalitis. PCR only detects the viruses being targeted by
The glucose ratio is usually normal in viral the panel of PCR assays used. Newer more
CNS infections, though it may be a little sensitive PCR methods, such as real-time and
reducedfor example, in mumps or enter- quantitative PCR have improved the clinical
ovirus infection.31 The CSF protein is often utility of this test, and are becoming available
slightly raised, between 0.5 and 1.0 g/l. for herpes viruses and enteroviruses.38
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Solomon, Hart, Beeching 299

One problem is that the high sensitivity of 1/200th of the serum concentration; hence in a
some of the recent PCR assays for herpes primary acute CNS infection, IgG rises later than
viruses, such as EBV and CMV, can make IgM both in CSF and serum. In reactivations and
positive results difficult to interpret. Most of secondary infections, IgG tends to rise earlier
the adult population have been infected with and to a greater extent than IgM.
these viruses and carry them in their The detection of oligoclonal bands is
lymphocytes. Therefore, there is debate about sometimes a useful non-specific indicator
whether detection of the viruses by PCR of that a patient has an inflammatory process in
the CSF represents true pathogenic infection, the CNS, rather than a non-inflammatory
rather than just the presence of infected cause of encephalopathy. Immunoblotting of
lymphocytes.39 Where there is uncertainty the bands against viral proteins has been
about the significance of a result, the amount used, but mostly as a research tool to help
of virus in the CSF compared with the blood determine the cause of the inflammationfor
(determined by quantitative PCR) usually example, HSV-1 or HSV-2.29, 34 However, the
helps resolve it. For example, in a patient detection of intrathecal anti-HSV antibody
with HIV, a CSF CMV PCR titre that is higher has a sensitivity of 50% by 10 days after
than that in the serum is usually significant. clinical presentation, and is thus only con-
sidered useful for retrospective diagnosis.
Our practice, at least for diagnosing HSV
Antibody testing infections, is to ask for PCR on CSF acutely. If
Antibody testing continues to play an impor- this is negative, but suspicion remains high,
tant role in the diagnosis of many viral CNS PCR of the CSF is repeated after a few days
infections. Traditional techniques required the (as indicated above PCR can sometimes be
demonstration of a fourfold rise in antibody negative if the sample is taken early in the
between acute and convalescent serum illness). If two CSFs are negative for HSV by
samples collected 24 weeks apart, and thus PCR then it is unlikely that the patient has
are not helpful in making an early diagnosis. HSV infection. If for logistic reasons CSFs
And in practice convalescent samples are were not taken at this time, or were not sent
often forgotten. for HSV PCR, then testing a late CSF (for
Newer enzyme immunoassays can detect example, later than 10 days of hospitalisa-
immunoglobulin (Ig)-M and IgG antibodies in tion) for the production of intrathecal anti-
the serum and CSF against most of the bodies against HSV, by IgM, IgG or antibody-
important viruses, as well as Mycoplasma mediated immunoblotting of oligoclonal
pneumoniae. Specific anti-viral IgM is often bands, can be useful.
produced within a few days of a primary
infection and can be measured by IgM
enzyme immunoassays. The detection of virus INVESTIGATION OF OTHER
specific IgM antibodies in the CSF in higher SAMPLES
titres than in serum indicates local production Other investigations include:
of antibody in the CNS in response to
infection. IgM does not normally cross the
N PCR and/or culture of throat and rectal
swabs for enteroviruses, mumps virus or
blood-brain barrier because of its size. measles virus.
However, if there is inflammation the barrier
is leaky to IgM, and other immunoglobulins. N PCR or antigen detection and culture of
nasopharyngeal aspirates for respiratory
In this circumstance, the ratio of CSF to
viruses such as adenoviruses, RSV, para-
serum for the specific IgM antibody can be influenza viruses or influenza viruses.
compared to the ratio for immunoglobulin as
a whole, to decide if this is local production N Urine culture for mumps virus.
rather than leak across an inflamed blood- N Chlamydia pneumoniae and Mycoplasma
brain barrier. IgM detection is especially pneumonia can also be detected in throat
useful for flavivirus infections, but less so swabs using PCR.
for herpes virus infections, which are often N Vesicles, for example in hand foot and
reactivations. In contrast to IgM, IgG is mouth disease, should be aspirated for
normally found in the CSF at a ratio of culture or PCR, for enteroviruses.
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300 Practical Neurology

investigated with CMV and EBV PCR. Further


Figure 4
investigations are guided by the clinical picture,
T2-weighted MRI brain scan showing
right temporal lobe hyperintensity in a especially the patients immune competence
patient with herpes encephalitis and the initial CSF findings. The opinion of a
(Photos: T Solomon). clinical virologist in assessing such patients is
invaluable.
With the advent of PCR, brain biopsy of
patients with suspected encephalitis has
become less common. Previously it was
considered the gold standard for diagnosis
of HSV-1 encephalitis. It may still have a role
in undiagnosed patients that are deteriorat-
ing. In one study approximately half of
patients with suspected HSV-1 encephalitis
who had a brain biopsy had an alternative
diagnosis, of which 40% were treatable.27

IMAGING AND EEG


As described above, in patients with ence-
phalopathy and fever, a CT scan is generally
done before the lumbar puncture if there are
clinical features of brain shift or a space-
occupying lesion. In HSV the scan may be
normal initially, or there may be subtle
swelling of the frontotemporal region with
loss of the normal gyral pattern (fig 1).
Subsequently there is hypodensity, or there
may be high signal change if haemorrhagic
transformation occurs. MRI is generally more
sensitive, showing high signal intensities in
the brain areas affected (fig 4), but even MRI
scans can look normal if performed very
N VZV or HSV can be detected in herpetic early.41 Diffusion-weighted MRI may be
rashes by cell culture, antigen detection especially useful for demonstrating early
by immunofluorescence or PCR. Electron changes.42
microscopy of vesicle fluids may also An EEG usually shows non-specific diffuse
demonstrate herpes viruses. high amplitude slow waves of encephalo-
In general, a virus detected in sterile sites, pathy, but can be useful to look for subtle
such as vesicles, is more likely to be causal epileptic seizures. Periodic lateralised epilepti-
than a virus from non-sterile sites. For form discharges were once thought to be
example, enteroviruses detected in vesicle diagnostic of HSV encephalitis, but have since
swabs indicate that they are temporally been seen in other conditions.43
associated with the acute infection, whereas
shedding from the rectum occurs for several MANAGEMENT
weeks after an acute infection.40 There are three elements to the management
The list of all possible investigations for of patients with encephalitis:
causes of viral CNS disease is clearly very long.
Our practice is to do the initial CSF PCR for HSV N the first is to consider whether there is
and VZV as soon as the samples are received, any antiviral or immunomodulatory treat-
because of their importance for early manage- ment to halt or reverse the disease
ment. PCR for enteroviruses and parechoviruses process;
is also usually done at this stage. In addition, N the second is to control the immediate
patients that are immunocompromised are complications of the encephalitis;
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Solomon, Hart, Beeching 301

TABLE 8 Treatment options to consider in encephalitis (modified from Boos and Esiri)52

Acute viral encephalitis


Herpes simplex virus 1 and 2 Aciclovir
Varicella zoster virus (incluing cerebellitis) Aciclovir plus corticosteroids
Human herpes virus-6 Ganciclovir, foscarnet
Rabies Ketamine*, amantidine, ribavirin
Subacute/chronic encephalitis
In the immunocompromised
Varicella-zoster virus Aciclovir
Cytomegalovirus Ganciclovir, foscarnet, cidofovir
Measles inclusion body encephalitis Ribavirin
Enterovirus Pleconaril, specific immunoglobulin
Progressive multifocal leukoencephalophy in HIV patients Highly active antiretroviral therapy (HAART), cidofovir
In the immunocompetent
Subacute sclerosing panencephalitis Interferon alpha (intraventricular), ribavirin inosiplex
Progressive multifocal leukoencephalopathy Consider cytosine arabinoside (ARA-C)
Progressive rubella panencephalitis Plasma exchange
Rasmussens encephalitis IVIg
Immune-mediated encephalitis
Acute disseminated encephalomyelitis{ Coricoteroids/IVIg/plasma exchange
Paraneoplastic Treatment of underlying tumour, consider immunosuppression
Voltage gated K channel limbic encephalitis IVIg/plasma exchange plus corticosteroids

*Considered experimental.
{Acute disseminated encephalomyelitis presents acutely; the others typically present with a subacute encephalitis.

N the third is to prevent some of the For example in much of Asia large outbreaks
secondary and late complications. of Japanese encephalitis occur; in parts of
Standard intensive care for patients with Asia and sub-Saharan Africa, HIV-associated
encephalitis include oxygen via a mask, CNS infections and cerebral malaria are
paying attention to fluid and hydration, common.
nasogastric or parenteral feeding, and treat- Aciclovir is a nucleoside analogue that is
ing the complications of infection such as highly effective against HSV and some of the
pneumonia. Patients with a reduced coma other herpes viruses, such as VZV and herpes
score or impaired gag reflex, should be B virus. Intravenous administration of aciclo-
assessed by an intensive care unit outreach vir at 10 mg/kg three times daily reduces the
team, with a view to early transfer. risk of a fatal outcome from approximately
70% to less than 20%.44, 45 Renal function
When to start aciclovir should be monitored closely and adequate
In most immunocompetent patients in devel- hydration maintained, because of the rare risk
oped countries aciclovir should be given as of renal failure. Other rare adverse effects
soon as there is a strong suspicion of viral include local inflammation at the site of the
encephalitis, based on the clinical presenta- intravenous canula, hepatitis, and bone
tion and initial CSF and/or imaging findings. If marrow failure.
performing these investigations is likely to
lead to long delays and the clinical suspicion When to stop aciclovir
is strong, then treatment should be started at Although the original aciclovir trials were for
once, for both viral encephalitis and possible 10 days treatment, most physicians continue
bacterial meningitis. The situation may be for 14 or 21 days, especially in patients with
different in developing countries, where the proven herpes encephalitis, because of the
cost of aciclovir may be an issue, and other risk of relapse after 10 days.46 Some advocate
causes of CNS infection are more common. repeating the CSF examination at the end of
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302 Practical Neurology

treatment and continuing with aciclovir if Other antiviral and


HSV is still detected by PCR. This approach is immunomodulatory treatments
being evaluated by the American There are few large, randomised controlled trials
Collaborative Antiviral Study Group, which is assessing the efficacy of antiviral treatments in
assessing the prognostic value of quantitative viral CNS infections, other than for HSV
PCR detection of viral DNA in the CSF at the encephalitis. Nonetheless treatments for other
end of three weeks treatment and prolonged conditions are given based on an understanding
high dose oral valaciclovir for three months. of the pathogenesis, in vitro data, anecdotal
If the initial CSF PCR is negative for HSV reports, or small clinical series, although these
but other features are consistent with HSV sometimes provide conflicting data (table 8).
encephalitis, then the aciclovir should not be If the clinical presentation and imaging
stopped, because false negative PCR results findings suggest a post- or para-infectious
can occur, particularly early on.47, 48 In such encephalitis such as ADEM, acute haemorrhagic
patients the lumbar puncture should be leukoencephalitis or diffuse encephalopathy
repeated because it may be positive 2448 h associated with systemic viral infection, immu-
later and, even if negative again, treatment nosuppressive drugs are given.52 High dose
continued for at least 10 days. However, if a corticosteroid treatment is often the initial
definitive alternative diagnosis has become treatment, followed by intravenous immuno-
apparent, or it seems very unlikely that the globulin, plasma exchange, or further treatment
patient has viral encephalitis, then it is with steroids, depending on the response to the
reasonable to stop the acyclovir earlier. initial treatment.
In some circumstances, both antiviral and
A role for oral valaciclovir? immunosuppressive drugs are given. For
In circumstances where ongoing intravenous example, in HSV encephalitis corticosteroids
treatment is proving difficult (for example, in are sometimes used in addition to aciclovir as
a child who is now fully conscious), oral described above. In VZV encephalitis cortico-
valaciclovir may be reasonable,49 although we steroids are used alongside aciclovir because
would only consider this after the first of the strong vasculitic component of the
10 days of intravenous treatment. disease.
Valaciclovir is the valene ester of aciclovir, Severe CMV and HHV-6 infections are
which is converted to aciclovir after absorp- treated with ganciclovir, foscarnet or cidofo-
tion, and has good oral bioavailability. vir, severe adenovirus infections have been
Although oral valaciclovir may have a role, treated with cidofovir or ribavirin and
oral aciclovir should not be used in HSV Pleconaril has been used for severe enter-
encephalitis, because the levels achieved in ovirus infections, particularly in the immuno-
the CSF are inadequate. compromised, although its overall role
remains unclear.53, 54 Interferon alpha has
been used in West Nile virus and other
Ancillary treatments flavivirus infections, but a randomised con-
In patients with brain swelling, corticosteroids
trolled trial in Japanese encephalitis showed it
and mannitol are often used to control raised
was not effective.55
intracranial pressure. A recent trial suggests
steroids may be beneficial even in patients
without marked swelling.50 Their role in HSV Management of seizures, raised
encephalitis merits further study.51 In patients intracranial pressure and other
with severe brain swelling, decompressive complications
hemicraniectomy is sometimes performed. Seizures are common in encephalitis, parti-
Antibiotic treatment with a cephalosporin is cularly in children. In adults, seizures can be
often also given, especially if the initial CSF useful in distinguishing acute viral encepha-
findings could be consistent with bacterial litis from para-infectious inflammatory ence-
disease (for algorithm see http://www. phalopathies. There may be obvious
britishinfectionsociety.org). If listeria is sus- generalised tonic clonic seizures or subtle
pected, ampicillin and gentamicin, or high motor seizures, which may manifest as
dose cotrimoxazole, should be given. twitching of a digit, or around the mouth or
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Solomon, Hart, Beeching 303

eyes, particularly in children. An EEG should


be performed if there is any uncertainty.
PRACTICE POINTS
Uncontrolled seizures lead to raised intra-
cranial pressure, increased metabolic activity,
l All patients with a febrile illness and altered behaviour or consciousness
should be investigated for a central nervous system (CNS) infection, unless
acidosis and vasodilatation, which in turn
there is very clear evidence of another diagnosis.
leads to further raised pressure. The resulting l Patients with a suspected CNS infection need a lumbar puncture as soon as
positive feedback cycle can ultimately pre- possible, unless there is an indication for a brain CT first.
cipitate brain shift and herniation. If seizures l Patients with a meningococcal rash and/or sepsis should receive immediate
are not easily controlled with phenytoin and antibiotics, but for most other patients investigation with lumbar puncture
low doses of benzodiazepines, patients should should be possible before starting treatment.
be intubated and ventilated mechanically, so
that higher doses of sedating anticonvulsive
drugs, including benzodiazepines and pheno- extent of any damage, and the help that
barbital, can be used. Electroencephalographic might be needed. Regular out-patient assess-
monitoring, with or without continuous ment following encephalitis is especially
function and analysing monitoring (CFAM), important in children. Behavioural and psy-
should be used to detect ongoing epileptic chiatric disturbances are common and may
activity. include depression or disinhibition.
Standard measures to control raised intra- Antidepressants and mild night-time seda-
cranial pressure include nursing the patient at tives may be necessary. Other disabilities in
30 head up, keeping the head straight to the recovery period or afterwards include
ensure there is no obstruction to venous seizures, post-encephalitic parkinsonism seen
return, and ventilating to maintain a low after encephalitis lethargica, and encephalitis
arterial pCO2. Although there are no good caused by flaviviruses. The risk of seizures is
data for viral encephalitis, data from other greatest in those who had seizures during the
infectious encephalopathies suggest that acute period; in one study the cumulative risk
osmotic diuretics produce a short-term of seizures at 5 years was 10% for patients
reduction in pressure.56 The role of anti- with no acute seizures, which increased to
inflammatory drugs in viral encephalitis is 20% for those with acute seizures.57
uncertain.51 To reduce the risk of deep venous Memory difficulties can be particularly
thrombosis and pulmonary embolism, prominent after HSV encephalitis. A range of
patients with reduced mobility should be practical approaches can help to overcome
fitted with compression stockings, and once it these difficulties such as the patient keeping
is clear that there is no major haemorrhagic a notebook and diary, labelling items around
component to the encephalitis, they should the house, and leaving messages as remin-
be given prophylactic heparin. Bed sores are a ders. More sophisticated aids being developed
risk in immobile patients, and appropriate include a neuropage system (http://www.
mattresses and regular turning are needed. neuropage.nhs.uk), which sends pager remin-
Patients with encephalitis are also at risk of der messages throughout the day, and a
secondary pneumonia, due to aspiration, and camera, worn around the neck, which auto-
urinary tract infections. Passive and active matically takes pictures throughout the day
limb movements will reduce the risk of limb as a reminder of what the patient has been
contractures, which can occur in patients doing (SenseCam). Excellent help and advice
with limb weakness, and splints and braces can be obtained from patient support groups,
may be needed to facilitate mobilisation. such as the encephalitis society (http://www.
encephalitis.info)
Management in the recovery
period PROGNOSTIC FACTORS AND
Ideally, a full neuropsychological assessment OUTCOME
should be organised at hospital discharge, or Although treatment with aciclovir has
soon after. This should include cognitive reduced the mortality of HSV, the morbidity
function, intelligence, memory and speech remains high.13 Poor prognostic factors after
assessment, because these help determine the HSV encephalitis include age above 60,
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304 Practical Neurology

reduced coma score on admission,44 especially 9. Bloom S, Wharton M. Mumps outbreak among
young adults in UK. BMJ 2005;331:E3634.
if (6,45 and delays between hospitalisation 10. Rantala H, Uhari M. Occurrence of childhood
and starting aciclovir treatment (especially encephalitis: a population-based study. Pediatr
delays of more than two days).14, 16 Two thirds Infect Dis J 1989;8:42630.
of survivors have significant neuropsychiatric 11. Koskiniemi M, Korppi M, Mustonen K, et al.
Epidemiology of encephalitis in children. A
sequelae, including memory impairment prospective multicentre study. Eur J Pediatr
(69%), personality and behavioural change 1997;156:5415.
(45%), dysphasia (41%) and epilepsy in up to 12. Davison KL, Crowcroft NS, Ramsay ME, et al. Viral
encephalitis in England, 19891998: what did we
25%.16 This means that in addition to the high miss? Emerg Infect Dis 2003;9:23440.
hospitalisation costs estimated in the USA at 13. Whitley RJ. Herpes simplex encephalitis:
$500 million for 1983 alone, there are adolescents and adults. Antiviral Res
considerable additional costs of long-term 2006;71:1418.
14. Raschilas F, Wolff M, Delatour F, et al. Outcome of
care and support. If the personal tragedies and prognostic factors for herpes simplex
themselves were not impetus enough, this encephalitis in adult patients: results of a
major financial burden emphasises the need multicenter study. Clin Infect Dis 2002;35:25460.
15. Fodor PA, Levin MJ, Weinberg A, et al. Atypical
for a rational approach to investigation and
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treatment of this devastating condition. amplification of viral DNA from CSF. Neurology
1998;51:5549.
ACKNOWLEDGEMENTS 16. McGrath N, Anderson NE, Croxson MC, et al. Herpes
simplex encephalitis treated with acyclovir:
We thank our clinical and laboratory colleagues diagnosis and long term outcome. J Neurol
at the Walton Centre for Neurology and Neurosurg Psychiatry 1997;63:3216.
Neurosurgery and the Royal Liverpool University 17. Whitty CJ, Lalloo D, Ustianowski A. Malaria: an
update on treatment of adults in non-endemic
Hospital for help in developing the Algorithm for
countries. BMJ 2006;333:2415.
the Early Management of Suspected Viral 18. Julian KG, Eidson M, Kipp AM, et al. Early season
Encephalitis in Adults, which is available from crow mortality as a sentinel for West Nile virus
http://www.liv.ac.uk/braininfections (under disease in humans, northeastern United States.
Vector Borne Zoonotic Dis 2002;2:14555.
Education). We are also grateful to members of 19. Solomon T, Marston D, Mallewa M, et al. Paralytic
the Encephalitis Society for sharing with us their rabies after a two week holiday in India. BMJ
experiences. 2005;331:5013.
20. Nathwani D, McIntyre PG, White K, et al. Fatal
This article was reviewed by Neil Scolding,
human rabies caused by European bat Lyssavirus
Bristol, UK. type 2a infection in Scotland. Clin Infect Dis
2003;37:598601.
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