Elsevier

Journal of Infection

Volume 64, Issue 4, April 2012, Pages 347-373
Journal of Infection

Management of suspected viral encephalitis in adults – Association of British Neurologists and British Infection Association National Guidelines

https://doi.org/10.1016/j.jinf.2011.11.014Get rights and content

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.

Introduction

Although encephalitis is a relatively rare, its importance lies in that fact that for many forms treatment is effective if started promptly; in contrast, delays in treatment can be devastating. Encephalitis means inflammation of the brain parenchyma, and strictly speaking this is a pathological diagnosis. However, because of the obvious practical limitations of this, surrogate clinical markers of inflammation are used (Table 1. Definitions).

The causes of encephalitis can be defined as those due to direct infection of the central nervous system (CNS), para-, or post-infectious causes, and non-infectious causes. Infectious causes include numerous viruses, bacteria (especially intracellular bacteria such as Mycoplasma pneumoniae), parasites and fungi (Table 2. Causes of viral encephalitis; Table 3. Non-viral causes of encephalitis and encephalopathy). Acute disseminated encephalomyelitis (ADEM) after measles is an example of a post-infectious encephalitis. Non-infectious causes include antibody-associated encephalitis, which may or may not be paraneoplastic. Most viral encephalitis is acute, but sub-acute and chronic presentations are characteristic of particular pathogens, especially in the immunocompromised (Table 4. Sub-acute and chronic encephalitis).

The global reported incidence of encephalitis varies according to the location, population studied, and differences in case definitions and research methods; however, the reported incidence in western settings ranges from 0.7 to 13.8 per 100,000 for all ages, being approximately 0.7–12.6 per 100,000 for adults and 10.5–13.8 per 100,000 children.1, 2, 3

Herpes simplex virus (HSV) encephalitis is the most commonly diagnosed viral encephalitis in industrialised nations, with an annual incidence of 1 in 250,000 to 500,000.4 The age specific incidence is bimodal, with peaks in the young and the elderly. Most HSV encephalitis is due to HSV-1, but about 10% is caused by HSV-2. The latter typically occurs in immunocompromised individuals and neonates, in whom it can 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 causes, encephalitis associated with antibodies to the voltage-gated potassium channel complex, or N-methyl-D-aspartate antibody (NMDA) receptors are increasingly recognised.5

In the 1980s the outcome of patients with HSV encephalitis was shown to be dramatically improved with aciclovir treatment.6, 7 Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis.8, 9 Several comprehensive reviews of the investigation and management of encephalitis have been published.10, 11, 12 However, their impact on day-to day clinical practice appears to be limited.2, 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 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 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, in an acute care setting such as acute medical unit or emergency department. 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.16, 17 At the end of the guidelines the special circumstances of returned travellers, immunocompromised patients and antibody-associated encephalitis 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 encephalitis patients 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 to 2008, to identify 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)’; ‘Immunocompromise’; ‘Arbovirus’). This yielded a total of 6948 citations, including many case series, which were grouped together in subject areas such as clinical presentation, diagnosis, imaging, treatment, outcome and immunocompromise. 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 Association of British Neurologists, 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.18 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).19

This document has been again internally peer-reviewed twice by the Guidelines Development Group and then by the wider Guidelines Stakeholders Group, which included representatives from the Royal College of Physicians and the British HIV Association. The document was then updated to include further comments from all contributing authors, incorporating references published in 2009–11. 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 patients over 16 years. National guidelines for the management of suspected viral encephalitis in children are also available as a separate document (Kneen, Michael, et al., 2012).

Section snippets

Recommendations

  • The constellation of a current or recent febrile illness with altered behaviour, cognition, personality or consciousness, or new seizures, or new focal neurological signs, should raise the possibility of encephalitis, or another CNS infection; and should trigger appropriate investigations (A, II)

  • Metabolic, toxic, autoimmune and non-CNS sources of sepsis as causes for encephalopathy should be considered early in patients presenting with encephalopathy (B, III), especially if there are features

Recommendations

  • Intravenous aciclovir (10 mg/kg three times daily) should be started if the initial CSF and/or imaging findings suggest viral encephalitis, or within 6 h of admission if these results will not be available, or if the patient is very unwell or deteriorating (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 h of admission whilst further diagnostic investigations (as outlined) are

Recommendations

  • 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

  • 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)

  • The advice of

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 authors, the following are members of the National Encephalitis Development Group: Solomon Almond, Enitan Carrol, Mehrengise Cooper, Cheryl Hemmingway, Paul Klapper, Ming Lim, Jean-Pierre Lin, Hermione Lyall, Kevin Mackway-Jones, Nick Makwana, Anthony Marson, Bimal Mehta, Esse Menson, Isam Osman, Andrew Riordan, Delane Shingadia, Aman Sohal, David Stoeter, Ed Wilkins

This article presents independent work funded by the National Institute for Health Research (NIHR) under its

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