Management of suspected viral encephalitis in children – Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group National Guidelines

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    B.D. Michael
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    r R. Kneen and B.D. Michael are joint first authors.
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    Institute of Infection and Global Health, University of Liverpool, 8th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK

    The Walton Centre Neurology NHS Foundation Trust, Lower Lane, Fazakerly, Liverpool L9 7JL, UK

    Department of Neurological Science, University of Liverpool, 8th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK
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    E. Menson
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    B. Mehta
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    A. Easton
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    C. Hemingway
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    A. Vincent
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    M. Lim
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    T. Solomon
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  • On behalf of the National Encephalitis Guidelines Development and Stakeholder Groups
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Published:November 21, 2011DOI:https://doi.org/10.1016/j.jinf.2011.11.013

      Summary

      In the 1980s the outcome of patients with herpes simplex encephalitis was shown to be dramatically improved with aciclovir treatment. Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis. Several comprehensive reviews of the investigation and management of encephalitis have been published. However, their impact on day-to-day clinical practice appears to be limited. The emergency management of meningitis in children and adults was revolutionised by the introduction of a simple algorithm as part of management guidelines.
      In February 2008 a group of clinicians met in Liverpool to begin the development process for clinical care guidelines based around a similar simple algorithm, supported by an evidence base, whose implementation is hoped would improve the management of patients with suspected encephalitis.

      Keywords

      Introduction

      Encephalitis is defined as a syndrome of neurological dysfunction caused by inflammation of the brain parenchyma. Encephalitis has many causes and some are specific to childhood, but fortunately it is relatively rare. However doctors who treat acutely ill children should be aware of how to manage a child with suspected encephalitis as some of the individual causes of encephalitis will respond to specific treatments and delays in the diagnosis in these children can be devastating. Strictly speaking, inflammation of the brain parenchyma is a pathological diagnosis, however due to the practical limitations of this, surrogate clinical markers of inflammation are used (Table 1. Definitions).
      Table 1Definitions.
      Encephalopathy
      • Clinical syndrome of altered mental status (manifesting as reduced consciousness or altered cognition, personality or behavior)
      • Has many causes including systemic infection, metabolic derangement, inherited metabolic encephalopathies, toxins, hypoxia, trauma, vasculitis, or central nervous system infection
      Encephalitis
      • Inflammation of the brain
      • Strictly a pathological diagnosis; but surrogate clinical markers often used, including inflammatory change in the cerebrospinal fluid or parenchyma inflammation on imaging
      • Causes include viruses, small intracellular bacteria that directly infect the brain parenchyma and some parasites
      • Can also occur without direct brain infection, for example in acute disseminated encephalitis myelitis (ADEM), or antibody-associated encephalitis

       Classification of encephalitis

      Encephalitis can be caused by many individual disease processes but can broadly be divided into those associated with infection (either directly or indirectly) and non-infectious causes. Direct infections of the central nervous system (CNS) can be caused by many viruses, bacteria (especially intracellular bacteria such as Mycoplasma pneumoniae), parasites and fungi (Table 2. Viral encephalitis; Table 3. Non-viral causes of encephalitis or encephalopathy). Those indirectly associated with infection include an acute demyelinating process, which is often temporally related to a prior infection outside of the CNS. This process may also follow immunisation and is known as acute disseminated encephalomyelitis (ADEM). Non-infectious causes include antibody-mediated encephalitis, which may be paraneoplastic for example limbic encephalitis associated with ovarian teratomas or may be an isolated finding. Initially these disorders were reported in adults, but they are being increasingly recognised in children.
      • Lebas A.
      • Husson B.
      • Didelot A.
      • Honnorat J.
      • Tardieu M.
      Expanding spectrum of encephalitis with NMDA receptor antibodies in young children.
      Most viral encephalitides are acute, but sub-acute or chronic presentations are characteristic of particular pathogens, especially in the immunocompromised (Table 4. Sub-acute and chronic encephalitis).
      Table 2Causes of acute viral encephalitis, with geographical clues modified from (Solomon and Whitley 2004; Solomon, Hart et al. 2007).
      • Solomon T.
      • Whitley R.J.
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      Note viral causes of chronic encephalitis such as JC viruses are not included here.
      GroupsVirusesComments
      Sporadic causes (not geographically restricted) listed by group
      Herpes viruses (family Herpesviridae)Herpes simplex virus type 1Most commonly diagnosed sporadic encephalitis
      Herpes simplex virus type 2Causes meningitis in adults (esp. recurrent); Meningoencephalitis occurs typically in the immunocompromised. Also causes a radiculitis.
      Varicella zoster virusPost-infective cerebellitis, or acute infective encephalitis or vasculopathy
      Epstein–Barr virusEncephalitis in the immunocompromised
      CytomegalovirusEncephalitis in the immunocompromised; also retinitis or radiculitis; often neutrophilic CSF with low glucose
      Human herpes virus 6 & 7Febrile convulsions in children (after roseola); encephalitis in immunocompromised
      Enteroviruses (family Picornaviridae)Enterovirus 70Epidemic haemorrhagic conjunctivitis, with CNS involvement
      Enterovirus 71Epidemic hand foot and mouth disease, with aseptic meningitis, brainstem encephalitis, myelitis
      PoliovirusMyelitis
      Coxsackieviruses, Echoviruses, ParechovirusMostly aseptic meningitis
      Paramyxoviruses (family Paramyxoviridae)Measles virusCauses acute post-infectious encephalitis, sub-acute encephalitis and sub-acute sclerosing panencephalitis
      Mumps virusParotitis, orchitis or pancreatitis may occur before, during or after meningoencephalitis
      Others (rarer causes)Influenza viruses, adenovirus, Erythrovirus B19, lymphocytic choreomeningitis virus, rubella virus,
      Arthropod-borne and zoonotic viruses
      Most are zoonotic – i.e. animals rather than humans are the main natural hosts, the exceptions being dengue and chikungunya viruses.
      Flaviviruses (family Flaviviridae)West Nile virusNorth America, Southern Europe, Africa, Middle East, West and Central Asia associated with flaccid paralysis and Parkinsonian movement disorders
      Japanese encephalitis virusAsia, associated with flaccid paralysis and Parkinsonian movement disorders
      Tick-borne encephalitis virusTravel in Eastern Europe, Former USSR; tick bite; upper limb flaccid paralysis
      Dengue viruses (types 1–4)Causes fever, arthralgia, rash and haemorrhagic disease, occasional CNS disease
      Alphaviruses (family Togaviridae)Western, Eastern and Venezuelan equine encephalitis virusesFound in the Americas; encephalitis of horses and humans
      Chikungunya virusAsia Pacific, Africa
      BunyavirusesLacrosse virusEncephalitis in America
      ColtivirusesColorado tick fever virusNorth America
      RhabdovirusesRabies, virus other lyssavirusesNon-arthropod-borne zoonitic viruses transmitted by dogs, cats, bats, depending on location
      Chandipura virusTransmitted by sandflies, causing outbreaks in India
      Henipah VirusesNipah virusTransmitted in faeces of fruit bats in Malaysia, Bangladesh
      a Most are zoonotic – i.e. animals rather than humans are the main natural hosts, the exceptions being dengue and chikungunya viruses.
      Table 3Non-viral causes of encephalitis and its mimics modified from (Solomon and Whitley 2004; Solomon 2009).
      • Solomon T.
      • Whitley R.J.
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      EncephalitisMimics
      CNS Infections
      Bacteria
       Small bacteria (mostly intracellular)
      Mycoplasma pneumoniaeMycobacterium tuberculosis
      ChlamydophilaStreptococcus pneumoniae
      Rickettsiae (including scrub typhus, Rocky Mountain 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 monocytogenes
       Spirochetes
      Trepenoma pallidum (Syphilis)Leptospirosis
      Borrelia burgdorferi (Lyme neuroborreliosis)
      Borrelia recurrentis (relapsing fever)
       Other bacteria
      NocardiosisInfective endocarditis
      ActinomycosisParameningeal infection

      Abscess/empyema
      Parasites
      Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (African sleeping sickness)Malaria
      Naegleria fowleri, Balamuthia mandrillaris (Amoebic encephalitis)Cysticercosis
      Angiostrongylus cantonensis (rat lung worm)Trichinosis
      Fungi
      CoccidioidomycosisCryptococcosis
      Histoplasmosis
      North American blastomycosis
      Para/post-infectious causes
       Inflammatory
      Acute disseminated encephalomyelitis (ADEM)
      Acute haemorrhagic leukoencephalopathy (AHLE)
      Acute necrotising encephalitis (ANE) in children
      Bickerstaff's encephalitis
       Toxic/Metabolic
      Reye's syndrome
       Systemic infection
      Septic encephalopathy

      Shigellosis
      Non-infectious causes
       Vascular
      Vasculitis
      Systemic lupus erythematosis
      Behçet's disease
      Subarachnoid & subdural haemorrhage
      Ischaemic cerebrovascular accidents
       Neoplastic
      Paraneoplastic encephalitisPrimary brain tumour

      Metastases
       Metabolic encephalopathy
      Hepatic encephalopathy
      Renal encephalopathy
      Hypoglycaemia
      Toxins (alcohol, drugs)
      Hashimoto's disease
      Septic encephalopathy
      Mitochondrial diseases
       Other
      Antibody-mediated encephalitis: VGKC complex or NMDA receptorDrug reactions
      Encephalitis lethargica  Haemophagocytic Lymphohistiocytosis (HLH) syndrome (usually  children)Epilepsy
      Functional disorder
      In this table some of the important aetiologies are classified into whether they cause an encephalitis, with inflammatory changes seen histopathologically in the brain parenchyma, or encephalopathy without inflammatory changes in the parenchyma, although for some aetiologies this is based on limited evidence.
      Abbreviations: VGKC, voltage-gated potassium channel; NMDA, N-methyl-D-Aspartic acid.
      Table 4Sub-acute and chronic central nervous system presentations – microbiological causes, modified from (Solomon, Hart et al., 2007; Solomon 2009).
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      • Solomon T.
      Arboviruses.
      Viruses
       In immunocompromised patients
      Measles virus (inclusion body encephalitis)
      Varicella zoster virus (causes a multi-focal  leukoencephalopathy)
      Cytomegalovirus
      Herpes simplex virus (especially HSV-2)
      Human herpes virus 6
      Enteroviruses
      JC/BK
      JC and BK viruses are named after the initials of the patients from whom they were first isolated.
      virus (progressive multi-focal leukoencephalopathy)
      HIV (dementia)
       In immunocompetent patients
      JC/BK
      JC and BK viruses are named after the initials of the patients from whom they were first isolated.
      virus (progressive multi-focal  leukoencephalopathy)
      Measles virus (sub-acute sclerosing panencephalitis)
      Bacteria
      Mycobacterium tuberculosis
      Treponema pallidum (syphilis)
      Borrelia burgdorferi (Lyme neuroborreliosis)
      Tropheryma whipplei (Whipple's Disease)
      Fungi
      Cryptococcus neoformans
      Parasites
      Trypanosoma brucei spp. (African trypanosomiasis)
      Toxoplasma gondii (toxoplasmosis)
      Prions
      Creutzfeldt-Jakob disease
      a JC and BK viruses are named after the initials of the patients from whom they were first isolated.

       Epidemiology

      The incidence of encephalitis in children is difficult to establish as reported studies have used different case definitions, methodologies and different geographic locations and study populations. However, in western settings reported incidences range from 6.3 to 7.4 per 100,000 for all ages (adults and children) and approximately 10.5–13.8 per 100,000 children.
      • Jmor F.
      • Emsley H.C.A.
      • Fischer M.
      • Solomon T.
      • Lewthwaite P.
      The incidence of acute encephalitis syndrome in Western industrialised and tropical countries.
      In the UK, this should equate to 1–2 children per year in a typical district general hospital and 8–10 in a large tertiary children's hospital. In industrialised nations, the most commonly diagnosed cause of encephalitis is herpes simplex virus (HSV) with an annual incidence of 1 in 250,000 to 500,000.
      • Whitley R.J.
      • Kimberlin D.W.
      Herpes simplex encephalitis: children and adolescents.
      The age specific incidence is bimodal, with peaks in childhood and the elderly. Most HSV encephalitis is due to HSV type 1 but about 10% is due to HSV type 2. The latter occurs typically in immunocompromised adults and in neonates in whom it can also cause a disseminated infection. Varicella zoster virus (VZV) is also a relatively common cause of viral encephalitis, especially in the immunocompromised, whilst cytomegalovirus (CMV) occurs almost exclusively in this group. Enteroviruses most often cause aseptic meningitis but can also be an important cause of encephalitis. Among the other non-infectious causes of encephalitis, immune mediated conditions are increasingly being recognised including ADEM and encephalitis associated with antibodies to the voltage-gated potassium channel complex, or N-methyl-D-aspartate antibody (NMDA) receptors.
      • Lebas A.
      • Husson B.
      • Didelot A.
      • Honnorat J.
      • Tardieu M.
      Expanding spectrum of encephalitis with NMDA receptor antibodies in young children.
      • Granerod J.
      • Ambrose H.E.
      • Davies N.W.
      • Clewley J.P.
      • Walsh A.L.
      • Morgan D.
      • on behalf of the UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group
      • et al.
      Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study.

       Aims and scope of the guideline

      In the 1980s the outcome of HSV encephalitis in adults was shown to be dramatically improved by aciclovir treatment.
      • Skoldenberg B.
      • Forsgren M.
      • Alestig K.
      • Burman L.
      • Dahlqvist E.
      • Forkman A.
      • et al.
      Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients.
      • Whitley R.J.
      • Alford C.A.
      • Hirsch M.S.
      • Schooley R.T.
      • Luby J.P.
      • Aoki F.Y.
      • et al.
      Vidarabine versus acyclovir therapy in herpes simplex encephalitis.
      Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis.
      • McGrath N.
      • Anderson N.E.
      • Croxson M.C.
      • Powell K.F.
      Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      Several comprehensive reviews of the investigation and management of encephalitis have been published,
      • Klapper P.E.
      • Cleator G.M.
      European guidelines for diagnosis and management of patients with suspected herpes simplex encephalitis.
      • Steiner I.
      • Budka H.
      • Chaudhuri A.
      • Koskiniemi M.
      • Sainio K.
      • Salonen O.
      • et al.
      Viral encephalitis: a review of diagnostic methods and guidelines for management.
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
      but their impact on day-to-day clinical practice appears to be limited.
      • Bell D.J.
      • Suckling R.
      • Rothburn M.M.
      • Blanchard T.
      • Stoeter D.
      • Michael B.D.
      • et al.
      Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital.
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      The emergency management of meningitis in children and adults was revolutionised by the introduction of a simple algorithm as part of management guidelines.
      • Pollard A.J.
      • Britto J.
      • Nadel S.
      • DeMunter C.
      • Habibi P.
      • Levin M.
      Emergency management of meningococcal disease.
      • National Instutute for Health and Clinical Excellence
      Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102).
      • Heyderman R.S.
      British Infection Society. Early management of suspected bacterial meningitis and meningococcal septicaemia in immunocompetent adults–second edition.
      In February 2008 a group of clinicians met in Liverpool to begin the development process for clinical care guidelines based around a similar simple algorithm (Fig. 1. Algorithm for the management of patients with suspected viral encephalitis, supported by an evidence base, whose implementation, it is hoped, would improve the management of patients with suspected encephalitis. The scope of the guideline is to cover the initial management of all patients with suspected encephalitis, up to the point of diagnosis and early treatment, in an acute care setting such as acute medical unit or emergency room. They are thus intended as a ready reference for clinicians encountering the more common causes of encephalitis, rather than specialists managing rarer causes. The guidelines also cover the specific treatments and further management of patients for whom a diagnosis of viral encephalitis is made, particularly that due to HSV, VZV and enteroviruses. Encephalitis due to CMV is almost exclusively seen in the immunocompromised and is not covered in detail; its diagnosis and management is covered in HIV guidelines.
      • Mofenson L.M.
      • Brady M.T.
      • Danner S.P.
      • Dominguez K.L.
      • Hazra R.
      • Handelsman E.
      • Centers for Disease Control and Prevention; National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America; Pediatric Infectious Diseases Society; American Academy of Pediatrics
      • et al.
      Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics.
      At the end of the guidelines the special circumstances of returned travellers, immunocompromised patients and encephalitis associated with antibodies are discussed. Many patients with suspected viral encephalitis ultimately prove to have another infectious or non-infectious cause for their illness. The further management and treatment of such patients is beyond the scope of this guideline, but we have included a section on follow-up and support for patients with encephalitis in both the healthcare and voluntary sectors after discharge from hospital. Finally, we have included some suggestions for audit standards to assess practice before and after implementation of the guidelines.
      Figure thumbnail gr1
      Figure 1Algorithm for the management of patients with suspected viral encephalitis.

       Methods

      A literature search was performed on the Medline database for the years 1998–2008, to identify for all (English language) publications using the key words (‘Encephalitis’ AND: ‘Symptoms’; ‘Signs’; ‘Management’; ‘Diagnosis’; ‘Investigation’; ‘Lumbar Puncture’; ‘Cerebrospinal Fluid’ (CSF); ‘Computed Tomography (CT)’; ‘Magnetic Resonance Imaging (MRI)’; ‘Single Photon Emission Tomogrophy (SPECT)’; ‘Electroencephalography (EEG)’; ‘Treatment’; ‘Antiviral’; ‘Aciclovir’; ‘Steroids/Dexamethasone’) separately and in combination with the following MESH terms: (‘Herpes Simplex Virus’; ‘Varicella Zoster Virus’; ‘Enterovirus’; ‘Human Immunodeficiency Virus (HIV)’; ‘Immune compromise’; ‘Arbovirus’. This yielded a total of 6948 citations, including many case reports, which were grouped together in subject areas including clinical presentation, diagnosis, imaging, treatment, outcome, immune compromise. These groups of papers were each screened by at least 2 of the group and scored for relevance, level of evidence and need for inclusion. Further sources were added from review of the bibliographies of these articles, textbooks, other reviews and personal collections of the screening group.
      Using these revised source reference lists each subsection of the manuscript was composed by two authors of the Guidelines Writing Group, from the fields of neurology, infectious diseases, microbiology, virology, acute medicine and the patient-sector. This included members from professional bodies including the British Infection Society (now British Infection Association), the British Paediatric Allergy Immunology and Infection Group, the British Paediatric Neurology Association, the Society for Acute Medicine and the Encephalitis Society. Each subsection was internally peer-reviewed. The contributions from the various sections of the guidelines that people wrote were assimilated into a single document in accordance with the principles of the AGREE (appraisal of guideline research and evaluation) collaboration.
      • AGREE Collaboration
      Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.
      In rating the strength of evidence we have used the GRADE approach, in which the strength of recommendations is rated from A to D, and the quality of the evidence supporting the recommendation is rated from I to III (Table 5. GRADE).
      • Atkins D.
      • Best D.
      • Briss P.A.
      • Eccles M.
      • Falck-Ytter Y.
      • Flottorp S.
      • et al.
      Grading quality of evidence and strength of recommendations.
      Table 5GRADE rating system for the strength of the guidelines recommendations and the quality of the evidence (Atkins, Best et al., 2004).
      • Atkins D.
      • Best D.
      • Briss P.A.
      • Eccles M.
      • Falck-Ytter Y.
      • Flottorp S.
      • et al.
      Grading quality of evidence and strength of recommendations.
      Strength of the recommendationQuality of the evidence
      A Strongly recommendedI Evidence from randomised controlled trials
      B Recommended, but other alternatives may be acceptableII Evidence from non-randomised studies
      C Weakly recommended: seek alternativesIII Expert opinion only
      D Never recommended
      This document has again been internally peer-reviewed twice by the Guidelines Development Group, and updated to include further comments from all contributing authors, incorporating references published in 2009–11. The guideline has also been peer-reviewed by the wider Guidelines Stakeholder Group. This included members from the Royal College of Paediatrics and Child Health, the Paediatric Intensive Care Society, the Children's HIV Association and the Meningitis Research Foundation. The guidelines are structured to answer common clinical questions posed during the work-up of a patient with possible encephalitis.

       Definition of childhood for this document

      This guideline is for the management of suspected viral encephalitis in children aged older that 28 days (outside the neonatal period) and younger than 16 years. The management of neonatal encephalitis (including premature infants) is outside the scope of this document. National guidelines for the management of suspected viral encephalitis in adults are also available as a separate document (Solomon, Michael, et al. 2012).

      Diagnosing encephalitis

       Which clinical features should lead to a suspicion of encephalitis in children, how do they differ from other encephalopathies, and can they be used to diagnose the underlying cause?

       Recommendation

      • The constellation of a current or recent febrile illness with altered behaviour, personality, cognition or consciousness or new onset seizures or new focal neurological signs should raise the possibility of encephalitis, or another CNS infection, and should trigger appropriate investigations (A, II)
      • The differential diagnosis of encephalopathy (due to metabolic, toxic, autoimmune causes or sepsis outside the CNS) should be considered early (B, III), especially if there are features suggestive of a non-encephalitic process, such as a past history of similar episodes, symmetrical neurological findings, myoclonus, clinical signs of liver failure, a lack of fever, acidosis or alkalosis (B, III)
      • Patients presenting with a sub-acute (weeks to months) encephalitis should trigger a search for autoimmune, paraneoplastic, metabolic aetiologies (C, III)
      • The priority of the investigations shown in Table 9 is determined by the patient’s clinical history and clinical presentation (C, III)

       Evidence

      The differential diagnosis of acute encephalitis in childhood is broad encompassing infectious, para-infectious immune-mediated, autoimmune, metabolic, vascular, neoplastic, paraneoplastic, and toxic aetiologies as well as brain dysfunction due to systemic sepsis (Tables 2and 3).
      • Kneen R.
      • Solomon T.
      • Appleton R.
      The role of lumbar puncture in children with suspected central nervous system infection.
      • Davies N.W.
      • Sharief M.K.
      • Howard R.S.
      Infection-associated encephalopathies: their investigation, diagnosis, and treatment.
      Nevertheless, defining the clinical features that should prompt the suspicion of acute encephalitis of childhood is essential in order to achieve prompt recognition, investigation and management because delays have been shown to impair outcome.
      However, differentiating infection-associated encephalitis from the other causes of encephalopathy on the basis of clinical findings poses a significant diagnostic challenge, especially in children in whom the clinical picture can be vague. For example, of Chaudhuri and Kennedy's list ‘useful clinical pointers to aid exclusion of non-infective causes of encephalopathy’, none are absolute.
      • Chaudhuri A.
      • Kennedy P.
      Diagnosis and treatment of viral encephalitis.
      In adults, fever and abnormal mental status, often with severe headache, nausea and vomiting, are the classical clinical features of infective encephalitis. Eighty-five (91%) of 93 adults with HSV-1 encephalitis in one study were febrile on admission
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      ; even those not febrile on admission will often have a history of febrile illness (Table 6. History). Disorientation (76%), speech disturbances (59%) and behavioural changes (41%) were the most common features, and one third of patients had seizures.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      However a normal Glasgow coma score at presentation was seen in some patients in this, and other studies, reflecting the fact that it is a crude tool for detecting subtle changes in behaviour.
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      Alterations in higher mental function include lethargy, drowsiness, confusion, disorientation and coma (Table 7. Examination).
      Table 6Questions to consider in the history when assessing a patient with suspected encephalitis, modified from (Solomon, Hart et al., 2007).
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      • Current or recent febrile or influenza-like illness?
      • Altered behaviour or cognition, personality change or altered consciousness?
      • New onset seizures?
      • Focal neurological symptoms?
      • Rash? (e.g. varicella zoster, roseola, enterovirus
      • Others in the family, neighbourhood ill? (e.g. measles, mumps, 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, Lyme disease, tick-borne encephalitis)
      • Known immunocompromise?
      • HIV risk factors?
      Abbreviations: ADEM Acute disseminated encephalomyelitis; HIV Human immunodeficiency virus.
      Table 7Examination findings of importance in assessing a patient with suspected encephalitis modified from (Solomon, Hart et al., 2007).
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      • Airways, Breathing, Circulation
      • Mini-mental state, cognitive function, behaviour (when possible)
      • Evidence of prior seizures (tongue biting, injury)
      • Subtle motor seizures (mouth, digit, eyelid twitching)
      • Meningism
      • Focal neurological signs
      • Papilloedema
      • Flaccid paralysis (anterior horn cell involvement)
      • Rash (purpuric – meningococcus; vesicular – hand foot and mouth disease; varicella zoster; rickettsial disease)
      • Injection sites of drug abuse
      • Bites from animals (rabies) or insects (arboviruses)
      • Movement disorders, including Parkinsonism
      Definition of the spectrum of clinical findings at presentation, and the pattern of subsequent manifestations in children is more difficult as documentation of the clinical presentation of children with encephalitis is less well described. Several studies include adults and children together making it difficult to comment on whether children may have a different presentation.
      • Glaser C.A.
      • Gilliam S.
      • Schnurr D.
      • Forghani B.
      • Honarmand S.
      • Khetsuriani N.
      • et al.
      In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project.
      • Studahl M.
      • Hagberg L.
      • Rekabdar E.
      • Bergstrom T.
      Herpesvirus DNA detection in cerebral spinal fluid: differences in clinical presentation between alpha-, beta-, and gamma-herpesviruses.
      • Davison K.L.
      • Crowcroft N.S.
      • Ramsay M.E.
      • Brown D.W.G.
      • Andrews N.J.
      Viral encephalitis in England, 1989–1998: what did we miss?.
      Furthermore, given that children are susceptible to different aetiological agents than adults and also present differently from adults with other causes of infection, the utility of the profiles defined in characterising encephalitis presentations in childhood is limited by the lack of breakdown by age. The most relevant studies have only reported findings in small numbers of children and the entry criteria were not proven encephalitis, but suspected encephalitis and are primarily hospital-based.
      • Kneen R.
      • Solomon T.
      • Appleton R.
      The role of lumbar puncture in children with suspected central nervous system infection.
      • Kolski H.
      • Ford-Jones E.
      • Richardson S.
      • Petric M.
      • Nelson S.
      • Jamieson F.
      • et al.
      Etiology of acute childhood encephalitis in the hospital for sick children.
      In the Toronto Acute Childhood Encephalitis study, 50 children with suspected encephalitis were reported with the most common presenting features being fever (80%), seizures (78%), focal neurological signs (78%) and decreased consciousness (47%).
      • Kolski H.
      • Ford-Jones E.
      • Richardson S.
      • Petric M.
      • Nelson S.
      • Jamieson F.
      • et al.
      Etiology of acute childhood encephalitis in the hospital for sick children.
      In Wang's study from Taiwan, 101 children with a final diagnosis of encephalitis were reported to have the following features; change in personality or reduction in consciousness (40%), seizures (33%), new neurological signs (36%) and meningism 22%, The number presenting with fever was not reported.
      • Wang I.J.
      • Lee P.I.
      • Huang L.M.
      • Chen C.J.
      • Chen C.L.
      • Lee W.T.
      The correlation between neurological evaluations and neurological outcome in acute encephalitis: a hospital-based study.
      In the more recent Liverpool study, 51 children were treated for suspected encephalitis and their most common presenting features included confusion, irritability or a behaviour change (76%), fever (67%), seizures (61%), vomiting (57%) and focal neurological signs (37%).
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      However, 14 of these children were ultimately not felt to have viral encephalitis and should not have received aciclovir so the list of presenting symptoms is likely to be inaccurate. Ill children are different to adults, young children cannot often adequately describe symptoms such as headache and infants frequently have non-specific symptoms and signs for many acute illnesses including feeding and respiratory difficulties. In Wang's study 54% of the children had concomitant signs of a respiratory infection and 21% had gastrointestinal symptoms.
      • Wang I.J.
      • Lee P.I.
      • Huang L.M.
      • Chen C.J.
      • Chen C.L.
      • Lee W.T.
      The correlation between neurological evaluations and neurological outcome in acute encephalitis: a hospital-based study.
      With the advent of CSF PCR more subtle presentations of HSV encephalitis have been recognised and described in adults and children.
      • Fodor P.A.
      • Levin M.J.
      • Weinberg A.
      • Sandberg E.
      • Sylman J.
      • Tyler K.L.
      Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF.
      These include low-grade pyrexia rather than a high fever, speech disturbances (dysphasia and aphasia), and behavioural changes which can mistaken for psychiatric illness, or the consequences of drugs or alcohol, occasionally with tragic consequences.
      • Marton R.
      • Gotlieb-Stematsky T.
      • Klein C.
      • Lahat E.
      • Arlazoroff A.
      Mild form of acute herpes simplex encephalitis in childhood.

       Distinguishing HSV encephalitis from other encephalopathies

      Several studies have documented the potential mimics of HSV encephalitis in adults and children.
      • Bell D.J.
      • Suckling R.
      • Rothburn M.M.
      • Blanchard T.
      • Stoeter D.
      • Michael B.D.
      • et al.
      Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital.
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      • Chataway J.
      • Davies N.W.
      • Farmer S.
      • Howard R.S.
      • Thompson E.J.
      • Ward K.N.
      Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests.
      • Whitley R.J.
      • Cobbs C.G.
      • Alford Jr., C.A.
      • Soong S.J.
      • Hirsch M.S.
      • Connor J.D.
      • et al.
      Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group.
      Whitley et al. demonstrated that of 432 (168 < 18 years old) patients undergoing brain biopsy for presumed HSV encephalitis: 195 (45%) had the diagnosis proven histologically and in a further 95 patients (22%) an alternative, often treatable, diagnosis was established.
      • Whitley R.J.
      • Cobbs C.G.
      • Alford Jr., C.A.
      • Soong S.J.
      • Hirsch M.S.
      • Connor J.D.
      • et al.
      Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group.
      However, the clinical presenting features of these two groups were very similar. Chataway et al. found that, of those patients initially considered to have HSV encephalitis, inflammatory aetiologies such as ADEM or multiple sclerosis were the most frequent mimics.
      • Chataway J.
      • Davies N.W.
      • Farmer S.
      • Howard R.S.
      • Thompson E.J.
      • Ward K.N.
      Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests.
      Some of the rarer paediatric diagnoses included epileptic encephalopathies such as Rasmussen's encephalitis and Alper's syndrome. Kneen et al. showed the broad range of final diagnoses in children initially treated with aciclovir for possible HSV encephalitis in children and Bell et al. and Michael et al. demonstrated that this was also similar in adult practice.
      • Bell D.J.
      • Suckling R.
      • Rothburn M.M.
      • Blanchard T.
      • Stoeter D.
      • Michael B.D.
      • et al.
      Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital.
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      The clinical picture clearly varies with disease severity but can also vary with aetiological agent; of the many viruses that cause acute encephalitis in children, some have a predilection for localised parts of the brain which can determine the initial clinical picture and the subsequent clinical course.
      • Baskin H.J.
      • Hedlund G.
      Neuroimaging of herpesvirus infections in children.
      Although, De Tiege et al.
      • De Tiege X.
      • Rozenburg F.
      • Heron B.
      The spectrum of herpes simplex encephalitis in children.
      endorse the view that the concept of a ‘‘classical’’ picture of HSV encephalitis in children is now out-dated and remind clinicians that the most common reason for failure to diagnose HSV encephalitis is non-specific initial clinical presenting symptoms and signs.
      • McGrath N.
      • Anderson N.E.
      • Croxson M.C.
      • Powell K.F.
      Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
      Seizures are more frequently found in patients presenting with encephalitic processes affecting the cortex, which are more often infectious in aetiology, as opposed to encephalitic processes predominantly affecting subcortical white matter that more frequently have an immune-mediated pathogenesis (e.g. ADEM). However, seizures and movement disorders are also often seen in children with encephalitis due to autoimmune antibody-mediated disease (see ‘Special circumstances’ section). Seizures can also be subtle and include subtle motor status: a syndrome of subtle continuous motor seizure activity. This often follows overt convulsive seizures or status epilepticus or non-convulsive status epilepticus (NCSE): a syndrome of encephalopathy with no overt motor seizure activity but an electrical seizure correlate on the EEG. A study of 144 (134 children) patients with encephalitis due to Japanese encephalitis virus found that 40 had witnessed seizures in hospital. Of these, 25 had one or more episodes of status epilepticus including 15 who went onto develop subtle motor status. Patients with witnessed convulsive or subtle motor status epilepticus were more likely to die (p = 0.0003).
      • Solomon T.
      • Dung N.M.
      • Kneen R.
      • Thao L.T.T.
      • Gainsborough M.
      • Nisalak A.
      • et al.
      Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis.
      However, it is very unusual for patients with encephalitis or other CNS infections and encephalopathy to present with de novo NCSE. A study of 236 consecutive intensive care unit patients (11% < 16 years) during the first 3 days of an illness with coma (and no witnessed overt or subtle seizures) identified that 19 (8%) were in NCSE. Of these, 2 were children. Only one adult had a CNS infection (diagnosis unspecified).
      • Towne A.R.
      • Waterhouse E.J.
      • Boggs J.G.
      • Garnett L.K.
      • Brown A.J.
      • Smith Jr., J.R.
      • et al.
      Prevalence of nonconvulsive status epilepticus in comatose patients.
      In another study of 45 consecutive adults diagnosed with NCSE, 20 had no previous diagnosis of epilepsy. Twenty-eight of the 45 patients had a remote risk factor for developing epilepsy including previous CNS infections in some (number not specified).
      • Haffey S.
      • McKernan A.
      • Pang K.
      Non-convulsive status epilepticus: a profile of patients diagnosed within a tertiary referral centre.
      Despite its relative rarity, NCSE can only be diagnosed with an EEG and as there are specific treatments available, an EEG should be considered in all patients with undiagnosed encephalopathy.
      • Cinque P.
      • Cleator G.M.
      • Weber T.
      • Monteyne P.
      • Sindic C.J.
      • van Loon A.M.
      The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis.
      In adult clinical practice the most frequently encountered infection-associated encephalopathy is septic encephalopathy, being found in 50–70% of septic patients.
      • Eidelman L.A.
      • Putterman D.
      • Putterman C.
      • Sprung C.L.
      The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities.
      This syndrome usually occurs in elderly patients with an extracranial focus of sepsis where the encephalopathy cannot be attributed to other organ dysfunction. Clinically, the diagnosis is one of exclusion. The syndrome is characterised neurologically by progression from a slowing of mentation and impaired attention to delirium and coma. Neurological examination findings are usually symmetrical. This syndrome is uncommon in paediatric practice but it can occur and is most frequently seen in association with bacterial infections of the urinary tract. It can also be seen in association with other rarer infective encephalopathies such as shigella or in association with typhoid fever.
      • Mishra S.K.
      • Newton R.J.C.
      Diagnosis and management of the neurological complications of falciparum malaria.
      • Ichikawa K.
      • Kajitani A.
      • Tsutsumi A.
      • Takeshita S.
      Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy.

       Diagnostic features for specific aetiologies

      The history is important in defining the spectrum of agents potentially responsible for encephalitis as this is influenced by age, immunocompetence, geography and exposure. Geographical restrictions are laid out in the Table 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 ultimately prove to have a different diagnosis. In adults, the finding of labial herpes (cold sores) has no diagnostic specificity for HSV encephalitis and is merely a marker of critical illness. However, in children who are more likely to develop encephalitis with a primary HSV infection, labial herpes may be noted.
      • Lahat E.
      • Barr J.
      • Barkai G.
      • Paret G.
      • Brand N.
      • Barzilai A.
      Long term neurological outcome of herpes encephalitis.
      • Elbers J.
      • Bitnun A.
      • Richardson S.E.
      • Ford-Jones E.L.
      • Tellier R.
      • Wald R.M.
      • et al.
      A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease?.
      Lahat reported 2 children with recent labial herpes in a series of 28 children aged from 3 months to 16 years with proven HSV encephalitis due to a primary infection
      • Lahat E.
      • Barr J.
      • Barkai G.
      • Paret G.
      • Brand N.
      • Barzilai A.
      Long term neurological outcome of herpes encephalitis.
      and Elbers reported active or a recent history of labial herpes in 4 out of 16 children with proven HSV encephalitis.
      • Elbers J.
      • Bitnun A.
      • Richardson S.E.
      • Ford-Jones E.L.
      • Tellier R.
      • Wald R.M.
      • et al.
      A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease?.
      Elbers also reported that 3 further children with positive CSF PCR for HSV-1 were excluded from his series because of an atypical presentation. These children all had a milder illness (all had fever, one had multiple seizures, one had a single seizure and ataxia and one had lethargy and headache) and normal cranial imaging. Elbers concluded that the CSF PCR results may be false positives or due to reactivation of the virus but it is also conceivable that HSV can cause a mild encephalitis and for this reason it should be considered in the differential diagnosis of children with less severe symptoms. A mild HSV encephalitis has also been reported in 2 previous children aged 3.5 and 15 years who recovered without treatment with aciclovir.
      • Marton R.
      • Gotlieb-Stematsky T.
      • Klein C.
      • Lahat E.
      • Arlazoroff A.
      Mild form of acute herpes simplex encephalitis in childhood.
      Children with HSV encephalitis may also present with an acute opercular syndrome (disturbance of voluntary control of the facio-linguo-glosso-pharyngeal muscles leading to oro-facial palsy, dysarthria and dysphagia).
      • van der Poel J.C.
      • Haenggeli C.A.
      • Overweg-Plandsoen W.C.
      Operculum syndrome: unusual feature of herpes simplex encephalitis.
      • Garcia-Ribes A.
      • Martinez-Gonzalez M.J.
      • Prats-Vinas J.M.
      Suspected herpes encephalitis and opercular syndrome in childhood.
      CNS disease caused by HSV-2 is rare outside the neonatal period. The most common manifestation in adults is aseptic meningitis which may be recurrent.
      • Tyler K.L.
      Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's.
      • Meylan S.
      • Robert D.
      • Estrade C.
      • Grimbuehler V.
      • Peter O.
      • Meylan P.R.
      • et al.
      Real-time PCR for type-specific identification of herpes simplex in clinical samples: evaluation of type- specific results in the context of CNS diseases.
      This has also been reported in children and the possibility of sexual abuse may need to be considered.
      • Kumar S.
      • Kumar S.
      • Kohlhoff S.A.
      Recurrent HSV-2 meningitis in a 9-year-old girl.
      Varicella zoster virus (VZV) can cause central nervous system manifestations through a post-infective immune-mediated cerebellitis, an acute infective viral encephalitis or a vasculopathy; the neurological presentation may be preceded by the vesicular rash of by days or weeks, though it occasionally occurs before the rash or even in patients with no rash.
      • Dangond F.
      • Engle E.
      • Yessayan L.
      • Sawyer M.H.
      Pre-eruptive varicella cerebellitis confirmed by PCR.
      • Gnann Jr., J.W.
      Varicella-zoster virus: atypical presentations and unusual complications.
      • Wagner H.J.
      • Seidel A.
      • Grande-Nagel I.
      • Kruse K.
      • Sperner J.
      Pre-eruptive varicella encephalitis: case report and review of literature.
      Encephalitis is more common in adults, especially those with cranial dermatome involvement or a disseminated rash or the immunocompromised. The presentation may be acute or sub-acute with fever, headache, altered consciousness, ataxia and seizures. A more common neurological presentation associated with VZV infection in children is post-infectious cerebellitis particularly in young children. This is usually a relatively mild and self limiting disorder but children can become unwell due to hydrocephalus secondary to swelling of the cerebellum in more severe cases.
      • Barnes D.W.
      • Whitley R.
      CNS diseases associated with varicella zoster virus and herpes simplex virus infection. Pathogenesis and current therapy.
      • Shkalim V.
      • Amir J.
      • Kornreich L.
      • Scheuerman O.
      • Straussberg R.
      Acute cerebellitis presenting as tonsillar herniation and hydrocephalus.
      Children usually present with a short history of unsteadiness or limb ataxia and nystagmus. The other relatively common association in childhood is between VZV infection and arterial ischaemic stroke, and is thought to account for up to one third of cases of arterial stokes in paediatric practice. The majority present with acute but permanent hemiparesis, acute chorea or facial weakness which is commonly transient;
      • Miravet E.
      • Danchaivijitr N.
      • Basu H.
      • Saunders D.E.
      • Ganesan V.
      Clinical and radiological features of childhood cerebral infarction following varicella zoster virus infection.
      seizures and visual or speech disturbances also occur. Patients usually present after the rash has cleared and the time period can be very delayed with a mean of 3 months (range 1 week to 48 months) reported in a recent London study.
      • Miravet E.
      • Danchaivijitr N.
      • Basu H.
      • Saunders D.E.
      • Ganesan V.
      Clinical and radiological features of childhood cerebral infarction following varicella zoster virus infection.
      However, early manifestations can occur within days of exposure,
      • Dangond F.
      • Engle E.
      • Yessayan L.
      • Sawyer M.H.
      Pre-eruptive varicella cerebellitis confirmed by PCR.
      well before the vesicular eruption, which may be uncharacteristically mild,
      • Wagner H.J.
      • Seidel A.
      • Grande-Nagel I.
      • Kruse K.
      • Sperner J.
      Pre-eruptive varicella encephalitis: case report and review of literature.
      making diagnosis more challenging, especially as onset of encephalitic features can be abrupt or gradual.
      • Gnann Jr., J.W.
      Varicella-zoster virus: atypical presentations and unusual complications.
      PCR for VZV DNA in the CSF is positive in around a third of patients. A more sensitive test (positive in over 90% patients) is measuring VZV specific IgG antibodies in CSF. The levels can be compared to a concomitant serum sample as a reduced serum/CSF ratio of VZV IgG confirms intrathecal synthesis.
      • Nagal M.A.
      • Cohrs R.J.
      • Mahalingham R.
      • Wellish M.C.
      • Forghani B.
      • Schiller A.
      • et al.
      The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features.
      Epstein–Barr virus (EBV) encephalitis most commonly affects teenagers (median age 13 years; but generally presents in the absence of signs of the typical mononucleosis clinical picture.
      • Doja A.
      • Bitnun A.
      • Ford Jones E.L.
      • Richardson S.
      • Tellier R.
      • Petric M.
      • et al.
      Pediatric Epstein-Barr virus—associated encephalitis: 10-year review.
      In Doja's series of 21 patients, 17 had a non-specific prodrome of fever and 14 had headache. Manifestations of EBV encephalitis and encephalomyelitis may also include an altered level of consciousness, seizures and visual hallucinations.
      • Doja A.
      • Bitnun A.
      • Ford Jones E.L.
      • Richardson S.
      • Tellier R.
      • Petric M.
      • et al.
      Pediatric Epstein-Barr virus—associated encephalitis: 10-year review.
      • Shian W.
      • Chi C.S.
      Epstein Barr-virus encephalitis and encephalomyelitis: MRI findings.
      • Cecil K.M.
      • Jones B.V.
      • Williams S.
      • Hedlund G.L.
      CT, MRI, and MRS of Epstein-Barr virus infection: case report.
      However, the temporal relationship between symptoms is highly variable, including CNS disease as the presenting manifestation, making aetiological diagnosis difficult on clinical grounds and highlighting the need to consider EBV in all cases of childhood encephalitis irrespective of symptoms.
      • Doja A.
      • Bitnun A.
      • Ford Jones E.L.
      • Richardson S.
      • Tellier R.
      • Petric M.
      • et al.
      Pediatric Epstein-Barr virus—associated encephalitis: 10-year review.
      Encephalitis may be associated with respiratory illnesses in children: most common pathogens include the influenza viruses, paramyxoviruses and the bacterium M. pneumoniae. There may be no preceding respiratory symptoms prior to the development of encephalitis in a significant proportion of patients.
      • Christie L.J.
      • Honarmand S.
      • Talkington D.F.
      • Gavali S.S.
      • Preas C.Y.
      • Yagi S.
      • et al.
      Pediatric encephalitis: what is the role of mycoplasma pneumoniae?.
      • Bitnun A.
      • Ford-Jones E.
      • Petric M.
      • MacGregor D.
      • Heuter H.
      • Nelson S.
      • et al.
      Acute childhood encephalitis and Mycoplasma pneumoniae.
      In a recent study of patients with M. pneumonia encephalitis, the affected children were an older cohort (median age 11 years old), presenting with a short prodrome of fever (70%), lethargy (68%), and altered consciousness (58%), while gastrointestinal (45%) and respiratory (44%) symptoms were less common.
      • Christie L.J.
      • Honarmand S.
      • Talkington D.F.
      • Gavali S.S.
      • Preas C.Y.
      • Yagi S.
      • et al.
      Pediatric encephalitis: what is the role of mycoplasma pneumoniae?.
      Their clinical course progressed rapidly (median 2 days from onset to hospitalization), and commonly required intensive care (55%). Seizures were less common in the clinical picture. Symptoms of progressive symmetrical external opthalmoplegia typify Bickerstaff brainstem encephalitis in association with M. pneumonia and can serve as a clue to diagnosis especially when accompanied by ataxia.
      • Steer A.C.
      • Starr M.
      • Kornberg A.J.
      Bickerstaff brainstem encephalitis associated with Mycoplasma pneumoniae infection.
      Influenza has been reported to be associated with a spectrum of neurological disorders in adults and children ranging through a mild encephalopathy with seizures, encephalitis, ADEM, encephalopathy with posterior reversible encephalopathy syndrome, malignant brain oedema syndrome and acute necrotising encephalopathy (ANE).
      • Wang G.F.
      • Li W.
      • Li K.
      Acute encephalopathy and encephalitis caused by influenza virus infection.
      • Akins P.A.
      • Belko J.
      • Uyeki T.M.
      • Axelrod Y.
      • Lee K.K.
      • Silverthorn J.
      H1N1 encephalitis with malignant edema and review of neurologic complications from influenza.
      Patients with influenza (particularly influenza B) can also have associated severe myositis.
      • Wang Y.H.
      • Huang Y.C.
      • Chang L.Y.
      • Kao H.T.
      • Lin P.Y.
      • Huang C.G.
      • et al.
      Clinical characteristics of children with influenza A virus infection requiring hospitalization.
      • Lin C.H.
      • Huang Y.C.
      • Chiu C.H.
      • Huang C.G.
      • Tsao K.C.
      • Lin T.Y.
      Neurologic manifestations in children with influenza B virus infection.
      Patients with influenza encephalopathy/encephalitis rarely have viral antigens or viral nucleic acid in CSF or neural tissue and the mechanisms for causing neurological illness are still unclear. Influenza A in particular, has been reported in association with ANE, a severe encephalopathy often associated with fever and in which typical MRI abnormalities have been reported in the thalami, brainstem and cerebral white matter.
      • Wang G.F.
      • Li W.
      • Li K.
      Acute encephalopathy and encephalitis caused by influenza virus infection.
      • Akins P.A.
      • Belko J.
      • Uyeki T.M.
      • Axelrod Y.
      • Lee K.K.
      • Silverthorn J.
      H1N1 encephalitis with malignant edema and review of neurologic complications from influenza.
      • Grose C.
      The puzzling picture of acute necrotising encephalopathy after influenza A and B infection in young children.
      ANE has most frequently been reported in young children in small outbreaks in Japan and other Southeast Asian countries. This disorder has been found to have an autosomal dominant inheritance pattern in some families with genetic mutations identified.
      • Neilson D.E.
      • Adams M.D.
      • Orr C.M.
      • Schelling D.K.
      • Eiben R.M.
      • Kerr D.S.
      • et al.
      Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore RANBP2.
      There is some very recent evidence that the H1N1 strain of Influenza A that emerged in 2009 may cause more neurological manifestations than seasonal flu. Ekstrand reported 18 children with H1N1and compared them to 16 with seasonal flu. Children with the H1N1 strain were more likely to have encephalopathy, focal neurological signs, aphasia and an abnormal EEG.
      • Ekstrand J.J.
      • Herbener A.
      • Rawlings J.
      • Turney B.
      • Ampofo K.
      • Korgenski E.K.
      • et al.
      Heightened neurologic complications in children with pandemic H1N1 influenza.
      Encephalitis associated with gastrointestinal symptoms includes infection with enteroviruses, rotavirus and human parechoviuses. Enteroviral encephalitis can be associated with a brainstem syndrome. Large outbreaks of encephalitis have been reported with enterovirus 71 in Bulgaria 1975, Hungary 1997, Malaysia 1997 and Taiwan 1997. Children under 5 are more commonly affected
      • Chen C.Y.
      • Yao Y.C.
      • Huang C.C.
      • Lui C.C.
      • Lee K.W.
      • Huang S.C.
      Acute flaccid paralysis in infants and young children with enterovirus 71 infection: MR imaging findings and clinical correlates.
      and the highest mortality is in those aged 6–12 months.
      • Lin T.Y.
      • Chang L.
      • Huang Y.C.
      • Hsu K.H.
      • Chiu C.H.
      • Yang K.D.
      Different proinflammatroy reactions in fatal and non-fatal enterovirus 71 infections: implications for early recognition and therapy.
      • Ho M.
      Enterovirus 71: the virus, its infections and outbreaks.
      Clues to infection with this virus include the typical papular lesions on the hands, feet and in the mouth but those with encephalitis often develop neurogenic pulmonary oedema
      • Prager P.
      • Nolan M.
      • Andrews I.P.
      • Williams G.D.
      Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformaly fatal but causes severe morbidty in survivors.
      on day 2–3 of illness which can rapidly progress to fatal cardiorespiratory collapse despite intervention.
      • Lin T.Y.
      • Chang L.
      • Huang Y.C.
      • Hsu K.H.
      • Chiu C.H.
      • Yang K.D.
      Different proinflammatroy reactions in fatal and non-fatal enterovirus 71 infections: implications for early recognition and therapy.
      Rotavirus encephalopathy has been reported to cause convulsions and cerebellar signs in some children.
      • Liu B.
      • Fujita Y.
      • Arakawa C.
      • Kohira R.
      • Fuchigami T.
      • Mugishima H.
      • et al.
      Detection of rotavirus RNA and antigens in serum and cerebrospinal fluid samples from diarrheic children with seizures.
      • Kobayashi S.
      • Negishi Y.
      • Ando N.
      • Ito T.
      • Nakano M.
      • Togari H.
      • et al.
      Two patients with acute rotavirus encephalitis associated with cerebellar signs and symptoms.
      Rashes may be seen in other encephalitides; for example a maculopapular or vesicular rash is seen in Rickettsial infections or the highly typical rash of measles virus infection. Measles can cause three separate encephalitic illnesses and is of particular concern given the recent rise in cases reported in children and young adults across Europe. The first is either an acute encephalitis or acute disseminated encephalomyelitis associated with the acute infection, although patients may present without the typical rash.
      • Wairagkar N.S.
      • Shaikh N.J.
      • Ratho R.K.
      • Ghosh D.
      • Mahajan R.C.
      • Singhi S.
      • et al.
      Isolation of measles virus from cerebrospinal fluid of children with acute encephalopathy without rash.
      The second is a sub-acute encephalopathy around six months after the primary infection in the immunocompromised with measles inclusion bodies in the brain often without a rash. The third is sub-acute sclerosing panencephalitis (SSPE) in the immunologically normal which can occur several years after the primary infection. Patients with the sub-acute forms usually present with a dementia, visual problems and later with seizures.
      • Gutierrez J.
      • Issacson R.S.
      • Koppel B.S.
      Subacute sclerosing panencephalitis: an update.
      HHV6 (and possibly HHV7) is a cause of encephalitis causing severe disease and long-term sequelae far beyond self-resolving febrile convulsions.
      • Ward K.N.
      • Leong H.N.
      • Thiruchelvam A.D.
      • Aykinson C.E.
      • Clark D.A.
      Human Herpesvirus 6 DNA levels in CSF due to primary infection differ from those due to chromosomal viral intergration and have implications for diagnosis of encephalitis.
      Typical below age 2 years
      • Mannonen L.
      • Herrgard E.
      • Valmari P.
      • Rautiainen P.
      • Uotila K.
      • Aine M.R.
      • et al.
      Primary human herpesvirus 6 infection in the central nervous system can cause severe disease.
      ataxia and prolonged convulsions are the major neurological manifestations and gastrointestinal symptoms can accompany the high fever and rash systemically, thus can be indistinguishable from the viral encephalitides typified by gastroenteritis.
      Sometimes the pattern of neurological deficit can be a clue as to the possible aetiology. Thus autonomic dysfunction, myoclonus and cranial neuropathies can indicate brainstem encephalitis, which is seen in listeriosis, brucellosis, some viral infections or rarely tuberculosis (Table 8. Brainstem encephalitis); there may be tremors and other movement disorders if the thalamus and other basal ganglia are involved, as seen in flaviviruses, such as West Nile virus and Japanese encephalitis, and alphaviruses such as Eastern equine encephalitis virus.
      • Solomon T.
      • Whitley R.J.
      • Harvala H.
      • Bremner J.
      • Kealey S.
      • Weller B.
      • McLellan S.
      • Lloyd G.
      • et al.
      Case report: eastern equine encephalitis virus imported to the UK.
      An encephalitis with an acute flaccid paralysis is characteristic of polio, and other enterovirsues, such as enterovirus 71, as well as flaviviruses.
      • Ooi M.H.
      • Wong S.C.
      • Lewthwaite P.
      • Cardosa M.J.
      • Solomon T.
      Clinical features, diagnosis and management of enterovirus 71.
      Table 8Brainstem encephalitis (rhombencephalitis) - clues and causes, from (Solomon, Hart et al., 2007).
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      Suggestive clinical features
       • Lower cranial nerve involvement
       • Myoclonus
       • Respiratory drive disturbance
       • Autonomic dysfunction
       • Locked-in syndrome
       • MRI changes in the brainstem, with gadolinium  enhancement of basal meninges
      Causes
       • Enteroviruses (especially EV-71)
       • Flaviviruses, e.g. West Nile virus, Japanese encephalitis  virus
       • Alphaviruses, e.g. Eastern equine encephalitis virus
       • Rabies
       • Listeriosis
       • Brucellosis
       • Lyme borreliosis
       • Tuberculosis
       • Toxoplasmosis
       • Primary or secondary central nervous system  malignancy
       • Paraneoplastic syndromes
      Table 9Additional investigations to consider in the differential diagnosis of encephalitis.
      Differential diagnosisInvestigations to consider
      Para-infectious immune-mediated encephalitisMRI brain and spine
      AntiDNAse B and ASO titre, influenza A and B PCR and/or antibody in CSF and serum
      CSF examination
      Brain and meningeal biopsy
      Autoimmune/Inflammatory encephalitisFBC, ESR, CRP, ANA, ENA, dsDNA, ANCA, C3, C4, lupus anticoagulant, cardiolipin, thyroglobulin, thyroperoxidase antibodies, ferritin, fibrinogen, trigylcerides.
      Voltage-gated potassium channel complex and NMDA receptor antibodies
      Serum and CSF ACE, Serum 25OH Vitamin D, 24hr urinary calcium
      Whole body CT
      Biopsy: Brain, meninges, skin, lymph node, peripheral nerve/muscle
      MetabolicRenal, liver, bone & thyroid profiles
      Arterial blood gas analysis
      Plasma and CSF lactate, ammonia, pyruvate, amino acids, very long-chain fatty acids, urinary organic acids
      Porphyrins: blood/urine/faeces
      Biopsy: skin, lymph node, peripheral nerve/muscle
      VascularCT or MRI head with venogram and/or angiogram
      NeoplasticMRI brain and MR spectroscopy
      CSF cytological analysis
      Brain and meningeal biopsy
      CT chest/abdomen/pelvis
      LDH, IgG/A/M, protein electrophoresis, urinary Bence-Jones protein (in adults), bone marrow trephine
      ParaneoplasticAnti-neuronal and onconeuronal antibodies
      CT or PET chest, abdomen and pelvis
      Biopsy of non CNS viscera
      Alpha fetoprotein, beta human chorionic gonadatrophin
      ToxicBlood film; blood or urine levels of alcohol, paracetamol, salicylate, tricyclic, heavy metals
      Urinary illicit drug screen
      Septic EncephalopathySerum microbiological cultures, serology and PCR
      Abbreviations: MRI magnetic resonance imaging; ASO antistreptolysin; PCR polymerase chain reaction; CSF cerebrospinal fluid; FBC full blood count; ESR erythrocyte sedimentation rate; CRP C-reactive protein; ANA antinuclear antibodies; ENA extraneuclear antibodies; dsDNA double stranded deoxyribonucleic acid antibodies; C3/4 complement; ACE angiotensin converting enzyme; CT computed tomography; LDH lactate dehydrogenase; IgG/M/A immunoglobulin; PET positron emission tomography; CNS central nervous system.

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

       Recommendation

      • All patients with suspected encephalitis should have a lumbar puncture as soon as possible after hospital admission, unless there is a clinical contraindication (Table 10. Contraindications to immediate lumbar puncture) (A, II)
      • Clinical assessment and not cranial CT should be used to determine if it is safe to perform a LP (A, II)
      • If there is a clinical contraindication indicating possible raised intracranial pressure due to or causing brain shift, a CT scan should be performed as soon as possible, (A, II). An immediate LP following this should ideally be considered on a case by case basis, unless the imaging reveals significant brain shift or tight basal cisterns due to or causing raised ICP, or an alternative diagnosis, 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 possible after the LP (A, II)
      • In anticoagulated patients, adequate reversal (with protamine for those on heparin and vitamin K, prothrombin complex concentrate, or fresh frozen plasma for those on warfarin) is mandatory before lumbar puncture (A, II). In patients with bleeding disorders, replacement therapy is indicated (B, II). If unclear how to proceed, advice should be sought from a haematologist (B, III)
      • In situations where an LP is not possible at first, the situation should be reviewed every 24 hours, and an LP performed when it is safe to do so (B, II)
      • If an initial LP is non-diagnostic, a second LP should be performed 24-48 hours later (B, II)
      • Children and young adults should be stabilised before performing a CT scan, and an anaesthetist, paediatrician or intensivist should be consulted. (A, III)
      • Lumbar punctures should be performed with needles that meet the standards set out by the National Patient Safety Agency (A, III)

       Evidence

      A lumbar puncture (LP) is an essential investigation in the management of children with suspected encephalitis to confirm the diagnosis and rule out other causes. Therefore all children with suspected encephalitis should have a LP unless a specific contraindication exists. Contraindications have been published in an evidenced based guideline for the management of decreased level conscious level in children (Table 10. Contraindications to immediate lumbar puncture).
      • Bowker R.
      • Stephenson P.
      • Baumer J.H.
      Guideline for the management of decreased level conscious level in children. Archives of Disease in Childhood.
      The risk of presenting with viral encephalitis following a febrile seizure is not known although the risk for bacterial meningitis following febrile seizures is quoted to occur in between 0.4 and 5%.
      • Waruiru C.
      • Appleton R.
      Febrile seizures: an update.
      • Offringa M.
      • Moyer V.A.
      Evidence based management of seizures associated with fever.
      This figure increases to 18% in children who present with febrile status epilepticus.
      • Chin R.F.M.
      • Neville B.G.R.
      • Scott R.
      Meningitis is a common cause of convulsive status epilepticus with fever.
      In addition, young children may present with meningitis without any signs of meningeal irritation; 6 children aged less than 18 months in a series of 95 children who presented with a simple (n = 87) or complex febrile seizure (n = 8) and without signs of meningeal irritation had underlying bacterial meningitis.
      • Laditan A.A.
      Analysis of the results of routine lumbar puncture after a first febrile convulsion in Hofuf, Al-Hassa, Saudi Arabia.
      Although others have reported that only 0.4–1.2% of children who present with a fever and a seizure, in the absence of signs of meningeal irritation will have bacterial meningitis.
      • Offringa M.
      • Moyer V.A.
      Evidence based management of seizures associated with fever.
      Nevertheless, children who do not make a full recovery within an hour following a typical, simple febrile convulsion should have a LP.
      • Armon K.
      • Stephenson T.
      • MacFaul R.
      • Hemingway P.
      • Werneke U.
      • Smith S.
      An evidence and consensus based guideline for the management of a child after a seizure.
      Table 10Contraindications to an immediate lumbar puncture in patients with suspected CNS infections, modified from (Kneen, Solomon, et al., 2002; Michael, Sidhu, et al., 2010; Hasbun, Abrahams, et al., 2002; NICE).
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      • National Instutute for Health and Clinical Excellence
      Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102).
      • Kneen R.
      • Solomon T.
      • Appleton R.
      The role of lumbar puncture in children with suspected central nervous system infection.
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      Imaging needed before lumbar puncture (to exclude brain shift, 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 or  poorly 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:
      ○ Coagulation results (if obtained) outside the normal    range
      ○ Platelet count <100 × 109/L
      ○ Anticoagulant therapy
       • Local infection at the lumbar puncture site
       • Respiratory insufficiency
       • Suspected meningococcal septicaemia (extensive or  spreading purpura)
      aThere is no agreement on the depth of coma that necessitates imaging before lumbar puncture; some argue Glasgow coma score < 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.
      There has been considerable controversy over the role of computer tomography (CT) and LP in patients with suspected central nervous system infection, in particular whether a CT is needed before an LP.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      • van Crevel H.
      • Hijdra A.
      • de Gans J.
      Lumbar puncture and the risk of herniation: when should we first perform CT?.
      • Joffe A.R.
      Lumbar puncture and brain herniation in acute bacterial meningitis: a review.
      Although there are few studies that specifically address this issue in patients with suspected encephalitis, much of the literature about suspected bacterial meningitis is pertinent because of overlap in the clinical presentations. As in patients with meningitis, in encephalitis the CT scan is not a reliable tool for the diagnosis of raised intracranial pressure, and should not be used to for this.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      • National Instutute for Health and Clinical Excellence
      Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102).
      In patients with suspected encephalitis, an early CT scan has two roles: suggesting the diagnosis of viral encephalitis and indicating an alternative diagnosis. An initial CT scan soon after admission will show a suggestive abnormality in about 80% of patients with herpes simplex virus (HSV) encephalitis;
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      almost all those with HSV encephalitis, and a negative initial scan will have abnormalities on a second scan.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      The sensitivity of the CT scan for detecting abnormalities is increased with the use of intravenous contrast media, however, it is not, on its own, diagnostic.
      The second role of an early CT scan is suggesting an alternative diagnoses, so that LP may no longer be necessary. For example in one study of 21 adults with suspected encephalitis, 2 (10%) patients did not have a LP after the CT scan showed a stroke;
      • Bell D.J.
      • Suckling R.
      • Rothburn M.M.
      • Blanchard T.
      • Stoeter D.
      • Michael B.D.
      • et al.
      Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital.
      however, in a larger study only 2 (1%) of 153 patients with suspected CNS infections who had a CT first did not subsequently need a LP.
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      If clinical contraindications to an immediate LP are present then an urgent CT should be performed. If this identifies shift of brain compartments or tight basal cisterns, due to mass lesions and/or oedema a subsequent LP may be dangerous. In patients with brain shift, a LP, by reducing the cerebrospinal fluid (CSF) pressure below the lesion, may precipitate herniation of the brainstem or cerebellar tonsils.
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      • Kneen R.
      • Solomon T.
      • Appleton R.
      Leading article: the role of lumbar puncture in suspected CNS infection – a disappearing skill?.
      For example this may occur in patients with brain abscess, subdural empyema, tumour, or a necrotic swollen lobe in HSV encephalitis. However unselected CT scanning all patients before a LP can cause unnecessary delays in many patients, in whom there were no contraindications to an immediate LP.
      • Bell D.J.
      • Suckling R.
      • Rothburn M.M.
      • Blanchard T.
      • Stoeter D.
      • Michael B.D.
      • et al.
      Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital.
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      For example in one recent study of 21 adults with suspected encephalitis, 17 had a LP, which was delayed for a CT scan in 15, though only one of them had any contraindications to an immediate LP. The median time to CT scan was 6 h, but the median time to LP was 24 h.
      • Bell D.J.
      • Suckling R.
      • Rothburn M.M.
      • Blanchard T.
      • Stoeter D.
      • Michael B.D.
      • et al.
      Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital.
      Furthermore, in a larger study of 217 patients with suspected CNS infections the median (range) time to LP was significantly longer if the patient had a CT scan first (18.5 [2–384] versus 6 [1–72] hours respectively, p < 0.0001).
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      The increasing availability of CT scans in emergency units since this work was published (due to implementation of national guidelines for stroke thrombolysis and acute head injury) will undoubtedly result in easier access to imaging for children with suspected encephalitis who are managed in a hospital that also treats adult emergency patients.
      A series of studies have examined which clinical signs can be used to determine which patients with suspected bacterial meningitis need a CT scan before LP.
      • van Crevel H.
      • Hijdra A.
      • de Gans J.
      Lumbar puncture and the risk of herniation: when should we first perform CT?.
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      In one study of 696 episodes of community acquired acute bacterial meningitis it was concluded that CT scan should precede LP in patients with new onset seizures, focal neurological signs, excluding cranial neuropathies, or moderate to severe impairment of consciousness, as indicated by a Glasgow coma score of 10 or less.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      Papilloedema, a direct indicator of raised intracranial pressure, is also an indication for imaging before a LP. NICE guidelines for the role of CT and LP in children with suspected bacterial meningitis have also been produced recently.
      • National Instutute for Health and Clinical Excellence
      Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102).
      Given the potential overlap of clinical features in patients with suspected meningitis and suspected encephalitis, this approach is also applied to patients with suspected encephalitis. Although there is good agreement about most of the indications for a CT scan before a LP, there is disagreement about the precise level of consciousness that should be taken as a contraindication to an immediate LP. Among seven commentaries reviewed by Joffe 2007,
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      three suggested “increasing stupor progressing to coma”, three suggested a “deterioration in consciousness level”, two suggested a GCS < 8, and one a GCS < 13.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      • Addy D.
      When not to do a lumbar puncture.
      • Haslam R.H.
      Role of computed tomography in the early management of bacterial meningitis.
      • Mellor D.
      The place of computed tomography and lumbar puncture in suspected bacterial meningitis.
      • Archer B.D.
      Computed tomography before lumbar puncture in acute meningitis: a review of the risks and benefits.
      • Riordan F.A.
      • Cant A.J.
      When to do a lumbar puncture.
      • Oliver W.J.
      • Shope T.C.
      • Kuhns L.R.
      Fatal lumbar puncture: fact versus fiction–an approach to a clinical dilemma.
      The recent NICE guidelines for bacterial meningitis recommend a CT scan before a LP if the GCS is <9 or fluctuating >2, so that an alternative diagnosis can be excluded.
      • National Instutute for Health and Clinical Excellence
      Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102).
      There is also lack of clarity about whether in such patients, a LP should then be performed at all, if the scan is normal, or whether a low coma score is an absolute contraindication, whatever the scan shows. Occasionally deterioration after LP has been reported in patients with bacterial meningitis and an apparently normal CT; but we are not aware of similar cases in patients with viral encephalitis; and most would argue that the information from the LP is essential to make a diagnosis and guide treatment. In one retrospective series of 222 adults with suspected encephalitis less than 5% of patients had imaging changes suggestive of raised intracranial pressure.
      • Chataway J.
      • Davies N.W.
      • Farmer S.
      • Howard R.S.
      • Thompson E.J.
      • Ward K.N.
      Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests.
      Other contraindications to LP include local skin infection at the site of puncture, a clinically unstable patient with circulatory shock or respiratory insufficiency, and any clinical suspicion of spinal cord compression. LP may also be harmful in patients with coagulopathy, because of the chance of needle-induced subarachnoid haemorrhage or of the development of spinal subdural and epidural haematomas. The standard recommendation is to perform a lumbar puncture only when the patient does not have a coagulopathy and has a platelet count of 100 × 109/L or greater, although platelet counts of 20 × 109/L or greater have also been recommended.
      • National Instutute for Health and Clinical Excellence
      Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102).
      • Evans R.W.
      Complications of lumbar puncture.
      A rapidly falling count is also a contraindication. Haemorrhage can occur in patients anticoagulated with heparin or warfarin, but in one large study, preoperative antiplatelet therapy with aspirin or nonsteroidal anti-inflammatory medications and subcutaneous heparin on the operative day were not risk factors for spinal haematoma in patients undergoing spinal or epidural anaesthesia.
      • Evans R.W.
      Complications of lumbar puncture.
      In summary, many children will need a CT before a LP, because of their clinical contraindications to an immediate LP; such patients should have a CT, and then ideally a LP should be considered on a case by case basis (if still indicated and no radiological contraindications are identified) within 6 h and then decisions made on antiviral treatment based on these results. In some children who do not have a clinical contraindication to immediate LP, and in whom CT is not immediately available, a prompt LP may be the most useful approach to get an early diagnosis.
      Lumbar punctures should be performed with needles that meet the standards set out by the National Patient Safety Agency.

       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 protein should be corrected for a bloody tap
        • -
          Protein, lactate and glucose, which should be compared with a plasma glucose taken just before the LP (A, II)
        • -
          A sample should be sent and stored for virological investigations or other future investigation as indicated in the next section (A, II)
        • -
          Culture for Mycobacterium tuberculosis when clinically indicated (A, II)
      • If there is a strong clinical diagnosis of encephalitis in a child, but the initial CSF results are normal, a second LP should be undertaken and all CSF tests repeated, including consideration for antibody detection (A, II)

       Evidence

      Patients with HSV encephalitis typically have moderate elevation of CSF opening pressure, a moderate CSF pleocytosis from tens to hundreds of cells × 106/L, a mildly elevated CSF protein and normal CSF to plasma glucose ratio.
      • McGrath N.
      • Anderson N.E.
      • Croxson M.C.
      • Powell K.F.
      Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      • Kennedy P.G.
      Viral encephalitis: causes, differential diagnosis, and management.
      Whilst measuring the CSF opening pressure is part of a standard LP, it is often more difficult to achieve this in children and is frequently omitted. Whilst the evidence base would recommend undertaking opening pressure, it is recognised that it is often impractical to do this in a child so the clinician responsible for undertaking the LP will have to make a balanced judgement as to the value of trying to achieve this. However, if the child is being anaesthetised for the procedure, the opening pressure should be measured with arterial blood gas results stabilised and CO2 noted. Occasionally polymorphonucelar cells predominate, or the CSF may be normal, especially early in the illness: in approximately 3–5% of adults with proven HSV encephalitis an initial CSF may be normal with no pleocytosis and a negative HSV PCR.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      • Steiner I.
      • Budka H.
      • Chaudhuri A.
      • Koskiniemi M.
      • Sainio K.
      • Salonen O.
      • et al.
      Viral encephalitis: a review of diagnostic methods and guidelines for management.
      The figure is even higher in patients with immunocompromise and in children, especially infants. However, if the first CSF is normal in HSV encephalitis, a second CSF examination 24–48 h is likely to be abnormal with a positive HSV PCR, although the viral load does reduce when patients are receiving aciclovir.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      • Steiner I.
      • Budka H.
      • Chaudhuri A.
      • Koskiniemi M.
      • Sainio K.
      • Salonen O.
      • et al.
      Viral encephalitis: a review of diagnostic methods and guidelines for management.
      A series of studies have shown the apparent difficulty in measuring plasma glucose at the same time as CSF glucose,
      • Bell D.J.
      • Suckling R.
      • Rothburn M.M.
      • Blanchard T.
      • Stoeter D.
      • Michael B.D.
      • et al.
      Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital.
      • Michael B.D.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.J.
      • Wilkins E.
      • et al.
      The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      but without the former, interpretation of the CSF results is very difficult. HSV encephalitis can be haemorrhagic, and the CSF red cell count is elevated in approximately 50% of cases.
      • Koskiniemi M.
      • Vaheri A.
      • Taskinen E.
      Cerebrospinal fluid alterations in herpes simplex virus encephalitis.
      An acellular CSF is also described for other viruses, VZV, EBV and CMV, and occurs more frequently in patients with immunocompromise.
      • Studahl M.
      • Hagberg L.
      • Rekabdar E.
      • Bergstrom T.
      Herpesvirus DNA detection in cerebral spinal fluid: differences in clinical presentation between alpha-, beta-, and gamma-herpesviruses.
      Although a lymphocytic CSF pleocytosis is typical of viral CNS infections, non-viral infection, particularly tuberculosis and listeriosis, and partially treated acute bacterial meningitis can give a similar picture. Usually the clinical setting and other CSF parameters (low glucose ratio and higher protein) will suggest these possibilities. CSF lactate may be helpful in distinguishing bacterial meningitis from viral CNS infections
      • Bailey E.M.
      • Domenico P.
      • Cunha B.A.
      Bacterial or viral meningitis? Measuring lactate in CSF can help you know quickly.
      • Cunha B.A.
      Distinguishing bacterial from viral meningitis: the critical importance of the CSF lactic acid levels.
      ; in particular a CSF lactate of <2 mmol/l is said to rule out bacterial disease.
      • Cunha B.A.
      Distinguishing bacterial from viral meningitis: the critical importance of the CSF lactic acid levels.
      A high CSF lactate may also be an indicator of a metabolic disorder, in particular a mitochondrial encephalopathy. If ADEM is in the differential diagnosis, the CSF (with a paired serum sample) should be sent for oligoclonal bands.
      • Menge T.
      • Hemmer B.
      • Nessler S.
      • Wiendl H.
      • Neuhaus O.
      • Hartung H.P.
      • et al.
      Acute disseminated encephalomyelitis: an update.
      In a traumatic tap white blood cells and protein from the blood can contaminate the cerebrospinal fluid.
      • Fishman R.A.
      Cerebrospinal fluid in diseases of the nervous system.
      There is little good evidence to support how to correct for this in children.
      • Novak R.W.
      Lack of validity of standard corrections for white blood cell counts of blood-contaminated cerebrospinal fluid in infants.
      However, the standard approximation would be to subtract 1 white cell for every 700 red blood cells × 106/L in the CSF and 0.1 g/dl for every 100 red blood cells.
      • Nigrovic L.E.
      • Shah S.S.
      • Neuman M.I.
      Correction of cerebrospinal fluid protein for the presence of red blood cells in children with a traumatic lumbar puncture.
      This approximation will suffice in most circumstances, though more complicated formulae allowing for anaemia etc are available.
      • Fishman R.A.
      Cerebrospinal fluid in diseases of the nervous system.
      However, in patients with HSV encephalitis a blood-stained CSF sample may reflect the haemorrhagic pathophysiology of the condition, this is more likely if serial CSF specimens are blood-stained.

       What virological investigations should be performed ?

       Recommendation

      • All patients with suspected encephalitis should have a CSF PCR test for HSV (1 and 2), VZV and enteroviruses as this will identify 90% of known viral cases and EBV considered (B, II)
      • Further testing should be directed towards specific pathogens as guided by the clinical features such as travel history and animal or insect contact (B, III)

       Evidence

      Although the list of viral causes of encephalitis is long,
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      HSV types1 & 2, VZV, and enteroviruses are the commonest causes of viral encephalitis in immunocompetent individuals in Europe & the United States.
      • Glaser C.A.
      • Gilliam S.
      • Schnurr D.
      • Forghani B.
      • Honarmand S.
      • Khetsuriani N.
      • et al.
      In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project.
      • Donoso Mantke O.
      • Vaheri A.
      • Ambrose H.
      • Koopmans M.
      • de Ory F.
      • Zeller H.
      • et al.
      The European Network for Diagnostics of ‘Imported’ Viral Diseases (ENIVD) Working Group for Viral CNS Diseases Analysis of the surveillance situation for viral encephalitis and meningitis in Europe.
      Our ability to diagnose encephalitis caused by herpes viruses & enteroviruses has been improved greatly by using polymerase chain reaction (PCR).
      • Read S.J.
      • Jeffery K.J.M.
      • Bangham C.R.M.
      Aseptic meningitis and encephalitis: the role of PCR in the diagnostic laboratory.
      • Tyler K.L.
      Update on herpes simplex encephalitis.
      CSF PCR for HSV during day 2–10 of illness has overall sensitivity and specificity of >95% for HSV encephalitis in immunocompetent adults.
      • Steiner I.
      • Budka H.
      • Chaudhuri A.
      • Koskiniemi M.
      • Sainio K.
      • Salonen O.
      • et al.
      Viral encephalitis: a review of diagnostic methods and guidelines for management.
      • Cinque P.
      • Cleator G.M.
      • Weber T.
      • Monteyne P.
      • Sindic C.J.
      • van Loon A.M.
      The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis.
      Although HSV PCR may be negative in the first few days of the illness
      • Tyler K.L.
      Update on herpes simplex encephalitis.
      a second CSF taken 2–7 days later will often be HSV positive, even if aciclovir treatment has been started.
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
      • Weil A.A.
      • Glaser C.A.
      • Amad Z.
      • Forghani B.
      Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result.
      Further microbiological investigations should be based on specific epidemiological factors (age, animal and insect contacts, immune status, recreational activities, geography and recent travel history, season of the year and vaccination history) and clinical findings (hepatitis, lymphadenopathy, rash, respiratory tract infection, retinitis, urinary symptoms and neurological syndrome (Table 11. Microbiological investigation of encephalitis).
      • Kennedy P.G.
      Viral encephalitis: causes, differential diagnosis, and management.
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      • Whitley R.J.
      • Gnann J.W.
      Viral encephalitis: familiar infections and emerging pathogens.
      • Sejvar J.J.
      The evolving epidemiology of viral encephalitis.
      Table 11Microbiological investigations in patients with encephalitis, modified from (Solomon, Hart et al., 2007).
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      CSF PCR
      1. All patients
       HSV-1, HSV-2, VZV
       Enterovirus, parechovirus
      2. If indicated
       EBV/CMV (especially if immunocompromised)
       HHV6,7 (especially if immunocompromised, or children)
       Adenovirus, influenza A &B, rotavirus (children)
       Measles, mumps
       Erythrovirus B19
       Chlamydia
      3. Special circumstances
       Rabies, West Nile virus, tick-borne encephalitis virus (if appropriate exposure)
      Antibody testing (when indicated – see text)
      Antibody detection in the serum identifies infection (past or recent depending on the type of antibodies) but does not necessarily mean this virus has caused the CNS disease.
      1. Viruses: IgM and IgG in CSF and serum (acute and convalescent), for antibodies against
       HSV-1 & 2, VZV, CMV, HHV6, HHV7, enteroviruses, RSV, Erythrovirus B19, adenovirus, influenza A & B
      2. If associated with atypical pneumonia, test serum for
       Mycoplasma serology
       chlamydophila serology
      Ancillary investigations (when indicated - These establish carriage or systemic infection, but not necessarily the cause of the CNS disease)
      • Throat swab, nasopharyngeal aspirate, rectal swab, faeces, urine
       PCR/culture of throat swab, rectal swab, faeces for enteroviruses
       PCR of throat swab for mycoplasma, chlamydophila
       PCR/antigen detection of nose/throat swab or nasopharyngeal aspirate for respiratory viruses, adenovirus, influenza virus (especially children)
       PCR/culture of parotid duct swab following parotid massage or buccal swab for mumps
       PCR/culture of urine for measles, mumps and rubella
      • Vesicle electron microscopy, PCR and culture
      Viral culture and electron microscopy less sensitive than PCR.
       Patients with herpetic lesions (for HSV, VZV)
       Children with hand foot and mouth disease (for enteroviruses)
      Brain Biopsy
       For culture, electron microscopy, PCR and immunohistochemistry
      Viral culture and electron microscopy less sensitive than PCR.
      a Antibody detection in the serum identifies infection (past or recent depending on the type of antibodies) but does not necessarily mean this virus has caused the CNS disease.
      b Viral culture and electron microscopy less sensitive than PCR.

       What antibody testing should be done on serum & CSF?

       Recommendation

      • Guidance from a specialist in microbiology, virology or infectious disease specialists should be sought in deciding on these investigations (B, III)
      • In patients with suspected encephalitis where PCR of the CSF was not performed acutely, a later CSF sample (at approximately 10-14 days after illness onset) should be sent for HSV specific IgG antibody testing (B, III)
      • In suspected flavivirus encephalitis CSF should be tested for IgM antibody (B, II)
      • Acute and convalescent blood samples should be taken as an adjunct to diagnostic investigation especially when EBV, arboviruses, lyme disease, cat scratch disease, rickettsiosis or ehrlichioses are suspected (B, II)

       Evidence

      Whilst all patients with suspected encephalitis should have PCR requested for the common viruses, decisions about antibody testing of serum and CSF are best made in conjunction with the specialist microbiology/virology or infectious diseases service.

       Cerebrospinal fluid

      Intrathecal synthesis of HSV-specific IgG antibodies is normally detected after 10–14 days of illness, peaks after one month and can persist for several years.
      • Vandvik B.
      • Vartdal F.
      • Norrby E.
      Herpes simplex virus encephalitis: intrathecal synthesis of oligoclonal virus-specific IgG, IgA and IgM antibodies.
      The detection of intrathecally synthesized HSV IgG antibodies, when available, may help to establish the diagnosis of HSV encephalitis in patients where the CSF is taken after day 10–12 of the illness. This is especially useful in patients for whom an earlier CSF was not taken, or was not tested for HSV by PCR. A European consensus statement recommended the combined approach of testing CSF by PCR and antibody detection, such that a negative HSV-PCR result early in the disease process coupled with a negative HSV-specific CSF antibody study sampled 10–14 days after symptom onset effectively ruled out the disease
      • Cinque P.
      • Cleator G.M.
      • Weber T.
      • Monteyne P.
      • Sindic C.J.
      • van Loon A.M.
      The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis.
      ; however, intrathecal immune responses may be delayed or absent when antiviral therapy is started early.
      • Linde A.
      • Klapper P.E.
      • Monteyne P.
      • Eschevarria J.M.
      • Cinque P.
      • Rozenberg F.
      • et al.
      Specific diagnostic methods for herpesvirus infections of the central nervous system. A consensus review by the European Union Concerted Action on Virus Meningitis and Encephalitis.
      Additionally, many laboratories do not provide CSF antibody detection services. The detection of oligoclonal bands in the CSF is a non-specific indicator of an inflammatory process in the CNS; immunoblotting of the bands against viral proteins from HSV can been used to detect anti-HSV antibody, although this is not routinely available.
      • Chataway J.
      • Davies N.W.
      • Farmer S.
      • Howard R.S.
      • Thompson E.J.
      • Ward K.N.
      Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests.
      • Cinque P.
      • Cleator G.M.
      • Weber T.
      • Monteyne P.
      • Sindic C.J.
      • van Loon A.M.
      The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis.
      Antibody detection can also be particularly useful in VZV encephalitis.
      • Gregoire S.M.
      • Van Pesch V.
      • Goffette S.
      • Peeters A.
      • Sindic C.J.M.
      Polymerase chain reaction analysis and oligoclonal antibody in the cerebrospinal fluid from 34 patients with varicella-zoster virus infection of the nervous system.
      The detection of virus specific IgM in CSF is usually indicative of an intrathecal antiviral immune response; this is especially useful for flaviviruses and other RNA viruses, which tend to be primary infections, rather than DNA viruses, which are often reactivations.
      • Solomon T.
      • Whitley R.J.

       Blood

      Acute and convalescent blood samples should be taken for appropriate serological testing based on the likely organisms identified from specific epidemiological and clinical features.
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
      Examples of infectious causes of encephalitis that can be diagnosed from serological investigations of blood include: EBV, arthropod-borne viruses (arboviruses), Borrelia burgdorferi (lyme disease), Bartonella hensae (cat scratch disease), rickettsioses, ehrlichioses, and mycoplasma. Serological testing for antibodies in autoimmune encephalitis is covered in the ‘Special circumstances’ section 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 collaboration between a specialist in microbiology, virology, infectious diseases and the clinical team (B, III)
      • In all patients with suspected viral encephalitis throat and rectal swabs for enterovirus investigations should be considered; and swabs should also be sent from vesicles, if present (B, II)
      • When there is a recent or concomitant respiratory tract infection, throat swab or sputum/lavage should be sent for PCR for respiratory viruses (B, II)
      • When there is suspicion of mumps CSF PCR should be performed for this and parotid gland duct or buccal swabs should be sent for viral culture or PCR (B, II)

       Evidence

      Investigation of sites outside the CNS can be useful to provide pointers as to possible aetiology (Table 11 Microbiological investigations); however it must be remembered that such infection might be coincidental rather than causal; this is especially the case for non-sterile sites, or sites where long term shedding of virus occurs (e.g. in the stool). In enterovirus encephalitis, the virus may be isolated by swabbing the throat and rectum, or, if present, vesicles.
      • Steiner I.
      • Budka H.
      • Chaudhuri A.
      • Koskiniemi M.
      • Sainio K.
      • Salonen O.
      • et al.
      Viral encephalitis: a review of diagnostic methods and guidelines for management.
      Of these vesicular swabs are most useful because they indicate acute and systemic infection, whereas carriage in the faeces, and to some extent the throat may be long term.
      • Ooi M.H.
      • Wong S.C.
      • Lewthwaite P.
      • Cardosa M.J.
      • Solomon T.
      Clinical features, diagnosis and management of enterovirus 71.
      Although many patients with enterovirus CNS infections do not have vesicles.
      If the clinical illness suggests a recent respiratory infection, samples taken from the respiratory tract (throat swab, nasal swab, nasopharyngeal aspirate, nasal washings, tracheal aspirate or brochoalveolar lavage) can be tested by PCR for respiratory viruses.
      Mumps encephalitis is most accurately confirmed by PCR of the CSF; serum or salivary mumps antibodies are also helpful. Viral culture or PCR performed on parotid gland duct swabs, taken after massaging the parotid gland for 30 s, or buccal (saliva) swabs are useful for the diagnosis of recent mumps virus infection, within 9 days of the onset of symptoms. A urine sample is less sensitive but may be positive for at least 5 days after detection in the mouth. Urine analysis if also useful if measles is suspected.
      Viral infection may be demonstrated by culture, detection of viral genomes (by PCR), viral antibodies (by serology), viral antigens (by direct immunofluoresence), or, if available, viral particles (by electron microscopy), although PCR is the most sensitive.
      • Klapper P.E.
      • Cleator G.M.
      European guidelines for diagnosis and management of patients with suspected herpes simplex encephalitis.
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.

       Which children with encephalitis should have an HIV test?

       Recommendation

      • We recommend that an HIV test be performed on all patients with encephalitis, or with suspected encephalitis irrespective of apparent risk factors (A, II)

       Evidence

      HIV is directly capable of causing an encephalopathy in young children
      • Price R.W.
      • Sudlich S.
      Antiretroviral therapy and central nervous system HIV type 1 infection.
      but infection with the virus also predisposes children to CNS infections from other specific pathogens. Antenatal screening for HIV infection is offered to all pregnant women in the United Kingdom and has a high uptake (90%). However it is not compulsory, and Mother to Child transmission of HIV can still occur in the UK.
      • Struik S.S.
      • Tudor-Williams G.
      • Taylor G.P.
      • Portsmouth S.D.
      • Foster C.J.
      • Walsh C.
      • et al.
      • Mercey D.
      • Helps B.A.
      • Copas A.
      • Petruckevitch A.
      • Johnson A.M.
      • Spencer J.
      Voluntary universal antenatal HIV testing.
      Migrants and travellers to the UK, from areas defined by the WHO as areas with high endemicity of HIV infection

      Childrens HIV Association. HIV Testing guidelines: ‘Don't forget the children’. www.chiva.org.uk/professionals/health/guidelines/testing/dontforget.html; [accessed 2011].

      particularly from sub-Saharan Africa, and Asia, including major parts of the former Soviet Union, should be regarded as being at risk of Mother to Child Transmission of HIV. It must be remembered that while HIV infection is rapidly progressive in 20% of infants,
      • Blanche S.
      • Newell M.L.
      • Mayaux M.J.
      • Dunn D.T.
      • Teglas J.P.
      • Rouzioux C.
      • et al.
      The French Pediatric HIV Infection Study Group and European Collaborative Study.
      • Little K.
      • Thorne C.
      • Luo C.
      • Bunders M.
      • Ngongo N.
      • McDermott P.
      • et al.
      Disease progression in children with vertically-acquired HIV infection in sub-Saharan Africa: reviewing the need for HIV treatment.
      late presentation of perinatally acquired HIV infection can occur at 13 years of age or older.
      • Judd A.
      • Ferrand R.A.
      • Jungmann E.
      • Foster C.
      • Masters J.
      • Rice B.
      • et al.
      Vertically acquired HIV diagnosed in adolescence and early adulthood in the United Kingdom and Ireland: findings from national surveillance.
      • Español T.
      • Figueras M.C.
      • Soriano V.
      • Caragol I.
      • Hernandez M.
      • Bertran J.M.
      Very late presentation of vertically transmitted HIV-1 infection.
      HIV should be considered in children with suspected encephalitis for three reasons. Children with undiagnosed advanced HIV disease can present with CNS infections from a number of the less common infectious causes, such as cytomegalovirus.
      • Wrzolek M.A.
      • Brudkowska J.
      • Kozlowski P.B.
      • Rao C.
      • Anzil A.P.
      • Klein E.A.
      • et al.
      Opportunistic infections of the central nervous system in children with HIV infection: report of 9 autopsy cases and review of literature.
      • Roullet E.
      Opportunistic infections of the central nervous system during HIV-1 infection.
      Secondly some of the more common CNS infections, such as Streptococcus pneumoniae or Mycoplasma tuberculosis have an increased incidence in patients with HIV. Thirdly, although uncommon in children, primary HIV-1 infection can present with an acute meningoencephalitis as part of a seroconversion illness.
      • Apoola A.
      • Ahmad S.
      • Radcliffe K.
      Primary HIV infection.
      The current UK guidelines on HIV testing

      Childrens HIV Association. HIV Testing guidelines: ‘Don't forget the children’. www.chiva.org.uk/professionals/health/guidelines/testing/dontforget.html; [accessed 2011].

      • British HIV Association (BHIVA), British Association for Sexual Health and HIV (BASHH), British Infection Society (BIS)
      UK National Guidelines for HIV Testing.
      emphasise that “all patients presenting for healthcare where HIV, including primary HIV infection, enters the differential diagnosis” should be tested for HIV and offers detailed guidance on the testing of infants, children and young people.

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

       Recommendation

      • Brain biopsy has no place in the initial assessment of suspected acute viral encephalitis in immunocompetent children. Stereotactic brain biopsy should be considered in a child with suspected encephalitis in whom no diagnosis has been made after the first week, especially if there are focal abnormalities on imaging and if the findings could change the child’s management (B, II)
      • If imaging shows nothing focal, an open biopsy, usually from the non-dominant frontal lobe, may be preferable (B, II)
      • The biopsy should be performed by an experienced paediatric neurosurgeon and the histology should be examined by an experienced neuropathologist (B, III)

       Evidence

      For many years brain biopsy was the preferred method for diagnosing HSV encephalitis, because clinically many conditions mimic HSV encephalitis,
      • Whitley R.J.
      • Cobbs C.G.
      • Alford Jr., C.A.
      • Soong S.J.
      • Hirsch M.S.
      • Connor J.D.
      • et al.
      Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group.
      the chances of culturing the virus from the CSF were low, and a biopsy was one of the few reliable means of making the diagnosis; although its sensitivity was low, specificity was high.
      • Whitley R.J.
      • Cobbs C.G.
      • Alford Jr., C.A.
      • Soong S.J.
      • Hirsch M.S.
      • Connor J.D.
      • et al.
      Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group.
      Subsequently CSF PCR for HSV DNA was developed, and proved a rapid and reliable diagnostic test,
      • Read S.J.
      • Jeffery K.J.M.
      • Bangham C.R.M.
      Aseptic meningitis and encephalitis: the role of PCR in the diagnostic laboratory.
      • Tyler K.L.
      Update on herpes simplex encephalitis.
      largely replacing biopsy for the diagnosis HSV encephalitis. However biopsy still has a role in the investigation of other patients. Although until recently it was considered highly invasive with a significant mortality and morbidity (through intracranial haemorrhage, or biopsy site oedema), with modern stereotactic approaches the incidence of serious adverse events is low, and it is now considered a relatively safe investigation.
      • Pulhorn H.
      • Quigley D.G.
      • Bosma J.
      • Kirollos R.
      • du Plessis D.
      • Jenkinson M.
      Impact of brain biopsy on the management of patients with non-neoplastic undiagnosed neurological disorders.
      • Wong S.H.
      • Jenkinson M.D.
      • Faragher B.
      • Thomas S.
      • Crooks D.
      • Solomon T.
      Brain biopsy in the management of neurology patients.
      There is no role for a brain biopsy in the initial assessment of patients with suspected HSV encephalitis. However it may have a role in patients with suspected HSV encephalitis who are PCR negative and deteriorate despite aciclovir, or to identify alternative causes, such as vasculitis
      • Salvarani C.
      • Brown Jr., R.D.
      • Calamia K.T.
      • Christianson T.J.
      • Weigand S.D.
      • Miller D.V.
      • et al.
      Primary central nervous system vasculitis: analysis of 101 patients.
      ; biopsy is especially helpful if there is a focal lesion on imaging
      • Pulhorn H.
      • Quigley D.G.
      • Bosma J.
      • Kirollos R.
      • du Plessis D.
      • Jenkinson M.
      Impact of brain biopsy on the management of patients with non-neoplastic undiagnosed neurological disorders.
      or in patients with immune compromise where the differential diagnosis is often wide. Tissue needs to be sent for pathogen detection (electron microscopy, culture, PCR and immunoflouresence) and for histopathology. Experienced neuropathologists are essential. In one series one fifth of patients with suspected HSV encephalitis had an alternative diagnosis made by biopsy, in half of whom it was a treatable condition.
      • Whitley R.J.
      • Cobbs C.G.
      • Alford Jr., C.A.
      • Soong S.J.
      • Hirsch M.S.
      • Connor J.D.
      • et al.
      Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group.

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

       Recommendation

      • MRI (including diffusion weighted imaging), should be performed as soon as possible on all patients with suspected encephalitis in whom the diagnosis is uncertain; ideally this should be within 24 hours of hospital admission, but certainly within 48 hours (B, II). Where the patient’s clinical condition precludes an MRI, urgent CT scanning may reveal an alternative diagnosis (A, II)
      • MRI sequences obtained need to be chosen appropriately for a paediatric population and images should be interpreted by an experienced paediatric neuroradiologist (B, II)
      • The role of MR spectroscopy is uncertain; SPECT and PET are not indicated in the assessment of suspected acute viral encephalitis (B, II)

       Evidence

      MRI is significantly more sensitive than CT in detecting the early cerebral changes of viral encephalitis. In HSV encephalitis a CT obtained early may be normal, or have only subtle abnormalities; in one small series only a quarter of patients with HSV encephalitis had an abnormality on initial CT scanning.
      • Behzad-Behbahani A.
      • Abdolvahab A.
      • Gholamali Y.P.
      • Roshanak B.
      • Mahmood R.
      Clinical signs as a guide for performing HSV-PCR in correct diagnosis of herpes simplex virus encephalitis.
      In contrast, MRI obtained within 48 h of hospital admission is abnormal in approximately 90% of patients.
      • Behzad-Behbahani A.
      • Abdolvahab A.
      • Gholamali Y.P.
      • Roshanak B.
      • Mahmood R.
      Clinical signs as a guide for performing HSV-PCR in correct diagnosis of herpes simplex virus encephalitis.
      • Tien R.D.
      • Felsberg G.J.
      • Osumi A.K.
      Herpesvirus infections of the CNS: MR findings.
      • Domingues R.B.
      • Fink M.C.
      • Tsanaclis A.M.C.
      • de Castro C.C.
      • Cerri G.G.
      • Mayo M.S.
      • et al.
      Diagnosis of herpes simplex encephalitis by MRI and PCR assay of CSF.
      • Höllinger P.
      • Matter L.
      • Sturzenegger M.
      Normal MRI findings in herpes simplex virus encephalitis.
      Early MRI changes occur in the cingulate gyrus and medial temporal lobe, and include gyral oedema on T-1 weighted images, and high signal intensity on T2-weighted and T2 fluid attenuated inversion recovery (FLAIR) images.
      • Marchbank N.D.
      • Howlett D.C.
      • Sallomi D.F.
      • Hughes D.V.
      Magnetic resonance imaging is preferred in diagnosing suspected cerebral infections.
      Later there may be haemorrhage. Diffusion-weighted MRI may be especially sensitive to early changes.
      • Sener R.N.
      Herpes simplex encephalitis: diffusion MR imaging findings.
      • McCabe K.
      • Tyler K.
      • Tanabe J.
      Diffusion-weighted MRI abnormalities as a clue to the diagnosis of herpes simplex encephalitis.
      • Kuker W.
      • Nagele T.
      • Schmidt F.
      • Heckl S.
      • Herrlinger U.
      Diffusion-weighted MRI in herpes simplex encephalitis: a report of three cases.
      Specific sequences, such as FLAIR and STIR (short-tau inversion recovery) sequences may be of particular value in young children due to normal brain maturation processes.
      • Saunders D.E.
      • Thompson C.
      • Gunny R.
      • Jones R.
      • Cox T.
      • Chong W.K.
      Magnetic resonance imaging protocols for paediatric neuroradiology.
      The MRI should be interpreted by an experienced neuroradiologist.
      The changes seen on MRI are reported to be specific (87.5%) for PCR-confirmed HSV encephalitis but can also identify alternative (often treatable) diagnoses in patients that are negative for HSV.
      • Domingues R.B.
      • Fink M.C.
      • Tsanaclis A.M.C.
      • de Castro C.C.
      • Cerri G.G.
      • Mayo M.S.
      • et al.
      Diagnosis of herpes simplex encephalitis by MRI and PCR assay of CSF.
      Thus it is important that an MRI is performed urgently. In small studies, the extent of MRI abnormality seen acutely in HSV encephalitis did not correlate with the clinical evolution of the disease
      • Domingues R.B.
      • Fink M.C.
      • Tsanaclis A.M.C.
      • de Castro C.C.
      • Cerri G.G.
      • Mayo M.S.
      • et al.
      Diagnosis of herpes simplex encephalitis by MRI and PCR assay of CSF.
      nor with depression afterwards,
      • Fazekas C.
      • Enzinger C.
      • Wallner M.
      • Kischka U.
      • Greimel E.
      • Kapeller P.
      • et al.
      Depressive symptoms following herpes simplex encephalitis – an underestimated phenomenon?.
      though a correlation between number of seizures in acute HSV encephalitis, and subsequent brain atrophy on MRI has been demonstrated.
      • Herrmann E.K.
      • Hahn K.
      • Krater C.
      • von Seggern I.
      • Zimmer C.
      • Scielke E.
      Status epilepticus as a risk factor for post-encephalitis parenchyma loss evaluated by ventricular brain ratio measurement on MR imaging.
      In VZV CNS disease in immuncocompetent children, the most common pathogenesis is a large vessel vasculitis, which presents with an ischaemic or haemorrhagic infarct often seen on MRI and angiography.
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • LaGuardia J.J.
      • Mahalingam R.
      • Cohrs R.J.
      Neurologic complications of the reactivation of varicella-zoster virus.
      • Redington J.J.
      • Tyler K.L.
      Viral infections of the nervous system, 2002: update on diagnosis and treatment.
      • Gilden D.
      Varicella zoster virus and central nervous system syndromes.
      In immunocompromised children, VZV may cause a multi-focal leukoencephalopathy which may be seen to follow a clear arterial distribution.
      • Baskin H.J.
      • Hedlund G.
      Neuroimaging of herpesvirus infections in children.
      Other pathogens may have typical abnormal findings. M. pneumoniae may show focal cortical lesions, deep white matter lesions and large areas of demyelination.
      • Bitnun A.
      • Ford-Jones E.
      • Petric M.
      • MacGregor D.
      • Heuter H.
      • Nelson S.
      • et al.
      Acute childhood encephalitis and Mycoplasma pneumoniae.
      Japanese B encephalitis typically involves the thalamus and basal ganglia with T2 hyperintensity. Enterovirus may result in generalised parenchymal destruction, or may predominately affect the brainstem, occasionally spreading posteriorly to involve the cerebellar denate nuclei or superiorly to involve the thalami and basal ganglia.
      • Barkovich J.
      Paediatric neuroimaging.
      In young children, white matter oedema is not easily distinguished from unmyelinated white matter, and without contrast may result in incorrect reporting.
      • Coren M.E.
      • Buchdahl R.M.
      • Cowan F.M.
      • Riches P.G.
      • Miles K.
      • Thompson E.J.
      Imaging and laboratory investigation in herpes simplex encephalitis.
      Although MRI is the investigation of choice, in young, acutely ill, comatose or confused children a general anaesthetic is usually required posing practical difficulties for many hospitals. In one series 70% of children required sedation or general anaesthesia.
      • Saunders D.E.
      • Thompson C.
      • Gunny R.
      • Jones R.
      • Cox T.
      • Chong W.K.
      Magnetic resonance imaging protocols for paediatric neuroradiology.
      Some would recommend that sedation not be used in this patient group and only anaesthetic support and formal anaesthesia used.
      • Thompson C.
      • Kneen R.
      • Riordan A.
      • Kelly D.
      • Pollard A.J.
      Encephalitis in children.
      In these circumstances, CT scanning may be the only urgent imaging available. However, the CT scan may be normal in children with CNS infections including severe bacterial meningitis and encephalitis so should not be relied upon to make or refute the diagnosis of these conditions.
      • Maschke M.
      • Kastrup O.
      • Forsting M.
      • Deiner H.C.
      Update on neuroimaging in infectious central nervous system disease.
      • Kastrup O.
      • Wanke I.
      • Maschke M.
      Neuroimaging of infections.
      A pragmatic approach is to perform a CT scan as the first cranial imaging investigation and then an MRI can be undertaken as soon as it can be arranged, often after transfer to the local tertiary centre.

       Other modalities

      MR spectroscopy identifies and quantifies concentrations of various brain metabolites, and so may help distinguish normal from diseased brain tissue, and characterise the nature of the damage, particularly distinguishing inflammatory from neoplastic processes; however there are no prospective studies assessing its diagnostic role. Single photon emission computed tomography (SPECT) may show focal hypoperfusion persisting after recovery from acute viral encephalitis.
      • Launes J.
      • Sirén J.
      • Valanne L.
      • Salonen O.
      • Nikkinen P.
      • Seppalainen A.M.
      • et al.
      Unilateral hyperfusion in brain-perfusion SPECT predicts poor prognosis in acute encephalitis.
      However, it has been used mainly as a research tool and appears to have little application in suspected acute encephalitis in practice. Fluorodeoxyglucose positron emission tomography (PET) shows abnormalities in acute viral encephalitis
      • Launes J.
      • Sirén J.
      • Valanne L.
      • Salonen O.
      • Nikkinen P.
      • Seppalainen A.M.
      • et al.
      Unilateral hyperfusion in brain-perfusion SPECT predicts poor prognosis in acute encephalitis.
      • Lee B.Y.
      • Newberg A.B.
      • Liebeskind D.S.
      • Kung J.
      • Alavia A.
      FDG-PET findings in patients with suspected encephalitis.
      with regions of FDG-PET hypermetabolism seen most frequently in the medial temporal lobes (sometimes reflecting seizure activity). However PET scanning is not practical or sufficiently informative to be used in children with suspected acute viral encephalitis.

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

       Recommendation

      • An EEG should not be performed routinely in all patients with suspected encephalitis; however, in patients with mildly altered behaviour, if it is uncertain whether there is a psychiatric or organic cause an EEG should be performed to establish whether there are encephalopathic changes (B, II)
      • EEG should also be performed if subtle motor, or subclinical seizures are suspected (B,II)
      • An EEG should be performed in children with suspected chronic viral encephalitis for example SSPE (B, II)

       Evidence

      The EEG is abnormal in most patients with encephalopathy, including more than 80% of those with acute viral encephalitis.
      • McGrath N.
      • Anderson N.E.
      • Croxson M.C.
      • Powell K.F.
      Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
      • Kolski H.
      • Ford-Jones E.
      • Richardson S.
      • Petric M.
      • Nelson S.
      • Jamieson F.
      • et al.
      Etiology of acute childhood encephalitis in the hospital for sick children.
      When patients have a more subtle presentation, it can be helpful in determining whether abnormal behaviour is due to psychiatric causes or is an early feature of encephalopathies. EEG is also useful in determining whether an individual has non-convulsive or subtle clinical seizures, which occur in both HSV encephalitis and other encephalopathies.
      • Treiman D.M.
      Electroclinical features of status epilepticus.
      • Misra U.K.
      • Kalita J.
      • Nair P.P.
      Status epilepticus in central nervous system infections: an experience from a developing country.
      In HSV encephalitis EEG abnormalities include non-specific diffuse high amplitude slow waves, sometimes with temporal lobe spike-and-wave activity and periodic lateralised epileptiform discharges (PLEDs).
      • García-Morales I.
      • García M.T.
      • Galan-Davila L.
      • Gomez-Escalonilla C.
      • Saiz-Diaz R.
      • Martinez-Sallo A.
      • et al.
      Periodic lateralized epileptiform discharges: etiology, clinical aspects, seizures, and evolution in 130 patients.
      Even though PLEDs occur in many cases of HSV encephalitis
      • Whitley R.J.
      • Cobbs C.G.
      • Alford Jr., C.A.
      • Soong S.J.
      • Hirsch M.S.
      • Connor J.D.
      • et al.
      Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group.
      and were at one stage considered pathognomonic, they are now recognised in other viral encephalitides
      • Solomon T.
      • Dung N.M.
      • Kneen R.
      • Thao L.T.T.
      • Gainsborough M.
      • Nisalak A.
      • et al.
      Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis.
      and non-infectious conditions, and it is accepted that there are no EEG changes diagnostic of HSV encephalitis.
      • Brick J.F.
      • Brick J.E.
      • Morgan J.J.
      • Gutierrez A.R.
      EEG and pathologic findings in patients undergoing brain biopsy for suspected encephalitis.
      For example when PLEDS are identified in patients with a sub-acute or chronic encephalopathy this would be suggestive of SSPE.
      • Gutierrez J.
      • Issacson R.S.
      • Koppel B.S.
      Subacute sclerosing panencephalitis: an update.
      • Praveen-Kumar S.
      • Sinha S.
      • Taly A.B.
      • Jayasree S.
      • Ravi V.
      • Vijayan J.
      • et al.
      Electroencephalographic and imaging profile in a subacute sclerosing panencephalitis (SSPE) cohort: a correlative study.

      Treatment of viral encephalitis

       For which patients should aciclovir treatment be started empirically?

       Recommendation

      • Children with suspected encephalitis should have intravenous aciclovir started if the initial CSF and/or imaging findings suggest viral encephalitis, and definitely within 6 hours of admission if these results are awaited (A, II).
      • If the first CSF microscopy or imaging is normal but the clinical suspicion of HSV or VZV encephalitis remains, aciclovir should still be started within 6 hours of admission whilst further diagnostic investigations (as outlined below) 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 with pre-existing renal impairment (A, II)
      • Patients with suspected encephalitis due to infection should be notified to the appropriate Consultant in Communicable Disease Control (In Scotland, only patients with a proven aetiology or those occurring as part of an unusual outbreak are notifiable) (A, III)
      • If meningitis is also suspected, the child should also be treated in accordance with the NICE meningitis guideline (A, II)

       Evidence

      Aciclovir is a nucleoside analogue with strong antiviral activity against HSV and related herpes viruses, including VZV. Two randomised trials have shown that aciclovir (10 mg/kg three times a day) improves the outcome in adults with HSV encephalitis from a mortality of about 70% to less than 20–30%.
      • Skoldenberg B.
      • Forsgren M.
      • Alestig K.
      • Burman L.
      • Dahlqvist E.
      • Forkman A.
      • et al.
      Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients.
      • Whitley R.J.
      • Alford C.A.
      • Hirsch M.S.
      • Schooley R.T.
      • Luby J.P.
      • Aoki F.Y.
      • et al.
      Vidarabine versus acyclovir therapy in herpes simplex encephalitis.
      Even with aciclovir treatment the outcome is often still poor, especially in patients with advanced age, a reduced coma score, or delays of more than 48 h between hospital admission and starting treatment.
      • McGrath N.
      • Anderson N.E.
      • Croxson M.C.
      • Powell K.F.
      Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      Because HSV encephalitis is the most commonly diagnosed viral encephalitis in industrialised countries, treatment with aciclovir is usually started once the initial CSF and/or imaging findings suggest viral encephalitis, without waiting for confirmation of HSV by PCR. However, unlike meningococcal septicaemia, where children can die within a few hours and thus immediate treatment with antibiotics is needed, in a patient with encephalopathy who has only mild confusion, investigation with a lumbar puncture before considering treatment is sensible; especially given the very wide differential diagnosis, and relative rarity of HSV encephalitis. Moreover, empirical use of antimicrobial and antiviral agents can prematurely halt the diagnostic pathway because clinicians feel falsely reassured, and this delays the identification of other aetiologies for which different treatments might be appropriate.
      Experience from paediatrics has shown that the practice of presumptive antiviral treatment for all patients with encephalopathy, with no regard to the likely diagnosis, is not beneficial.
      • Kneen R.
      • Jakka S.
      • Mithyantha R.
      • Riordan A.
      • Solomon T.
      The management of infants and children treated with aciclovir for suspected viral encephalitis.
      However if there is a strong clinical suspicion of encephalitis, and there will be delays before a lumbar puncture can be performed, or if the child is very sick or deteriorating, then aciclovir should be started sooner, as should treatment for possible bacterial meningitis.
      • National Instutute for Health and Clinical Excellence
      Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102).
      Even if aciclovir has already been started in a patient with HSV encephalitis the CSF PCR is likely to remain positive for up to 7–10 days,
      • Tunkel A.R.
      • Glaser C.A.
      • Bloch K.C.
      • Sejvar J.J.
      • Marra C.M.
      • Roos K.L.
      • et al.
      The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.
      meaning that a later lumbar puncture can still confirm the diagnosis.
      Although aciclovir is relatively safe there are important side effects, particularly renal impairment secondary to crystalluria and obstructive nephropathy.
      • Sawyer M.H.
      • Webb D.E.
      • Balow J.E.
      • Straus S.E.
      Acyclovir-induced renal failure. Clinical course and histology.
      This reversible nephropathy usually manifests after 4 days of intravenous therapy and can affect up to 20% of patients.
      • Bianchetti M.G.
      • Roduit C.
      • Oetliker O.H.
      Acyclovir-induced renal failure: course and risk factors.
      • Pacheco L.R.
      • Tavares H.M.
      • Moyses Neto M.
      • Dantas M.
      • Rocha L.S.
      • Ribeiro K.M.
      • et al.
      Acute renal failure related to intravenous acyclovir.
      The risk of nephropathy can be reduced by maintaining adequate hydration and monitoring renal function. In addition, the dose of aciclovir should be reduced in patients with pre-existing renal impairment, because it is excreted via the kidneys. Other rare adverse events include hepatitis, bone marrow failure and encephalopathy.

       How long should aciclovir be continued in proven HSV encephalitis, and is there a role for oral treatment?

       Recommendation

      • In children with proven HSV encephalitis, intravenous aciclovir treatment should be continued for 14-21 days (A, II), and a repeat LP considered at this time to confirm the CSF is negative for HSV by PCR (B, II); particularly if there are concerns that the treatment is ineffective (severe disease, immune-compromise, previous relapses).
      • If the CSF is still positive for HSV by PCR, aciclovir should continue, with weekly CSF PCR until it is negative (B, II)
      • In children aged 3 months-12 years a minimum of 21 days of aciclovir should be given before repeating the LP (B, III)

       Evidence

      The original randomised trials of aciclovir for HSV encephalitis were for 10 days. However, reports of clinical relapse after 10 days of treatment were published subsequently.
      • VanLandingham K.E.
      • Marsteller H.B.
      • Ross G.W.
      • Hayden F.G.
      Relapse of herpes simplex encephalitis after conventional acyclovir therapy.
      • Dennett C.
      • Klapper P.E.
      • Cleator G.M.
      Polymerase chain reaction in the investigation of “relapse” following herpes simplex encephalitis.
      In children, relapse rates may be as high as 26–29%, particularly if the duration of treatment is <14 days.
      • Ito Y.
      • Kimura H.
      • Yabuta Y.
      • Ando Y.
      • Murakami T.
      • Shiomi M.
      • et al.
      Exacerbation of herpes simplex encephalitis after successful treatment with aciclovir.
      Although an on-going immune-mediated and inflammatory reaction to the infection is now thought by many to be the major pathogenic process,
      • VanLandingham K.E.
      • Marsteller H.B.
      • Ross G.W.
      • Hayden F.G.
      Relapse of herpes simplex encephalitis after conventional acyclovir therapy.
      • Dennett C.
      • Klapper P.E.
      • Cleator G.M.
      Polymerase chain reaction in the investigation of “relapse” following herpes simplex encephalitis.
      • Ito Y.
      • Kimura H.
      • Yabuta Y.
      • Ando Y.
      • Murakami T.
      • Shiomi M.
      • et al.
      Exacerbation of herpes simplex encephalitis after successful treatment with aciclovir.
      • Skoldenberg B.
      • Aurelius E.
      • Hjalmarsson A.
      • Sabri F.
      • Forsgren M.
      • Andersson B.
      • et al.
      Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults.
      there is evidence for continuing viral replication in some cases.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      • VanLandingham K.E.
      • Marsteller H.B.
      • Ross G.W.
      • Hayden F.G.
      Relapse of herpes simplex encephalitis after conventional acyclovir therapy.
      • Ito Y.
      • Kimura H.
      • Yabuta Y.
      • Ando Y.
      • Murakami T.
      • Shiomi M.
      • et al.
      Exacerbation of herpes simplex encephalitis after successful treatment with aciclovir.
      • Yamada S.
      • Kameyama T.
      • Nagaya S.
      • Hashizume Y.
      • Yoshida M.
      Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation.
      As a consequence most clinicians now use at least 14–21 days intravenous treatment in confirmed cases, though later relapses can occur.
      • Raschilas F.
      • Wolff M.
      • Delatour F.
      • Chaffaut C.
      • De Broucker T.
      • Chevret S.
      • et al.
      Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study.
      The risk of relapse may be highest in children aged 3 months-12 years, up to 29%, and some have advocated that this group should receive a minimum of 21 days of intravenous aciclovir.
      • Thompson C.
      • Kneen R.
      • Riordan A.
      • Kelly D.
      • Pollard A.J.
      Encephalitis in children.
      Some advocate repeating a CSF examination at 14–21 days, and continuing treatment until the CSF is negative for virus by PCR
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      ; this is supported by a European Consensus Statement.
      • Cinque P.
      • Cleator G.M.
      • Weber T.
      • Monteyne P.
      • Sindic C.J.
      • van Loon A.M.
      The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis.
      Oral aciclovir does not achieve adequate levels in the CSF and is not suitable for treating HSV encephalitis; however its valine ester valaciclovir has good oral bioavailability, and is converted to aciclovir after absorption.
      • Lycke J.
      • Malmestrom C.
      • Stahle L.
      Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir.
      Valaciclovir has been occasionally used in paediatric practice to treat HSV encephalitis after at least 10–14 days of intravenous aciclovir, when maintaining intravenous access proved difficult.
      • Chan P.K.
      • Chow P.C.
      • Peiris J.S.
      • Mak A.W.
      • Huen K.F.
      Use of oral valaciclovir in a 12-year-old boy with herpes simplex encephalitis.
      Although CNS penetration is difficult to monitor some have reported CSF trough levels that are >50% of plasma trough levels.
      • Lim M.
      • Menson E.
      • Tong C.Y.
      • Lin J.P.
      Use of therapeutic drug monitoring in the long-term valaciclovir therapy of relapsing herpes simplex virus encephalitis in children.
      However valaciclovir is not licenced for use in children and is only available in tablet form. The American National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group is assessing the role of high dose valaciclovir (2 g three times daily) for three months.

      National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Long term treatment of herpes simplex encephalitis (HSE) with Valtrex. http://clinicaltrials.gov/ct2/show/NCT00031486, [accessed 01.10.2011].

       When can presumptive treatment with aciclovir be safely stopped, in patients that are HSV PCR negative?

       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 24-48 hours apart, and MRI imaging (performed >72 hours after symptom onset), is not characteristic for HSV encephalitis, or
        • -
          HSV PCR in the CSF is negative once >72 hours after neurological symptom onset, with normal level of consciousness, normal MRI (performed >72 hours after symptom onset), and a CSF white cell count of less than 5 × 106/L (B, III)

       Evidence

      For most patients with suspected HSV encephalitis, presumptive aciclovir treatment is started on the basis of a clinical picture and initial CSF findings consistent with viral encephalitis. This initial CSF may subsequently reveal an alternative diagnosis such as bacterial infection, in which case aciclovir can be stopped. However, an initial CSF PCR can occasionally be negative in HSV encephalitis, especially if it is taken early in the illness (<72 h after symptom onset), or after some days on aciclovir treatment when the virus has cleared. Thus if viral encephalitis is still strongly suspected, aciclovir treatment should not be stopped on the basis of a single negative CSF PCR only. A European consensus statement recommended the combined approach to diagnosis of testing CSF by PCR and antibody detection, such that a negative HSV-PCR result early in the disease process coupled with a negative HSV-specific CSF antibody study sampled 10–14 days after symptom onset effectively ruled out the disease.
      • Cinque P.
      • Cleator G.M.
      • Weber T.
      • Monteyne P.
      • Sindic C.J.
      • van Loon A.M.
      The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis.
      Given that CSF antibody studies can only rule out diagnosis late in the disease process and that there can be considerable delay in obtaining results from these assays, an alternative strategy has been proposed for halting aciclovir treatment.
      • Tyler K.L.
      Update on herpes simplex encephalitis.
      This proposes that if a negative HSV PCR result is obtained from CSF sampled >72 h into the disease process and the patient has a low probability of HSV encephalitis (e.g. normal neuroimaging, CSF <5 × 106/L WBCs/mm3, and normal level of consciousness) then aciclovir treatment might be safely halted. However in reality, a more common situation is the patient with a negative initial CSF PCR who continues to have altered consciousness, or has a CSF pleocytosis, or imaging abnormalities. In this situation many clinicians would repeat the CSF examination at 24–48 h to determine whether it is still negative for HSV by PCR; HSV encephalitis is very unlikely in such patients if there are two negative CSF PCRs for HSV.

       What is the role of corticosteroids in HSV encephalitis?

       Recommendation

      • Whilst awaiting the results of a randomised placebo-controlled trial corticosteroids should not be used routinely in patients with HSV encephalitis (B, III)
      • Corticosteroids may have a role in patients with HSV encephalitis under specialist supervision, but data establishing this are needed and the results of a prospective RCT are awaited (C, III)

       Evidence

      The role of steroids in the treatment of HSV encephalitis is not established.
      • Openshaw H.
      • Cantin E.
      Corticosteroids in herpes simplex virus encephalitis.
      Even before antiviral drugs became available, many clinicians considered that corticosteroids were beneficial in HSV encephalitis, though others disagreed.
      • Upton A.R.
      • Foster J.B.
      • Barwick D.D.
      Dexamethasone treatment in herpes-simplex encephalitis.
      • Habel A.H.
      • Brown J.K.
      Dexamethasone in herpes-simplex encephalitis.
      Since the advent of aciclovir, corticosteroids have often be used, especially in patients with marked cerebral oedema, brain shift or raised intracranial pressure, but their role remains controversial because as well as reducing swelling, corticosteroids have strong immunomodulatory effects, which in theory could facilitate viral replication. However a retrospective analysis of 45 patients with HSV encephalitis showed that older age, lower Glasgow coma score at admission and lack of administration of corticosteroids were significant independent predictors of a poor outcome.
      • Kamei S.
      • Sekizawa T.
      • Shiota H.
      • Mizutani T.
      • Itoyama Y.
      • Takasu T.
      • et al.
      Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis.
      An accompanying editorial made a strong case for a randomised placebo-controlled trial,
      • Openshaw H.
      • Cantin E.
      Corticosteroids in herpes simplex virus encephalitis.
      which is now being carried out across several European countries.
      • Martinez-Torres F.
      • Menon S.
      • Pritsch M.
      • Victor N.
      • Jenetzky E.
      • Jensen K.
      • et al.
      GACHE Investigators. Protocol for German trial of Acyclovir and Corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial.

       What should be the specific management of VZV encephalitis?

       Recommendation

      • No specific treatment is needed for VZV cerebellitis (B, II).
      • For VZV encephalitis, whether a primary infection or a reactivation, intravenous aciclovir 500mg/m2 (if aged 3 months-12 years) or 10-15mg/kg (if aged >12 years) three times daily is recommended (B, II);
      • If there is a vascopathy (i.e. stroke), there is a case for using corticosteroids (B, II)

       Evidence

      In immunocompetent children, VZV can cause CNS disease through three mechanisms; a post-VZV cerebellitis, an acute VZV encephalitis and a VZV vasculopathy.
      In cerebellitis caused by VZV, antiviral treatments are not normally used because the disease is usually self limiting, resolving in one to three weeks, and the primary pathogenic process is thought to be immune-mediated demyelination, rather than viral cytopathology.
      • Hausler M.
      • Schaade L.
      • Schaade L.
      • Kemeny S.
      • Scheizer K.
      • Schoenmackers C.
      • et al.
      Encephalitis related to primary varicella-zoster virus infection in immunocompetent children.
      Although there are no good studies in primary VZV encephalitis, this condition is usually treated with antiviral drugs and, possibly corticosteroids.
      • Hausler M.
      • Schaade L.
      • Schaade L.
      • Kemeny S.
      • Scheizer K.
      • Schoenmackers C.
      • et al.
      Encephalitis related to primary varicella-zoster virus infection in immunocompetent children.
      Aciclovir 10 mg/kg three times daily is often recommended,
      • Dworkin R.H.
      • Johnson R.W.
      • Breuer J.
      • Gnann J.W.
      • Levin M.J.
      • Backonja M.
      • et al.
      Recommendations for the management of herpes zoster.
      but because VZV is less sensitive to aciclovir than HSV, 15 mg/kg three times daily has also been suggested if renal function is normal,
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • LaGuardia J.J.
      • Mahalingam R.
      • Cohrs R.J.
      Neurologic complications of the reactivation of varicella-zoster virus.
      for up to 14 days,
      • Hato N.
      • Matsumoto S.
      • Kisaki H.
      • Takahashi H.
      • Wakisaka H.
      • Honda N.
      • et al.
      Efficacy of early treatment of Bell's palsy with oral acyclovir and prednisolone.
      especially if it can be started within a few days of symptom onset.
      • Dworkin R.H.
      • Johnson R.W.
      • Breuer J.
      • Gnann J.W.
      • Levin M.J.
      • Backonja M.
      • et al.
      Recommendations for the management of herpes zoster.
      A VZV vasculopathy presents with an acute stroke-like episode following VZV infection and is routinely treated with both aciclovir, as outlined, and corticosteroids, although there is limited evidence to support this.
      • Lanthier S.
      • Armstrong D.
      • Domi T.
      • deVeber G.
      Post-varicella arteriopathy of childhood: natural history of vascular stenosis.
      The course of steroids (for example 60–80 mg of prednisolone daily for 3–5 days) is often given, because of the inflammatory nature of the lesion.
      • Gilden D.H.
      • Kleinschmidt-DeMasters B.K.
      • LaGuardia J.J.
      • Mahalingam R.
      • Cohrs R.J.
      Neurologic complications of the reactivation of varicella-zoster virus.
      In immunocompromised patients with VZV encephalitis a prolonged course of intravenous aciclovir may be needed.

       What should be the specific management of enterovirus meningoencephalitis?

       Recommendation

      • No specific treatment is recommended for enterovirus encephalitis; in patients with severe disease pleconaril (if available) or intravenous immunoglobulin may be worth considering (C, III)

       Evidence

      Pleconaril is a drug that binds within a hydrophobic pocket at the base of the receptor-binding canyon in the viral capsid protein of enteroviruses, thus inhibiting the virus from binding to its cellular receptor. The drug has broad activity against most enteroviruses at low concentrations (<0.1 μg per mL), and has good oral bioavailability. In phase III clinical trials pleconaril reduced symptoms of aseptic meningitis, particularly headache, by approximately two days, compared with placebo controls, but it is not used widely for this condition.
      • Desmond R.A.
      • Accortt N.A.
      • Talley L.
      • Villano S.A.
      • Soong S.J.
      • Whitley R.J.
      Enteroviral meningitis: natural history and outcome of pleconaril therapy.
      The drug has also been used in patients with chronic enterovirus infection due to agammaglobulinaemia, enterovirus myocarditis, poliovirus vaccine associated paralysis and neonatal infection. However there have been no trials assessing its role in enterovirus encephalitis, and it is often not available.
      Intravenous immunoglobulin is used in patients with chronic enterovirus meningitis,
      • McKinney Jr., R.E.
      • Katz S.L.
      • Wilfert C.M.
      Chronic enteroviral meningoencephalitis in agammaglobulinemic patients.
      and may also be useful in patients with severe enterovirus 71 infection, though no randomised trials have been conducted.
      • Nolan M.A.
      • Craig M.E.
      • Lahra M.M.
      • Rawlinson W.D.
      • Prager P.C.
      • Williams G.D.
      • et al.
      Survival after pulmonary edema due to enterovirus 71 encephalitis.

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

       Recommendation

      • Patients with falling level of consciousness require urgent assessment by paediatric Intensive Care Unit staff for airway protection and ventilatory support, management of raised intracranial pressure, optimisation of cerebral perfusion pressure and correction of electrolyte imbalances. (A, III).
      • Patients with suspected acute encephalitis should have access to a paediatric neurological specialist opinion and should be seen as soon as possible and definitely within 24 hours of referral (B, III)
      • There should be access to neuroimaging (both MRI and CT), under general anaesthetic if needed, and neurophysiology (EEG), which may mean transfer to a specialist paediatric neuroscience unit (B, III)
      • As CSF diagnostic assays are critical to confirming diagnosis, the results of CSF PCR assays should be available within 24-48 hours of a lumbar puncture being performed. (B, III)
      • When a diagnosis is not rapidly established or a patient fails to improve with therapy, transfer to a paediatric neurological unit is recommended. The transfer should occur as soon as possible and definitely within 24 hours of being requested (B, III)

       Evidence

      Currently in the UK there is sparse evidence and little guidance for the inpatient care of patients with suspected viral encephalitis. A charity-commissioned nationwide survey of encephalitis patients' experiences of hospital care revealed that only 39% were cared for on a neurological ward.
      • Easton A.
      • Atkin K.
      • Hare P.
      ‘A light in a very dark place’: the role of a voluntary organisation providing support for those affected by encephalitis.
      Many patients with suspected acute encephalitis are critically ill. Their behaviour is often disturbed and they are at risk of seizures, malignant raised intracranial pressure, aspiration, systemic complications of infection, electrolyte disturbances, and death. Because it is a relatively rare condition, medical teams caring for patients with encephalitis often have limited experience of the condition. Patients require close monitoring in a quiet environment but do not routinely require isolation. Unlike stroke in adults, where clear evidence exists to support patient management in specialist units, no such studies have been undertaken for encephalitis.
      • Easton A.
      • Dowell E.
      Encephalitis, a service orphan: the need for more research and access to neuropsychology.
      Appropriate environments for managing patients with encephalitis include neurological wards, high dependency units, or intensive care units.
      The acute care of a child with suspected encephalitis is multidisciplinary, potentially requiring the input of not only paediatric neurologists, but infectious disease paediatricians, virologists, microbiologists, neurophysiologists, neuroradiologists, paediatric neurosurgeons, neurologically and/or psychiatrically-trained nursing staff, and paediatric intensive care staff. Many of these personnel are only available through specialist paediatric neuroscience centres at tertiary hospitals. The role of members of the multidisciplinary team varies during the acute illness and rehabilitation.

       What rehabilitation and support services should be available for children affected by encephalitis and their families?

       Recommendation

      • Parents and older children (where their cognitive ability permits) should be made aware of the support provided by voluntary sector partners such as the Encephalitis Society (www.encephalitis.info) (B, III)
      • At the time of discharge, children should have either a definite or suspected diagnosis. Arrangements for outpatient follow-up and plans for on-going therapy and/or rehabilitation should be formulated at a discharge meeting (A, III)
      • All children should have access to assessment for rehabilitation (A, III)

       Evidence

      The sequelae of encephalitis may not be immediately apparent when a patient is discharged from hospital following the acute illness. However, anxiety, depression and behavioural problems such as intrusive obsessive behaviour, challenging behaviour or hyperactivity/concentration difficulties often become evident subsequently, and may be more likely after encephalitis than other causes of acute brain injury.
      • Moorthi S.
      • Schneider W.N.
      • Dombovy M.L.
      Rehabilitation outcomes in encephalitis – a retrospective study 1990–1997.
      A charity-commissioned study of encephalitis patients found that 33% were discharged without out-patient follow-up although 96% reported on-going complications from their illness.
      • Easton A.
      • Atkin K.
      • Hare P.
      ‘A light in a very dark place’: the role of a voluntary organisation providing support for those affected by encephalitis.
      A broad and comprehensive approach to both assessment and rehabilitation is necessary, with neuropsychology and child and adolescent mental health teams as central components,
      • Macniven J.A.
      • Poz R.
      • Bainbridge K.
      • Gracey F.
      • Wilson B.A.
      Emotional adjustment following cognitive recovery from ‘persistent vegetative state’: psychological and personal perspectives.
      and access to speech and language therapists, neuro-physiotherapists, and occupational therapists. Access to specialist brain injury rehabilitation services is key to recovery in many cases.
      • Easton A.
      The Encephalitis Society. Encephalitis patient experiences of neurological services in the UK.
      Children affected by encephalitis, their families and other people involved in supporting them, such as teaching staff, require information on the condition and its consequences and directions on how access this information.
      • Solomon T.
      • Hart I.
      • Beeching N.J.
      Viral Encephalitis: a clinician's guide.
      In one survey one third of patients were discharged from hospital without them or their families being informed of the diagnosis.
      • Easton A.
      • Atkin K.
      • Hare P.
      ‘A light in a very dark place’: the role of a voluntary organisation providing support for those affected by encephalitis.
      Information and support reduces isolation, helps family adjustment and can provide useful signposting to other services as appropriate.
      • Easton A.
      The Encephalitis Society. Encephalitis patient experiences of neurological services in the UK.