Management of suspected viral encephalitis in children – Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group National Guidelines
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).
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.1 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).
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.2 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 500,000.3 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.1, 4
In the 1980s the outcome of HSV encephalitis in adults was shown to be dramatically improved by aciclovir treatment.5, 6 Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis.7, 8 Several comprehensive reviews of the investigation and management of encephalitis have been published,9, 10, 11 but their impact on day-to-day clinical practice appears to be limited.12, 13, 14 The emergency management of meningitis in children and adults was revolutionised by the introduction of a simple algorithm as part of management guidelines.15, 16, 17 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.18 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.
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.19 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).20
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.
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).
Section snippets
Recommendation
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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)
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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
Recommendation
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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).
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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)
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The dose of
Recommendation
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Patients returning from malaria endemic areas should have rapid blood malaria antigen tests and ideally three thick and thin blood films examined for malaria parasites (A, II). Thrombocytopenia, or malaria pigment in neutrophils and monocytes may be a clue to malaria, even if the films are negative.
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If cerebral malaria seems likely, and there will be a delay in obtaining the malaria film result, anti-malarial treatment should be considered and specialist advice obtained (A, III)
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The advice of the
Guideline implementation and audit
These clinical guidelines have been written to aid early recognition and appropriate investigation and management of patients with suspected encephalitis. There are many barriers to the implementation of such guidelines. The first step needed to convince clinicians to change behaviour is often the performance of a simple operational audit, to identify levels of good and poor practice. This can encourage use of standardised clinical approaches to management, the success of which can be
Acknowledgements
In addition to the named authors, the following are currently members of the National Encephalitis Guidelines Development Group: Phil Smith, Nick Davies, Frances Sanderson, Ian Hart, Nick Beeching, Mark Holland, Camilla Buckley, Solomon Almond, Peter Burnham, Mehrengise Cooper, Jean-Pierre Lin, Hermione Lyall, Kevin Mackway-Jones, Nick Makwana, Anthony Marson, Isam Osman, Andrew Riordan, Delane Shingadia, Aman Sohal, David Stoeter, Edmund Wilkins.
References (209)
- et al.
Herpes simplex encephalitis: children and adolescents
Semin In Ped Infect Dis
(2005) - et al.
Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study
Lancet Infect Dis
(2010) - et al.
Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients
Lancet
(1984) - et al.
European guidelines for diagnosis and management of patients with suspected herpes simplex encephalitis
Clin Microbiol Infect
(1998) British Infection Society. Early management of suspected bacterial meningitis and meningococcal septicaemia in immunocompetent adults–second edition
J Infect
(2005)- et al.
The correlation between neurological evaluations and neurological outcome in acute encephalitis: a hospital-based study
Eur J Paediatr Neurol
(2007) - et al.
Mild form of acute herpes simplex encephalitis in childhood
Brain Dev
(1995) - et al.
The spectrum of herpes simplex encephalitis in children
Eur J Pead Neurol
(2008) - et al.
Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy
Brain Dev
(2009) - et al.
Operculum syndrome: unusual feature of herpes simplex encephalitis
Pediatr Neurol
(1995)
Suspected herpes encephalitis and opercular syndrome in childhood
Pediatr Neurol
Pre-eruptive varicella cerebellitis confirmed by PCR
Paed Neurol
Acute cerebellitis presenting as tonsillar herniation and hydrocephalus
Pediatr Neurol
Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore RANBP2
Am J Hum Genet
Primary human herpesvirus 6 infection in the central nervous system can cause severe disease
Pediatr Neurol
Clinical features, diagnosis and management of enterovirus 71
Lancet Neurol
Role of computed tomography in the early management of bacterial meningitis
J Pediatr
Complications of lumbar puncture
Neurol Clin
Expanding spectrum of encephalitis with NMDA receptor antibodies in young children
J Child Neurol
The incidence of acute encephalitis syndrome in Western industrialised and tropical countries
Virol J
Vidarabine versus acyclovir therapy in herpes simplex encephalitis
N Eng J Med
Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome
J Neurol Neurosurg Psychiatry
Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study
Clin Infect Dis
Viral encephalitis: a review of diagnostic methods and guidelines for management
Eur J Neurol
The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America
Clin Infect Dis
Management of suspected herpes simplex virus encephalitis in adults in a UK teaching hospital
Clin Med
The epidemiology and management of adult suspected central nervous system infections – a retrospective cohort study in the NHS northwest region
Q J Med
The management of infants and children treated with aciclovir for suspected viral encephalitis
Arch Dis Child
Emergency management of meningococcal disease
Arch Dis Child
Management of bacterial meningitis and meningococcal septicaemia in children and young people, younger than 16 years in primary and secondary care (CG102)
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
MMWR Recomm Rep
Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project
Qual Saf Health Care
Grading quality of evidence and strength of recommendations
Br Med J
The role of lumbar puncture in children with suspected central nervous system infection
BMC Pediatrics
Infection-associated encephalopathies: their investigation, diagnosis, and treatment
J Neurol
Diagnosis and treatment of viral encephalitis
Postgrad Med J
In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project
Clin Infect Dis
Herpesvirus DNA detection in cerebral spinal fluid: differences in clinical presentation between alpha-, beta-, and gamma-herpesviruses
Scand J Infect Dis
Viral encephalitis in England, 1989–1998: what did we miss?
Emerg Infect Dis
Etiology of acute childhood encephalitis in the hospital for sick children
Clin Infect Dis
Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF
Neurology
Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests
Q J Med
Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group
JAMA
Neuroimaging of herpesvirus infections in children
Pediatr Radiol
Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis
Brain
Prevalence of nonconvulsive status epilepticus in comatose patients
Neurology
Non-convulsive status epilepticus: a profile of patients diagnosed within a tertiary referral centre
J Neurol Neurosurg Psychiatry
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
J Neurol Neurosurg Psychiatry
The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities
JAMA
Diagnosis and management of the neurological complications of falciparum malaria
Nat Rev Neurol
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