Journal of Infection (2012) 64, 449e477

www.elsevierhealth.com/journals/jinf

Management of suspected viral encephalitis inchildren e Association of British Neurologists andBritish Paediatric Allergy, Immunology and InfectionGroup National Guidelines

R. Kneen a,b,r,*, B.D. Michael b,c,i,j,r, E. Menson d,k, B. Mehta a,l, A. Easton e,m,C. Hemingway f,n, P.E. Klapper g,o, A. Vincent h,p, M. Lim d,k, E. Carrol a,q,T. Solomon b,c,i,j, On behalf of the National Encephalitis GuidelinesDevelopment and Stakeholder Groups

aAlder Hey Children’s NHS Foundation Trust, Eaton Road, West Derby, Liverpool L12 2AP, UKb Institute of Infection and Global Health, University of Liverpool, 8th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UKcThe Walton Centre Neurology NHS Foundation Trust, Lower Lane, Fazakerly, Liverpool L9 7JL, UKd Evelina Children’s Hospital London, Guys and St Thomas’, Westminster Bridge Road, London SE1 7EH, UKe Encephalitis Society, 32 Castlegate, Malton, North Yorkshire, Y017 7DT, UKfGreat Ormond Street Hospital, 40 Bernard Street, London WC1N 1LE, UKgUniversity of Manchester, 2nd Floor, Clinical Sciences Building 2, Manchester Royal Infirmary, Oxford Road,Manchester, M13 9WL, UKhOxford Ion Channel and Disease Initiative, Department of Clinical and Experimental Neuroimmunology, WeatherallInstitute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKiDepartment of Neurological Science, University of Liverpool, 8th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK

Accepted 13 November 2011Available online 18 November 2011

* Corresponding author. Tel.: þ44 151 228 4811; fax: þ44 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 (A. Easton), heminc@gosh.nhs.uk (C. Hemingway), paul.klapper@cmft.nhs.uk (P.E. Klapper), angela.vincent@clneuro.ox.ac.uk (A. Vincent), ming.lim@gstt.nhs.uk (M. Lim), edcarrol@liverpool.ac.uk (E. Carrol), tsolomon@liv.ac.uk (T. Solomon).

j Tel.: þ44 151 529 5460; fax: þ44 151 529 5465.k Tel.: þ44 20 7188 7188.l Tel.: þ44 151 228 4811; fax: þ44 151 228 032.m Tel.: þ44 1653 692 583; fax: þ44 1653 604 369.n Tel.: þ44 207 405 9200x8308; fax: þ44 20 7813 8279.o Tel.: þ44 161 276 8853; fax: þ44 161 276 5744.p Tel.: þ44 1865 280528; fax: þ44 1865 280535.q Tel.: þ44 151 252 5160.r R. Kneen and B.D. Michael are joint first authors.

0163-4453/$36 ª 2012 Published by Elsevier Ltd on behalf of The British Infection Association.doi:10.1016/j.jinf.2011.11.013

450

KEYWORDSEncephalitis;Viral encephalitis;Herpes simplex virus;Immunocompromised;Varicella zoster virus;Enterovirus;Antibody-associatedencephalitis

Summary In the 1980s the outcome of patients with herpes simplex encephalitis was shownto 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 emergencymanagement of meningitis in children and adults was revolutionised by the introduction ofa simple algorithm as part of management guidelines.

In February 2008 a group of clinicians met in Liverpool to begin the development process forclinical care guidelines based around a similar simple algorithm, supported by an evidencebase, whose implementation is hoped would improve the management of patients with sus-pected encephalitis.ª 2012 Published by Elsevier Ltd on behalf of The British Infection Association.

R. Kneen et al.

Introduction

Encephalitis is defined as a syndrome of neurologicaldysfunction caused by inflammation of the brain paren-chyma. Encephalitis has many causes and some are specificto childhood, but fortunately it is relatively rare. Howeverdoctors who treat acutely ill children should be aware of howtomanage a child with suspected encephalitis as some of theindividual causes of encephalitis will respond to specifictreatments and delays in the diagnosis in these children canbe devastating. Strictly speaking, inflammation of the brainparenchyma is a pathological diagnosis, however due to thepractical limitations of this, surrogate clinical markers ofinflammation are used (Table 1. Definitions).

Table 1 Definitions.

Encephalopathy� Clinical syndrome of altered mental status (manifestingas reduced consciousness or altered cognition,personality or behavior)

� Has many causes including systemic infection, metabolicderangement, inherited metabolic encephalopathies,toxins, hypoxia, trauma, vasculitis, or central nervoussystem infection

Encephalitis� Inflammation of the brain� Strictly a pathological diagnosis; but surrogate clinicalmarkers often used, including inflammatory change in

Classification of encephalitis

Encephalitis can be caused by many individual diseaseprocesses but can broadly be divided into those associatedwith infection (either directly or indirectly) and non-infectious causes. Direct infections of the central nervoussystem (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. Non-viral causes of encephalitis or encephalopathy).Those indirectly associated with infection include an acutedemyelinating process, which is often temporally related toa prior infection outside of the CNS. This processmay also fol-low immunisation and is known as acute disseminated en-cephalomyelitis (ADEM). Non-infectious causes includeantibody-mediated encephalitis, which may be paraneoplas-tic for example limbic encephalitis associated with ovarianteratomas or may be an isolated finding. Initially these disor-ders were reported in adults, but they are being increasinglyrecognised in children.1 Most viral encephalitides are acute,but sub-acute or chronic presentations are characteristic ofparticular pathogens, especially in the immunocompromised(Table 4. Sub-acute and chronic encephalitis).

the cerebrospinal fluid or parenchyma inflammation onimaging

� Causes include viruses, small intracellular bacteria thatdirectly infect the brain parenchyma and some parasites

� Can also occur without direct brain infection, forexample in acute disseminated encephalitis myelitis(ADEM), or antibody-associated encephalitis

Epidemiology

The incidence of encephalitis in children is difficult toestablish as reported studies have used different casedefinitions, methodologies and different geographic

locations and study populations. However, in westernsettings reported incidences range from 6.3 to 7.4 per100,000 for all ages (adults and children) and approximately10.5e13.8 per 100,000 children.2 In the UK, this shouldequate to 1e2 children per year in a typical district generalhospital and 8e10 in a large tertiary children’s hospital. Inindustrialised nations, the most commonly diagnosed causeof encephalitis is herpes simplex virus (HSV) with an annualincidence of 1 in 250,000 to 500,000.3 The age specific inci-dence is bimodal, with peaks in childhood and the elderly.Most HSV encephalitis is due to HSV type 1 but about 10% isdue to HSV type 2. The latter occurs typically in immuno-compromised adults and in neonates in whom it can alsocause a disseminated infection. Varicella zoster virus(VZV) is also a relatively common cause of viral encephali-tis, especially in the immunocompromised, whilst cytomeg-alovirus (CMV) occurs almost exclusively in this group.Enteroviruses most often cause aseptic meningitis but canalso be an important cause of encephalitis. Among theother non-infectious causes of encephalitis, immune medi-ated conditions are increasingly being recognised includingADEM and encephalitis associated with antibodies to thevoltage-gated potassium channel complex, or N-methyl-D-aspartate antibody (NMDA) receptors.1,4

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 451

Aims and scope of the guideline

In the 1980s the outcome of HSV encephalitis in adults wasshown to be dramatically improved by aciclovir treat-ment.5,6 Delays in starting treatment, particularly beyond

Table 2 Causes of acute viral encephalitis, with geographical clet al. 2007).80,110 Note viral causes of chronic encephalitis such a

Groups Viruses

Sporadic causes (not geographically restricted) listed by groupHerpes viruses(family Herpesviridae)

Herpes simplex virus type 1Herpes simplex virus type 2

Varicella zoster virus

EpsteineBarr virusCytomegalovirus

Human herpes virus 6 & 7

Enteroviruses (familyPicornaviridae)

Enterovirus 70

Enterovirus 71

PoliovirusCoxsackieviruses, Echoviruses,Parechovirus

Paramyxoviruses(family Paramyxoviridae)

Measles virus

Mumps virus

Others (rarer causes) Influenza viruses, adenovirus,Erythrovirus B19, lymphocyticchoreomeningitis virus, rubella vir

Arthropod-borne and zoonotic virusesa

Flaviviruses(family Flaviviridae)

West Nile virus

Japanese encephalitis virus

Tick-borne encephalitis virus

Dengue viruses (types 1e4)

Alphaviruses(family Togaviridae)

Western, Eastern and Venezuelanequine encephalitis virusesChikungunya virus

Bunyaviruses Lacrosse virusColtiviruses Colorado tick fever virusRhabdoviruses Rabies, virus other lyssaviruses

Chandipura virus

Henipah Viruses Nipah virus

a Most are zoonotic e i.e. animals rather than humans are the maviruses.

48 h after hospital admission, are associated with a worseprognosis.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 clinicalpractice appears to be limited.12e14 The emergency

ues modified from (Solomon and Whitley 2004; Solomon, Harts JC viruses are not included here.

Comments

Most commonly diagnosed sporadic encephalitisCauses meningitis in adults (esp. recurrent);Meningoencephalitis occurs typically in theimmunocompromised. Also causes a radiculitis.Post-infective cerebellitis, or acute infectiveencephalitis or vasculopathyEncephalitis in the immunocompromisedEncephalitis in the immunocompromised; also retinitisor radiculitis; often neutrophilic CSF with low glucoseFebrile convulsions in children (after roseola);encephalitis in immunocompromisedEpidemic haemorrhagic conjunctivitis, withCNS involvementEpidemic hand foot and mouth disease, with asepticmeningitis, brainstem encephalitis, myelitisMyelitisMostly aseptic meningitis

Causes acute post-infectious encephalitis,sub-acute encephalitis and sub-acute sclerosingpanencephalitisParotitis, orchitis or pancreatitis may occur before,during or after meningoencephalitis

us,

North America, Southern Europe, Africa, Middle East,West and Central Asia associated with flaccid paralysisand Parkinsonian movement disordersAsia, associated with flaccid paralysis andParkinsonian movement disordersTravel in Eastern Europe, Former USSR; tick bite;upper limb flaccid paralysisCauses fever, arthralgia, rash and haemorrhagicdisease, occasional CNS diseaseFound in the Americas; encephalitis of horses andhumansAsia Pacific, AfricaEncephalitis in AmericaNorth AmericaNon-arthropod-borne zoonitic viruses transmittedby dogs, cats, bats, depending on locationTransmitted by sandflies, causing outbreaksin IndiaTransmitted in faeces of fruit bats in Malaysia,Bangladesh

in natural hosts, the exceptions being dengue and chikungunya

Table 3 Non-viral causes of encephalitis and its mimicsmodified from (Solomon and Whitley 2004; Solomon2009).80,110

Encephalitis Mimics

CNS Infections

BacteriaSmall bacteria (mostly intracellular)

Mycoplasmapneumoniae

Mycobacterium tuberculosis

Chlamydophila Streptococcus pneumoniaeRickettsiae (including

scrub typhus, RockyMountain spotted fever)

Haemophilus influenza

Ehrlichiosis(anaplasmosis)

Neisseria meningitidis

Coxiella burnetti(Q fever)

Bartonella hensellae(cat scratch fever)

Tropheryma whipplei(Whipple’s disease)

Brucella sp.(brucellosis)

Listeria monocytogenesSpirochetes

Trepenoma pallidum(Syphilis)

Leptospirosis

Borrelia burgdorferi(Lyme neuroborreliosis)

Borrelia recurrentis(relapsing fever)Other bacteria

Nocardiosis Infective endocarditisActinomycosis Parameningeal infection

Abscess/empyemaParasites

Trypanosoma bruceigambiense andTrypanosoma bruceirhodesiense(African sleeping sickness)

Malaria

Naegleria fowleri,Balamuthia mandrillaris(Amoebic encephalitis)

Cysticercosis

Angiostrongyluscantonensis (rat lungworm)

Trichinosis

FungiCoccidioidomycosis CryptococcosisHistoplasmosisNorth American

blastomycosisPara/post-infectious causes

InflammatoryAcute disseminated

encephalomyelitis (ADEM)Acute haemorrhagic

leukoencephalopathy(AHLE)

Table 3 (continued )

Encephalitis Mimics

Acute necrotisingencephalitis (ANE) inchildren

Bickerstaff’sencephalitisToxic/Metabolic

Reye’s syndromeSystemic infection

Septic encephalopathyShigellosis

Non-infectious causes

VascularVasculitisSystemic lupuserythematosisBehcet’s diseaseSubarachnoid & subduralhaemorrhageIschaemic cerebrovascularaccidents

NeoplasticParaneoplastic

encephalitisPrimary brain tumourMetastases

Metabolic encephalopathyHepatic encephalopathyRenal encephalopathyHypoglycaemiaToxins (alcohol, drugs)Hashimoto’s diseaseSeptic encephalopathyMitochondrial diseases

OtherAntibody-mediated

encephalitis: VGKCcomplex or NMDAreceptor

Drug reactions

Encephalitis lethargicaHaemophagocytic

Lymphohistiocytosis (HLH)syndrome (usually

children)

Epilepsy

Functional disorder

In this table some of the important aetiologies are classifiedinto whether they cause an encephalitis, with inflammatorychanges seen histopathologically in the brain parenchyma, orencephalopathy without inflammatory changes in the paren-chyma, although for some aetiologies this is based on limitedevidence.Abbreviations: VGKC, voltage-gated potassium channel; NMDA,N-methyl-D-Aspartic acid.

452 R. Kneen et al.

management of meningitis in children and adults was rev-olutionised by the introduction of a simple algorithm aspart of management guidelines.15e17 In February 2008a group of clinicians met in Liverpool to begin the devel-opment process for clinical care guidelines based arounda similar simple algorithm (Fig. 1. Algorithm for the man-agement of patients with suspected viral encephalitis,

Table 4 Sub-acute and chronic central nervous systempresentations e microbiological causes, modified from(Solomon, Hart et al., 2007; Solomon 2009).110,211

VirusesIn immunocompromised patientsMeasles virus (inclusion body encephalitis)Varicella zoster virus (causes a multi-focalleukoencephalopathy)CytomegalovirusHerpes simplex virus (especially HSV-2)Human herpes virus 6EnterovirusesJC/BKa virus (progressive multi-focal

leukoencephalopathy)HIV (dementia)

In immunocompetent patientsJC/BKa virus (progressive multi-focalleukoencephalopathy)Measles virus (sub-acute sclerosing panencephalitis)

BacteriaMycobacterium tuberculosisTreponema pallidum (syphilis)Borrelia burgdorferi (Lyme neuroborreliosis)Tropheryma whipplei (Whipple’s Disease)

FungiCryptococcus neoformans

ParasitesTrypanosoma brucei spp. (African trypanosomiasis)Toxoplasma gondii (toxoplasmosis)

PrionsCreutzfeldt-Jakob disease

a JC and BK viruses are named after the initials of the patientsfrom whom they were first isolated.

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 453

supported by an evidence base, whose implementation, itis hoped, would improve the management of patients withsuspected encephalitis. The scope of the guideline is tocover the initial management of all patients with sus-pected encephalitis, up to the point of diagnosis and earlytreatment, in an acute care setting such as acute medicalunit or emergency room. They are thus intended as a readyreference for clinicians encountering the more commoncauses of encephalitis, rather than specialists managingrarer causes. The guidelines also cover the specific treat-ments and further management of patients for whom a di-agnosis of viral encephalitis is made, particularly that dueto HSV, VZV and enteroviruses. Encephalitis due to CMV isalmost exclusively seen in the immunocompromised and isnot covered in detail; its diagnosis and management iscovered in HIV guidelines.18 At the end of the guidelinesthe special circumstances of returned travellers, immuno-compromised patients and encephalitis associated withantibodies are discussed. Many patients with suspected vi-ral encephalitis ultimately prove to have another infec-tious or non-infectious cause for their illness. Thefurther management and treatment of such patients is be-yond the scope of this guideline, but we have includeda 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 practicebefore and after implementation of the guidelines.

Methods

A literature search was performed on the Medline databasefor the years 1998e2008, to identify for all (English lan-guage) publications using the key words (‘Encephalitis’ AND:‘Symptoms’; ‘Signs’; ‘Management’; ‘Diagnosis’; ‘Investiga-tion’; ‘Lumbar Puncture’; ‘Cerebrospinal Fluid’ (CSF);‘Computed Tomography (CT)’; ‘Magnetic Resonance Imaging(MRI)’; ‘Single Photon Emission Tomogrophy (SPECT)’; ‘Elec-troencephalography (EEG)’; ‘Treatment’; ‘Antiviral’; ‘Aci-clovir’; ‘Steroids/Dexamethasone’) separately and incombination with the following MESH terms: (‘HerpesSimplex Virus’; ‘Varicella Zoster Virus’; ‘Enterovirus’; ‘Hu-man Immunodeficiency Virus (HIV)’; ‘Immune compromise’;‘Arbovirus’. This yielded a total of 6948 citations, includingmany case reports, which were grouped together in subjectareas including clinical presentation, diagnosis, imaging,treatment, outcome, immune compromise. These groups ofpapers were each screened by at least 2 of the group andscored for relevance, level of evidence and need for in-clusion. Further sources were added from review of thebibliographies of these articles, textbooks, other reviewsand personal collections of the screening group.

Using these revised source reference lists each sub-section of the manuscript was composed by two authors ofthe Guidelines Writing Group, from the fields of neurology,infectious diseases, microbiology, virology, acute medicineand the patient-sector. This included members from pro-fessional bodies including the British Infection Society (nowBritish Infection Association), the British Paediatric AllergyImmunology and Infection Group, the British PaediatricNeurology Association, the Society for Acute Medicine andthe Encephalitis Society. Each subsection was internallypeer-reviewed. The contributions from the various sectionsof the guidelines that people wrote were assimilated intoa single document in accordance with the principles of theAGREE (appraisal of guideline research and evaluation)collaboration.19 In rating the strength of evidence wehave used the GRADE approach, in which the strength ofrecommendations is rated from A to D, and the quality ofthe evidence supporting the recommendation is ratedfrom I to III (Table 5. GRADE).20

This document has again been internally peer-reviewedtwice by the Guidelines Development Group, and updated toinclude further comments from all contributing authors,incorporating references published in 2009e11. The guide-line has also been peer-reviewed by the wider GuidelinesStakeholder Group. This included members from the RoyalCollege of Paediatrics and Child Health, the PaediatricIntensive Care Society, the Children’s HIV Association andthe Meningitis Research Foundation. The guidelines arestructured to answer common clinical questions posed duringthe work-up of a patient with possible encephalitis.

Definition of childhood for this document

This guideline is for the management of suspected viralencephalitis in children aged older that 28 days (outside the

Figure 1 Algorithm for the management of patients with suspected viral encephalitis.

454 R. Kneen et al.

Table 5 GRADE rating system for the strength of theguidelines recommendations and the quality of the evi-dence (Atkins, Best et al., 2004).20

Strength of therecommendation

Quality of the evidence

A Strongly recommended I Evidence fromrandomised controlled trials

B Recommended,but other alternativesmay be acceptable

II Evidence fromnon-randomised studies

C Weakly recommended:seek alternatives

III Expert opinion only

D Never recommended

Table 6 Questions to consider in the history when assess-ing a patient with suspected encephalitis, modified from(Solomon, Hart et al., 2007).110

� Current or recent febrile or influenza-like illness?� Altered behaviour or cognition, personality change oraltered consciousness?

� New onset seizures?� Focal neurological symptoms?� Rash? (e.g. varicella zoster, roseola, enterovirus� Others in the family, neighbourhood ill? (e.g. measles,mumps, influenza)

� 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, Lymedisease, tick-borne encephalitis)

� Known immunocompromise?� HIV risk factors?

Abbreviations: ADEM Acute disseminated encephalomyelitis;HIV Human immunodeficiency virus.

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 455

neonatal period) and younger than 16 years. The manage-ment of neonatal encephalitis (including premature in-fants) is outside the scope of this document. Nationalguidelines for the management of suspected viral enceph-alitis in adults are also available as a separate document(Solomon, Michael, et al. 2012).

Diagnosing encephalitis

Which clinical features should lead to a suspicion ofencephalitis in children, how do they differ fromother encephalopathies, and can they be used todiagnose the underlying cause?

Recommendation

� The constellation of a current or recent febrile illnesswith altered behaviour, personality, cognition or con-sciousness or new onset seizures or new focal neurolog-ical signs should raise the possibility of encephalitis, oranother CNS infection, and should trigger appropriateinvestigations (A, II)

� The differential diagnosis of encephalopathy (due tometabolic, toxic, autoimmune causes or sepsis outsidethe CNS) should be considered early (B, III), especiallyif there are features suggestive of a non-encephaliticprocess, such as a past history of similar episodes, sym-metrical neurological findings, myoclonus, clinical signsof 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 patient’s clinical history and clinicalpresentation (C, III)

EvidenceThe differential diagnosis of acute encephalitis in childhoodis broad encompassing infectious, para-infectious immune-mediated, autoimmune, metabolic, vascular, neoplastic,paraneoplastic, and toxic aetiologies as well as braindysfunction due to systemic sepsis (Tables 2and 3).21,22

Nevertheless, defining the clinical features that shouldprompt the suspicion of acute encephalitis of childhood isessential in order to achieve prompt recognition,

investigation and management because delays have beenshown to impair outcome.

However, differentiating infection-associated encepha-litis from the other causes of encephalopathy on the basisof clinical findings poses a significant diagnostic challenge,especially in children in whom the clinical picture can bevague. For example, of Chaudhuri and Kennedy’s list‘useful clinical pointers to aid exclusion of non-infectivecauses of encephalopathy’, none are absolute.23 In adults,fever and abnormal mental status, often with severe head-ache, nausea and vomiting, are the classical clinical fea-tures of infective encephalitis. Eighty-five (91%) of 93adults with HSV-1 encephalitis in one study were febrileon admission8; even those not febrile on admission will of-ten have a history of febrile illness (Table 6. History). Dis-orientation (76%), speech disturbances (59%) andbehavioural changes (41%) were the most common fea-tures, and one third of patients had seizures.8 Howevera normal Glasgow coma score at presentation was seen insome patients in this, and other studies, reflecting thefact that it is a crude tool for detecting subtle changes inbehaviour.13 Alterations in higher mental function includelethargy, drowsiness, confusion, disorientation and coma(Table 7. Examination).

Definition of the spectrum of clinical findings at pre-sentation, and the pattern of subsequent manifestations inchildren is more difficult as documentation of the clinicalpresentation of children with encephalitis is less welldescribed. Several studies include adults and childrentogether making it difficult to comment on whetherchildren may have a different presentation.24e26 Further-more, given that children are susceptible to different aetio-logical agents than adults and also present differently fromadults with other causes of infection, the utility of the pro-files defined in characterising encephalitis presentations inchildhood is limited by the lack of breakdown by age. Themost relevant studies have only reported findings in small

Table 7 Examination findings of importance in assessinga patient with suspected encephalitis modified from (Solo-mon, Hart et al., 2007).110

� Airways, Breathing, Circulation� Mini-mental state, cognitive function, behaviour (whenpossible)

� 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 footand mouth disease; varicella zoster; rickettsial disease)

� Injection sites of drug abuse� Bites from animals (rabies) or insects (arboviruses)� Movement disorders, including Parkinsonism

456 R. Kneen et al.

numbers of children and the entry criteria were not provenencephalitis, but suspected encephalitis and are primarilyhospital-based.21,27 In the Toronto Acute Childhood En-cephalitis study, 50 children with suspected encephalitiswere reported with the most common presenting featuresbeing fever (80%), seizures (78%), focal neurological signs(78%) and decreased consciousness (47%).27 In Wang’s studyfrom Taiwan, 101 children with a final diagnosis of enceph-alitis were reported to have the following features; changein personality or reduction in consciousness (40%), seizures(33%), new neurological signs (36%) and meningism 22%, Thenumber presenting with fever was not reported.28 In themore recent Liverpool study, 51 children were treated forsuspected encephalitis and their most common presentingfeatures included confusion, irritability or a behaviourchange (76%), fever (67%), seizures (61%), vomiting (57%)and focal neurological signs (37%).14 However, 14 of thesechildren were ultimately not felt to have viral encephalitisand should not have received aciclovir so the list of pre-senting symptoms is likely to be inaccurate. Ill childrenare different to adults, young children cannot often ade-quately describe symptoms such as headache and infantsfrequently have non-specific symptoms and signs for manyacute illnesses including feeding and respiratory difficul-ties. In Wang’s study 54% of the children had concomitantsigns of a respiratory infection and 21% had gastrointestinalsymptoms.28

With the advent of CSF PCR more subtle presentations ofHSV encephalitis have been recognised and described inadults and children.30 These include low-grade pyrexiarather than a high fever, speech disturbances (dysphasiaand aphasia), and behavioural changes which can mistakenfor psychiatric illness, or the consequences of drugs or alco-hol, occasionally with tragic consequences.31

Distinguishing HSV encephalitis from otherencephalopathies

Several studies have documented the potential mimics ofHSV encephalitis in adults and children.12e14,32,33 Whitley

et al. demonstrated that of 432 (168 < 18 years old)patients undergoing brain biopsy for presumed HSV en-cephalitis: 195 (45%) had the diagnosis proven histologi-cally and in a further 95 patients (22%) an alternative,often treatable, diagnosis was established.33 However,the clinical presenting features of these two groups werevery similar. Chataway et al. found that, of those patientsinitially considered to have HSV encephalitis, inflamma-tory aetiologies such as ADEM or multiple sclerosis werethe most frequent mimics.32 Some of the rarer paediatricdiagnoses included epileptic encephalopathies such asRasmussen’s encephalitis and Alper’s syndrome. Kneen etal. showed the broad range of final diagnoses in childreninitially treated with aciclovir for possible HSV encephali-tis in children and Bell et al. and Michael et al. demon-strated that this was also similar in adult practice.12e14

The clinical picture clearly varies with disease severitybut can also vary with aetiological agent; of the many vi-ruses that cause acute encephalitis in children, somehave a predilection for localised parts of the brain whichcan determine the initial clinical picture and the subse-quent clinical course.34 Although, De Tiege et al.35 en-dorse the view that the concept of a ‘‘classical’’ pictureof HSV encephalitis in children is now out-dated and re-mind clinicians that the most common reason for failureto diagnose HSV encephalitis is non-specific initial clinicalpresenting symptoms and signs.7

Seizures are more frequently found in patients present-ing with encephalitic processes affecting the cortex, whichare more often infectious in aetiology, as opposed toencephalitic processes predominantly affecting subcorticalwhite matter that more frequently have an immune-mediated pathogenesis (e.g. ADEM). However, seizuresand movement disorders are also often seen in childrenwith encephalitis due to autoimmune antibody-mediateddisease (see ‘Special circumstances’ section). Seizures canalso be subtle and include subtle motor status: a syndromeof subtle continuous motor seizure activity. This oftenfollows overt convulsive seizures or status epilepticus ornon-convulsive status epilepticus (NCSE): a syndrome ofencephalopathy with no overt motor seizure activity but anelectrical seizure correlate on the EEG. A study of 144 (134children) patients with encephalitis due to Japaneseencephalitis virus found that 40 had witnessed seizures inhospital. Of these, 25 had one or more episodes of statusepilepticus including 15 who went onto develop subtlemotor status. Patients with witnessed convulsive or subtlemotor status epilepticus were more likely to die(p Z 0.0003).36 However, it is very unusual for patientswith encephalitis or other CNS infections and encephalopa-thy to present with de novo NCSE. A study of 236 consecu-tive intensive care unit patients (11% < 16 years) during thefirst 3 days of an illness with coma (and no witnessed overtor subtle seizures) identified that 19 (8%) were in NCSE. Ofthese, 2 were children. Only one adult had a CNS infection(diagnosis unspecified).37 In another study of 45 consecu-tive adults diagnosed with NCSE, 20 had no previous diagno-sis of epilepsy. Twenty-eight of the 45 patients hada remote risk factor for developing epilepsy includingprevious CNS infections in some (number not specified).38

Despite its relative rarity, NCSE can only be diagnosedwith an EEG and as there are specific treatments available,

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 457

an EEG should be considered in all patients with undiag-nosed encephalopathy.39

In adult clinical practice the most frequently encoun-tered infection-associated encephalopathy is septic en-cephalopathy, being found in 50e70% of septic patients.40

This syndrome usually occurs in elderly patients with anextracranial focus of sepsis where the encephalopathycannot be attributed to other organ dysfunction. Clinically,the diagnosis is one of exclusion. The syndrome is charac-terised neurologically by progression from a slowing ofmentation and impaired attention to delirium and coma.Neurological examination findings are usually symmetrical.This syndrome is uncommon in paediatric practice but itcan occur and is most frequently seen in association withbacterial infections of the urinary tract. It can also beseen in association with other rarer infective encephalop-athies such as shigella or in association with typhoidfever.41,42

Diagnostic features for specific aetiologiesThe history is important in defining the spectrum ofagents potentially responsible for encephalitis as this isinfluenced by age, immunocompetence, geography andexposure. Geographical restrictions are laid out in theTable 2. These are particularly significant for arthropod-borne infections.

As indicated above the features for HSV are non-specific:many patients with suspected HSV encephalitis ultimatelyprove to have a different diagnosis. In adults, the finding oflabial herpes (cold sores) has no diagnostic specificity forHSV encephalitis and is merely a marker of critical illness.However, in children who are more likely to developencephalitis with a primary HSV infection, labial herpesmay be noted.43,44 Lahat reported 2 children with recent la-bial herpes in a series of 28 children aged from 3 months to16 years with proven HSV encephalitis due to a primary in-fection43 and Elbers reported active or a recent history oflabial herpes in 4 out of 16 children with proven HSV en-cephalitis.44 Elbers also reported that 3 further childrenwith positive CSF PCR for HSV-1 were excluded from his se-ries because of an atypical presentation. These children allhad a milder illness (all had fever, one had multiple sei-zures, one had a single seizure and ataxia and one had leth-argy and headache) and normal cranial imaging. Elbersconcluded that the CSF PCR results may be false positivesor due to reactivation of the virus but it is also conceivablethat HSV can cause a mild encephalitis and for this reason itshould be considered in the differential diagnosis of chil-dren with less severe symptoms. A mild HSV encephalitishas also been reported in 2 previous children aged 3.5 and15 years who recovered without treatment with aciclovir.31

Children with HSV encephalitis may also present with anacute opercular syndrome (disturbance of voluntary controlof the facio-linguo-glosso-pharyngeal muscles leading tooro-facial palsy, dysarthria and dysphagia).45,46 CNS diseasecaused by HSV-2 is rare outside the neonatal period. Themost common manifestation in adults is aseptic meningitiswhich may be recurrent.47,48 This has also been reportedin children and the possibility of sexual abuse may needto be considered.49

Varicella zoster virus (VZV) can cause central nervoussystem manifestations through a post-infective immune-

mediated cerebellitis, an acute infective viral encephalitisor a vasculopathy; the neurological presentation may bepreceded by the vesicular rash of by days or weeks, thoughit occasionally occurs before the rash or even in patientswith no rash.50e52 Encephalitis is more common in adults,especially those with cranial dermatome involvement ora disseminated rash or the immunocompromised. The pre-sentation may be acute or sub-acute with fever, headache,altered consciousness, ataxia and seizures. A more commonneurological presentation associated with VZV infection inchildren is post-infectious cerebellitis particularly in youngchildren. This is usually a relatively mild and self limitingdisorder but children can become unwell due to hydroceph-alus secondary to swelling of the cerebellum in more severecases.53,54 Children usually present with a short history ofunsteadiness 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 toaccount for up to one third of cases of arterial stokes inpaediatric practice. The majority present with acute butpermanent hemiparesis, acute chorea or facial weaknesswhich is commonly transient;55 seizures and visual orspeech disturbances also occur. Patients usually present af-ter the rash has cleared and the time period can be very de-layed with a mean of 3 months (range 1 week to 48 months)reported in a recent London study.55 However, early mani-festations can occur within days of exposure,50 well beforethe vesicular eruption, which may be uncharacteristicallymild,52 making diagnosis more challenging, especially as on-set of encephalitic features can be abrupt or gradual.51 PCRfor VZV DNA in the CSF is positive in around a third of pa-tients. A more sensitive test (positive in over 90% patients)is measuring VZV specific IgG antibodies in CSF. The levelscan be compared to a concomitant serum sample as a re-duced serum/CSF ratio of VZV IgG confirms intrathecalsynthesis.56

EpsteineBarr virus (EBV) encephalitis most commonlyaffects teenagers (median age 13 years; but generallypresents in the absence of signs of the typical mono-nucleosis clinical picture.57 In Doja’s series of 21 patients,17 had a non-specific prodrome of fever and 14 had head-ache. Manifestations of EBV encephalitis and encephalomy-elitis may also include an altered level of consciousness,seizures and visual hallucinations.57e59 However, the tem-poral relationship between symptoms is highly variable, in-cluding CNS disease as the presenting manifestation,making aetiological diagnosis difficult on clinical groundsand highlighting the need to consider EBV in all cases ofchildhood encephalitis irrespective of symptoms.57

Encephalitis may be associated with respiratory illnessesin children: most common pathogens include the influenzaviruses, paramyxoviruses and the bacterium M. pneumo-niae. There may be no preceding respiratory symptomsprior to the development of encephalitis in a significantproportion of patients.60,61 In a recent study of patientswith M. pneumonia encephalitis, the affected childrenwere an older cohort (median age 11 years old), presentingwith a short prodrome of fever (70%), lethargy (68%), andaltered consciousness (58%), while gastrointestinal (45%)and respiratory (44%) symptoms were less common.60 Theirclinical course progressed rapidly (median 2 days from on-set to hospitalization), and commonly required intensive

Table 8 Brainstem encephalitis (rhombencephalitis) -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 gadoliniumenhancement of basal meninges

Causes� Enteroviruses (especially EV-71)� Flaviviruses, e.g. West Nile virus, Japanese encephalitisvirus

� Alphaviruses, e.g. Eastern equine encephalitis virus� Rabies� Listeriosis� Brucellosis� Lyme borreliosis� Tuberculosis� Toxoplasmosis� Primary or secondary central nervous systemmalignancy

� Paraneoplastic syndromes

458 R. Kneen et al.

care (55%). Seizures were less common in the clinical pic-ture. Symptoms of progressive symmetrical external op-thalmoplegia typify Bickerstaff brainstem encephalitis inassociation with M. pneumonia and can serve as a clue todiagnosis especially when accompanied by ataxia.62 Influ-enza has been reported to be associated with a spectrumof neurological disorders in adults and children rangingthrough a mild encephalopathy with seizures, encephalitis,ADEM, encephalopathy with posterior reversible encepha-lopathy syndrome, malignant brain oedema syndrome andacute necrotising encephalopathy (ANE).65,66 Patientswith influenza (particularly influenza B) can also have as-sociated severe myositis.63,64 Patients with influenza en-cephalopathy/encephalitis rarely have viral antigens orviral nucleic acid in CSF or neural tissue and the mecha-nisms for causing neurological illness are still unclear. In-fluenza A in particular, has been reported in associationwith ANE, a severe encephalopathy often associated withfever and in which typical MRI abnormalities have been re-ported in the thalami, brainstem and cerebral whitematter.65e67 ANE has most frequently been reported inyoung children in small outbreaks in Japan and otherSoutheast Asian countries. This disorder has been foundto have an autosomal dominant inheritance pattern insome families with genetic mutations identified.68 Thereis some very recent evidence that the H1N1 strain of Influ-enza A that emerged in 2009 may cause more neurologicalmanifestations than seasonal flu. Ekstrand reported 18children with H1N1and compared them to 16 with seasonalflu. Children with the H1N1 strain were more likely to haveencephalopathy, focal neurological signs, aphasia and anabnormal EEG.69

Encephalitis associated with gastrointestinal symptomsincludes infection with enteroviruses, rotavirus and humanparechoviuses. Enteroviral encephalitis can be associatedwith a brainstem syndrome. Large outbreaks of encephalitishave been reported with enterovirus 71 in Bulgaria 1975,Hungary 1997, Malaysia 1997 and Taiwan 1997. Childrenunder 5 are more commonly affected70 and the highestmortality is in those aged 6e12 months.71,72 Clues to infec-tion with this virus include the typical papular lesions onthe hands, feet and in the mouth but those with encepha-litis often develop neurogenic pulmonary oedema73 onday 2e3 of illness which can rapidly progress to fatal car-diorespiratory collapse despite intervention.71 Rotavirusencephalopathy has been reported to cause convulsionsand cerebellar signs in some children.74,75

Rashes may be seen in other encephalitides; for examplea maculopapular or vesicular rash is seen in Rickettsialinfections or the highly typical rash of measles virusinfection. Measles can cause three separate encephaliticillnesses and is of particular concern given the recent rise incases reported in children and young adults across Europe.The first is either an acute encephalitis or acute dissemi-nated encephalomyelitis associated with the acute infec-tion, although patients may present without the typicalrash.76 The second is a sub-acute encephalopathy aroundsix months after the primary infection in the immunocom-promised with measles inclusion bodies in the brain oftenwithout 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, visualproblems and later with seizures.77

HHV6 (and possibly HHV7) is a cause of encephalitiscausing severe disease and long-term sequelae far beyondself-resolving febrile convulsions.78 Typical below age 2years79 ataxia and prolonged convulsions are the majorneurological manifestations and gastrointestinal symptomscan accompany the high fever and rash systemically, thuscan be indistinguishable from the viral encephalitides typi-fied by gastroenteritis.

Sometimes the pattern of neurological deficit can bea clue as to the possible aetiology. Thus autonomicdysfunction, myoclonus and cranial neuropathies can in-dicate brainstem encephalitis, which is seen in listeriosis,brucellosis, some viral infections or rarely tuberculosis(Table 8. Brainstem encephalitis); there may be tremorsand other movement disorders if the thalamus and otherbasal ganglia are involved, as seen in flaviviruses, such asWest Nile virus and Japanese encephalitis, and alphavirusessuch as Eastern equine encephalitis virus.80,81 An encepha-litis with an acute flaccid paralysis is characteristic of polio,and other enterovirsues, such as enterovirus 71, as well asflaviviruses.82

Which patients with suspected encephalitis shouldhave a lumbar puncture (LP), and in which shouldthis be preceded by a computed tomography (CT)scan?

Recommendation

� All patients with suspected encephalitis should havea lumbar puncture as soon as possible after hospital

Table 9 Additional investigations to consider in the differential diagnosis of encephalitis.

Differential diagnosis Investigations to consider

Para-infectious immune-mediatedencephalitis

MRI brain and spineAntiDNAse B and ASO titre, influenza A and B PCR and/orantibody in CSF and serum

CSF examinationBrain and meningeal biopsy

Autoimmune/Inflammatoryencephalitis

FBC, ESR, CRP, ANA, ENA, dsDNA, ANCA, C3, C4, lupusanticoagulant, cardiolipin, thyroglobulin, thyroperoxidaseantibodies, ferritin, fibrinogen, trigylcerides.Voltage-gated potassium channel complex and NMDA receptorantibodies

Serum and CSF ACE, Serum 25OH Vitamin D, 24hr urinary calciumWhole body CTBiopsy: Brain, meninges, skin, lymph node, peripheral nerve/muscle

Metabolic Renal, liver, bone & thyroid profilesArterial blood gas analysisPlasma and CSF lactate, ammonia, pyruvate, amino acids, verylong-chain fatty acids, urinary organic acids

Porphyrins: blood/urine/faecesBiopsy: skin, lymph node, peripheral nerve/muscle

Vascular CT or MRI head with venogram and/or angiogramNeoplastic MRI brain and MR spectroscopy

CSF cytological analysisBrain and meningeal biopsyCT chest/abdomen/pelvisLDH, IgG/A/M, protein electrophoresis, urinary Bence-Jones protein(in adults), bone marrow trephine

Paraneoplastic Anti-neuronal and onconeuronal antibodiesCT or PET chest, abdomen and pelvisBiopsy of non CNS visceraAlpha fetoprotein, beta human chorionic gonadatrophin

Toxic Blood film; blood or urine levels of alcohol, paracetamol, salicylate,tricyclic, heavy metalsUrinary illicit drug screen

Septic Encephalopathy Serum microbiological cultures, serology and PCR

Abbreviations: MRI magnetic resonance imaging; ASO antistreptolysin; PCR polymerase chain reaction; CSF cerebrospinal fluid; FBC fullblood 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.

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 459

admission, unless there is a clinical contraindication(Table 10. Contraindications to immediate lumbarpuncture) (A, II)

� Clinical assessment and not cranial CT should be used todetermine if it is safe to perform a LP (A, II)

� If there is a clinical contraindication indicating possibleraised intracranial pressure due to or causing brainshift, 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 theimaging reveals significant brain shift or tight basal cis-terns due to or causing raised ICP, or an alternative di-agnosis, or the child’s 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 (withprotamine for those on heparin and vitamin K,

prothrombin complex concentrate, or fresh frozenplasma for those on warfarin) is mandatory before lum-bar puncture (A, II). In patients with bleeding disorders,replacement therapy is indicated (B, II). If unclear howto proceed, advice should be sought from a haematolo-gist (B, III)

� In situations where an LP is not possible at first, the sit-uation should be reviewed every 24 hours, and an LPperformed when it is safe to do so (B, II)

� If an initial LP is non-diagnostic, a second LP should beperformed 24-48 hours later (B, II)

� Children and young adults should be stabilisedbefore performing a CT scan, and an anaesthetist,paediatrician or intensivist should be consulted.(A, III)

� Lumbar punctures should be performed with needlesthat meet the standards set out by the National PatientSafety Agency (A, III)

460 R. Kneen et al.

EvidenceA lumbar puncture (LP) is an essential investigation inthe management of children with suspected encephalitisto confirm the diagnosis and rule out other causes.Therefore all children with suspected encephalitis shouldhave a LP unless a specific contraindication exists.Contraindications have been published in an evidencedbased guideline for the management of decreased levelconscious level in children (Table 10. Contraindicationsto immediate lumbar puncture).83 The risk of presentingwith viral encephalitis following a febrile seizure is notknown although the risk for bacterial meningitis follow-ing febrile seizures is quoted to occur in between 0.4and 5%.84,85 This figure increases to 18% in children whopresent with febrile status epilepticus.86 In addition,young children may present with meningitis without anysigns of meningeal irritation; 6 children aged less than18 months in a series of 95 children who presented witha simple (n Z 87) or complex febrile seizure (n Z 8)and without signs of meningeal irritation had underlyingbacterial meningitis.87 Although others have reportedthat only 0.4e1.2% of children who present with a fever

Table 10 Contraindications to an immediate lumbarpuncture in patients with suspected CNS infections, modi-fied from (Kneen, Solomon, et al., 2002; Michael, Sidhu,et al., 2010; Hasbun, Abrahams, et al., 2002;NICE).13,16,21,92,110

Imaging needed before lumbar puncture (to exclude brainshift, swelling, or space occupying lesion)� Moderate to severe impairment of consciousness(GCS < 13)a or fall in GCS of >2� Focal neurological signs (including unequal, dilated orpoorly responsive pupils)

� Abnormal posture or posturing� Papilloedema� After seizures until stabilised� Relative bradycardia with hypertension� Abnormal ‘doll’s eye’ movements� Immunocompromise

Other contraindications� Systemic shock� Coagulation abnormalities:

B Coagulation results (if obtained) outside the normalrange

B Platelet count <100 � 109/LB Anticoagulant therapy

� Local infection at the lumbar puncture site� Respiratory insufficiency� Suspected meningococcal septicaemia (extensive orspreading purpura)

aThere is no agreement on the depth of coma that necessitatesimaging before lumbar puncture; some argue Glasgow comascore < 12, others Glasgow coma score < 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 may still be possible if the platelet count is

50 � 109/L; Seek haematological advice.

and a seizure, in the absence of signs of meningeal irrita-tion will have bacterial meningitis.85 Nevertheless, chil-dren who do not make a full recovery within an hourfollowing a typical, simple febrile convulsion shouldhave a LP.88

There has been considerable controversy over the role ofcomputer tomography (CT) and LP in patients with sus-pected central nervous system infection, in particularwhether a CT is needed before an LP.14,90,91 Although thereare few studies that specifically address this issue in pa-tients with suspected encephalitis, much of the literatureabout suspected bacterial meningitis is pertinent becauseof overlap in the clinical presentations. As in patientswith meningitis, in encephalitis the CT scan is not a reliabletool for the diagnosis of raised intracranial pressure, andshould not be used to for this.14,16

In patients with suspected encephalitis, an early CTscan has two roles: suggesting the diagnosis of viralencephalitis and indicating an alternative diagnosis. Aninitial CT scan soon after admission will show a suggestiveabnormality in about 80% of patients with herpes simplexvirus (HSV) encephalitis;8 almost all those with HSV en-cephalitis, and a negative initial scan will have abnormal-ities on a second scan.8 The sensitivity of the CT scan fordetecting abnormalities is increased with the use of intra-venous contrast media, however, it is not, on its own,diagnostic.

The second role of an early CT scan is suggesting analternative diagnoses, so that LP may no longer be neces-sary. For example in one study of 21 adults with suspectedencephalitis, 2 (10%) patients did not have a LP after the CTscan showed a stroke;12 however, in a larger study only 2 (1%)of 153 patients with suspected CNS infections who had a CTfirst did not subsequently need a LP.13

If clinical contraindications to an immediate LP arepresent then an urgent CT should be performed. If thisidentifies shift of brain compartments or tight basalcisterns, due to mass lesions and/or oedema a subsequentLP may be dangerous. In patients with brain shift, a LP, byreducing the cerebrospinal fluid (CSF) pressure below thelesion, may precipitate herniation of the brainstem orcerebellar tonsils.92,93 For example this may occur in pa-tients with brain abscess, subdural empyema, tumour, ora 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 wereno contraindications to an immediate LP.12,13 For examplein 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 animmediate LP. The median time to CT scan was 6 h, butthe median time to LP was 24 h.12 Furthermore, in a largerstudy of 217 patients with suspected CNS infections the me-dian (range) time to LP was significantly longer if the pa-tient had a CT scan first (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 forstroke 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 alsotreats adult emergency patients.

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 461

A series of studies have examined which clinical signscan be used to determine which patients with suspectedbacterial meningitis need a CT scan before LP.90,92,94 In onestudy of 696 episodes of community acquired acute bacte-rial meningitis it was concluded that CT scan should pre-cede LP in patients with new onset seizures, focalneurological signs, excluding cranial neuropathies, or mod-erate to severe impairment of consciousness, as indicatedby a Glasgow coma score of 10 or less.94 Papilloedema, a di-rect indicator of raised intracranial pressure, is also an in-dication for imaging before a LP. NICE guidelines for therole of CT and LP in children with suspected bacterial men-ingitis have also been produced recently.16 Given the po-tential overlap of clinical features in patients withsuspected meningitis and suspected encephalitis, this ap-proach is also applied to patients with suspected encepha-litis. Although there is good agreement about most of theindications for a CT scan before a LP, there is disagreementabout the precise level of consciousness that should betaken as a contraindication to an immediate LP. Amongseven commentaries reviewed by Joffe 2007,92 three sug-gested “increasing stupor progressing to coma”, three sug-gested a “deterioration in consciousness level”, twosuggested a GCS < 8, and one a GCS < 13.14,95e100 The re-cent NICE guidelines for bacterial meningitis recommenda CT scan before a LP if the GCS is <9 or fluctuating >2,so that an alternative diagnosis can be excluded.16 Thereis also lack of clarity about whether in such patients, a LPshould then be performed at all, if the scan is normal, orwhether a low coma score is an absolute contraindication,whatever the scan shows. Occasionally deterioration afterLP has been reported in patients with bacterial meningitisand an apparently normal CT; but we are not aware of sim-ilar cases in patients with viral encephalitis; and mostwould argue that the information from the LP is essentialto make a diagnosis and guide treatment. In one retrospec-tive series of 222 adults with suspected encephalitis lessthan 5% of patients had imaging changes suggestive ofraised intracranial pressure.32

Other contraindications toLP include local skin infectionatthe site of puncture, a clinically unstable patient withcirculatory shock or respiratory insufficiency, and any clinicalsuspicion of spinal cord compression. LP may also be harmfulin patients with coagulopathy, because of the chance ofneedle-induced subarachnoid haemorrhage or of the devel-opment of spinal subdural and epidural haematomas. Thestandard recommendation is to perform a lumbar punctureonly when the patient does not have a coagulopathy and hasa platelet count of 100 � 109/L or greater, although plateletcounts of 20 � 109/L or greater have also been recommen-ded.16,101 A rapidly falling count is also a contraindication.Haemorrhage can occur in patients anticoagulated with hep-arin or warfarin, but in one large study, preoperative antipla-telet therapy with aspirin or nonsteroidal anti-inflammatorymedications and subcutaneous heparin on the operative daywere not risk factors for spinal haematoma in patients under-going spinal or epidural anaesthesia.101

In summary, many children will need a CT before a LP,because of their clinical contraindications to an immediateLP; such patients should have a CT, and then ideally a LPshould be considered on a case by case basis (if stillindicated and no radiological contraindications are

identified) within 6 h and then decisions made on antiviraltreatment based on these results. In some children who donot have a clinical contraindication to immediate LP, and inwhom CT is not immediately available, a prompt LP may bethe most useful approach to get an early diagnosis.

Lumbar punctures should be performed with needlesthat meet the standards set out by the National PatientSafety Agency.

What information should be gathered from the LP?

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 proteinshould be corrected for a bloody tap

- Protein, lactate and glucose, which should be com-pared with a plasma glucose taken just before theLP (A, II)

- A sample should be sent and stored for virological in-vestigations or other future investigation as indicatedin the next section (A, II)

- Culture for Mycobacterium tuberculosis when clini-cally indicated (A, II)

� If there is a strong clinical diagnosis of encephalitis ina child, but the initial CSF results are normal, a secondLP should be undertaken and all CSF tests repeated, in-cluding consideration for antibody detection (A, II)

EvidencePatients with HSV encephalitis typically have moderateelevation of CSF opening pressure, a moderate CSFpleocytosis from tens to hundreds of cells � 106/L,a mildly elevated CSF protein and normal CSF to plasmaglucose ratio.7,8,102 Whilst measuring the CSF openingpressure is part of a standard LP, it is often more difficultto achieve this in children and is frequently omitted.Whilst the evidence base would recommend undertakingopening pressure, it is recognised that it is often imprac-tical to do this in a child so the clinician responsible forundertaking the LP will have to make a balanced judge-ment as to the value of trying to achieve this. However,if the child is being anaesthetised for the procedure, theopening pressure should be measured with arterial bloodgas results stabilised and CO2 noted. Occasionally poly-morphonucelar cells predominate, or the CSF may be nor-mal, especially early in the illness: in approximately 3e5%of adults with proven HSV encephalitis an initial CSF maybe normal with no pleocytosis and a negative HSV PCR.8,10

The figure is even higher in patients with immunocompro-mise and in children, especially infants. However, if thefirst CSF is normal in HSV encephalitis, a second CSF exam-ination 24e48 h is likely to be abnormal with a positiveHSV PCR, although the viral load does reduce when pa-tients are receiving aciclovir.8,10

A series of studies have shown the apparent difficulty inmeasuring plasma glucose at the same time as CSF

Table 11 Microbiological investigations in patients withencephalitis, modified from (Solomon, Hart et al., 2007).110

CSF PCR1. All patientsHSV-1, HSV-2, VZVEnterovirus, parechovirus

2. If indicatedEBV/CMV (especially if immunocompromised)HHV6,7 (especially if immunocompromised, or children)Adenovirus, influenza A &B, rotavirus (children)Measles, mumpsErythrovirus B19Chlamydia

3. Special circumstancesRabies, 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 andconvalescent), for antibodies againstHSV-1 & 2, VZV, CMV, HHV6, HHV7, enteroviruses, RSV,Erythrovirus B19, adenovirus, influenza A & B

2. If associated with atypical pneumonia, test serum for

462 R. Kneen et al.

glucose,12e14 but without the former, interpretation ofthe CSF results is very difficult. HSV encephalitis can behaemorrhagic, and the CSF red cell count is elevated inapproximately 50% of cases.103 An acellular CSF is also de-scribed for other viruses, VZV, EBV and CMV, and occursmore frequently in patients with immunocompromise.25

Although a lymphocytic CSF pleocytosis is typical ofviral CNS infections, non-viral infection, particularly tu-berculosis and listeriosis, and partially treated acutebacterial meningitis can give a similar picture. Usuallythe clinical setting and other CSF parameters (low glucoseratio and higher protein) will suggest these possibilities.CSF lactate may be helpful in distinguishing bacterialmeningitis from viral CNS infections104,105; in particulara CSF lactate of <2 mmol/l is said to rule out bacterial dis-ease.105 A high CSF lactate may also be an indicator ofa metabolic disorder, in particular a mitochondrial en-cephalopathy. If ADEM is in the differential diagnosis,the CSF (with a paired serum sample) should be sent foroligoclonal bands.106

In a traumatic tap white blood cells and protein fromthe blood can contaminate the cerebrospinal fluid.107

There is little good evidence to support how to correctfor this in children.108 However, the standard approxima-tion would be to subtract 1 white cell for every 700 redblood cells � 106/L in the CSF and 0.1 g/dl for every 100red blood cells.109 This approximation will suffice in mostcircumstances, though more complicated formulae allow-ing for anaemia etc are available.107 However, in patientswith HSV encephalitis a blood-stained CSF sample may re-flect the haemorrhagic pathophysiology of the condition,this is more likely if serial CSF specimens are blood-stained.

Mycoplasma serologychlamydophila serology

Ancillary investigations (when indicated - Theseestablish carriage or systemic infection, but notnecessarily the cause of the CNS disease)

� Throat swab, nasopharyngeal aspirate, rectal swab,faeces, urinePCR/culture of throat swab, rectal swab, faeces forenterovirusesPCR of throat swab for mycoplasma, chlamydophilaPCR/antigen detection of nose/throat swab ornasopharyngeal aspirate for respiratory viruses,adenovirus, influenza virus (especially children)PCR/culture of parotid duct swab followingparotid massage or buccal swab for mumpsPCR/culture of urine for measles, mumps and rubella

� Vesicle electron microscopy, PCR and cultureb

Patients with herpetic lesions (for HSV, VZV)Children with hand foot and mouth disease (forenteroviruses)

Brain BiopsyFor culture, electron microscopy, PCR andimmunohistochemistryb

a Antibody detection in the serum identifies infection (pastor recent depending on the type of antibodies) but does notnecessarily mean this virus has caused the CNS disease.b Viral culture and electron microscopy less sensitive than

PCR.

What virological investigations should beperformed ?

Recommendation

� All patients with suspected encephalitis should havea CSF PCR test for HSV (1 and 2), VZV and enterovirusesas this will identify 90% of known viral cases and EBVconsidered (B, II)

� Further testing should be directed towards specificpathogens as guided by the clinical features such astravel history and animal or insect contact (B, III)

EvidenceAlthough the list of viral causes of encephalitis is long,110

HSV types1 & 2, VZV, and enteroviruses are the commonestcauses of viral encephalitis in immunocompetent individ-uals in Europe & the United States.24,111 Our ability to diag-nose encephalitis caused by herpes viruses & enteroviruseshas been improved greatly by using polymerase chainreaction (PCR).112,113 CSF PCR for HSV during day 2e10of illness has overall sensitivity and specificity of >95%for HSV encephalitis in immunocompetent adults.10,39

Although HSV PCR may be negative in the first few daysof the illness113 a second CSF taken 2e7 days later willoften be HSV positive, even if aciclovir treatment hasbeen started.11,114

Further microbiological investigations should be basedon specific epidemiological factors (age, animal and insectcontacts, immune status, recreational activities, geographyand recent travel history, season of the year and vaccina-tion history) and clinical findings (hepatitis, lymphadenop-athy, rash, respiratory tract infection, retinitis, urinarysymptoms and neurological syndrome (Table 11.Microbiological investigation of encephalitis).102,110,115,116

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 463

What antibody testing should be done on serum &CSF?

Recommendation

� Guidance from a specialist in microbiology, virology orinfectious disease specialists should be sought in decid-ing on these investigations (B, III)

� In patients with suspected encephalitis where PCR ofthe CSF was not performed acutely, a later CSF sample(at approximately 10-14 days after illness onset) shouldbe sent for HSV specific IgG antibody testing (B, III)

� In suspected flavivirus encephalitis CSF should betested for IgM antibody (B, II)

� Acute and convalescent blood samples should be takenas an adjunct to diagnostic investigation especiallywhen EBV, arboviruses, lyme disease, cat scratch dis-ease, rickettsiosis or ehrlichioses are suspected (B, II)

EvidenceWhilst all patients with suspected encephalitis should havePCR requested for the common viruses, decisions aboutantibody testing of serum and CSF are best made inconjunction with the specialist microbiology/virology orinfectious diseases service.

Cerebrospinal fluidIntrathecal synthesis of HSV-specific IgG antibodies isnormally detected after 10e14 days of illness, peaksafter one month and can persist for several years.117 Thedetection of intrathecally synthesized HSV IgG antibodies,when available, may help to establish the diagnosis of HSVencephalitis in patients where the CSF is taken after day10e12 of the illness. This is especially useful in patientsfor whom an earlier CSF was not taken, or was not testedfor HSV by PCR. A European consensus statement recom-mended the combined approach of testing CSF by PCRand antibody detection, such that a negative HSV-PCR re-sult early in the disease process coupled with a negativeHSV-specific CSF antibody study sampled 10e14 days aftersymptom onset effectively ruled out the disease39; how-ever, intrathecal immune responses may be delayed orabsent when antiviral therapy is started early.118 Addition-ally, many laboratories do not provide CSF antibodydetection services. The detection of oligoclonal bands inthe CSF is a non-specific indicator of an inflammatory pro-cess in the CNS; immunoblotting of the bands against viralproteins from HSV can been used to detect anti-HSVantibody, although this is not routinely available.32,39 Anti-body detection can also be particularly useful in VZVencephalitis.119

The detection of virus specific IgM in CSF is usuallyindicative of an intrathecal antiviral immune response; thisis especially useful for flaviviruses and other RNA viruses,which tend to be primary infections, rather than DNAviruses, which are often reactivations.80

BloodAcute and convalescent blood samples should be taken forappropriate serological testing based on the likely organ-isms identified from specific epidemiological and clinical

features.11 Examples of infectious causes of encephalitisthat can be diagnosed from serological investigations ofblood 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 autoimmuneencephalitis is covered in the ‘Special circumstances’ sec-tion of the guideline.

What PCR/culture should be done on other samples(e.g. throat swab, stool, vesicle etc)?

Recommendation

� Investigation should be undertaken through close col-laboration between a specialist in microbiology, virol-ogy, infectious diseases and the clinical team (B, III)

� In all patients with suspected viral encephalitis throatand rectal swabs for enterovirus investigations shouldbe considered; and swabs should also be sent from ves-icles, if present (B, II)

� When there is a recent or concomitant respiratory tractinfection, throat swab or sputum/lavage should be sentfor PCR for respiratory viruses (B, II)

� When there is suspicion of mumps CSF PCR should beperformed for this and parotid gland duct or buccalswabs should be sent for viral culture or PCR (B, II)

EvidenceInvestigation of sites outside the CNS can be useful to providepointers as to possible aetiology (Table 11 Microbiologicalinvestigations); however it must be remembered that suchinfectionmight be coincidental rather than causal; this is es-pecially the case for non-sterile sites, or sites where longterm shedding of virus occurs (e.g. in the stool). In enterovi-rus encephalitis, the virus may be isolated by swabbing thethroat and rectum, or, if present, vesicles.10 Of these vesic-ular swabs are most useful because they indicate acute andsystemic infection, whereas carriage in the faeces, and tosome extent the throat may be long term.82 Although manypatientswithenterovirusCNS infectionsdonot havevesicles.

If the clinical illness suggests a recent respiratoryinfection, samples taken from the respiratory tract (throatswab, nasal swab, nasopharyngeal aspirate, nasal washings,tracheal aspirate or brochoalveolar lavage) can be testedby PCR for respiratory viruses.

Mumps encephalitis is most accurately confirmed byPCR of the CSF; serum or salivary mumps antibodies arealso helpful. Viral culture or PCR performed on parotidgland duct swabs, taken after massaging the parotid glandfor 30 s, or buccal (saliva) swabs are useful for thediagnosis of recent mumps virus infection, within 9 daysof the onset of symptoms. A urine sample is less sensitivebut may be positive for at least 5 days after detection inthe mouth. Urine analysis if also useful if measles issuspected.

Viral infection may be demonstrated by culture, de-tection of viral genomes (by PCR), viral antibodies (byserology), viral antigens (by direct immunofluoresence), or,if available, viral particles (by electron microscopy),although PCR is the most sensitive.9,11

464 R. Kneen et al.

Which children with encephalitis should have anHIV test?

Recommendation

� We recommend that an HIV test be performed on all pa-tients with encephalitis, or with suspected encephalitisirrespective of apparent risk factors (A, II)

EvidenceHIV is directly capable of causing an encephalopathy inyoung children120 but infection with the virus also predis-poses children to CNS infections from other specific patho-gens. Antenatal screening for HIV infection is offered to allpregnant women in the United Kingdom and has a high up-take (90%). However it is not compulsory, and Mother toChild transmission of HIV can still occur in the UK.121,122 Mi-grants and travellers to the UK, from areas defined by theWHO as areas with high endemicity of HIV infection123 par-ticularly from sub-Saharan Africa, and Asia, including majorparts of the former Soviet Union, should be regarded as be-ing at risk of Mother to Child Transmission of HIV. It must beremembered that while HIV infection is rapidly progressivein 20% of infants,124,125 late presentation of perinatally ac-quired HIV infection can occur at 13 years of age orolder.126,127 HIV should be considered in children with sus-pected encephalitis for three reasons. Children with undi-agnosed advanced HIV disease can present with CNSinfections from a number of the less common infectiouscauses, such as cytomegalovirus.128,129 Secondly some ofthe more common CNS infections, such as Streptococcuspneumoniae or Mycoplasma tuberculosis have an increasedincidence in patients with HIV. Thirdly, although uncom-mon in children, primary HIV-1 infection can present withan acute meningoencephalitis as part of a seroconversionillness.130 The current UK guidelines on HIV testing123,131

emphasise that “all patients presenting for healthcarewhere HIV, including primary HIV infection, enters the dif-ferential diagnosis” should be tested for HIV and offers de-tailed guidance on the testing of infants, children andyoung people.

What is the role of brain biopsy in children withsuspected viral encephalitis?

Recommendation

� Brain biopsy has no place in the initial assessmentof suspected acute viral encephalitis in immunocompe-tent children. Stereotactic brain biopsy should be con-sidered in a child with suspected encephalitis in whomno diagnosis has been made after the first week, espe-cially if there are focal abnormalities on imaging and ifthe findings could change the child’s management(B, II)

� If imaging shows nothing focal, an open biopsy, usuallyfrom 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)

EvidenceFor many years brain biopsy was the preferred method fordiagnosing HSV encephalitis, because clinically many con-ditions mimic HSV encephalitis,33 the chances of culturingthe virus from the CSF were low, and a biopsy was one ofthe few reliable means of making the diagnosis; althoughits sensitivity was low, specificity was high.33 SubsequentlyCSF PCR for HSV DNA was developed, and proved a rapidand reliable diagnostic test,112,113 largely replacing biopsyfor the diagnosis HSV encephalitis. However biopsy stillhas a role in the investigation of other patients. Althoughuntil recently it was considered highly invasive with a signif-icant mortality and morbidity (through intracranial haemor-rhage, or biopsy site oedema), with modern stereotacticapproaches the incidence of serious adverse events islow, and it is now considered a relatively safeinvestigation.132,133

There is no role for a brain biopsy in the initialassessment of patients with suspected HSV encephalitis.However it may have a role in patients with suspected HSVencephalitis who are PCR negative and deteriorate despiteaciclovir, or to identify alternative causes, such as vascu-litis134; biopsy is especially helpful if there is a focal lesionon imaging132 or in patients with immune compromisewhere the differential diagnosis is often wide. Tissue needsto be sent for pathogen detection (electron microscopy,culture, PCR and immunoflouresence) and for histopathol-ogy. Experienced neuropathologists are essential. In one se-ries one fifth of patients with suspected HSV encephalitishad an alternative diagnosis made by biopsy, in half ofwhom it was a treatable condition.33

What is the role of magnetic resonance imaging(MRI) and other advanced imaging techniques inchildren with suspected viral encephalitis?

Recommendation

� MRI (including diffusion weighted imaging), should beperformed as soon as possible on all patients with sus-pected encephalitis in whom the diagnosis is uncertain;ideally this should be within 24 hours of hospital admis-sion, but certainly within 48 hours (B, II). Where the pa-tient’s clinical condition precludes an MRI, urgent CTscanning may reveal an alternative diagnosis (A, II)

� MRI sequences obtained need to be chosen appropri-ately for a paediatric population and images shouldbe interpreted by an experienced paediatric neuroradi-ologist (B, II)

� The role of MR spectroscopy is uncertain; SPECT andPET are not indicated in the assessment of suspectedacute viral encephalitis (B, II)

EvidenceMRI is significantly more sensitive than CT in detecting theearly cerebral changes of viral encephalitis. In HSV enceph-alitis a CT obtained early may be normal, or have onlysubtle abnormalities; in one small series only a quarter ofpatients with HSV encephalitis had an abnormality on initialCT scanning.135 In contrast, MRI obtained within 48 h ofhospital admission is abnormal in approximately 90% of

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 465

patients.135e138 Early MRI changes occur in the cingulate gy-rus and medial temporal lobe, and include gyral oedema onT-1 weighted images, and high signal intensity on T2-weighted and T2 fluid attenuated inversion recovery(FLAIR) images.139 Later there may be haemorrhage. Diffu-sion-weighted MRI may be especially sensitive to earlychanges.140e142 Specific sequences, such as FLAIR andSTIR (short-tau inversion recovery) sequences may be ofparticular value in young children due to normal brain mat-uration processes.143 The MRI should be interpreted by anexperienced neuroradiologist.

The changes seen on MRI are reported to be specific(87.5%) for PCR-confirmed HSV encephalitis but can alsoidentify alternative (often treatable) diagnoses in patientsthat are negative for HSV.137 Thus it is important that anMRI is performed urgently. In small studies, the extentof MRI abnormality seen acutely in HSV encephalitis didnot correlate with the clinical evolution of the disease137

nor with depression afterwards,144 though a correlationbetween 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 vesselvasculitis, 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 followa clear arterial distribution.34 Other pathogens may havetypical abnormal findings. M. pneumoniae may show focalcortical lesions, deep white matter lesions and large areasof demyelination.61 Japanese B encephalitis typically in-volves the thalamus and basal ganglia with T2 hyperinten-sity. Enterovirus may result in generalised parenchymaldestruction, or may predominately affect the brainstem,occasionally spreading posteriorly to involve the cerebel-lar denate nuclei or superiorly to involve the thalamiand basal ganglia.149 In young children, white matter oe-dema is not easily distinguished from unmyelinated whitematter, and without contrast may result in incorrectreporting.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 difficulties formany hospitals. In one series 70% of children requiredsedation or general anaesthesia.143 Some would recom-mend that sedation not be used in this patient group andonly anaesthetic support and formal anaesthesia used.151

In these circumstances, CT scanning may be the only urgentimaging available. However, the CT scan may be normal inchildren with CNS infections including severe bacterialmeningitis and encephalitis so should not be relied uponto make or refute the diagnosis of these conditions.152,153

A pragmatic approach is to perform a CT scan as the firstcranial imaging investigation and then an MRI can be under-taken as soon as it can be arranged, often after transfer tothe local tertiary centre.

Other modalitiesMR spectroscopy identifies and quantifies concentrations ofvarious brain metabolites, and so may help distinguishnormal from diseased brain tissue, and characterise thenature of the damage, particularly distinguishing

inflammatory from neoplastic processes; however there areno prospective studies assessing its diagnostic role. Singlephoton emission computed tomography (SPECT) may showfocal hypoperfusion persisting after recovery from acuteviral encephalitis.154 However, it has been used mainly asa research tool and appears to have little application in sus-pected acute encephalitis in practice. Fluorodeoxyglucosepositron emission tomography (PET) shows abnormalities inacute viral encephalitis154,155 with regions of FDG-PET hyper-metabolism seen most frequently in the medial temporallobes (sometimes reflecting seizure activity). However PETscanning is not practical or sufficiently informative to beused in children with suspected acute viral encephalitis.

Which children with suspected viral encephalitisshould have an electroencephalogram (EEG)?

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 uncertainwhether there is a psychiatric or organic cause an EEGshould 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 suspectedchronic viral encephalitis for example SSPE (B, II)

EvidenceThe 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, itcan be helpful in determining whether abnormal behaviouris due to psychiatric causes or is an early feature of ence-phalopathies. EEG is also useful in determining whetheran individual has non-convulsive or subtle clinical seizures,which occur in both HSV encephalitis and otherencephalopathies.156,157

In HSV encephalitis EEG abnormalities include non-spe-cific diffuse high amplitude slow waves, sometimes withtemporal lobe spike-and-wave activity and periodic lateral-ised epileptiform discharges (PLEDs).158 Even though PLEDsoccur in many cases of HSV encephalitis33 and were at onestage considered pathognomonic, they are now recognisedin other viral encephalitides36 and non-infectious conditions,and it is accepted that there are no EEGchanges diagnostic ofHSV encephalitis.159 For example when PLEDS are identifiedin patients with a sub-acute or chronic encephalopathy thiswould be suggestive of SSPE.77,160

Treatment of viral encephalitis

For which patients should aciclovir treatment bestarted empirically?

Recommendation

� Children with suspected encephalitis should have intra-venous aciclovir started if the initial CSF and/or imag-ing findings suggest viral encephalitis, and definitely

466 R. Kneen et al.

within 6 hours of admission if these results are awaited(A, II).

� If the first CSF microscopy or imaging is normal but theclinical suspicion of HSV or VZV encephalitis remains,aciclovir should still be started within 6 hours of admis-sion whilst further diagnostic investigations (as outlinedbelow) are awaited (A, II)

� The dose of intravenous aciclovir should be:- 3 months-12 years 500mg/m2 8 hourly- >12 years 10mg/kg 8 hourly

� The dose of aciclovir should be reduced in patients withpre-existing renal impairment (A, II)

� Patients with suspected encephalitis due to infectionshould be notified to the appropriate Consultant inCommunicable Disease Control (In Scotland, only pa-tients with a proven aetiology or those occurring aspart of an unusual outbreak are notifiable) (A, III)

� If meningitis is also suspected, the child should also betreated in accordance with the NICE meningitis guide-line (A, II)

EvidenceAciclovir is a nucleoside analogue with strong antiviralactivity against HSV and related herpes viruses, includingVZV. Two randomised trials have shown that aciclovir (10mg/kg three times a day) improves the outcome in adults withHSV encephalitis from a mortality of about 70% to less than20e30%.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 betweenhospital admission and starting treatment.7,8 Because HSVencephalitis is the most commonly diagnosed viral encepha-litis in industrialised countries, treatment with aciclovir isusually started once the initial CSF and/or imaging findingssuggest viral encephalitis, without waiting for confirmationof 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 withencephalopathy who has only mild confusion, investigationwith a lumbar puncture before considering treatment is sen-sible; especially given the very wide differential diagnosis,and relative rarity of HSV encephalitis. Moreover, empiricaluse of antimicrobial and antiviral agents can prematurelyhalt the diagnostic pathway because clinicians feel falselyreassured, and this delays the identification of otheraetiologies for which different treatments might beappropriate.

Experience from paediatrics has shown that the practiceof presumptive antiviral treatment for all patients withencephalopathy, with no regard to the likely diagnosis, isnot beneficial.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 ordeteriorating, then aciclovir should be started sooner, asshould treatment for possible bacterial meningitis.16 Evenif aciclovir has already been started in a patient with HSVencephalitis the CSF PCR is likely to remain positive forup to 7e10 days,11 meaning that a later lumbar puncturecan still confirm the diagnosis.

Although aciclovir is relatively safe there are importantside effects, particularly renal impairment secondary tocrystalluria and obstructive nephropathy.161 This reversible

nephropathy usually manifests after 4 days of intravenoustherapy and can affect up to 20% of patients.162,163 Therisk 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 thekidneys. Other rare adverse events include hepatitis,bone marrow failure and encephalopathy.

How long should aciclovir be continued in provenHSV encephalitis, and is there a role for oraltreatment?

Recommendation

� In children with proven HSV encephalitis, intravenousaciclovir treatment should be continued for 14-21days (A, II), and a repeat LP considered at this timeto confirm the CSF is negative for HSV by PCR (B, II);particularly if there are concerns that the treatmentis ineffective (severe disease, immune-compromise,previous relapses).

� If the CSF is still positive for HSV by PCR, aciclovirshould continue, with weekly CSF PCR until it is nega-tive (B, II)

� In children aged 3 months-12 years a minimum of 21days of aciclovir should be given before repeating theLP (B, III)

EvidenceThe original randomised trials of aciclovir for HSV enceph-alitis were for 10 days. However, reports of clinicalrelapse after 10 days of treatment were published sub-sequently.164,165 In children, relapse rates may be as highas 26e29%, particularly if the duration of treatment is <14days.166 Although an on-going immune-mediated and in-flammatory reaction to the infection is now thought bymany to be the major pathogenic process,164e167 there isevidence for continuing viral replication in somecases.8,164,166,168 As a consequence most clinicians nowuse at least 14e21 days intravenous treatment in con-firmed cases, though later relapses can occur.8 The riskof relapse may be highest in children aged 3 months-12years, up to 29%, and some have advocated that this groupshould receive a minimum of 21 days of intravenousaciclovir.151

Some advocate repeating a CSF examination at 14e21days, and continuing treatment until the CSF is negative forvirus by PCR110; this is supported by a European ConsensusStatement.39

Oral aciclovir does not achieve adequate levels in theCSF 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 inpaediatric practice to treat HSV encephalitis after at least10e14 days of intravenous aciclovir, when maintaining in-travenous access proved difficult.170 Although CNS pene-tration is difficult to monitor some have reported CSFtrough levels that are >50% of plasma trough levels.171

However valaciclovir is not licenced for use in children

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 467

and is only available in tablet form. The American NationalInstitute of Allergy and Infectious Disease CollaborativeAntiviral Study Group is assessing the role of high dose va-laciclovir (2 g three times daily) for three months.172

When can presumptive treatment with aciclovir besafely stopped, in patients that are HSV PCRnegative?

Recommendation

� Aciclovir can be stopped in an immunocompetent child,if- An alternative diagnosis has been made, or- HSV PCR in the CSF is negative on two occasions 24-48hours apart, and MRI imaging (performed >72 hoursafter symptom onset), is not characteristic for HSVencephalitis, or

- HSV PCR in the CSF is negative once >72 hours afterneurological symptom onset, with normal level ofconsciousness, normal MRI (performed >72 hours af-ter symptom onset), and a CSF white cell count ofless than 5 � 106/L (B, III)

EvidenceFor most patients with suspected HSV encephalitis, pre-sumptive aciclovir treatment is started on the basis ofa clinical picture and initial CSF findings consistent withviral encephalitis. This initial CSF may subsequently revealan alternative diagnosis such as bacterial infection, inwhich case aciclovir can be stopped. However, an initialCSF PCR can occasionally be negative in HSV encephalitis,especially if it is taken early in the illness (<72 h aftersymptom onset), or after some days on aciclovir treatmentwhen the virus has cleared. Thus if viral encephalitis is stillstrongly suspected, aciclovir treatment should not bestopped on the basis of a single negative CSF PCR only. AEuropean consensus statement recommended the com-bined approach to diagnosis of testing CSF by PCR andantibody detection, such that a negative HSV-PCR resultearly in the disease process coupled with a negative HSV-specific CSF antibody study sampled 10e14 days aftersymptom onset effectively ruled out the disease.39 Giventhat CSF antibody studies can only rule out diagnosis latein the disease process and that there can be considerabledelay in obtaining results from these assays, an alternativestrategy has been proposed for halting aciclovir treat-ment.113 This proposes that if a negative HSV PCR result isobtained from CSF sampled >72 h into the disease processand the patient has a low probability of HSV encephalitis(e.g. normal neuroimaging, CSF <5 � 106/L WBCs/mm3,and normal level of consciousness) then aciclovir treatmentmight be safely halted. However in reality, a more commonsituation is the patient with a negative initial CSF PCR whocontinues to have altered consciousness, or has a CSF pleo-cytosis, or imaging abnormalities. In this situation many cli-nicians would repeat the CSF examination at 24e48 h todetermine whether it is still negative for HSV by PCR; HSVencephalitis is very unlikely in such patients if there aretwo negative CSF PCRs for HSV.

What is the role of corticosteroids in HSVencephalitis?

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 estab-lishing this are needed and the results of a prospectiveRCT are awaited (C, III)

EvidenceThe role of steroids in the treatment of HSV encephalitis isnot established.173 Even before antiviral drugs became avail-able, many clinicians considered that corticosteroids werebeneficial in HSV encephalitis, though others dis-agreed.174,175 Since the advent of aciclovir, corticosteroidshave often be used, especially in patients with marked cere-bral oedema, brain shift or raised intracranial pressure, buttheir role remains controversial because as well as reducingswelling, corticosteroids have strong immunomodulatory ef-fects, which in theory could facilitate viral replication. How-ever a retrospective analysis of 45 patients with HSVencephalitis showed that older age, lower Glasgow comascore at admission and lack of administration of corticoste-roids were significant independent predictors of a poor out-come.176 An accompanying editorial made a strong case fora randomised placebo-controlled trial,173 which is now beingcarried out across several European countries.177

What should be the specific management of VZVencephalitis?

Recommendation

� No specific treatment is needed for VZV cerebellitis (B,II).

� For VZV encephalitis, whether a primary infection ora reactivation, intravenous aciclovir 500mg/m2 (ifaged 3 months-12 years) or 10-15mg/kg (if aged >12years) three times daily is recommended (B, II);

� If there is a vascopathy (i.e. stroke), there is a case forusing corticosteroids (B, II)

EvidenceIn immunocompetent children, VZV can cause CNS diseasethrough three mechanisms; a post-VZV cerebellitis, anacute VZV encephalitis and a VZV vasculopathy.

In cerebellitis caused by VZV, antiviral treatments are notnormally used because the disease is usually self limiting,resolving in one to three weeks, and the primary pathogenicprocess is thought to be immune-mediated demyelination,rather than viral cytopathology.178 Although there are nogood studies in primary VZV encephalitis, this condition isusually 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 thanHSV, 15mg/kg three times daily has also been suggested if re-nal function is normal,146 for up to 14 days,180 especially if it

468 R. Kneen et al.

can be started within a few days of symptom onset.179 A VZVvasculopathy presents with an acute stroke-like episode fol-lowing VZV infection and is routinely treated with both aci-clovir, as outlined, and corticosteroids, although there islimited evidence to support this.181

The course of steroids (for example 60e80 mg ofprednisolone daily for 3e5 days) is often given, becauseof the inflammatory nature of the lesion.146 In immunocom-promised patients with VZV encephalitis a prolonged courseof intravenous aciclovir may be needed.

What should be the specific management ofenterovirus meningoencephalitis?

Recommendation

� No specific treatment is recommended for enterovirusencephalitis; in patients with severe disease pleconaril(if available) or intravenous immunoglobulin may beworth considering (C, III)

EvidencePleconaril is a drug that binds within a hydrophobicpocket at the base of the receptor-binding canyon inthe viral capsid protein of enteroviruses, thus inhibitingthe virus from binding to its cellular receptor. The drughas broad activity against most enteroviruses at lowconcentrations (<0.1 mg per mL), and has good oralbioavailability. In phase III clinical trials pleconaril re-duced symptoms of aseptic meningitis, particularly head-ache, by approximately two days, compared with placebocontrols, but it is not used widely for this condition.182

The drug has also been used in patients with chronic en-terovirus infection due to agammaglobulinaemia, entero-virus myocarditis, poliovirus vaccine associated paralysisand neonatal infection. However there have been no tri-als assessing its role in enterovirus encephalitis, and it isoften not available.

Intravenous immunoglobulin is used in patients withchronic enterovirus meningitis,183 and may also be usefulin patients with severe enterovirus 71 infection, thoughno randomised trials have been conducted.184

What acute facilities should be available and whichpatients should be transferred to a specialist unit?

Recommendation

� Patients with falling level of consciousness require ur-gent assessment by paediatric Intensive Care Unit stafffor airway protection and ventilatory support, manage-ment of raised intracranial pressure, optimisation ofcerebral perfusion pressure and correction of electro-lyte imbalances. (A, III).

� Patients with suspected acute encephalitis should haveaccess to a paediatric neurological specialist opinionand should be seen as soon as possible and definitelywithin 24 hours of referral (B, III)

� There should be access to neuroimaging (both MRI andCT), under general anaesthetic if needed, and

neurophysiology (EEG), which may mean transfer toa specialist paediatric neuroscience unit (B, III)

� As CSF diagnostic assays are critical to confirming diag-nosis, the results of CSF PCR assays should be availablewithin 24-48 hours of a lumbar puncture being per-formed. (B, III)

� When a diagnosis is not rapidly established or a patientfails to improve with therapy, transfer to a paediatricneurological unit is recommended. The transfer shouldoccur as soon as possible and definitely within 24 hoursof being requested (B, III)

EvidenceCurrently in theUKthere is sparseevidenceand little guidancefor the inpatient care of patients with suspected viralencephalitis. A charity-commissioned nationwide survey ofencephalitis patients’ experiences of hospital care revealedthat only 39% were cared for on a neurological ward.185

Many patients with suspected acute encephalitis arecritically ill. Their behaviour is often disturbed and theyare at risk of seizures, malignant raised intracranial pres-sure, aspiration, systemic complications of infection, elec-trolyte disturbances, and death. Because it is a relativelyrare condition, medical teams caring for patients withencephalitis often have limited experience of the condition.Patients require close monitoring in a quiet environment butdo not routinely require isolation. Unlike stroke in adults,where clear evidence exists to support patient managementin specialist units, no such studies have been undertaken forencephalitis.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 ismultidisciplinary, potentially requiring the input of not onlypaediatric neurologists, but infectious disease paediatri-cians, virologists, microbiologists, neurophysiologists, neu-roradiologists, paediatric neurosurgeons, neurologicallyand/or psychiatrically-trained nursing staff, and paediatricintensive care staff. Many of these personnel are onlyavailable through specialist paediatric neuroscience cen-tres at tertiary hospitals. The role of members of themultidisciplinary team varies during the acute illness andrehabilitation.

What rehabilitation and support services should beavailable for children affected by encephalitis andtheir families?

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 theEncephalitis Society (www.encephalitis.info) (B, III)

� At the time of discharge, children should have eithera definite or suspected diagnosis. Arrangements for out-patient follow-up and plans for on-going therapy and/orrehabilitation should be formulated at a dischargemeeting (A, III)

� All children should have access to assessment for reha-bilitation (A, III)

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 469

EvidenceThe sequelae of encephalitis may not be immediately appar-ent when a patient is discharged from hospital following theacute illness. However, anxiety, depression and behaviouralproblems such as intrusive obsessive behaviour, challengingbehaviour or hyperactivity/concentration difficulties oftenbecome evident subsequently, and may be more likely afterencephalitis than other causes of acute brain injury.187 A char-ity-commissioned study of encephalitis patients found that33% were discharged without out-patient follow-up although96% reported on-going complications from their illness.185

A broad and comprehensive approach to both assess-ment and rehabilitation is necessary, with neuropsychologyand child and adolescent mental health teams as centralcomponents,188 and access to speech and language thera-pists, neuro-physiotherapists, and occupational therapists.Access to specialist brain injury rehabilitation services iskey to recovery in many cases.189

Children affected by encephalitis, their families andother people involved in supporting them, such as teachingstaff, 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 fromhospital without them or their families being informed ofthe diagnosis.185 Information and support reduces isolation,helps family adjustment and can provide useful signpostingto other services as appropriate.189

Special circumstances

What is the management of suspected encephalitisin children returning from travelling overseas?

Recommendation

� Patients returning from malaria endemic areas shouldhave rapid blood malaria antigen tests and ideally threethick and thin blood films examined for malaria para-sites (A, II). Thrombocytopenia, or malaria pigment inneutrophils and monocytes may be a clue to malaria,even if the films are negative.

� If cerebralmalaria seems likely, and therewill beadelay inobtaining the malaria film result, anti-malarial treatmentshould be considered and specialist advice obtained (A, III)

� The advice of the regional paediatric infectious dis-eases, and paediatric neuroscience units should besought regarding appropriate investigations and treat-ment for the other possible causes of encephalitis ina returning traveller (Table 2) (B, III)

EvidenceChildren travelling overseas are at risk of a range ofinfectious causes of encephalitis and encephalopathy, inaddition to those found in the UK.190 More common causes ofencephalopathy in returning travellers include malaria andtuberculous meningitis, and encephalopathy related to diar-rhoea and dehydration. There are typically 5-15 deaths everyyear in the UK frommalaria.191 Malaria is diagnosed by exam-ination of thick and thin blood films for malaria parasites.192

Thrombocytopaenia, or malaria pigment in neutrophils andmonocytes may be a clue to malaria, even if the films are

negative. Testing for malaria is important even in patientsthat have taken anti-malarial prophylaxis, or residentsfrom endemic areas who are thought to be immune, becausein both cases disease can occur. If cerebral malaria seemslikely, and therewill be delays in diagnostic tests, then treat-ment shouldbe started.192,193 ChildrenwithTBmeningitis of-ten have a history of recent tuberculosis contact and theirfamily often originates from an area with a high incidenceof TB. UK guidelines on the management of TBM have re-cently been produced.194

In addition occasional cases have been reported ofdengue 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 theseviral 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 encephalopathyin returning travellers include eosinophilic meningitis,typhoid encephalopathy and typanosomiasis (sleeping sick-ness).190 Cysticercosis and schistosomiasis typically presentwith space occupying lesions (often causing seizures in thecase of cysticercosis), rather than an encephalitis.

What differences are there in the management ofsuspected encephalitis in theimmunocompromised?

Recommendations

� Encephalitis should be considered in immunocompro-mised patients with altered mental status, even if thehistory is prolonged, the clinical features are subtle,or there is no febrile element (A, III)

� In patients with known severe immunocompromise a CTscan before LP should be considered (B, III). If a pa-tient’s immune status is not known, there is no needto 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 infectionsinclude (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 Cryptococcusneoformans,

- Antibody testing of serum and if positive CSF PCR forToxoplasma 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 HHV 6 and 7- Erythrovirus B19- Measles

470 R. Kneen et al.

- 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 orother complex problems should be treated in a regionalhub or London Lead Centre (A,II)

� Immunocompromised patients with encephalitis causedby HSV-1 or 2, should be treated with intravenous aciclo-vir (10mg/kg three times daily) for at least 21 days, andreassessed with a CSF PCR assay; following this longterm oral treatment should be considered until the CDcount is>200x106/L, or if CD4%,15% if<5 years old (A, II)

� Acute concomitant VZV infection causing encephalitisshould be treated with intravenous aciclovir (A, II)

� CNS CMV infections should be treated with ganciclovir,oral valganciclovir, foscarnet or cidofovir (A, II)

� Children with VZV encephalitis should be treated withintravenous acyclovir 500mg/m2 for at least 10 days, al-though immunocompromised children may require lon-ger treatment (B, III)

EvidenceImmune compromise presents specific challenges in allaspects of the management of patients with suspectedencephalitis, including the range of causative pathogens,and presenting clinical features, and differences in theinvestigations, and treatment.196 Although many of theprinciples of management of the immunocompromised arethe same as those covered for the immunocompetent,above, there are some specific features, as outlined below.

CausesIn patients with immune compromise there is a wider rangeof pathogens that may cause an encephalitis presentation;these include bacterial diseases such as tuberculous men-ingitis or listeria, fungi, such as cryptococcus, parasiticdiseases, for example toxoplasma, and viruses; the virusesimplicated include cytomegalovirus, particularly in veryadvanced HIV with CD4 cell counts less than 50 � 106/L,measles and EBV.9,11,24,102,160,197 Progressive multi-focalencephalopathy (PML), due to JC and possibly BK viruses,is very rare in children and usually presents with featuresof dementia, rather than acute encephalitis. Non-infectiveconsiderations include primary CNS lymphomas, which areusually EBV-driven. In one study looking for herpes virusesin 180 non-selected CSF samples from 141 adult and paedi-atric patients, 23 patients were HIV positive198 among theseCMV was the virus most frequently identified (13%), fol-lowed by EBV (10.6%), VZV (5.3%) and finally HSV-1 andHSV-2 (both 1.3%). HSV-2, EBV and VZV were detected inthe 11 HIV-negative immunocompromised patients.

In addition to the pathogens outlined above, for whichall immunocompromised patients with suspected encepha-litis should be investigated, less common pathogens toconsider, depending on the circumstances, include Cocci-dioides species, Histoplasma capsulatum and West Nilevirus.116,129

HistoryImmunocompromised patients aremore likely to have subtleand sub-acute presentations of viruses which cause an acute

encephalitis in the immunocompetent, such as HSV199 andenterovirus, aswell as for viruses specific to the immunocom-promised, such as HHV6 (Table 4 Sub-acute and chronic).

Role of imagingBecause of an impaired inflammatory and immune response,severely immunocompromised patients may have lesions onCT which are not associated with focal neurological pre-sentations or papilloedema,200 prompting some to suggestthat a CT scan should be performed in all immunocompro-mised patients before LP. There are no studies comparingimaging options in patients with suspected viral encephalitiswith or without immuocompromise. However, immunocom-promised patients are vulnerable to a broader range of en-cephalitides (including PML) and the clinical changes maybe masked by immunocompromise. MRI is therefore the im-aging modality of choice in immunocompromised patients.

CSF findingsIn immunocompromised patients with encephalitis, the CSFis more likely to be acellular, even though such patients areat increased risk of CNS infection.25 Thus CSF investigationsfor microbial pathogens should be performed irrespectiveof the CSF cell count.

TreatmentThe UK Standards for HIV clinical care recommend thatchildren with HIV suffering from severe infections or othercomplex problems should be referred to the regional hub orthe London Lead Centre.123

The initial treatment of HSV encephalitis in immuno-compromised patients is the same as for the immunocom-petent; however, achieving viral clearance can be harder,and prolonged treatment may be needed.199 Although thereare no good trials for CMV encephalitis, open label studiessuggest that ganciclovir (and valganciclovir), foscarnet orcidofovir may be helpful.201

What differences are there in the presentation andmanagement of encephalitis associated withantibodies?

Recommendations

� Antibody-mediated encephalitis should be consideredin all patients with suspected encephalitis as theyhave a poorer outcome if untreated. Moreover the clin-ical phenotypes of these recently described disordersare still expanding (B, III)

� Clinical features, such as limbic encephalitis, a sub-acute presentation, speech and movement disordersand intractable seizures may suggest an antibody-medi-ated encephalitis, although these features are not ex-clusive to antibody-mediated disease (B, III)

� Although tumours occur less frequently in children, allpatients with proven VGKC or NMDAR-receptor antibodyassociated encephalitis should have screening for a neo-plasm (C, III), andextended surveillance for several years(C, III)

� Annual tumour screening should be conducted in pa-tients with NMDA-receptor antibody associated

Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines 471

encephalitis if no tumour has been found, especially ifthe patient has a poor response to therapy or there arerelapses (B, III)

� Early immune suppression and tumour removal shouldbe undertaken when possible (B, III)

EvidenceIn childrenwithanacuteormorecommonly sub-acuteonsetofencephalitis, immune-mediated encephalitis should be con-sidered as the treatment is very different and early interven-tion significantly improves outcome. A growing number ofcases immune-mediated encephalitis have been reported inchildren, comprising of autoantibodies targeting the voltage-gated potassium channel (VGKC)-complex proteins,202,203

N-methyl-D-Aspartic acid (NMDA) receptor,204e206 and otherCNS antigens.207 In amulticentre UK Health Protection Agency(HPA) aetiology of encephalitis study4 20% of patients thatwere identified to have an autoantibody aetiology were chil-dren (Granerod and Crowcroft; unpublished observation). Inparticular, all patients should have appropriate imaging toidentify an associated tumour, such as an ovarian tertoma.

Encephalitis associated with antibodies to thevoltage-gated potassium channel (VGKC)-complexproteins

PresentationVGKC-complex antibodies are beginning to be identified inchildren. In a small case series of children presenting withlimbic encephalitis, 4/12 (30%) of patients were positive forVGKC-complex antibodies.207 In another series of childrenpresenting 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 withVGKC autoimmunity, a proportion of these children had en-cephalopathy or neuroregression probably representinga sub-acute encephalopathy.202 These case series are smalland appear to focus on specific subgroups thus making di-rect comparison between them and the overall encephalitisliterature difficult. Nevertheless, cases reported of VGKC-complex antibody-associated encephalitis in childrenshares similar features with adult patients when presentingas limbic encephalitis (disorientation and confusion withseizures). However, the low plasma sodium found in about60% of adult patients does not appear to be reported inthese childhood cases.208

Investigative findingsThe MRI may reveal either features of limbic encephali-tis,202,207 basal ganglia changes202 or other white matterand sub-cortical changes.203 The EEG reveals generalisedslowing with or without an ictal focus.203 Significant CSF ab-normalities are uncommon. Association with tumours likeneuroblastomas has been reported.202

TreatmentIn all of the reported series, the latency to treatment hasbeen long (months to years), and hence any interpretationof treatment efficacy is unreliable. Treatment startedwithin 4 weeks of symptom onset confers the best re-covery.202 Although prompt immunosuppression is

advocated, there is no definitive evidenced based approachto treating VGKC-complex autoimmunity. Immunosuppres-sion as reported in the case series comprise of high dose in-travenous corticosteroid use and regular IVIG therapy, usedindependently or in conjunction. Mild to moderate responseto treatment have been reported particularly in patientspresenting with seizures and limbic encephalitis.202

What are the differences in patients withencephalitis associated with antibodies toN-methyl-D-Aspartic acid (NMDA) receptor?

PresentationUnlike VGKC-complex antibodies, antibodies targeting theNMDA receptor are more commonly observed in childrenand adolescents than adults.205,206 In a comprehensive sin-gle national reference centre study of patients presentinganti-NMDA-receptor antibody associated encephalitis, 40%(32/81) were age 18 or below.204 In this study, an overall fe-male preponderance and tumour preponderance in femalepatients were identified. The risk of a tumour was lowerin younger girls (56% in women >18 years old, 31% in girls<19 years old, and 9% in girls <15 years old). Of the 32 chil-dren and adolescents, 87.5% had a history of behavioural orpersonality change, sometimes associated with seizuresand frequent sleep dysfunction; 9.5% with dyskinesias ordystonia; and 3% with speech impairment. On admission,53% had clinical evidence of severe speech deficits. Eventu-ally, 77% developed seizures, 84% stereotyped movements,86% autonomic instability, and 23% hypoventilation; mirror-ing the biphasic presentation noted in adults where the cor-tical features (seizures, confusion, amnesia and psychosis)appear to precede the sub-cortical features (choreathetosisand oro-facial dyskinesia, fluctuations in conscious level,dysautonomia and central hypoventilation).205

Investigation findingsThe CSF is frequently abnormal in patients consisting ofa lymphocytosis (27/31), an elevated protein (4/13) andpresence of oligoclonal bands.204 Brain MRI is abnormal inup 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 isoften abnormal with focal or diffuse slowing, and demon-strates epileptic activity in only 30% of patients.204

TreatmentOptimal treatment regimes are still being developed forthese patients but immunosuppressive strategies withhigh dose intravenous corticosteroids, IVIG and plasma-pharesis have been used. In contrast to patients withVGKC-complex associated encephalitis, adult patientswith NMDA-receptor antibody associated encephalitiscan relapse in approximately 30%,205 and this appearsto be the case with childhood and adolescent onset pa-tients where neurological relapses are reported in 25%of patients,204 and this is not predicted by presence oftumour either at outset or at recurrence. Responses toimmunotherapy can be slow (over months) and variable;often requiring a multidisciplinary team input includingphysical rehabilitation and psychiatric management of

472 R. Kneen et al.

protracted behavioural symptoms. Overall, 74% had fullor substantial recovery at 1 year, after immunotherapyor tumour removal.204 Indeed, as described in adults,children who had a teratoma and were treated with tu-mour removal and immunotherapy had more frequentfull recovery.204,209 In patients that relapse or appear un-responsive to treatment, escalation of immunosuppres-sion to include treatments like rituximab have beenused with some success.210 Tumour screening should beperformed annually for several years particularly if thetreatment response is poor or relapses occur.

Guideline implementation and audit

These clinical guidelines have been written to aid earlyrecognition and appropriate investigation and managementof patients with suspected encephalitis. There are manybarriers to the implementation of such guidelines. The firststep needed to convince clinicians to change behaviour isoften the performance of a simple operational audit, toidentify 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 ina standardised manner, and which can be adapted forlocal use (Table S1. Audit parameters for nationalencephalitis guideline, available to download fromScience Direct).

Acknowledgements

In addition to the named authors, the following are currentlymembers of the National Encephalitis Guidelines Develop-ment Group: Phil Smith, Nick Davies, Frances Sanderson, IanHart, Nick Beeching, Mark Holland, Camilla Buckley, SolomonAlmond, Peter Burnham, Mehrengise Cooper, Jean-PierreLin, Hermione Lyall, Kevin Mackway-Jones, Nick Makwana,Anthony Marson, Isam Osman, Andrew Riordan, DelaneShingadia, Aman Sohal, David Stoeter, Edmund Wilkins.

Supplementary material

Supplementary material associated with this article can befound, in the online version, at doi:10.1016/j.jinf.2012.11.013.

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