Guia - Encefalitis Viral

National guideline for the management of suspected
viral encephalitis in children

Q2
Q11
R. Kneen
a,m,
*, B.D. Michael
b,c,m,n
, E. Menson
d,m,o
, B. Mehta
e,m,p
,
A.
Q12
Easton
f,m,q
, C. Hemingway
g,m,r
, P.E. Klapper
h,m,s
, A. Vincent
i,m,t
,
M. Lim
j,m,o
, E. Carrol
k,m,u
, T. Solomon
c,l,m,n
a
Department of Neurology, Littlewoods Neuroscience Unit, Alder Hey Childrens NHS Foundation Trust, Eaton Road,
West Derby, Liverpool L12 2AP, UK
Q3
b
Institute for Infection and Global Health, University of Liverpool, 8th Floor Duncan Building, Daulby Street,
Liverpool L69 3GA, UK
c
The Walton Centre Neurology NHS Foundation Trust, Lower lane, Fazakerly, Liverpool L9 7JL, UK
d
Evelina Childrens Hospital London, Westminster Bridge Road, London SE1 7EH, UK
e
Alder Hey Childrens NHS Foundation Trust, Eaton Road, West Derby, Liverpool L12 2AP, UK
f
7B Saville Street, Malton, North Yorkshire YO17 7LL, UK
g
Great Ormond Street Hospital, 40 Bernard Street, London WC1N 1LE, UK
h
University of Manchester, 2nd Floor, Clinical Sciences Building 2, Manchester Royal Inrmary, Oxford Road, Manchester,
M13 9WL, UK
i
Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, University of Oxford,
Oxford OX3 9DS, UK
j
Guys and St. Thomas Hospital, London, Westminster Bridge Road, London SE1 7EH, UK
k
University of Liverpool, Royal Liverpool Childrens Hospital, Alder Hey, Eaton Road, L12 2AP, UK
l
Department of Neurological Science, University of Liverpool, 8th Floor Duncan Building, Daulby Street, Liverpool L69 3GA,
UK
Accepted 13 November 2011
* Corresponding author. Tel.: 44 151 228 4811; fax: 44 151 228 032.
E-mail addresses: Rachel.Kneen@alderhey.nhs.uk (R. Kneen), Benedict.michael@liv.ac.uk (B.D. Michael), Esse.Menson@gstt.nhs.uk (E.
Menson), bimal.mehta@rlc.nhs.uk (B. Mehta), avaeaston@yahoo.co.uk (C. Easton), heminc@gosh.nhs.uk (C. Hemingway), Paul.Klapper@
cmft.nhs.uk (P.E. Klapper), angela.vincent@clneuro.ox.ac.uk, camilla.buckley@clinical-neurology.oxford.ac.uk (A. Vincent), ming.lim@
gstt.nhs.uk (E. Lim), edcarrol@liverpool.ac.uk (E. Carrol), tsolomon@liv.ac.uk (T. Solomon).
m
On behalf of the National Encephalitis Guidelines Development and Stakeholder Groups.
n
Tel.: 44 151 529 5460; fax: 44 151 529 5465.
o
Tel.: 44 20 7188 7188.
p
Tel.: 44 151 228 4811; fax: 44 151 228 032.
q
Tel.: 44 1653 692 583; fax: 44 1653 604 369.
r
Tel.: 44 207 405 9200x8308; fax: 44 20 7813 8279.
s
Tel.: 44 161 276 8853; fax: 44 161 276 5744.
t
Tel.: 44 1865 280528; fax: 44 1865 280535.
u
Tel.: 44 (0)151 252 5160.
0163-4453/$36 2011 Published by Elsevier Ltd on behalf of The British Infection Association.
doi:10.1016/j.jinf.2011.11.013
www.elsevierhealth.com/journals/jinf
Journal of Infection (2011) xx, 1e31
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YJINF2822_proof 25 November 2011 1/31
Please cite this article in press as: Kneen R, et al., National guideline for the management of suspected viral encephalitis in children, J
Infect (2011), doi:10.1016/j.jinf.2011.11.013
KEYWORDS
Encephalitis;
Viral encephalitis;
Herpes simplex virus;
Paediatric
Summary In the 1980s the outcome of patients with herpes simplex encephalitis was shown
to be dramatically improved with aciclovir treatment. Delays in starting treatment, particu-
larly beyond 48 h after hospital admission, are associated with a worse prognosis. Several com-
prehensive reviews of the investigation and management of encephalitis have been published.
However, their impact on day-to day clinical practice appears to be limited. The emergency
management of meningitis in children and adults was revolutionised by the introduction of
a simple algorithm as part of management guidelines.
In February 2008 a group of clinicians met in Liverpool to begin the development process for
clinical care guidelines based around a similar simple algorithm, supported by an evidence
base, whose implementation is hoped would improve the management of patients with sus-
pected encephalitis.
2011 Published by Elsevier Ltd on behalf of The British Infection Association.
Introduction
Q4
Encephalitis is dened as a syndrome of neurological
dysfunction caused by inammation of the brain paren-
chyma. Encephalitis has many causes and some are specic
to childhood, but fortunately it is relatively rare. However
doctors who treat acutely ill children should be aware of
how to manage a child with suspected encephalitis as some
of the individual causes of encephalitis will respond to
specic treatments and delays in the diagnosis in these
children can be devastating. Strictly speaking, inamma-
tion of the brain parenchyma is a pathological diagnosis,
however due to the practical limitations of this, surrogate
clinical markers of inammation are used (Table 1.
Denitions).
Classication of encephalitis
Encephalitis can be caused by many individual disease
processes but can broadly be divided into those associated
with infection (either directly or indirectly) and non-
infectious causes. Direct infections of the cranial nervous
system (CNS) can be caused by many viruses, bacteria
(especially intracellular bacteria such as Mycoplasma pneu-
moniae), parasites and fungi (Table 2. Viral encephalitis;
Table 3. Other causes of encephalitis or encephalopathy).
Those indirectly associated with infection include an acute
demyelinating process, which is often temporally related to
a prior infection outside of the CNS. This process may also
follow immunisation and is known as acute disseminated
encephalomyelitis (ADEM). Non-infectious causes include
antibody-mediated encephalitis, which may be paraneo-
plastic for example limbic encephalitis associated with
ovarian teratomas or may be an isolated nding. Initially
these disorders were reported in adults, but they are being
increasingly recognised in children.
1
Most viral encephaliti-
des are acute, but sub-acute or chronic presentations are
characteristic of particular pathogens, especially in the im-
munocompromised (Table 4. Sub-acute and chronic
encephalitis).
Epidemiology
The incidence of encephalitis in children is difcult to
establish as reported studies have used different case
denitions, methodologies and different geographic loca-
tions and study populations. However, in western settings
reported incidences range from 6.3 to 7.4 per 100,000 for
all ages (adults and children) and approximately 10.5e13.8
per 100,000 children.
2
In the UK, this should equate to 1e2
children per year in a typical district general hospital and
8e10 in a large tertiary childrens hospital. In industrialised
nations, the most commonly diagnosed cause of encephali-
tis is herpes simplex virus (HSV) with an annual incidence of
1 in 250,000 to 500,000.
3
The age specic incidence is bi-
modal, with peaks in childhood and the elderly. Most
Table 1 Denitions.
Q8
Encephalopathy
Clinical syndrome of altered mental status (manifesting as reduced consciousness or altered cognition or behaviour)
Has many causes including systemic infection, metabolic derangement, inherited metabolic encephalopathies,
toxins, hypoxia, trauma, vasculitis, or central nervous system infection
Encephalitis
Inammation of the brain
Strictly a pathological diagnosis; but surrogate clinical markers often used, including inammatory change in
the cerebrospinal uid or parenchyma inammation on imaging.
Causes include viruses, small intracellular bacteria that directly infect the brain parenchyma and some parasites
Can also occur without direct brain infection, for example in acute disseminated encephalitis myelitis (ADEM), or antibody-
associated encephalitis
2 R. Kneen et al.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
HSV encephalitis is due to HSV type 1 but about 10% is due
to HSV type 2. The latter occurs typically in immunocom-
promised adults and in neonates in whom it can also cause
a disseminated infection. Varicella zoster virus (VZV) is also
a relatively common cause of viral encephalitis, especially
in the immunocompromised, whilst cytomegalovirus (CMV)
occurs almost exclusively in this group. Enteroviruses
most often cause aseptic meningitis but can also be an im-
portant cause of encephalitis. Among the other non-
infectious causes of encephalitis, immune-mediated condi-
tions are increasingly being recognised including ADEM and
encephalitis associated with antibodies to the voltage-
Table 2 Causes of acute viral encephalitis, with geographical clues modied from (Solomon and Whitley 2004; Solomon, Hart
Q1
et al. 2007).
80,110
Q9
Groups Viruses Comments
Sporadic causes (not geographically restricted) listed by group
Herpes viruses
(family Herpesviridae)
Herpes simplex virus type 1 Most commonly diagnosed sporadic encephalitis
Herpes simplex virus type 2 Causes meningitis in adults (esp. recurrent);
Meningoencephalitis occurs typically in the
immunocompromised. Also causes a radiculitis.
Varicella zoster virus Post-infective cerebellitis, or acute infective
encephalitis or vasculopathy
EpsteineBarr virus Encephalitis in the immunocompromised
Cytomegalovirus Encephalitis in the immunocompromised; also
retinitis or radiculitis; often neutrophilic CSF
with low glucose
Human herpes virus 6 & 7 Febrile convulsions in children (after roseola);
encephalitis in immunocompromised
Enteroviruses
(family Picornaviridae)
Enterovirus 70 Epidemic haemorrhagic conjunctivitis, with
CNS involvement
Enterovirus 71 Epidemic hand foot and mouth disease, with
aseptic meningitis, brainstem encephalitis, myelitis
Poliovirus Myelitis
Coxsackieviruses, Echoviruses,
Parechovirus
Mostly aseptic meningitis
Paramyxoviruses
(family Paramyxoviridae)
Measles virus Causes acute post-infectious encephalitis, sub-acute
encephalitis and sub-acute sclerosing panencephalitis
Mumps virus Parotitis, orchitis or pancreatitis may occur before,
during or after meningoencephalitis
Others (rarer causes) Inuenza viruses, adenovirus,
parvovirus B19, lymphocytic
choreomeningitis virus, rubella virus,
Arthropod-borne and zoonotic viruses
a
Flaviviruses
(family Flaviviridae)
West Nile virus North America, Southern Europe, Africa, Middle East,
West and Central Asia associated with accid paralysis
and Parkinsonian movement disorders
Japanese encephalitis virus Asia, associated with accid paralysis and Parkinsonian
movement disorders
Tick-borne encephalitis virus Travel in Eastern Europe, Former USSR; tick bite; upper
limb accid paralysis
Dengue viruses (types 1e4) Causes fever, arthralgia, rash and haemorrhagic disease,
occasional CNS disease
Alphaviruses
(family Togaviridae)
Western, Eastern and Venezuelan
equine encephalitis
viruses
Found in the Americas; encephalitis of horses and humans
Chikungunya virus Asia Pacic, Africa
Bunyaviruses Lacrosse virus Encephalitis in America
Coltiviruses Colorado tick fever virus North America
Rhabdoviruses Rabies, virus other lyssaviruses Non-arthropod-borne zoonitic viruses transmitted by dogs,
cats, bats, depending on location
Chandipura virus Transmitted by sandies, causing outbreaks in India
Henipah Viruses Nipah virus Transmitted in faeces of fruit bats in Malaysia, Bangladesh
Note viral causes of chronic encephalitis such as JC viruses are not included here.
Most are zoonotic e i.e. animals rather than humans are the main natural hosts, the exceptions being dengue and chikungunya viruses.
National guideline for the management of suspected viral encephalitis in children 3
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Table 3 Non-viral causes of encephalitis and its mimics modied from (Solomon and Whitley 2004; Solomon 2009).
80,110
Q10
Encephalitis Mimics
CNS Infections
Bacteria
Small bacteria (mostly intracellular)
Mycoplasma pneumoniae Mycobacterium tuberculosis
Chlamydophila Streptococcus pneumoniae
Rickettsiae (including scrub typhus, Rocky Mountain spotted fever) Haemophilus inuenza
Ehrlichiosis (anaplasmosis) Neisseria meningitidis
Coxiella burnetti (Q fever)
Bartonella hensellae (cat scratch fever) Salmonella typhi
Tropherema whipplei (Whipples disease)
Brucella (Brucellosis)
Listeria monocytogenes
Spirochetes
Trepenoma pallidum (Syphilis) Leptospira
Borrelia burgdorferi (Lyme neuroborreliosis)
Borrelia recurrentis (relapsing fever)
Other bacteria
Nocardiosis Sub-acute bacterial endocarditis
Actinomycosis Parameningeal infection
Abscess/empyema
Parasites
Trypanosoma brucei gambiense and Trypanosoma brucei
rhodesiense (sleeping sickness)
Malaria
Naegleria fowleri, Balamuthia mandrellis (Amoebic encephalitis) Cysticercosis
Angiostrongylus cantonensis (rat lung worm) Trichinosis
Fungi
Coccidiomycosis Cryptococcosis
Histoplasmosis
North American blastomycosis
Para/post-infectious causes
Inammatory
Acute disseminated encephalomyelitis (ADEM)
Acute haemorrhagic leukoencephalopathy (AHLE)
Acute necrotising encephalitis (ANE) in children
Bickerstaffs encephalitis
Toxic/Metabolic
Reyes syndrome
Systemic infection
Septic encephalopathy
Shigellosis
Non-infectious causes
Vascular
Vasculitis
Systemic lupus erythematosis
Behcets disease
Subarachnoid & subdural haemorrhage
Ischaemic cerebrovascular accidents
Neoplastic
Paraneoplastic encephalitis Primary brain tumour
Metastases
Metabolic encephalopathy
Hepatic encephalopathy
Renal encephalopathy
Hypoglycaemia
Toxins (alcohol, drugs)
Hashimotos disease
Septic encephalopathy
4 R. Kneen et al.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
gated potassium channel complex, or N-methyl-D-aspartate
antibody (NMDA) receptors.
1,4
Aims and scope of the guideline
In the 1980s the outcome of HSV encephalitis in adults was
shown to be dramatically improved by aciclovir treat-
ment.
5,6
Delays in starting treatment, particularly beyond
48 h after hospital admission, are associated with a worse
prognosis.
7,8
Several comprehensive reviews of the inves-
tigation and management of encephalitis have been pub-
lished,
9e11
but their impact on day-to day clinical
practice appears to be limited.
12e14
The emergency man-
agement of meningitis in children and adults was revolu-
tionised by the introduction of a simple algorithm as
part of management guidelines.
15e17
In February 2008
a group of clinicians met in Liverpool to begin the devel-
opment process for clinical care guidelines based around
a similar simple algorithm (Fig. 1. Algorithm for the man-
agement of patients with suspected encephalitis, sup-
ported by an evidence base, whose implementation, it is
hoped, would improve the management of patients with
suspected encephalitis. The scope of the guideline is to
cover the initial management of all patients with sus-
pected encephalitis, up to the point of diagnosis and early
treatment, in an acute care setting such as acute medical
unit or emergency room. They are thus intended as a ready
reference for clinicians encountering the more common
causes of encephalitis, rather than specialists managing
rarer causes. The guidelines also cover the specic treat-
ments and further management of patients for whom a di-
agnosis of viral encephalitis is made, particularly that due
to HSV, VZV and enteroviruses. Encephalitis due to CMV is
almost exclusively seen in the immunocompromised and is
not covered in detail; its diagnosis and management is
covered in HIV guidelines.
18
At the end of the guidelines
the special circumstances of returned travellers, immuno-
compromised patients and encephalitis associated with
antibodies are discussed. Many patients with suspected vi-
ral encephalitis ultimately prove to have another infec-
tious or non-infectious cause for their illness. The
further management and treatment of such patients is be-
yond the scope of this guideline, but we have included
a section on follow-up and support for patients with en-
cephalitis in both the healthcare and voluntary sectors af-
ter discharge from hospital. Finally, we have included
some suggestions for audit standards to assess practice
before and after implementation of the guidelines.
Methods
A literature search was performed on the Medline database
for the years 1998e2008, to identify for all (English
language) publications using the key words (Encephalitis
AND: Symptoms; Signs; Management; Diagnosis; In-
vestigation; Lumbar Puncture; Cerebrospinal Fluid
(CSF); Computed Tomography (CT); Magnetic Resonance
Imaging (MRI); Single Photon Emission Tomogrophy
(SPECT); Electroencephalography (EEG); Treatment;
Antiviral; Aciclovir; Steroids/Dexamethasone) sepa-
rately and in combination with the following MESH terms:
(Herpes Simplex Virus; Varicella Zoster Virus; Entero-
virus; Human Immunodeciency Virus (HIV); Immune
compromise; Arbovirus. This yielded a total of 6948 cita-
tions, including many case reports, which were grouped
together in subject areas including clinical presentation,
diagnosis, imaging, treatment, outcome, immune compro-
mise. These groups of papers were each screened by at
least 2 of the group and scored for relevance, level of ev-
idence and need for inclusion. Further sources were added
from review of the bibliographies of these articles, text-
books, other reviews and personal collections of the
screening group.
Using these revised source reference lists each sub-
section of the manuscript was composed by two authors
of the Guidelines Writing Group, from the elds of
neurology, infectious diseases, microbiology, virology,
acute medicine and the patient-sector. This included
members from professional bodies including the British
Infection Society (now British Infection Association), the
British Paediatric Neurology Association, the Society for
Acute Medicine and the Encephalitis Society. Each sub-
section was internally peer-reviewed. The contributions
from the various sections of the guidelines that people
wrote were assimilated into a single document in accor-
dance with the principles of the AGREE (appraisal of
guideline research and evaluation) collaboration.
19
In rat-
ing the strength of evidence we have used the GRADE ap-
proach, in which the strength of recommendations is
rated from A to D, and the quality of the evidence sup-
porting the recommendation is rated from I to III
(Table 5. GRADE).
20
Table 3 (continued)
Encephalitis Mimics
Mitochondrial diseases
Other
Antibody-mediated encephalitis: VGKC complex or NMDA receptor Drug reactions
Encephalitis lethargica Epilepsy
Functional disorder
a
Almost every infectious and non-infectious condition can occasionally present with an encephalitis-like illness.
In this table some of the important aetiologies are classied into whether they cause an encephalitis, with inammatory changes seen
histopathologically in the brain parenchyma, or encephalopathy without inammatory changes in the parenchyma, although for some
aetiologies this is based on limited evidence.
Abbreviations: VGKC, voltage-gated potassium channel; NMDA, N-Methyl-D-Aspartic acid.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Figure 1 Algorithm for the management of patients with suspected encephalitis.
6 R. Kneen et al.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
This document has been again been internally peer-
reviewed twice by the Guidelines Development Group, and
updated to include further comments from all contributing
authors, incorporating references published in 2009e11.
The guideline has also been peer-reviewed by the wider
Guidelines Stakeholder Group. This included members from
the Royal College of Paediatrics and Child Health, the
British Paediatric Allergy, Immunity and Infection Group,
the Paediatric Intensive Care Society, the Childrens HIV As-
sociation and the Meningitis Research Foundation. The
guidelines are structured to answer common clinical ques-
tions posed during the work-up of a patient with possible
encephalitis.
Denition of childhood for this document
This guideline is for the management of suspected viral
encephalitis in children aged older that 28 days (outside the
neonatal period) and younger than 16 years. The manage-
ment of neonatal encephalitis (including premature in-
fants) is outside the scope of this document. National
guidelines for the management of suspected viral enceph-
alitis in adults are also available as a separate document
(Solomon, Michael, et al. 2011).
Diagnosing encephalitis
Which clinical features should lead to a suspicion of
encephalitis in children, how do they differ from
other encephalopathies, and can they be used to
diagnose the underlying cause?
The differential diagnosis of acute encephalitis in childhood
is broad encompassing infectious, para-infectious immune-
mediated, autoimmune, metabolic, vascular, neoplastic,
paraneoplastic, and toxic aetiologies as well as brain
dysfunction due to systemic sepsis (Tables 2 and 3).
21,22
Nevertheless, dening the clinical features that should
prompt the suspicion of acute encephalitis of childhood is
essential in order to achieve prompt recognition, investiga-
tion and management because delays have been shown to
impair outcome.
However, differentiating infection-associated encepha-
litis from the other causes of encephalopathy on the basis
of clinical ndings poses a signicant diagnostic challenge,
especially in children in whom the clinical picture can be
vague. For example, of Chaudhuri and Kennedys list use-
ful clinical pointers to aid exclusion of non-infective causes
of encephalopathy, none are absolute.
23
In adults, fever
and abnormal mental status, often with severe headache,
nausea and vomiting, are the classical clinical features of
infective encephalitis. Eighty-ve (91%) of 93 adults with
HSV-1 encephalitis in one study were febrile on admission
8
;
even those not febrile on admission will often have a history
of febrile illness (Table 6. History). Disorientation (76%),
speech disturbances (59%) and behavioural changes (41%)
were the most common features, and one third of patients
had seizures.
8
However a normal Glasgow coma score at
presentation was seen in some patients in this, and other
studies, reecting the fact that it is a crude tool for detect-
ing subtle changes in behaviour.
13
Alterations in higher
mental function include lethargy, drowsiness, confusion,
disorientation and coma (Table 7. Examination).
Table 4 Sub-acute and chronic central nervous system
presentations e microbiological causes, modied from (Sol-
omon, Hart et al., 2007; Solomon 2009).
110,211
Viruses
In immunocompromised patients
Measles virus (inclusion body encephalitis)
Varicella zoster virus (causes a multi-focal
leukoencephalopathy)
Cytomegalovirus
Herpes simplex virus (especially HSV-2)
Human herpes virus 6
Enteroviruses
JC/BK
a
virus (progressive multi-focal
HIV (dementia)
In immunocompetent patients
JC/BK
a
virus (progressive multi-focal
Measles virus (sub-acute sclerosing panencephalitis,
years after primary infection)
Bacteria
Mycobacterium tuberculosis
Treponema pallidum (syphilis)
Borrelia burgdorferi (Lyme neuroborreliosis)
Tropheryma whipplei (Whipples Disease)
Fungi
Cryptococcus neoformans
Parasites
Trypanosoma brucei (African trypanosomiasis)
Toxoplasma gondii (Toxoplasmosis)
Prions
Creutzfeldt-Jakob disease
a
JC and BK viruses are named after the initials of the patients
from whom they were rst isolated.
Table 5 GRADE rating system for the strength of the guidelines recommendations and the quality of the evidence (Atkins, Best
et al., 2004).
20
Strength of the recommendation Quality of the evidence
A Strongly recommended I Evidence from randomised controlled trials
B Recommended, but other alternatives may
be acceptable
II Evidence from non-randomised studies
C Weakly recommended: seek alternatives III Expert opinion only
D Never recommended
745
746
747
748
749
750
751
752
753
754
755
756
757
758
759
760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
868
Infect (2011), doi:10.1016/j.jinf.2011.11.013
Denition of the spectrum of clinical ndings at pre-
sentation, and the pattern of subsequent manifestations in
children is more difcult as documentation of the clinical
presentation of children with encephalitis is less well de-
scribed. Several studies include adults and children together
making it difcult to comment on whether children may
have a different presentation.
24e26
Furthermore, given that
children are susceptible to different aetiological agents than
adults and also present differently from adults with other
causes of infection, the utility of the proles dened in char-
acterising encephalitis presentations in childhood is limited
by the lack of breakdown by age. The most relevant studies
have only reported ndings in small numbers of children and
the entry criteria were not proven encephalitis, but sus-
pected encephalitis and are primarily hospital-based.
21,27
In the Toronto Acute Childhood Encephalitis study, 50 chil-
dren with suspected encephalitis were reported with the
most common presenting features being fever (80%), sei-
zures (78%), focal neurological signs (78%) and decreased
consciousness (47%).
27
In Wangs study from Taiwan, 101
children with a nal diagnosis of encephalitis were reported
to have the following features; change in personality or re-
duction in consciousness (40%), seizures (33%), new neuro-
logical signs (36%) and meningism 22%, The number
presenting with fever was not reported.
28
In the more recent
Liverpool study, 51 children were treated for suspected en-
cephalitis and their most common presenting features in-
cluded confusion, irritability or a behaviour change (76%),
fever (67%), seizures (61%), vomiting (57%) and focal neuro-
logical signs (37%).
29
However, 14 of these children were ul-
timately not felt to have viral encephalitis and should not
have received aciclovir so the list of presenting symptoms
is likely to be inaccurate. Ill children are different to adults:
young children cannot often adequately describe symptoms
such as headache and infants frequently have non-specic
symptoms and signs for many acute illnesses including feed-
ing and respiratory difculties. In Wangs study 54% of the
children had concomitant signs of a respiratory infection
and 21% had gastrointestinal symptoms.
28
With the advent of CSF PCR more subtle presentations of
HSV encephalitis have been recognised and described in
adults and children.
30
These include 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 alco-
hol, occasionally with tragic consequences.
31
Distinguishing HSV encephalitis from other
encephalopathies
Several studies have documented the potential mimics of
HSV encephalitis in adults and children.
12,13,29,32,33
Whitley
et al. demonstrated that of 432 (168 < 18 years old) pa-
tients undergoing brain biopsy for presumed HSV encepha-
litis: 195 (45%) had the diagnosis proven histologically and
in a further 95 patients (22%) an alternative, often treat-
able, diagnosis was established.
33
However, the clinical
presenting features of these two groups were very similar.
Chataway et al. found that of those patients initially con-
sidered to have HSV encephalitis, inammatory aetiologies
such as ADEM or multiple sclerosis were the most frequent
mimics.
32
Some of the rarer paediatric diagnoses included
epileptic encephalopathies such as Rasmussens encephali-
tis and Alpers syndrome. Kneen et al. showed the broad
range of nal diagnoses in children initially treated with
aciclovir for possible HSV encephalitis in children and Bell
et al. and Michael et al. demonstrated that this was also
very similar in adult practice.
12,13,29
The clinical picture
clearly varies with disease severity but can also vary with
aetiological agent; of the many viruses that cause acute en-
cephalitis in children, some have a predilection for local-
ised parts of the brain which can determine the initial
clinical picture and the subsequent clinical course.
34
Al-
though, De Tiege et al.
35
endorse the view that the concept
of a classical picture of HSV encephalitis in children is
now out-dated and remind clinicians that the most common
reason for failure to diagnose HSV encephalitis is non-
specic initial clinical presenting symptoms and signs.
7
Seizures are more frequently found in patients presenting
with encephalitic processes affecting the cortex, which are
more often infectious in aetiology, as opposed to
Table 6 Questions to consider in the history when assess-
ing a patient with suspected encephalitis, modied from
(Solomon, Hart et al., 2007).
110
Current or recent febrile or inuenza-like illness?
Altered behaviour or cognition, personality change or
altered consciousness?
New onset seizures?
Focal neurological symptoms?
Rash? (e.g. varicella zoster, roseola, enterovirus
Others in the family, neighbourhood ill? (e.g. measles,
mumps, inuenza)
Travel History? (e.g. prophylaxis and exposure for malaria,
arboviral encephalitis, rabies, trypanosomiasis)
Recent vaccination? (e.g. ADEM)
Contact with animals? (e.g. rabies)
Contact with fresh water (e.g. leptospirosis)
Exposure to mosquito or tick bites (e.g. arboviruses, lyme
disease, tick-borne encephalitis)
Known immunocompromise?
HIV risk factors?
Abbreviations: ADEM Acute disseminated encephalomyelitis;
HIV Human immunodeciency virus.
Table 7 Examination ndings of importance in assessing
a patient with suspected encephalitis modied from (Solo-
mon, Hart et al., 2007).
110
Airways, Breathing, Circulation
Mini-mental state, cognitive function, behaviour (when
possible)
Evidence of prior seizures? (tongue biting, injury)
Subtle motor seizures? (mouth, digit, eyelid twitching)
Meningism
Focal neurological signs
Papilloedema
Flaccid paralysis (anterior horn cell involvement)
Rash? (purpuric e meningococcus; vesicular e hand foot
and mouth disease; varicella zoster; rickettsial disease)
Injection sites of drug abuse?
Bites from animals (rabies) or insects (arboviruses)
Movement disorders, including Parkinsonism
8 R. Kneen et al.
869
870
871
872
873
874
875
876
877
878
879
880
881
882
883
884
885
886
887
888
889
890
891
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
921
922
923
924
925
926
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
952
953
954
955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
972
973
974
975
976
977
978
979
980
981
982
983
984
985
986
987
988
989
990
991
992
Infect (2011), doi:10.1016/j.jinf.2011.11.013
encephalitic processes predominantly affecting subcortical
white matter that more frequently have an immune-
mediated pathogenesis (e.g. ADEM). However, seizures and
movement disorders are also often seen in children with
encephalitis due to autoimmune antibody-mediated disease
(see Special circumstances section). Seizures can also be
subtle and include subtle motor status: a syndrome of subtle
continuous motor seizure activity. This often follows overt
convulsive seizures or status epilepticus or non-convulsive
status epilepticus (NCSE): a syndrome of encephalopathy
with no overt motor seizure activity but an electrical seizure
correlate on the EEG. A study of 144 (134 children) patients
with encephalitis due to Japanese encephalitis virus found
that 40 had witnessed seizures in hospital. Of these, 25 had
one or more episodes of status epilepticus including 15 who
went onto develop subtle motor status. Patients with
witnessed convulsive or subtle motor status epilepticus
were more likely to die (p Z 0.0003).
36
However, it is very
unusual for patients with encephalitis or other CNS infec-
tions and encephalopathy to present with de novo NCSE. A
study of 236 consecutive intensive care unit patients
(11% < 16 years) during the rst 3 days of an illness with
coma (and no witnessed overt or subtle seizures) identied
that 19 (8%) were in NCSE. Of these, 2 were children. Only
one adult had a CNS infection (diagnosis unspecied).
37
In
another study of 45 consecutive adults diagnosed with
NCSE, 20 had no previous diagnosis of epilepsy. Twenty-
eight of the 45 patients had a remote risk factor for develop-
ing epilepsy including previous CNS infections in some (num-
ber not specied).
38
Despite its relative rarity, NCSE can
only be diagnosed with an EEG and as there are specic
treatments available, an EEG should be considered in all pa-
tients with undiagnosed encephalopathy.
39
In adult clinical practice the most frequently encoun-
tered infection-associated encephalopathy is septic
encephalopathy, being found in 50e70% of septic pa-
tients.
40
This syndrome usually occurs in elderly patients
with an extracranial focus of sepsis where the encephalop-
athy cannot be attributed to other organ dysfunction. Clin-
ically, the diagnosis is one of exclusion. The syndrome is
characterised neurologically by progression from a slowing
of mentation and impaired attention to delirium and
coma. Neurological examination ndings are usually sym-
metrical. This syndrome is uncommon in paediatric practice
but it can occur and is most frequently seen in association
with bacterial infections of the urinary tract. It can also be
seen in association with other rarer infective encephalopa-
thies such as shigella or in association with typhoid
fever.
41,42
Diagnostic features for specic aetiologies
The history is important in dening the spectrum of agents
potentially responsible for encephalitis as this is inuenced
by age, immunocompetence, geography and exposure.
Geographical restrictions are laid out in the Table 2. These
are particularly signicant for arthropod-borne infections.
As indicated above the features for HSV are non-specic:
many patients with suspected HSV encephalitis ultimately
prove to have a different diagnosis. In adults, the nding of
labial herpes (cold sores) has no diagnostic specicity for
HSV encephalitis and is merely a marker of critical illness.
However, in children who are more likely to develop
encephalitis with a primary HSV infection, labial herpes
may be noted.
43,44
Lahat reported 2 children with recent la-
bial herpes in a series of 28 children aged from3 months to 16
years with proven HSV encephalitis due to a primary infec-
tion
43
and Elbers reported active or a recent history of labial
herpes in 4 out of 16 children with proven HSVencephalitis.
44
Elbers also reported that 3 further children with positive CSF
PCR for HSV-1 were excluded from his series because of an
atypical presentation. These children all had a milder illness
(all had fever, one had multiple seizures, one had a single
seizure and ataxia and one had lethargy and headache)
and normal cranial imaging. Elbers concluded that the CSF
PCR results may be false positives or due to reactivation of
the virus but it is also conceivable that HSV can cause
a mild encephalitis and for this reason it should be consid-
ered in the differential diagnosis of children with less severe
symptoms. A mild HSV encephalitis has also been reported in
2 previous children aged 3.5 and 15 years who recovered
without treatment with aciclovir.
31
Children with HSV encephalitis may also present with an
acute opercular syndrome (disturbance of voluntary control
of the facio-linguo-glosso-pharyngeal muscles leading to
oro-facial palsy, dysarthria and dysphagia).
45,46
CNS disease
caused by HSV-2 is rare outside the neonatal period. The
most common manifestation in adults is aseptic meningitis
which may be recurrent.
47,48
This has also been reported
in children and the possibility of sexual abuse may need
to be considered.
49
Varicella zoster virus (VZV) can cause central nervous
system manifestations through a post-infective immune-
mediated cerebellitis, an acute infective viral encephalitis
or a vasculopathy; the neurological presentation may be
preceded by the vesicular rash of by days or weeks, though it
occasionally occurs before the rash or even in patients with
no rash.
50e52
Encephalitis is more common in adults,
Table 8 Brainstem encephalitis (rhombencephalitis) e
clues and causes, from (Solomon, Hart et al., 2007).
110
Suggestive clinical features
Lower cranial nerve involvement
Myoclonus
Respiratory drive disturbance
Autonomic dysfunction
Locked-in syndrome
MRI changes in the brainstem, with gadolinium
enhancement of basal meninges
Causes
Enteroviruses (especially EV-71)
Flaviviruses, e.g. West Nile virus, Japanese encephalitis
virus
Alphaviruses, e.g. Eastern equine encephalitis virus
Rabies
Listeriosis
Brucellosis
Lyme borreliosis
Tuberculosis
Toxoplasmosis
Primary or secondary central nervous system
malignancy
Paraneoplastic syndromes
993
994
995
996
997
998
999
1000
1001
1002
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
1023
1024
1025
1026
1027
1028
1029
1030
1031
1032
1033
1034
1035
1036
1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
1047
1048
1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
1070
1071
1072
1073
1074
1075
1076
1077
1078
1079
1080
1081
1082
1083
1084
1085
1086
1087
1088
1089
1090
1091
1092
1093
1094
1095
1096
1097
1098
1099
1100
1101
1102
1103
1104
1105
1106
1107
1108
1109
1110
1111
1112
1113
1114
1115
1116
Infect (2011), doi:10.1016/j.jinf.2011.11.013
especially those with cranial dermatome involvement or
a disseminated rash or the immunocompromised. The pre-
sentation may be acute or sub-acute with fever, headache,
altered consciousness, ataxia and seizures. A more common
neurological presentation associated with VZV infection in
children is post-infectious cerebellitis particularly in young
children. This is usually a relatively mild and self limiting dis-
order but children can become unwell due to hydrocephalus
secondary to swelling of the cerebellum in more severe
cases.
53,54
Children usually present with a short history of
unsteadiness or limb ataxia and nystagmus. The other rela-
tively common association in childhood is between VZV in-
fection and arterial ischaemic stroke, and is thought to
account for up to one third of cases of arterial stokes in pae-
diatric practice. The majority present with acute but perma-
nent hemiparesis, acute chorea or facial weakness which is
commonly transient
55
; seizures and visual or speech distur-
bances also occur. Patients usually present after the rash
has cleared and the time period can be very delayed with
a mean of 3 months (range 1 week to 48 months) reported
in a recent London study.
55
However, early manifestations
can occur within days of exposure,
50
well before the vesicu-
lar eruption, which may be uncharacteristically mild,
52
make diagnosis more challenging, especially as onset of en-
cephalitic features can be abrupt or gradual.
51
PCR for VZV
DNA in the CSF is positive in around a third of patients. A
more sensitive test (positive in over 90% patients) is measur-
ing VZV specic IgGantibodies in CSF. The levels can be com-
pared to a concomitant serum sample as a reduced serum/
CSF ratio of VZV IgG conrms intrathecal synthesis.
56
EpsteineBarr virus (EBV) encephalitis most commonly
affects teenagers (median age 13 years; but generally pres-
ents in the absence of signs of the typical mononucleosis
clinical picture.
57
In Dojas series of 21 patients, 17 had
a non-specic prodrome of fever and 14 had headache.
Manifestations of EBV encephalitis and encephalomyelitis
may also include an altered level of consciousness, seizures
and visual hallucinations.
57e59
However, the temporal rela-
tionship between symptoms is highly variable, including
CNS disease as the presenting manifestation, making aetio-
logical diagnosis difcult on clinical grounds and highlight-
ing the need to consider EBV in all cases of childhood
encephalitis irrespective of symptoms.
57
Encephalitis may be associated with respiratory illnesses
in children: most common pathogens include the inuenza
viruses, paramyxoviruses and the bacteriumM. pneumoniae.
Theremay be no preceding respiratory symptoms prior to the
development of encephalitis in a signicant proportion of pa-
tients.
60,61
In a recent study of patients with M. pneumonia
encephalitis,
60
the affected children were an older cohort
(median age 11 years old), presenting with a short prodrome
of fever (70%), lethargy (68%), and altered consciousness
(58%), while gastrointestinal (45%) and respiratory (44%)
symptoms were less common. Their clinical course pro-
gressed rapidly (median 2 days from onset to hospitaliza-
tion), and commonly required intensive care (55%).
Seizures were less common in the clinical picture. Symptoms
of progressive symmetrical external opthalmoplegia typify
Bickerstaff brainstem encephalitis in association with M.
pneumonia and can serve as a clue to diagnosis especially
when accompanied by ataxia.
62
Patients with inuenza (par-
ticularly inuenza B) can also have associated severe
myositis.
63,64
Inuenza has been reported to be associated
with a spectrum of neurological disorders in adults and chil-
dren ranging through a mild encephalopathy with seizures,
encephalitis, ADEM, encephalopathy with posterior revers-
ible encephalopathy syndrome, malignant brain oedema
syndrome and acute necrotising encephalopathy (ANE).
65,66
Patients with inuenza encephalopathy/encephalitis rarely
have viral antigens or viral nucleic acid in CSF or neural tissue
and the mechanisms for causing neurological illness are still
unclear. Inuenza A in particular, has been reported in asso-
ciation with ANE, a severe encephalopathy often associated
with fever and in which typical MRI abnormalities have been
reported in the thalami, brainstem and cerebral white
matter.
65e67
ANE has most frequently been reported in young
children in small outbreaks in Japan and other Southeast
Asian countries. This disorder has been found to have an au-
tosomal dominant inheritance pattern in some families with
genetic mutations identied.
68
There is some very recent ev-
idence that the H1N1 strain of Inuenza A that emerged in
2009 may cause more neurological manifestations than sea-
sonal u. Ekstrand reported 18 children with H1N1and com-
pared them to 16 with seasonal u. Children with the H1N1
strain were more likely to have encephalopathy, focal neuro-
logical signs, aphasia and an abnormal EEG.
69
Encephalitis associated with gastrointestinal symptoms
includes infection with enteroviruses, rotavirus and human
parechoviuses. Enteroviral encephalitis can be associated
with a brainstem syndrome. Large outbreaks of encephalitis
have been reported with enterovirus 71 in Bulgaria 1975,
Hungary 1997, Malaysia 1997 and Taiwan 1997. Children
under 5 more are commonly affected
70
and the highest
mortality is in those aged 6e12 months.
71,72
Clues to infec-
tion with this virus include the typical papular lesions on
the hands, feet and in the mouth but those with encepha-
litis often develop neurogenic pulmonary oedema
73
on
day 2e3 of illness which can rapidly progress to fatal car-
diorespiratory collapse despite intervention.
71
Rotavirus
encephalopathy has been reported to cause convulsions
and cerebellar signs in some children.
74,75
Rashes may be seen in other encephalitides; for example
a maculopapular or vesicular rash is seen in Rickettsial
infections or the highly typical rash of measles virus
infection. Measles can cause three separate encephalitic
illnesses and is of particular concern given the recent rise in
cases reported in children and young adults across Europe.
The rst is either an acute encephalitis or acute dissemi-
nated encephalomyelitis associated with the acute infec-
tion, although patients may present without the typical
rash.
76
The second is a sub-acute encephalopathy around
six months after the primary infection in the immunocom-
promised with measles inclusion bodies in the brain often
without a rash. The third is sub-acute sclerosing panence-
phalitis (SSPE) in the immunologically normal which can oc-
cur several years after the primary infection. Patients with
the sub-acute forms usually present with a dementia, visual
problems and later with seizures.
77
HHV6 (and possibly HHV7) is a cause of encephalitis
causing severe disease and long-term sequelae far beyond
self-resolving febrile convulsions.
78
Typical below age 2
years
79
ataxia and prolonged convulsions are the major neu-
rological manifestations and gastrointestinal symptoms can
accompany the high fever and rash systemically, thus can
10 R. Kneen et al.
1117
1118
1119
1120
1121
1122
1123
1124
1125
1126
1127
1128
1129
1130
1131
1132
1133
1134
1135
1136
1137
1138
1139
1140
1141
1142
1143
1144
1145
1146
1147
1148
1149
1150
1151
1152
1153
1154
1155
1156
1157
1158
1159
1160
1161
1162
1163
1164
1165
1166
1167
1168
1169
1170
1171
1172
1173
1174
1175
1176
1177
1178
1179
1180
1181
1182
1183
1184
1185
1186
1187
1188
1189
1190
1191
1192
1193
1194
1195
1196
1197
1198
1199
1200
1201
1202
1203
1204
1205
1206
1207
1208
1209
1210
1211
1212
1213
1214
1215
1216
1217
1218
1219
1220
1221
1222
1223
1224
1225
1226
1227
1228
1229
1230
1231
1232
1233
1234
1235
1236
1237
1238
1239
1240
Infect (2011), doi:10.1016/j.jinf.2011.11.013
be indistinguishable fromthe viral encephalitides typied by
gastroenteritis.
Sometimes the pattern of neurological decit can be
a clue as to the possible aetiology. Thus autonomic dysfunc-
tion, myoclonus and cranial neuropathies can indicate
brainstem encephalitis, which is seen in listeriosis, brucel-
losis, some viral infections or rarely tuberculosis (Table 8.
Brainstem encephalitis); there may be tremors and other
movement disorders if the thalamus and other basal ganglia
are involved, as seen in aviviruses, such as West Nile virus
and Japanese encephalitis, and alphaviruses such as Eastern
equine encephalitis virus.
80,81
An encephalitis with an acute
accid paralysis is characteristic of polio, and other entero-
virsues, such as enterovirus 71, as well as aviviruses.
82
Recommendation
The constellation of a current or recent febrile illness
with altered behaviour, cognition or consciousness or
new onset seizures or new focal neurological signs
should raise the possibility of encephalitis, or another
CNS infection, and should trigger appropriate investiga-
tions (A, II)
The differential diagnosis of encephalopathy (due to
metabolic, toxic, autoimmune causes or sepsis outside
the CNS) should be considered early (B, III), especially
if there are features suggestive of a non-encephalitic
process, such as a past history of similar episodes, sym-
metrical neurological ndings, myoclonus, clinical signs
of liver failure, a lack of fever, acidosis or alkalosis (B,
III)
Patients presenting with a sub-acute (weeks to months)
encephalitis should trigger a search for autoimmune,
paraneoplastic, metabolic aetiologies (C, III)
The priority of the investigations shown in Table 9 is de-
termined by the patients clinical history and clinical
presentation (C, III)
Table 9 Additional investigations to consider to in the differential diagnosis of encephalitis.
Differential diagnosis Investigations to consider
Para-infectious immune-mediated encephalitis MRI brain and spine
AntiDNAse B and ASO titre, inuenza A and B PCR and/or antibody in
CSF and serum
CSF examination
Brain and meningeal biopsy
Autoimmune/Inammatory encephalitis FBC, ESR, CRP, ANA, ENA, dsDNA, ANCA, C3, C4, lupus anticoagulant,
cardiolipin, thyroglobulin, thyroperoxidase antibodies.
Voltage-gated potassium channel complex and NMDA receptor
antibodies
Serum and CSF ACE, Serum 25OH Vitamin D, 24hr urinary calcium
Whole body CT
Biopsy: Brain, meninges, skin, lymph node, peripheral nerve/muscle
Metabolic Renal, liver, bone & thyroid proles
Arterial blood gas analysis
Plasma and CSF lactate, ammonia, pyruvate, amino acids, very long-
chain fatty acids, urinary organic acids
Porphyrins: blood/urine/faeces
Biopsy: skin, lymph node, peripheral nerve/muscle
Vascular CT or MRI head with venogram and/or angiogram
Neoplastic MRI brain and MR spectroscopy
CSF cytological analysis
Brain and meningeal biopsy
CT chest/abdomen/pelvis
LDH, IgG/A/M, protein electrophoresis, urinary Bence-Jones protein
(in adults), bone marrow trephine
Paraneoplastic Anti-neuronal and onconeuronal antibodies
CT or PET chest, abdomen and pelvis
Biopsy of non CNS viscera
Alpha fetoprotein, beta human chorionic gonadatrophin
Toxic Blood lm; blood or urine levels of alcohol, paracetamol, salicylate,
tricyclic, heavy metals
Urinary illicit drug screen
Septic Encephalopathy Serum microbiological cultures, serology and PCR
Abbreviations: MRI magnetic resonance imaging; ASO antistreptolysin; PCR polymerase chain reaction; CSF cerebrospinal uid; FBC full
blood count; ESR erythrocyte sedimentation rate; CRP C-reactive protein; ANA antinuclear antibodies; ENA extraneuclear antibodies;
dsDNA double stranded deoxyribonucleic acid antibodies; C3/4 complement; ACE angiotensin converting enzyme; CT computed tomog-
raphy; LDH lactate dehydrogenase; IgG/M/A immunoglobulin; PET positron emission tomography; CNS central nervous system.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Which patients with suspected encephalitis should
have a lumbar puncture (LP), and in which should
this be preceded by a computed tomography (CT)
scan?
A lumbar puncture (LP) is an essential investigation in the
management of children with suspected encephalitis to
conrm the diagnosis and rule out other causes. Therefore
all children with suspected encephalitis should have a LP
unless a specic contraindication exists. Contraindications
have been published in an evidenced based guideline for
the management of decreased level conscious level in
children (Table 10. Contraindications to immediate lumbar
puncture).
83
The risk of presenting with viral encephalitis
following a febrile seizure is not known although the risk
for bacterial meningitis following febrile seizures is quoted
to occur in between 0.4 and 5%.
84,85
This gure increases to
18% in children who present with febrile status epilepti-
cus.
86
In addition, young children may present with menin-
gitis without any signs of meningeal irritation; 6 children
aged less than 18 months in a series of 95 children who pre-
sented with a simple (n Z 87) or complex febrile seizure
(n Z8) and without signs of meningeal irritation had under-
lying bacterial meningitis.
87
Although others have reported
that only 0.4e1.2% of children who present with a fever and
a seizure, in the absence of signs of meningeal irritation
will have bacterial meningitis.
85
Nevertheless, children
who do not make a full recovery within an hour following
a typical, simple febrile convulsion should have a LP.
88
There has been considerable controversy over the role of
computer tomography (CT) and LP in patients with sus-
pected central nervous system infection, in particular
whether a CT is needed before an LP.
89e91
Although there
are few studies that specically address this issue in pa-
tients with suspected encephalitis, much of the literature
about suspected bacterial meningitis is pertinent because
of overlap in the clinical presentations. As in patients
with meningitis, in encephalitis the CT scan is not a reliable
tool for the diagnosis of raised intracranial pressure, and
should not be used to for this.
16,89
In patients with suspected encephalitis, an early CT scan
has two roles: suggesting the diagnosis of viral encephalitis
and indicating an alternative diagnosis. An initial CT scan
soon after admission will show a suggestive abnormality in
about 80% of patients with herpes simplex virus (HSV)
encephalitis
8
; almost all those with HSV encephalitis, and
a negative initial scan will have abnormalities on a second
scan.
8
The sensitivity of the CT scan for detecting abnor-
malities is increased with the use of intravenous contrast
media, however, it is not, on its own, diagnostic.
The second role of an early CT scan is suggesting an
alternative diagnoses, so that LP may no longer be
necessary. For example in one study of 21 adults with
suspected encephalitis, 2 (10%) patients did not have a LP
after the CT scan showed a stroke
12
; however, in a larger
study only 2 (1%) of 153 patients with suspected CNS infec-
tions who had a CT rst did not subsequently need a LP.
13
If clinical contraindications to an immediate LP are
present then an urgent CT should be performed. If this
identies shift of brain compartments or tight basal
cisterns, due to mass lesions and/or oedema a subsequent
LP may be dangerous. In patients with brain shift a LP, by
reducing the cerebrospinal uid (CSF) pressure below the
lesion, may precipitate herniation of the brainstem or
cerebellar tonsils.
92,93
For example this may occur in pa-
tients with brain abscess, subdural empyema, tumour, or
a necrotic swollen lobe in HSV encephalitis. However unse-
lected CT scanning all patients before a LP can cause un-
necessary delays in many patients, in whom there were
no contraindications to an immediate LP.
12,13
For example
in one recent study of 21 adults with suspected encephali-
tis, 17 had a LP, which was delayed for a CT scan in 15,
though only one of them had any contraindications to an
immediate LP. The median time to CT scan was 6 h, but
the median time to LP was 24 h.
12
Furthermore, in a larger
study of 217 patients with suspected CNS infections the me-
dian (range) time to LP was signicantly longer if the pa-
tient had a CT scan rst (18.5 [2e384] versus 6 [1e72]
hours respectively, p < 0.0001).
13
The increasing availabil-
ity of CT scans in emergency units since this work was pub-
lished (due to implementation of national guidelines for
stroke thrombolysis and acute head injury) will undoubt-
edly result in easier access to imaging for children with sus-
pected encephalitis who are managed in a hospital that also
treats adult emergency patients.
A series of studies have examined which clinical signs can
be used to determine which patients with suspected bacte-
rial meningitis need a CT scan before LP.
90,92,94
In one study
of 696 episodes of community acquired acute bacterial men-
ingitis it was concluded that CTscan should precede LPin pa-
tients with new onset seizures, focal neurological signs,
excluding cranial neuropathies or moderate to severe im-
pairment of consciousness, as indicated by a Glasgow coma
score of 10 or less.
94
Papilloedema, a direct indicator of
raised intracranial pressure, is also an indication for imaging
before a LP. NICE guidelines for the role of CT and LP in chil-
dren with suspected bacterial meningitis have also been pro-
duced recently.
16
Given the potential overlap of clinical
features in patients with suspected meningitis and sus-
pected encephalitis, this approach is also applied to patients
with suspected encephalitis. Although there is good agree-
ment about most of the indications for a CT scan before
a LP, there is disagreement about the precise level of con-
sciousness that should be taken as a contraindication to an
immediate LP. Among seven commentaries reviewed in Joffe
2007,
92
three suggested increasing stupor progressing to
coma, three suggested a deterioration in consciousness
level, two suggested a GCS < 8, and one a GCS <
13.
89,95e100
The recent NICE guidelines for bacterial menin-
gitis recommend a CT scan before a LP if the GCS is <9 or
uctuating >2, so that an alternative diagnosis can be ex-
cluded.
16
There is also lack of clarity about whether in
such patients, a LP should then be performed at all, if the
scan is normal, or whether a low coma score is an absolute
contraindication, whatever the scan shows. Occasionally de-
terioration after LP has been reported in patients with bac-
terial meningitis and an apparently normal CT; but we are
not aware of similar cases in patients with viral encephalitis;
and most would argue that the information from the LP is es-
sential to make a diagnosis and guide treatment. In one ret-
rospective series of 222 adults with suspected encephalitis
less than 5% of patients had imaging changes suggestive of
raised intracranial pressure.
32
12 R. Kneen et al.
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1369
1370
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Other contraindications to LP include local skin infection
at the site of puncture, a clinically unstable patient with
circulatory shock or respiratory insufciency, and any
clinical suspicion of spinal cord compression. LP may also
be harmful in patients with coagulopathy, because of the
chance of needle-induced subarachnoid haemorrhage or of
the development of spinal subdural and epidural haemato-
mas. The standard recommendation is to perform a lumbar
puncture only when the patient does not have a coagulop-
athy and has a platelet count of 100 10
9
/L or greater, al-
though platelet counts of 20 10
9
/L or greater have also
been recommended.
16,101
A rapidly falling count is also
a contraindication. Haemorrhage can occur in patients anti-
coagulated with heparin or warfarin, but in one large study,
preoperative antiplatelet therapy with aspirin or nonsteroi-
dal anti-inammatory medications and subcutaneous hepa-
rin on the operative day were not risk factors for spinal
haematoma in patients undergoing spinal or epidural
anaesthesia.
101
In summary, many children will need a CT before a LP,
because of their clinical contraindications to an immediate
LP; such patients should have a CT, and then ideally a LP
should be considered on a case by case basis (if still
indicated and no radiological contraindications are identi-
ed) within 6 h and then decisions made on antiviral
treatment based on these results. In some children who
do not have a clinical contraindication to immediate LP,
and in whom CT is not immediately available, a prompt LP
may be the most useful approach to get an early diagnosis.
Lumbar punctures should be performed with needles
that meet the standards set out by the National Patient
Safety Agency.
All patients with suspected encephalitis should have
a lumbar puncture as soon as possible after hospital ad-
mission, unless there is a clinical contraindication
(Table 10. Contraindications to immediate lumbar
puncture) (A, II)
Clinical assessment and not cranial CT should be used to
determine if it is safe to perform a LP (A, II)
If there is a clinical contraindication indicating possible
raised intracranial pressure due to or causing brain
shift, a CT scan should be performed as soon as possi-
ble, (A, II). An immediate LP following this should ide-
ally be considered on a case-by-case basis, unless the
imaging reveals signicant brain shift or tight basal cis-
terns due to or causing raised ICP, or an alternative di-
agnosis, or the childs clinical condition changes (B, III).
If an immediate CT is not indicated, imaging (CT or,
preferably, MRI) should be performed as soon as possi-
ble after the LP (A, II)
In anticoagulated patients, adequate reversal (with
protamine for those on heparin and vitamin K, pro-
thrombin complex concentrate, or fresh frozen plasma
for those on warfarin) is mandatory before lumbar
puncture (A, II). In patients with bleeding disorders, re-
placement therapy is indicated (B, II). If unclear how to
proceed, advice should be sought from a haematologist
(B, III)
In situations where an LP is not possible at rst, the sit-
uation should be reviewed every 24 h, and an LP per-
formed when it is safe to do so (B, II)
If an initial LP is non-diagnostic, a second LP should be
performed 24e48 h later (B, II)
Children and young adults should be stabilised before
performing a CT scan, and an anaesthetist, paediatri-
cian or intensivist should be consulted. (A, III)
Lumbar punctures should be performed with needles
that meet the standards set out by the National Patient
Safety Agency (A, III)
What information should be gathered from the LP?
Patients with HSV encephalitis typically have moderate
elevation of CSF opening pressure, a moderate CSF pleocy-
tosis from tens to hundreds of cells per ml, with a mildly
elevated CSF protein and normal CSF to plasma glucose
ratio.
7,8,102
Whilst measuring the CSF opening pressure is
part of a standard LP, it is often more difcult to achieve
this in children and is frequently omitted. Whilst the evi-
dence base would recommend undertaking opening pres-
sure, it is recognised that it is often impractical to do this
in a child so the clinician responsible for undertaking the
Table 10 Contraindications to an immediate lumbar
puncture in patients with suspected CNS infections, modi-
ed from (Kneen, Solomon, et al., 2002; Michael, Sidhu,
et al., 2010; Hasbun, Abrahams, et al., 2002;
NICE).
13,16,21,92
Imaging needed before lumbar puncture (to exclude brain
shift, swelling, or space occupying lesion)
Moderate to severe impairment of consciousness
a
or fall
in GCS of >2
Focal neurological signs (including unequal, dilated or
poorly responsive pupils)
Abnormal posture or posturing
Papilloedema
After seizures until stabilised
Relative bradycardia with hypertension
Abnormal dolls eye movements
Immunocompromise
Other contraindications
Systemic shock
Coagulation abnormalities:
B Coagulation results (if obtained) outside the normal
range
B Platelet count <100 10
9
/l
B Anticoagulant therapy
Local infection at the lumbar puncture site
Respiratory insufciency
Suspected meningococcal septicaemia (extensive or
spreading purpura)
a
There is no agreement on the depth of coma that necessitates
imaging before lumbar puncture; some argue Glasgow coma
score < 12, others Glasgow coma < 9.
Patients on warfarin should be treated with heparin instead,
and this stopped before lumbar puncture.
Consider imaging before lumbar puncture in patients with
known severe immunocompromise (e.g. advanced HIV).
A lumbar puncture is still possible if the platelet count is
50 10
9
/L; Seek haematological advice.
1489
1490
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1493
1494
1495
1496
1497
1498
1499
1500
1501
1502
1503
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1507
1508
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1510
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1515
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
LP will have to make a balanced judgement as to the value
of trying to achieve this. However, if the child is being
anaesthetised for the procedure, the opening pressure
should be measured with arterial blood gas results stabi-
lised and CO
2
noted. Occasionally polymorphonucelar cells
predominate, or the CSF may be normal, especially early in
the illness: in approximately 3e5% of adults with proven
HSV encephalitis an initial CSF may be normal with no pleo-
cytosis and a negative HSV PCR.
8,10
The gure is even higher
in patients with immunocompromise and in children, espe-
cially infants. However, if the rst CSF is normal in HSV en-
cephalitis, a second CSF examination 24e48 h is likely to be
abnormal with a positive HSV PCR, although the viral load
does reduce when patients are receiving aciclovir.
8,10
A series of studies have shown the apparent difculty in
measuring plasma glucose at the same time as CSF
glucose,
12,13,89
but without the former, interpretation of
the CSF results is very difcult. HSV encephalitis can be
haemorrhagic, and the CSF red cell count is elevated in ap-
proximately 50% of cases.
103
An acellular CSF is also de-
scribed for other viruses, VZV, EBV and CMV, and occurs
more frequently in patients with immunocompromise.
25
Although a lymphocytic CSF pleocytosis is typical of viral
CNS infections, non-viral infection, particularly tuberculo-
sis and listeriosis, and partially treated acute bacterial
meningitis can give a similar picture. Usually the clinical
setting and other CSF parameters (low glucose ratio and
higher protein) will suggest these possibilities. CSF lactate
may be helpful in distinguishing bacterial meningitis from
viral CNS infections
104,105
; in particular a CSF lactate of
<2 mmol/l is said to rule out bacterial disease.
105
A high
CSF lactate may also be an indicator of a metabolic disor-
der, in particular a mitochondrial encephalopathy. If
ADEM is in the differential diagnosis, the CSF (with a paired
serum sample) should be sent for oligoclonal bands.
106
In a traumatic tap white blood cells and protein from
the blood can contaminate the cerebrospinal uid.
107
There is little good evidence to support how to correct
for this in children.
108
However, the standard approxima-
tion would be to subtract 1 white cell for every 700 red
blood cells/mm3 in the CSF, and 1.1 mg/dL for every
1000 red blood cells/mm3.
109
This approximation will suf-
ce in most circumstances, though more complicated for-
mulae allowing for anaemia etc are available.
107
However,
in patients with HSV encephalitis a blood-stained CSF sam-
ple may reect the haemorrhagic pathophysiology of the
condition, this is more likely if serial CSF specimens are
blood-stained.
Recommendations
CSF investigations should include:
- Opening pressure when possible (A, II)
- Total and differential white cell count, red cell count,
microscopy, culture and sensitivities for bacteria
(A, II)
- If necessary, the white cell count and protein
should be corrected for a bloody tap
- Protein, lactate and glucose, which should be com-
pared with a plasma glucose taken just before the
LP (A, II)
- A sample should be sent and stored for virological in-
vestigations or other future investigation as indicated
in the next section (A, II)
- Culture for Mycobacterium tuberculosis when clini-
cally indicated (A, II)
If there is a strong clinical diagnosis of encephalitis in
a child, but the initial CSF results are normal, a second
LP should be undertaken and all CSF tests repeated, in-
cluding consideration for antibody detection (A, II)
What virological investigations should be
performed?
Although the list of viral causes of encephalitis is long,
110
HSV types1 & 2, VZV, and enteroviruses are the commonest
causes of viral encephalitis in immunocompetent individ-
uals in Europe & the United States.
24,111
Our ability to diag-
nose encephalitis caused by herpes viruses & enteroviruses
has been improved greatly by using polymerase chain reac-
tion (PCR).
112,113
CSF PCR for HSV during day 2e10 of illness
has overall sensitivity and specicity of >95% for HSV en-
cephalitis in immunocompetent adults.
10,39
Although HSV
PCR may be negative in the rst few days of the illness
113
a second CSF taken 2e7 days later will often be HSV posi-
tive, even if aciclovir treatment has been started.
11,114
Further microbiological investigations should be based
on specic epidemiological factors (age, animal and insect
contacts, immune status, recreational activities, geography
and recent travel history, season of the year and vaccina-
tion history) and clinical ndings (hepatitis, lymphadenop-
athy, rash, respiratory tract infection, retinitis, urinary
symptoms and neurological syndrome (Table 12. Microbio-
logical investigation of encephalitis).
102,110,115,116
Recommendation
All patients with suspected encephalitis should have
a CSF PCR test for HSV (1 and 2), VZV and enteroviruses
as this will identify 90% of known viral cases and EBV
considered (B, II)
Further testing should be directed towards specic
pathogens as guided by the clinical features such as
travel history and animal or insect contact (B, III)
What antibody testing should be done on serum &
CSF?
Whilst all patients with suspected encephalitis should have
PCR requested for the common viruses, decisions about
antibody testing of serum and CSF are best made in
conjunction with the specialist microbiology/virology or
infectious diseases service.
Cerebrospinal uid
Intrathecal synthesis of HSV-specic IgG antibodies is nor-
mally detected after 10e14 days of illness, peaks after
one month and can persist for several years.
117
The detec-
tion of intrathecally synthesized HSV IgG antibodies, when
available, may help to establish the diagnosis of HSV en-
cephalitis in patients where the CSF is taken after day
10e12 of the illness. This is especially useful in patients
14 R. Kneen et al.
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1640
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1642
1643
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1645
1646
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1649
1650
1651
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1653
1654
1655
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
for whom an earlier CSF was not taken, or was not tested
for HSV by PCR. A European consensus statement recom-
mended the combined approach of testing CSF by PCR
and antibody detection, such that a negative HSV-PCR re-
sult early in the disease process coupled with a negative
HSV-specic CSF antibody study sampled 10e14 days after
symptom onset effectively ruled out the disease
39
; how-
ever, intrathecal immune responses may be delayed or ab-
sent when antiviral therapy is started early.
118
Additionally,
many laboratories do not provide CSF antibody detection
services. The detection of oligoclonal bands in the CSF is
a non-specic indicator of an inammatory process in the
CNS; immunoblotting of the bands against viral proteins
from HSV can been used to detect anti-HSV antibody, al-
though this is not routinely available.
32,39
Antibody detec-
tion can also be particularly useful in VZV encephalitis.
119
The detection of virus specic IgM in CSF is usually
indicative of an intrathecal antiviral immune response; this
is especially useful for aviviruses and other RNA viruses,
which tend to be primary infections, rather than DNA
viruses, which are often reactivations.
80
Blood
Acute and convalescent blood samples should be taken for
appropriate serological testing based on the likely organ-
isms identied from specic epidemiological and clinical
features.
11
Examples of infectious causes of encephalitis
that can be diagnosed from serological investigations of
blood include: EBV, arthropod-borne viruses (arboviruses),
Borrelia burgdorferi (lyme disease), Bartonella hensae
(cat scratch disease), rickettsioses, ehrlichioses, and myco-
plasma. Serological testing for antibodies in autoimmune
encephalitis is covered in the Special circumstances sec-
tion of the guideline.
Recommendation
Guidance from microbiological/virological or infectious
disease specialists should be sought in deciding on
these investigations (B, III)
In patients with suspected encephalitis where PCR of
the CSF was not performed acutely, a later CSF sample
(at approximately 10e14 days after illness onset)
should be sent for HSV-specic IgG antibody testing
(B, III)
In suspected avivirus encephalitis CSF should be
tested for IgM antibody (B, II)
Acute and convalescent blood samples should be taken
as an adjunct to diagnostic investigation especially
when EBV, arboviruses, lyme disease, cat scratch dis-
ease, rickettsiosis or ehrlichioses are suspected (B, II)
What PCR/culture should be done on other samples
(e.g. throat swab, stool, vesicle etc)?
Investigation of sites outside the CNS can be useful to
provide pointers as to possible aetiology (Table 11 Viral in-
vestigations); however it must be remembered that such in-
fection might be co-incidental rather than causal; this is
especially the case for non-sterile sites, or sites where
long term shedding of virus occurs (e.g. in the stool). In
enterovirus encephalitis, the virus may be isolated by swab-
bing the throat and rectum, or, if present, vesicles.
10
Of
these vesicular swabs are most useful because they indicate
acute and systemic infection, where-as carriage in the fae-
ces, and to some extent the throat may be long term.
82
Al-
though many patients with enterovirus CNS infections do
not have vesicles.
If the clinical illness suggests a recent respiratory
infection, samples taken from the respiratory tract (throat
swab, nasal swab, nasopharyngeal aspirate, nasal washings,
tracheal aspirate or brochoalveolar lavage) can be tested
by PCR for respiratory viruses.
Mumps encephalitis is most accurately conrmed by PCR
of the CSF; serum or salivary mumps antibodies are also
helpful. Viral culture or PCR performed on parotid gland
duct swabs, taken after massaging the parotid gland for
30 s, or buccal (saliva) swabs are useful for the diagnosis of
recent mumps virus infection, within 9 days of the onset of
symptoms. A urine sample is less sensitive but may be
positive for at least 5 days after detection in the mouth.
Urine analysis is also useful is measles is suspected.
Viral infection may be demonstrated by culture, de-
tection of viral genomes (by PCR), viral antibodies (by
serology), viral antigens (by direct immunouoresence), or,
if available, viral particles (by electron microscopy),
although PCR is the most sensitive.
9,11
Recommendation
Investigation should be undertaken through close col-
laboration between a laboratory specialist in microbiol-
ogy, virology, infectious diseases and the clinical team
(B, III)
In all patients with suspected viral encephalitis throat
and rectal swabs for enterovirus investigations should
be considered (B, II); and swabs should also be sent
from vesicles, if present
When there is a recent or concomitant respiratory tract
infection, throat swab or sputum/lavage should be sent
for PCR for respiratory viruses (B, II)
When there is suspicion of mumps CSF PCR should be
performed for this and parotid gland duct or buccal
swabs should be sent for viral culture or PCR (B, II)
Which children with encephalitis should have an
HIV test?
HIV is directly capable of causing an encephalopathy in
young children
120
but infection with the virus also predis-
poses children to CNS infections from other specic path-
ogens. Antenatal screening for HIV infection is offered to
all pregnant women in the United Kingdom and has a high
uptake (90%). However it is not compulsory, and Mother to
Child transmission of HIV can still occur in the UK.
121,122
Migrants and travellers to the UK, from areas dened by
the WHO as areas with high endemicity of HIV infection
123
particularly from sub-Saharan Africa, and Asia, including
major parts of the former Soviet Union, should be re-
garded as being at risk of Mother to Child Transmission
of HIV. It must be remembered that while HIV infection
is rapidly progressive in 20% of infants,
124,125
late
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
presentation of perinatally acquired HIV infection can oc-
cur at 13 years of age or older.
126,127
HIV should be consid-
ered in children with suspected encephalitis for three
reasons. Children with undiagnosed advanced HIV disease
can present with CNS infections from a number of the less
common infectious causes, such as cytomegalovirus.
128,129
Secondly some of the more common CNS infections, such
as Streptococcus pneumoniae or Mycoplasma tuberculosis
have an increased incidence in patients with HIV. Thirdly,
although uncommon in children, primary HIV-1 infection
can present with an acute meningoencephalitis as part
of a seroconversion illness.
130
The current UK guidelines
on HIV testing
123,131
emphasise that all patients present-
ing for healthcare where HIV, including primary HIV infec-
tion, enters the differential diagnosis should be tested
for HIV and offers detailed guidance on the testing of in-
fants, children and young people.
Recommendation
We recommend that an HIV test be performed on all pa-
tients with encephalitis, or with suspected encephalitis
irrespective of apparent risk factors (A, II)
What is the role of brain biopsy in children with
suspected viral encephalitis?
For many years brain biopsy was the preferred method for
diagnosing HSV encephalitis, because clinically many con-
ditions mimic HSV encephalitis,
33
the chances of culturing
the virus from the CSF were low, and a biopsy was one of
the few reliable means of making the diagnosis; although
its sensitivity was low, specicity was high.
33
Subsequently
CSF PCR for HSV DNA was developed, and proved a rapid
and reliable diagnostic test,
112,113
largely replacing biopsy
for the diagnosis HSV encephalitis. However biopsy still
has a role in the investigation of other patients. Although
until recently it was considered highly invasive with a -
signicant mortality and morbidity (through intracranial
haemorrhage, or biopsy site oedema), with modern stereo-
tactic approaches the incidence of serious adverse events
is low, and it is now considered a relatively safe
investigation.
132,133
There is no role for a brain biopsy in the initial
assessment of patients with suspected HSV encephalitis.
However it may have a role in patients with suspected
HSV encephalitis who are PCR negative and deteriorate
despite aciclovir, or to identify alternative causes, such
as vasculitis
134
; biopsy is especially helpful if there is
a focal lesion on imaging
132
or in patients with immune
compromise where the differential diagnosis is often
wide. Tissue needs to be sent for pathogen detection
(electron microscopy, culture, PCR and immunooure-
sence) and for histopathology. Experienced neuropathol-
ogists are essential. In one series one fth of patients
with suspected HSV encephalitis had an alternative diag-
nosis made by biopsy, in half of whom it was a treatable
condition.
33
Recommendation
Brain biopsy has no place in the initial assessment of
suspected acute viral encephalitis in immunocompe-
tant children. Stereotactic brain biopsy should be con-
sidered in a child with suspected encephalitis in whom
no diagnosis has been made after the rst week, espe-
cially if there are focal abnormalities on imaging and if
the ndings could change the childs management
(B, II)
Table 11 Microbiological investigations in patients with
encephalitis, modied from (Solomon, Hart et al., 2007).
110
CSF PCR
1. All patients
HSV-1, HSV-2, VZV
Enterovirus, parechovirus
2. If indicated
EBV/CMV (especially if immunocompromised)
HHV6,7 (especially if immunocompromised, or children)
Adenovirus, inuenza A &B, rotavirus (children)
Measles, mumps
Parvovirus B19
Chlamydia
3. Special circumstances
Rabies, West Nile virus, tick-borne encephalitis virus (if
appropriate exposure)
Antibody testing (when indicated e see text)
a
1. Viruses: IgM and IgG in CSF and serum (acute and
convalescent), for antibodies against
HSV-1 & 2, VZV, CMV, HHV6, HHV7, enteroviruses, RSV,
parvovirus B19, adenovirus, inuenza A & B
2. If associated with atypical pneumonia, test serum for
Mycoplasma serology
Chlamydophila serology
Ancillary investigations (when indicated - These establish
carriage or systemic infection, but not necessarily the
cause of the CNS disease)
Throat swab, nasopharyngeal aspirate, rectal swab,
faeces, urine
PCR/culture of throat swab, rectal swab, faeces for
enteroviruses
PCR of throat swab for mycoplasma, Chlamydophila
PCR/antigen detection of nose/throat swab or
nasopharyngeal aspirate for respiratory viruses,
adenovirus, inuenza virus (especially children)
PCR/culture of parotid duct swab following parotid
massage or buccal swab for mumps
PCR/culture of urine for measles, mumps and rubella
Vesicle electron microscopy, PCR and culture
b
Patients with herpetic lesions (for HSV, VZV)
Children with hand foot and mouth disease (for
enteroviruses)
Brain Biopsy
For culture, electron microscopy, PCR and
immunohistochemistry
b
Antibody detection in the serum identies infection (past or re-
cent depending on the type of antibodies) but does not neces-
sarily mean this virus has caused the CNS disease.
b
Viral culture and electron microscopy less sensitive than
PCR.
16 R. Kneen et al.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
If imaging shows nothing focal, an open biopsy, usually
from the non-dominant frontal lobe, may be preferable
(B, II)
The biopsy should be performed by an experienced pae-
diatric neurosurgeon and the histology should be exam-
ined by an experienced neuropathologist (B, III)
What is the role of magnetic resonance imaging
(MRI) and other advanced imaging techniques in
children with suspected viral encephalitis?
MRI is signicantly more sensitive than CT in detecting the
early cerebral changes of viral encephalitis. In HSV enceph-
alitis a CT obtained early may be normal, or have only
subtle abnormalities; in one small series only a quarter of
patients with HSV encephalitis had an abnormality on initial
CT scanning.
135
In contrast, MRI obtained within 48 h of hos-
pital admission is abnormal in approximately 90% of pa-
tients.
135e138
Early MRI changes occur in the cingulate
gyrus and medial temporal lobe, and include gyral oedema
on T-1 weighted images, and high signal intensity on T2-
weighted and T2 uid attenuated inversion recovery
(FLAIR) images.
139
Later there may be haemorrhage.
Diffusion-weighted MRI may be especially sensitive to early
changes.
140e142
Specic sequences, such as FLAIR and STIR
(short-tau inversion recovery) sequences may be of partic-
ular value in young children due to normal brain maturation
processes.
143
The MRI should be interpreted by an experi-
enced neuroradiologist.
The changes seen on MRI are reported to be specic
(87.5%) for PCR-conrmed HSV encephalitis but can also
identify alternative (often treatable) diagnoses in patients
that are negative for HSV.
137
Thus it is important that an
MRI is performed urgently. In small studies, the extent of
MRI abnormality seen acutely in HSV encephalitis did not
correlate with the clinical evolution of the disease
137
nor
with depression afterwards,
144
though a correlation be-
tween number of seizures in acute HSV encephalitis, and
subsequent brain atrophy on MRI has been demon-
strated.
145
In VZV CNS disease in immuncocompetent chil-
dren, the most common pathogenesis is a large vessel
vasculitis, which presents with an ischaemic or haemor-
rhagic infarct often seen on MRI and angiography.
146e148
In immunocompromised children, VZV may cause a multi-
focal leukoencephalopathy which may be seen to follow
a clear arterial distribution.
34
Other pathogens may have
typical abnormal ndings. M. pneumoniae may show focal
cortical lesions, deep white matter lesions and large areas
of demyelination.
61
Japanese B encephalitis typically in-
volves the thalamus and basal ganglia with T2 hyperinten-
sity. Enterovirus may result in generalised parenchymal
destruction, or may predominately affect the brainstem,
occasionally spreading posteriorly to involve the cerebellar
denate nuclei or superiorly to involve the thalami and basal
ganglia.
149
In young children, white matter oedema is not
easily distinguished from unmyelinated white matter, and
without contrast may result in incorrect reporting.
150
Although MRI is the investigation of choice, in young,
acutely ill, comatose or confused children a general anaes-
thetic is usually required posing practical difculties for
many hospitals. In one series 70% of children required
sedation or general anaesthesia.
143
Some would recom-
mend that sedation not be used in this patient group and
only anaesthetic support and formal anaesthesia used.
151
In these circumstances, CT scanning may be the only urgent
imaging available. However, the CT scan may be normal in
children with CNS infections including severe bacterial
meningitis and encephalitis so should not be relied upon
to make or refute the diagnosis of these conditions.
152,153
A pragmatic approach is to perform a CT scan as the rst
cranial imaging investigation and then an MRI can be under-
taken as soon as it can be arranged, often after transfer to
the local tertiary centre.
Other modalities
MR spectroscopy identies and quanties concentrations of
various brain metabolites, and so may help distinguish
normal from diseased brain tissue, and characterise the
nature of the damage, particularly distinguishing inamma-
tory from neoplastic processes; however there are no pro-
spective studies assessing its diagnostic role. Single photon
emission computed tomography (SPECT) may show focal
hypoperfusion persisting after recovery from acute viral
encephalitis.
154
However, it has been used mainly as a re-
search tool and appears to have little application in sus-
pected acute encephalitis in practice. Fluorodeoxyglucose
positron emission tomography (PET) shows abnormalities in
acute viral encephalitis
154,155
with regions of FDG-PET hy-
permetabolism seen most frequently in the medial temporal
lobes (sometimes reecting seizure activity). However PET
scanning is not practical or sufciently informative to be
used in children with suspected acute viral encephalitis.
Recommendation
MRI (including diffusion-weighted imaging), should be
performed as soon as possible on all patients with sus-
pected encephalitis in whom the diagnosis is uncertain;
ideally this should be within 24 h of hospital admission,
but certainly within 48 h (B, II). Where the patients
clinical condition precludes an MRI, urgent CT scanning
may reveal an alternative diagnosis (A, II)
MRI sequences obtained need to be chosen appropri-
ately for a paediatric population and images should
be interpreted by an experienced paediatric neuroradi-
ologist (B, II)
The role of MR spectroscopy is uncertain; SPECT and
PET are not indicated in the assessment of suspected
acute viral encephalitis (B, II)
Which children with suspected viral encephalitis
should have an electroencephalogram (EEG)?
The EEG is abnormal in most patients with encephalopathy,
including more than 80% of those with acute viral enceph-
alitis.
7,27
When patients have a more subtle presentation, it
can be helpful in determining whether abnormal behaviour
is due to psychiatric causes or is an early feature of enceph-
alitis. EEG is also useful in determining whether an
individual has non-convulsive or subtle clinical seizures,
which occur in both HSV encephalitis and other
encephalopathies.
156,157
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In HSV encephalitis EEG abnormalities include non-
specic diffuse high amplitude slow waves, sometimes
with temporal lobe spike-and-wave activity and periodic
lateralised epileptiform discharges (PLEDs). Even though
PLEDs occur in many cases of HSV encephalitis
33
and were at
one stage considered pathognomonic, they are now recog-
nised in other viral encephalitides
36
and non-infectious con-
ditions, and it is accepted that there are no EEG changes
diagnostic of HSV encephalitis.
159
For example when PLEDS
are identied in patients with a sub-acute or chronic en-
cephalopathy this would be suggestive of SSPE.
77,160
Recommendation
An EEG should not be performed routinely in all pa-
tients with suspected encephalitis; however, in pa-
tients with mildly altered behaviour, if it is uncertain
whether there is a psychiatric or organic cause an EEG
should be performed to establish whether there are en-
cephalopathic changes (B, II)
EEG should also be performed if subtle motor, or sub-
clinical seizures are suspected (B,II)
An EEG should be performed in children with suspected
chronic viral encephalitis for example SSPE (B, II)
Treatment of viral encephalitis
For which patients should aciclovir treatment be
started empirically?
Aciclovir is a nucleoside analogue with strong antiviral
activity against HSV and related herpes viruses, including
VZV. Two randomisedtrials haveshownthat aciclovir (10 mg/
kg three times a day) improves the outcome in adults with
HSV encephalitis from a mortality of about 70% to less than
20e30%.
5,6
Even with aciclovir treatment the outcome is of-
ten still poor, especially in patients with advanced age, a re-
duced coma score, or delays of more than 48 h between
hospital admission and starting treatment.
7,8
Because HSV
encephalitis is the most commonly diagnosed viral encepha-
litis in industrialised countries, treatment with aciclovir is
usually started once the initial CSF and/or imaging ndings
suggest viral encephalitis, without waiting for conrmation
of HSV by PCR. However, unlike meningococcal septicaemia,
where children can die within a few hours and thus immedi-
ate treatment with antibiotics is needed, in a patient with
encephalopathy who has only mild confusion, investigation
with a lumbar puncture before considering treatment is sen-
sible; especially given the very wide differential diagnosis,
and relative rarity of HSV encephalitis. Moreover, empirical
use of antimicrobial and antiviral agents can prematurely
halt the diagnostic pathway because clinicians feel falsely
reassured, and this delays the identication of other aetiol-
ogies for which different treatments might be appropriate.
Experience from paediatrics has shown that the practice
of presumptive antiviral treatment for all patients with
encephalopathy, with no regard to the likely diagnosis, is
not benecial.
14
However if there is a strong clinical suspi-
cion of encephalitis, and there will be delays before a lum-
bar puncture can be performed, or if the child is very sick or
deteriorating, then aciclovir should be started sooner, as
should treatment for possible bacterial meningitis.
16
Even
if aciclovir has already been started in a patient with HSV
encephalitis the CSF is likely to remain positive for up to
7e10 days,
11
meaning that a later lumbar puncture can still
conrm the diagnosis.
Although aciclovir is relatively safe there are important
side effects, particularly renal impairment secondary to
crystalluria and obstructive nephropathy.
161
This reversible
nephropathy usually manifests after 4 days of intravenous
therapy and can affect up to 20% of patients.
162,163
The
risk of nephropathy can be reduced by maintaining ade-
quate hydration and monitoring renal function. In addition,
the dose of aciclovir should be reduced in patients with pre-
existing renal impairment, because it is excreted via the
kidneys. Other rare adverse events include hepatitis,
bone marrow failure and encephalopathy.
Recommendation
Children with suspected encephalitis should have intra-
venous aciclovir started if the initial CSF and/or imaging
ndings suggest viral encephalitis, and denitely within
6 h of admission if these results are awaited (A, I).
If the rst CSF microscopy or imaging is normal but the
clinical suspicion of HSV or VZV encephalitis remains,
aciclovir should still be started within 6 h of admission
whilst further diagnostic investigations (as outlined be-
low) are awaited (A, I)
The dose of intravenous aciclovir should be:
- 3 months-12 years 500 mg/m
2
8 hourly
- >12 years 10 mg/kg 8 hourly
The dose of aciclovir should be reduced in patients with
pre-existing renal impairment (A, II)
Patients with suspected encephalitis due to infection
should be notied to the appropriate Consultant in
Communicable Disease Control (In Scotland, only pa-
tients with a proven aetiology or those occurring as
part of an unusual outbreak are notiable) (A, III)
If meningitis is also suspected, the child should also be
treated in accordance with the NICE meningitis guide-
line (A, II)
How long should aciclovir be continued in proven
HSV encephalitis, and is there a role for oral
treatment?
The original randomised trials of aciclovir for HSV enceph-
alitis were for 10 days. However, reports of clinical relapse
after 10 days treatment were published subsequently.
164,165
In children, relapse rates may be as high as 26e29%, partic-
ularly if the duration of treatment is <14 days.
166
Although
an on-going immune-mediated and inammatory reaction
to the infection is now thought by many to be the major
pathogenic process,
164e167
there is evidence for continuing
viral replication in some cases.
8,164,166,168
As a consequence
most clinicians now use at least 14e21 days intravenous
treatment in conrmed cases, though later relapses can oc-
cur.
8
The risk of relapse may be highest in children aged 3
months-12 years, up to 26%, and some have advocated
that this group should receive a minimum of 21 days of in-
travenous aciclovir.
151
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Some advocate repeating a CSF examination at 14e21
days, and continuing treatment until the CSF is negative for
virus by PCR
110
; this is supported by a European Consensus
Statement.
39
Oral aciclovir does not achieve adequate levels in the
CSF and is not suitable for treating HSV encephalitis;
however its valine ester valaciclovir has good oral bio-
availability, and is converted to aciclovir after absorp-
tion.
169
Valaciclovir has been occasionally used in
paediatric practice to treat HSV encephalitis after at least
10e14 days of intravenous aciclovir, when maintaining in-
travenous access proved difcult.
170
Although CNS pene-
tration is difcult to monitor some have reported CSF
trough levels that are >50% of plasma trough levels.
171
However valaciclovir is not licenced for use in children
and is only available in tablet form. The American NIAID
Collaborative Antiviral Study Group is assessing the role
of high dose valaciclovir (2 g three times daily) for three
months.
172
Recommendation
In children with proven HSV encephalitis, intravenous
aciclovir treatment should be continued for 14e21
days (A, II), and a repeat LP considered at this time
to conrm the CSF is negative for HSV by PCR (B, II);
particularly if there are concerns that the treatment
is ineffective (severe disease, immune compromise,
previous relapses).
If the CSF is still positive for HSV by PCR, aciclovir
should continue, with weekly CSF PCR until it is nega-
tive (B, II)
In children aged 3 months-12 years a minimum of 21
days of aciclovir should be given before repeating the
LP (B, III)
When can presumptive treatment with aciclovir be
safely stopped, in patients that are HSV PCR
negative?
For most patients with suspected HSV encephalitis, pre-
sumptive aciclovir treatment is started on the basis of
a clinical picture and initial CSF ndings consistent with
viral encephalitis. This initial CSF may subsequently reveal
an alternative diagnosis such as bacterial infection, in
which case aciclovir can be stopped. However, an initial
CSF PCR can occasionally be negative in HSV encephalitis,
especially if it is taken early in the illness (<72 h after
symptom onset), or after some days on aciclovir treatment
when the virus has cleared. Thus if viral encephalitis is
still strongly suspected, aciclovir treatment should not
be stopped on the basis of a single negative CSF PCR
only. A European consensus statement recommended the
combined approach to diagnosis of testing CSR by PCR
and antibody detection, such that a negative HSV-PCR re-
sult early in the disease process coupled with a negative
HSV-specic CSF antibody study sampled 10e14 days after
symptom onset effectively ruled out the disease.
39
Given
that CSF antibody studies can only rule out diagnosis
late in the disease process and that there can be consider-
able delay in obtaining results from these assays, an
alternative strategy has been proposed for halting aciclo-
vir treatment.
113
This proposes that if a negative HSV
PCR result is obtained from CSF sampled >72 h into the
disease process and the patient has a low probability of
HSV encephalitis (e.g. normal neuroimaging, CSF
<5 WBCs/mm
3
, and normal level of consciousness) then
aciclovir treatment might be safely halted. However in re-
ality, a more common situation is the patient with a nega-
tive initial CSF PCR who continues to have altered
consciousness, or has a CSF pleocytosis, or imaging abnor-
malities. In this situation many clinicians would repeat the
CSF examination at 24e48 h to determine whether it is
still negative for HSV by PCR; HSV encephalitis is very un-
likely in such patients if there are two negative CSF PCRs
for HSV.
Recommendation
Aciclovir canbestoppedinanimmunocompetent child, if
- An alternative diagnosis has been made, or
- HSV PCRin the CSF is negative on two occasions 24e48 h
apart, and MRI imaging (performed >72 h after symp-
tomonset), is not characteristic for HSVencephalitis, or
- HSV PCR in the CSF is negative once >72 h after neu-
rological symptom onset, with normal level of con-
sciousness, normal MRI (performed >72 h after
symptom onset), and a CSF white cell count of less
than 5/mm
3
(B, III)
What is the role of corticosteroids in HSV
encephalitis?
The role of steroids in the treatment of HSV encephalitis is
not established.
173
Even before antiviral drugs became
available, many clinicians considered that corticosteroids
were benecial in HSV encephalitis, though others dis-
agreed.
174,175
Since the advent of aciclovir, corticosteroids
have often be used, especially in patients with marked ce-
rebral oedema, brain shift or raised intracranial pressure,
but their role remains controversial because as well as re-
ducing swelling, corticosteroids have strong immunomodu-
latory effects, which in theory could facilitate viral
replication. However a retrospective analysis of 45 patients
with HSV encephalitis showed that older age, lower Glas-
gow coma score at admission and lack of administration
of corticosteroids were signicant independent predictors
of a poor outcome.
176
An accompanying editorial made
a strong case for a randomised placebo-controlled trial,
173
which is now being carried out across several European
countries.
177
Recommendation
Whilst awaiting the results of a randomised placebo-
controlled trial corticosteroids should not be used rou-
tinely in patients with HSV encephalitis (B, III)
Corticosteroids may have a role in patients with HSV en-
cephalitis under specialist supervision, but data
establishing this are needed and the results of a pro-
spective RCT are awaited (C, III)
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
What should be the specic management of VZV
encephalitis?
In immunocompetent children, VZV can cause CNS disease
through three mechanisms; a post-VZV cerebellitis, an
acute VZV encephalitis and a VZV vasculopathy.
In cerebellitis caused by VZV, antiviral treatments are not
normally used because the disease is usually self limiting,
resolving in one to three weeks, and the primary pathogenic
process is thought to be immune-mediated demyelination,
rather than viral cytopathology.
178
Although there are no
good studies in primary VZV encephalitis, this condition is
usually treated with antiviral drugs and, possibly corticoste-
roids.
178
Aciclovir 10 mg/kg three times daily is often recom-
mended,
179
but because VZV is less sensitive to aciclovir
than HSV, 15 mg/kg three times daily has also been sug-
gested if renal function is normal,
146
for up to 14 days,
180
es-
pecially if it can be started within a few days of symptom
onset.
179
A VZV vasculopathy presents with an acute
stroke-like episode following VZV infection and is routinely
treated with both aciclovir, as outlined, and corticosteroids,
although there is limited evidence to support this.
181
The course of steroids (for example 60e80 mg of
prednisolone daily for 3e5 days) is often given, because
of the inammatory nature of the lesion.
146
In immunocom-
promised patients with VZV encephalitis a prolonged course
of intravenous aciclovir may be needed.
Recommendation
No specic treatment is needed for VZV cerebellitis
(B, II).
For VZV encephalitis, whether a primary infection or
a reactivation, intravenous aciclovir 500 mg/m
2
or
10e15 mg/kg three times daily is recommended (B, II);
If there is a vascopathy (i.e. stroke), there is a case for
using corticosteroids (B, II)
What should be the specic management of
enterovirus meningoencephalitis?
Pleconaril is a drug that binds within a hydrophobic pocket
at the base of the receptor-binding canyon in the viral
capsid protein of enteroviruses, thus inhibiting the virus
from binding to its cellular receptor. The drug has broad
activity against most enteroviruses at low concentrations
(<0.1 mg per mL), and has good oral bioavailability. In phase
III clinical trials pleconaril reduced symptoms of aseptic
meningitis, particularly headache, by approximately two
days, compared with placebo controls, but it is not used
widely for this condition.
182
The drug has also been used in
patients with chronic enterovirus infection due to agamma-
globulinaemia, enterovirus myocarditis, poliovirus vaccine
associated paralysis and neonatal infection. However there
have been no trials assessing its role in enterovirus enceph-
alitis, and it is often not available.
Intravenous immunoglobulin is used in patients with
chronic enterovirus meningitis,
183
and may also be useful
in patients with severe enterovirus 71 infection, though
no randomised trials have been conducted.
184
Recommendation
No specic treatment is recommended for enterovirus
encephalitis; in patients with severe disease pleconaril
(if available) or intravenous immunoglobulin may be
worth considering (C, III)
What acute facilities should be available and which
patients should be transferred to a specialist unit?
Currently in the UK there is sparse evidence and little
guidance for the inpatient care of patients with suspected
viral encephalitis. A charity-commissioned nationwide survey
of encephalitis patients experiences of hospital care re-
vealedthat only 39%werecaredfor onaneurological ward.
185
Many patients with suspected acute encephalitis are
critically ill. Their behaviour is often disturbed and they
are at risk of seizures, malignant raised intracranial pres-
sure, aspiration, systemic complications of infection, elec-
trolyte disturbances, and death. Because it is a relatively
rare condition, medical teams caring for patients with
encephalitis often have limited experience of the condition.
Patients require close monitoring in a quiet environment but
do not routinely require isolation. Unlike stroke in adults,
where clear evidence exists to support patient management
in specialist units, no such studies have been undertaken for
encephalitis.
186
Appropriate environments for managing pa-
tients with encephalitis include neurological wards, high de-
pendency units, or intensive care units.
The acute care of a child with suspected encephalitis is
multidisciplinary, potentially requiring the input of not only
paediatric neurologists, but infectious disease paediatri-
cians, virologists, microbiologists, neurophysiologists, neu-
roradiologists, paediatric neurosurgeons, neurologically
and/or psychiatrically-trained nursing staff, and paediatric
intensive care staff. Many of these personnel are only avail-
able through specialist paediatric neuroscience centres at
tertiary hospitals. The role of members of the multidisciplin-
ary team varies during the acute illness and rehabilitation.
Recommendation
Patients with suspected acute encephalitis should have
access to a paediatric neurological specialist opinion
and should be seen as soon as possible and denitely
within 24 h of referral (B, III)
There should be access to neuroimaging (both MRI and
CT), under general anaesthetic if needed, and neuro-
physiology (EEG), which may mean transfer to a special-
ist paediatric neuroscience unit (B, III)
As CSF diagnostic assays are critical to conrming diag-
nosis, the results of CSF PCR assays should be available
within 24e48 h of a lumbar puncture being performed.
(B, III)
When a diagnosis is not rapidly established or a patient
fails to improve with therapy, transfer to a paediatric
neurological unit is recommended. The transfer should
occur as soon as possible and denitely within 24 h of
being requested (B, III)
Patients with falling level of consciousness require ur-
gent assessment by paediatric Intensive Care Unit staff
20 R. Kneen et al.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
for airway protection and ventilatory support, manage-
ment of raised intracranial pressure, optimisation of
cerebral perfusion pressure and correction of electro-
lyte imbalances. (A, III).
What rehabilitation and support services should be
available for children affected by encephalitis and
their families?
The sequelae of encephalitis may not be immediately
apparent when a patient is discharged from hospital
following the acute illness. However, anxiety, depression
and behavioural problems such as intrusive obsessive
behaviour, challenging behaviour or hyperactivity/concen-
tration difculties often become evident subsequently, and
may be more likely after encephalitis than other causes of
acute brain injury.
187
A charity-commissioned study of en-
cephalitis patients found that 33% were discharged without
out-patient follow-up although 96% reported on-going com-
plications from their illness.
185
A broad and comprehensive approach to both assess-
ment and rehabilitation is necessary, with neuropsychology
and child and adolescent mental health teams as central
components,
188
and access to speech and language thera-
pists, neuro-physiotherapists, and occupational therapists.
Access to specialist brain injury rehabilitation services is
key to recovery in many cases.
189
Children affected by encephalitis, their families and
other people involved in supporting them, such as teaching
staff, require information on the condition and its conse-
quences and directions on how access this information.
110
In one survey one third of patients were discharged from
hospital without they or their families being informed of
the diagnosis.
185
Information and support reduces isolation,
helps family adjustment and can provide useful signposting
to other services as appropriate.
189
Recommendation
Parents and older children (where their cognitive abil-
ity permits) should be made aware of the support pro-
vided by voluntary sector partners such as the
Encephalitis Society (www.encephalitis.info) (B, III)
At the time of discharge, children should have either
a denite or suspected diagnosis. Arrangements for
out-patient follow-up and plans for on-going therapy
and/or rehabilitation should be formulated at a dis-
charge meeting (A, III)
All children should have access to assessment for reha-
bilitation (A, III)
Special circumstances
What is the management of suspected encephalitis
in children returning from travelling overseas?
Children travelling overseas are at risk of a range of
infectious causes of encephalitis and encephalopathy, in
addition to those found in the UK.
190
More common causes of
encephalopathy in returning travellers include malaria and
tuberculous meningitis, and encephalopathy related to diar-
rhoea and dehydration. There are typically 5-15 deaths ev-
ery year in the UK from malaria.
191
Malaria is diagnosed by
examination of thick and thin blood lms for malaria para-
sites.
192
Thrombocytopaenia, or malaria pigment in neutro-
phils and monocytes may be a clue to malaria, even if the
lms are negative. Testing for malaria is important even in
patients that have taken anti-malarial prophylaxis, or resi-
dents from endemic areas who are thought to be immune,
because in both cases disease can occur. If cerebral malaria
seems likely, and there will be delays in diagnostic tests,
then treatment should be started.
192,193
Children with TB
meningitis often have a history of recent tuberculosis con-
tact and their family often originates from an area with
a high incidence of TB. UK guidelines on the management
of TBM have recently been produced.
194
In addition occasional cases have been reported of
dengue encephalopathy, rabies, Japanese encephalitis,
eastern equine encephalitis, West Nile virus encephalitis,
and tick-borne encephalitis.
81,195
Table 2 gives an indica-
tion of the geographical risk factors associated with these
viral CNS infections. Close liaison with the Paediatric infec-
tious diseases units, and national specialists testing labora-
tories is needed in deciding on appropriate investigations.
Other relatively rare non-viral causes of encephalopathy
in returning travellers include eosinophilic meningitis,
typhoid encephalopathy and typanosomiasis (sleeping sick-
ness).
190
Cysticercosis and schistosomiasis typically present
with space occupying lesions (often causing seizures in the
case of cysticercosis), rather than an encephalitis.
Recommendation
Patients returning from malaria endemic areas should
have rapid blood malaria antigen tests and ideally three
thick and thin blood lms examined for malaria para-
sites (A, II). Thrombocytopaenia, or malaria pigment
in neutrophils and monocytes may be a clue to malaria,
even if the lms are negative.
If cerebral malaria seems likely, and there will be a de-
lay in obtaining the malaria lm result, anti-malarial
treatment should be considered and specialist advice
obtained (A, III)
The advice of the regional paediatric infectious dis-
eases, and paediatric neuroscience units should be
sought regarding appropriate investigations and treat-
ment for the other possible causes of encephalitis in
a returning traveller (B, III)
What differences are there in the management of
suspected encephalitis in the
immunocompromised?
Immune compromise presents specic challenges in all
aspects of the management of patients with suspected
encephalitis, including the range of causative pathogens,
and presenting clinical features, and differences in the
investigations, and treatment.
196
Although many of the
principles of management of the immunocompromised are
the same as those covered for the immunocompetent,
above, there are some specic features, as outlined below.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Table 12 National guideline for the management of suspected viral encephalitis e audit tool.
National encephalitis guideline audit tool Results
A Centre
Study Number
Age (years)
Sex (please circle) M/F
Immunocompromised? Y/N
Month and year (MM/YYYY)
B Final Diagnosis
(please circle one
only)
Encephalitis HSV-1/2
VZV
Viral Enterovirus
Other (please
specify)
VGKC
Autoimmune NMDA
Other (please
specify)
Mycobacteria TB
Other (please
specify)
Fungal (please specify)
Other (please specify)
Cause unknown
1 Is the time from presentation to suspicion of encephalitis recorded? Y/N
If Y what was it? (hours)
If Y what was it <6 h? Y/N
2 Is the time from admission to LP recorded? Y/N
If Y what was it? (hours)
If Y what was it <6 h? Y/N
Were there any clinical contraindications to an LP? Y/N
If Y what was it? (please
tick all that apply)
Seizures
Focal neurological signs
Abnormal posturing
Respiratory insufciency
Bradycardia and hypertension
GCS<13 or fall>2
Systemic shock
Infection at LP site
Coagulation disorder
Immune compromise
Papilloedema
If N was imaging performed before LP? Y/N
What was the time to LP? (hours)
If Y was imaging performed before LP? Y/N
What was the time to LP? (hours)
3 Were the following
CSF tests sent?
Protein Y/N
Total WCC Y/N
Differential WCC Y/N
Microscopy and gram stain Y/N
Bacterial culture Y/N
Glucose Y/N
Blood Glucose Y/N
PCR for viruses Y/N
HSV Y/N
VSV Y/N
22 R. Kneen et al.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Causes
In patients with immune compromise there is a wider range
of pathogens that may cause an encephalitis presentation;
these include bacterial diseases such as tuberculous men-
ingitis or listeria, fungi, such as cryptococcus, parasitic
diseases, for example toxoplasma, and viruses; the viruses
implicated include cytomegalovirus, particularly in ad-
vanced HIV with CD4 counts less that 50/ml, measles and
EBV.
9,11,24,102,160,197
Progressive multi-focal encephalopa-
thy (PML), due to JC and possibly BK viruses, is very rare
in children and usually presents with features of
dementia, rather than acute encephalitis. Non-infective
considerations include primary CNS lymphomas, which are
usually EBV-driven. In one study looking for herpes viruses
in 180 non-selected CSF samples from 141 adult and paedi-
atric patients, 23 patients were HIV positive
198
among these
CMV was the virus most frequently identied (13%), fol-
lowed by EBV (10.6%), VZV (5.3%) and nally HSV-1 and
HSV-2 (both 1.3%). HSV-2, EBV and VZV were detected in
the 11 HIV-negative immunocompromised patients.
In addition to the pathogens outlined above, for
which all immunocompromised patients with suspected
encephalitis should be investigated, less common patho-
gens to consider, depending on the circumstances, include
Table 12 (continued)
National encephalitis guideline audit tool Results
Enterovirus Y/N
Other (please specify)
ZN stain for TB Y/N
Culture for TB Y/N
4 Was CSF diagnostic? Y/N
If Y what was it? HSV Y/N
VZV Y/N
Enterovirus Y/N
Other (please specify) Y/N
5 Was a HIV test
offered?
Y/N
Was it accepted? Y/N
6 Was an MRI brain
performed?
Y/N
What was the time to it? (hours)
Was this <48 h Y/N
7 Was specialist advice
sought?
Y/N
Infectious diseases Y/N
Time to review (hours)
Microbiology Y/N
Virology Y/N
Neurology Y/N
8 Was aciclovir started? Y/N
Was this before LP? Y/N
Was this: <6 h Y/N
6e12 h Y/N
12e24 h Y/N
>24 h Y/N
Was the correct dose given? Y/N
9 Was HSV proven? Y/N
Was HSV suspected? Y/N
If Y to either Was aciclovir given IV for 14-12 days? Y/N
Was the LP repeated? Y/N
If Y, was it
positive?
Y/N
If positive, was aciclovir only stopped when negative? Y/N
If Y to latter only Was aciclovir stopped only when: Y/N
patient is immunocompetent and alternative diagnosis is made or HSV PCR of CSF on 2 occasions
24e48 h apart is negative and MRI is not characteristic for HSV or HSV PCR of the CSF is negative once
>72 h after symptom onset, with unaltered consciousness a normal MRI>72 h and a CSF white cell
count <5
10 Was follow-up arranged? Y/N
Was the patient made aware of voluntary sector support? Y/N
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Coccidioides species, Histoplasma capsulatum and West
Nile virus.
116,129
History
Immunocompromised patients are more likely to have
subtle and sub-acute presentations of viruses which cause
an acute encephalitis in the immunocompetent, such as
HSV
199
and enterovirus, as well as for viruses specic to the
immunocompromised, such as HHV6 (Table 4 Sub-acute and
chronic).
Role of imaging
Because of an impaired inammatory and immune re-
sponse, severely immunocompromised patients may have
lesions on CT which are not associated with focal neuro-
logical presentations or papilloedema,
200
prompting some
to suggest that a CT scan should be performed in all immu-
nocompromised patients before LP. There are no studies
comparing imaging options in patients with suspected viral
encephalitis with or without immuocompromise. However,
immunocompromised patients are vulnerable to a broader
range of encephalitides (including PML) and the clinical
changes may be masked by immunocompromise. MRI is
therefore the imaging modality of choice in immunocom-
promised patients.
CSF ndings
In immunocompromised patients with encephalitis, the CSF
is more likely to be acellular, even though such patients are
at increased risk of CNS infection.
25
Thus CSF investigations
for microbial pathogens should be performed irrespective
of the CSF cell count.
Treatment
The UK Standards for HIV clinical care recommend that
children with HIV suffering from severe infections or other
complex problems should be referred to the regional hub or
the London Lead.
Centre.
123
The initial treatment of HSV encephalitis in
immunocompromised patients is the same as for the immu-
nocompetent; however, achieving viral clearance can be
harder, and prolonged treatment may be needed.
199
Al-
though there are no good trials for CMV encephalitis,
open label studies suggest that ganciclovir (and valganciclo-
vir), foscarnet or cidofovir may be helpful.
201
Recommendations
Encephalitis should be considered in immunocompro-
mised patients with altered mental status, even if the
history is prolonged, the clinical features are subtle,
or there is no febrile element (A, III)
In patients with known severe immunocompromise a CT
scan before LP should be considered (B, III). If a pa-
tients immune status is not known, there is no need
to await the result of an HIV test before performing a LP
MRI should be performed as soon as possible in all pa-
tients (A, II)
Diagnostic microbiological investigations for all immu-
nocompromised patients with suspected CNS infections
include (B, II):
- CSF PCR for HSV-1 & 2, VZV and enteroviruses
- CSF PCR for EBV, and CMV
- CSF acid-fast bacillus staining and culture for Myco-
bacterium tuberculosis
- CSF and blood culture for Listeria monocytogenes
- Indian ink staining and/or cryptococcal antigen
(CRAG) testing of CSF and serum for Cryptococcus
neoformans,
- Antibody testing of serum and if positive CSF PCR for
Toxoplasma gondii,
- Antibody testing of serum and if positive CSF for syph-
ilis (B, II)
Other investigations to consider, depending on the cir-
cumstances, include (C, III):
- CSF PCR for HHV6 and 7
- Parvovirus B19
- Measles
- West Nile virus encephalitis
- CSF PCR for JC/BK virus
- CSF examination for Coccidioides species, and Histo-
plasma species
Children with HIV suffering from severe infections or
other complex problems should be treated in a regional
hub or London Lead Centre (A,II)
Immunocompromised patients with encephalitis caused
by HSV-1 or 2, should be treated with intravenous aci-
clovir (10 mg/kg three times daily) for at least 21
days, and reassessed with a CSF PCR assay; following
this long term oral treatment should be considered until
the CD count is >200 106/L, or if CD4%,15% if <5
years old (A, II)
Acute concomitant VZV infection causing encephalitis
should be treated with intravenous aciclovir (A, II)
CNS CMV infections should be treated with ganciclovir,
foscarnet or cidofovir (A, II)
Children with VZV encephalitis should be treated with
intravenous aciclovir 500 mg/m
2
for at least 10 days, al-
though immunocompromised children may require lon-
ger treatment (B, III)
What differences are there in the presentation and
management of encephalitis associated with
antibodies?
In children with an acute or more commonly sub-acute
onset of encephalitis, immune-mediated encephalitis
should be considered as the treatment is very different
and early intervention signicantly improves outcome. A
growing number of cases immune-mediated encephalitis
have been reported in children, comprising of autoanti-
bodies targeting the voltage-gated potassium channel
(VGKC)-complex proteins,
202,203
N-Methy-D-Aspartic acid
(NMDA) receptor,
204e206
and other CNS antigens.
207
In
a multicentre UK Health Protection Agency (HPA) aetiol-
ogy of encephalitis study
4
20% of patients that were iden-
tied to have an autoantibody aetiology were children
(Granerod and Crowcroft; unpublished observation). In
particular, all patients should have appropriate imaging
to identify an associated tumour, such as an ovarian
tertoma.
24 R. Kneen et al.
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
What differences are there in patients with
encephalitis associated with antibodies to the
voltage-gated potassium channel (VGKC)-complex
proteins?
Presentation
VGKC-complex antibodies are beginning to be identied in
children. In a small case series of children presenting with
limbic encephalitis, 4/12 (30%) of patients were positive
for VGKC-complex antibodies.
207
In another series of chil-
dren presenting with encephalopathy and status epilepticus,
4/10 (40%) of patients were found to be VGKC-complex anti-
body positive.
203
Finally, in a review of children with VGKC
autoimmunity, a proportion of these children had encepha-
lopathy or neuroregression probably representing a sub-
acute encephalopathy.
202
These case series are small and
appear to focus on specic subgroups thus making direct
comparison between them and adult literature difcult.
Nevertheless, cases reported of VGKC-complex antibody-as-
sociated encephalitis in children shares similar features with
adult patients when presenting as limbic encephalitis (dis-
orientation and confusion with seizures). However, the low
plasma sodium found in about 60% of adult patients does
not appear to be reported in these childhood cases.
208
Investigative ndings
The MRI may reveal either features of limbic encephali-
tis,
202,207
basal ganglia changes
202
or other white matter
and sub-cortical changes.
203
The EEG reveals generalised
slowing with or without an ictal focus.
203
Signicant CSF ab-
normalities are uncommon. Association with tumours like
neuroblastomas has been reported.
202
Treatment
In all of the reported series, the latency to treatment has
been long (months to years), and hence any interpretation
of treatment efcacy is unreliable. Treatment started
within 4 weeks of symptom onset confers the best re-
covery.
202
Although prompt immunosuppression is advo-
cated, there is no denitive evidenced based approach to
treating VGKC-complex autoimmunity. Immunosuppression
as reported in the case series comprise of high dose intrave-
nous corticosteroid use and regular IVIG therapy, used inde-
pendently or in conjunction. Mild to moderate response to
treatment have been reported particularly in patients pre-
senting with seizures and limbic encephalitis.
202
What are the differences in patients with
encephalitis associated with antibodies to N-
methy-D-Aspartic acid (NMDA) receptor?
Presentation
Unlike VGKC-complex antibodies, antibodies targeting the
NMDA receptor are more commonly observed in children
and adolescents than adults.
205,206
In a comprehensive sin-
gle national reference centre study of patients presenting
anti-NMDAR encephalitis, 40% (32/81) were age 18 or be-
low.
204
In this study, an overall female preponderance
and tumour preponderance in female patients were identi-
ed. The risk of a tumour was lower in younger girls (56% in
women >18 years old, 31% in girls <19 years old, and 9% in
girls <15 years old). Of the 32 children and adolescents,
87.5% had a history of behavioural or personality change,
sometimes associated with seizures and frequent sleep dys-
function; 9.5% with dyskinesias or dystonia; and 3% with
speech impairment. On admission, 53% had clinical evi-
dence of severe speech decits. Eventually, 77% developed
seizures, 84% stereotyped movements, 86% autonomic in-
stability, and 23% hypoventilation; mirroring the biphasic
presentation noted in adults where the cortical features
(seizures, confusion, amnesia and psychosis) appear to pre-
cede the sub-cortical features (choreathetosis and oro-fa-
cial dyskinesia, uctuations in conscious level,
dysautonomia and central hypoventilation).
205
Investigation ndings
The CSF is frequently abnormal in patients consisting of
a lymphocytosis (27/31), an elevated protein (4/13) and
presence of oligoclonal bands.
204
Brain MRI is abnormal in
up to 30% of patients and abnormalities often represent ei-
ther FLAIR or T2 signal intensity in one or more areas (me-
dial temporal lobe, periventricular, cerebellar). EEG is
often abnormal with focal or diffuse slowing, and demon-
strates epileptic activity in only 30% of patients.
204
Treatment
Optimal treatment regimes are still being developed for
these patients but immunosuppressive strategies with high
dose intravenous corticosteroids, IVIG and plasmapharesis
have been used. In contrast to patients with VGKC-complex
associated encephalitis, adult patients with NMDAR-associ-
ated encephalitis can relapse in approximately 30%,
205
and
this appears to be the case with childhood and adolescent on-
set patients where neurological relapses are reported in 25%
of patients,
204
and this is not predicted by presence of tu-
mour either at outset or at recurrence. Responses to immuno-
therapy can be slow (over months) and variable; often
requiring a multidisciplinary teaminput including physical re-
habilitation and psychiatric management of protracted be-
havioural symptoms. Overall, 74% had full or substantial
recovery at 1 year, after immunotherapy or tumour re-
moval.
204
Indeed as described in adults children who had
a teratoma and were treated with tumour removal and immu-
notherapy had more frequent full recovery.
204,209
In patients
that relapse or appear unresponsive to treatment, escalation
of immunosuppression to include treatments like rituximab
have been used with some success.
210
Tumour screening
should be performed annually for several years particularly
if the treatment response is poor or relapses occur.
Recommendations
Antibody-mediated encephalitis should be considered
in all patients with suspected encephalitis as they
have a poorer outcome if untreated. Moreover the clin-
ical phenotypes of these recently described disorders
are still expanding (B, III)
Clinical features, such as limbic encephalitis, a sub-
acute presentation, speech and movement disorders
and intractable seizures may suggest an antibody-
mediated encephalitis, although these features are
not exclusive to antibody-mediated disease (B, III)
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Infect (2011), doi:10.1016/j.jinf.2011.11.013
Although tumours occur less frequently in children, all
patients with proven VGKC or NMDAR-associated en-
cephalitis should have screening for neoplasm (C, III),
and extended surveillance for several years (C, III)
Annual tumour screening should be conducted in pa-
tients with NMDAR antibody-associated encephalitis if
no tumour has been found, especially if the patient
has a poor response to therapy or there are relapses
(B, III)
Early immune suppression and tumour removal should
be undertaken when possible (B, III)
Guideline implementation and audit
These clinical guidelines have been written to aid early
recognition and appropriate investigation and management
of patients with suspected encephalitis. There are many
barriers to the implementation of such guidelines. The rst
step needed to convince clinicians to change behaviour is
often the performance of a simple operational audit, to
identify levels of good and poor practice. This can encour-
age use of standardised clinical approaches to manage-
ment, the success of which can be re-audited.
We have included a table of suggested clinical and op-
erational issues that are relatively easy to audit in
a standardised manner, and which can be adapted for
local use (Table 12. Audit parameters for national en-
cephalitis guideline).
Uncited reference
158.
Acknowledgements
The following are currently members of the National
Encephalitis Guidelines Development Group: Phil Smith,
Nick Davies, Frances Sanderson, Ian Hart, Nick Beeching,
Mark Holland, Camilla Buckley, Solomon Almond, Peter
Burnham, Mehrengise Cooper, Jean-Pieere Lin, Hermione
Lyall, Kevin Mackway-Jones, Nick Makwana, Anthony Mar-
son, Isam Osman, Andrew Riordan, Delane Shingadia, Aman
Sohal, David Stoeter, Edmund Wilkins.
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