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Review

Encephalitis in children
Clara Thompson,1 Rachel Kneen,2 Andrew Riordan,3 Dominic Kelly,1 Andrew J Pollard1
of Paediatrics, University of Oxford, Childrens Hospital, Oxford, UK 2Department of Neurology, Littlewoods Neuroscience Centre, Alder Hey Childrens NHS Foundation Trust, Liverpool, UK 3Paediatric Infectious Diseases and Immunology, Alder Hey Childrens NHS Foundation Trust, Liverpool, UK Correspondence to Dr Clara Thompson, C/o Professor AJ Pollard, Department of Paediatrics, University of Oxford, Level 2 Childrens Hospital, Oxford OX3 9DU, UK; clara.thompson@doctors. org.uk Accepted 11 May 2011 Published Online First 28 June 2011
1Department

ABSTRACT Encephalitis is an uncommon but potentially devastating neurological syndrome with different aetiologies including direct central nervous system infection with different agents (most commonly viral) and those mediated by the immune system. Whilst there have been several recent publications and guidelines on the management of bacterial central nervous system infections in adults and children, viral infections have been relatively neglected. Guidelines have been published for adults with encephalitis (www.liv.ac.uk/ braininfections) but none exist for children. For these reasons, we have reviewed the literature on encephalitis and have formulated a suggested management strategy for children with suspected, clinically diagnosed and proven encephalitis. We have excluded neonates, as encephalitis in this age group has different clinical features and is beyond the scope of this review. INTRODUCTION
Encephalitis is an uncommon but potentially devastating neurological syndrome with different aetiologies. In general, affected children have been previously healthy and have no other neurological problems, but there are specic considerations that must be given to those who are likely to be immunosuppressed or have travelled overseas. The management of patients with encephalitis has changed dramatically in recent years for several reasons including improved diagnostic and brain imaging techniques, better antiviral and immunomodulatory treatments and more advanced neurointensive care and rehabilitation. A typical district general hospital in the UK can expect to see approximately 5 children with encephalitis per year1. It is important to recognise encephalitis because specic treatments given early can improve the outcome in certain cases2 3. Despite being uncommon, the symptoms and signs with which children with encephalitis present are often non-specic. For this reason, many children are initiated on treatment for encephalitis even if they do not really have a signicant likelihood of having the syndrome. Conversely, a recent study has shown that the management of children with encephalitis is haphazard and could be improved4. Paediatricians should therefore have a safe and robust management plan for children who present with suspected encephalitis.

microorganisms) or those caused by other in ammatory pathologies (see boxes 2 and 3). In many cases, a cause is not identied despite extensive investigations. Recently there has been increased interest in immune mediated encephalitis. This group includes acute disseminated encephalomyelitis (ADEM), which most often follows infections or vaccinations (box 2), and the more recently described group of encephalitides associated with autoantibodies. 5 6 Strictly speaking, encephalitis is a pathological diagnosis that should only be made if there is tissue con rmation (autopsy or brain biopsy). This is clearly not very practical. Therefore, most patients are diagnosed with encephalitis if they have the appropriate clinical presentation and surrogate markers of brain in ammation, such as in ammatory cells in the cerebrospinal uid (CSF) or changes on brain imaging suggestive of inammation. Encephalitis is not the same as encephalopathy, which is the clinical syndrome of reduced consciousness associated with some infectious diseases, metabolic disorders and drugs. Metabolic and toxic causes of encephalopathy can usually be distinguished from encephalitis by the lack of an acute febrile illness, more gradual onset, lack of a CSF pleocytosis and absence of focal changes on MRI.7 The management of children with a reduced level of consciousness from any cause has been the subject of a guideline endorsed by the Royal College of Paediatrics and Child Health (RCPCH).8

PATHOLOGY OF ENCEPHALITIS
Although encephalitis may be caused by a variety of agents, both infectious and non-infectious, direct viral infection is one of the commoner causes. To cause direct infection, viruses must cross the bloodbrain barrier. Herpes simplex virus (HSV) is the most common cause of sporadic encephalitis and primary infection with HSV type 1 occurs at the oral mucosa. Following primary infection, the virus travels centripetally along the trigeminal nerve to give latent infection in the trigeminal ganglion. About 70% of all cases of HSV encephalitis already have antibody present, indicating that reactivation of virus is the most common mechanism,9 although it is not clear whether this is reactivation of virus in the trigeminal ganglion, or virus that had already established latency in the brain itself.10 Why HSV sometimes reactivates is not known. In young adults and children, HSV encephalitis is more likely to occur during primary infection. Genetic studies have found two mutations in children that result in impaired interferon production and a predisposition to herpes encephalitis. 33 The other major route of viral entry into the nervous

DEFINITION OF ENCEPHALITIS
Encephalitis means inammation of the brain parenchyma. The clinical syndrome of encephalitis has many different causes and there is a wide differential diagnosis. Broadly, causes can be divided into those associated either directly or indirectly with infectious agents (viruses or other
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Table 1 Possible aetiological agents based on risk factors
Risk factor Unvaccinated status Animal contact Bird contact Insect contact Ingested meat/unpasteurised milk Sexual contact Swimming Camping/hunting WNV, West Nile virus. Possible aetiological agent Polio, measles, mumps, rubella viruses Rabies virus, cat scratch disease, Hendra virus, Q fever WNV, Japanese encephalitis, Cryptococcus neoformans Malaria, WNV, tick-borne encephalitis virus, typhus, Lyme disease, trypanosomiasis Toxoplasmosis, listeria, Q fever HIV, syphilis Enteroviruses, Naegleria fowleri Malaria, tick-borne encephalitis virus, typhus

EPIDEMIOLOGY
The epidemiology of encephalitis is not well de ned due to the lack of a standard case de nition and variations in diagnostic criteria. There are also signicant differences in surveillance systems used across different countries. The results from a recent survey of central nervous system (CNS) diseases in Europe demonstrated that, whereas bacterial causes of encephalitis are thoroughly investigated and the data reporting is good, there are large differences between countries in the notication of viral causes of encephalitis.12 Current surveillance is thought to greatly underestimate the incidence of viral encephalitis. The epidemiology of encephalitis is changing for various reasons. Viruses are constantly emerging and spreading; two arboviruses provide an example: WNV spread across North America a decade ago causing an epidemic and JEV has spread across Asia.13 14 There have been large epidemics of enteroviruses in parts of Asia and previously unknown viruses emerged in Asia and Australia causing encephalitis (Nipah and Hendra viruses15 16 ). There are more patients with immunocompromise due to primary immunodeciency, HIV infection, treatment for cancer (both transplantation and chemotherapy) or treatment with immunomodulatory agents for rheumatological and inammatory conditions. These patients are more likely to get encephalitis from different viruses including cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6) and human herpes virus 7 (HHV-7). Some viral causes of encephalitis have decreased due to the increased availability and uptake of specic vaccinations, for example, mumps and measles. Encephalitis associated with antibodies to voltage-gated potassium channel, or N-methyl-D-aspartate antibody (NMDA) receptors are being increasingly recognised in children.17

Table 2 Possible aetiological agents based on clinical presentation

Clinical presentation Cranial nerve abnormalities Cerebellar ataxia Dementia Poliomyelitis-like accid paralysis Parkinsonism Retinitis Rash Possible aetiological agent HSV, EBV, listeria, tuberculous meningitis, syphilis, Lyme disease, Cryptococcus neoformans VZV, EBV, mumps virus, trypanosomiasis HIV, measles virus, syphilis, human transmissible spongiform encephalopathies JEV, poliovirus, enteroviruses, WNV, tick-borne encephalitis virus JEV, WNV, Nipah virus CMV, WNV, cat scratch disease, syphilis VZV, HHV-6, rubella virus, typhus, syphilis, Lyme disease, WNV, HIV, enteroviruses, Mycoplasma pneumoniae Flu virus, adenovirus, M pneumoniae, Mycobacterium tuberculosis, Q fever Mumps virus HIV, EBV, CMV, measles virus, rubella virus, WNV, syphilis, cat scratch disease, tuberculous meningitis, toxoplasmosis, trypanosomiasis Q fever

Respiratory tract ndings Parotitis Lymphadenopathy

INCIDENCE OF ENCEPHALITIS
Worldwide data report an annual incidence of acute encephalitis ranging from 3.5 to 7.4/100 000, rising to 16/100 000 in children.18 In the UK, the Health Protection Agency identied an annual rate of 1.5 cases/100 000 in the general population and 2.8/100 000 in children, with the highest incidence in infants under 1 year of age, 8.7/100 000.19 There is no sex difference in the rate of encephalitis (2.9 in boys vs 2.8/100 000 in girls).

Hepatitis

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpes virus 6; HSV, herpes simplex virus; JEV, Japanese encephalitis virus; VZV, varicella zoster virus; WNV, West Nile virus.

system is following a viraemia and subsequent spread across the bloodbrain barrier; this occurs for enteroviruses such as polio and arboviruses such as Japanese encephalitis virus (JEV) and West Nile virus (WNV). Having an understanding of the pathology of encephalitis can help the clinician recognise the underlying cause and then consider appropriate treatments. In viral encephalitis, the pathogenesis often consists of a mixture of direct viral cytopathology and a parainfectious or postinfectious in ammatory or immune-mediated response.11 For most viruses, the brain parenchyma and neuronal cells are primarily infected, but for some, the blood vessels can be attacked, giving a strong vasculitic component. Demyelination following infection can also contribute. For example, HSV primarily, but not exclusively, targets the brain parenchyma in the temporal lobes, sometimes with frontal or parietal involvement. Mumps virus can cause an acute viral encephalitis, or an immune mediated delayed-onset encephalitis. Measles virus causes a postinfectious encephalitis, which may have a severe haemorrhagic component (acute haemorrhagic leukoencephalitis). For inuenza A virus, a diffuse cerebral oedema can be a major feature in the pathogenesis, while for varicella zoster virus (VZV), vasculitis is a major pathogenic process.
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PRESENTATION OF ENCEPHALITIS
Classically, children present with a brief u-like prodrome followed by severe headaches, nausea, vomiting and altered consciousness. They may also have meningism, seizures and focal neurological signs. There is therefore an overlap with children who have acute bacterial meningitis, as either syndrome may have common features including fever, headache and meningism. In this situation, patients are often described as having meningoencephalitis. Patients with severe bacterial meningitis can also have a reduced level of consciousness, usually caused by raised intracranial pressure due to complications including venous sinus thrombosis and infarction, cerebritis, metabolic disturbances, subdural collections or septic embolic infarctions. Patients with either meningitis or encephalitis may have seizures. A minority of patients may have more subtle presentations. These patients may not be febrile or only have a low grade fever at presentation and a history of previous fever may be missed. Such individuals may present with behavioural changes or speech and language disturbances but then become more obviously encephalopathic
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or experience a seizure. 20 Children who are immunocompromised may have a more subacute presentation. mumps. The social history may be relevant. The mother may be known to have HIV or have risk factors including previous residence in an endemic area or being an intravenous drug misuser (or the partner of one). HIV testing should be considered in any child with encephalitis. Travel history is important. For the returning traveller consider rabies if there is a history of a dog scratch, a bite or close contact with bats. While rare, other aetiologies to consider include arboviruses (viruses transmitted via an insect or tick vector) from south Asia and central Europe (see table 1 and box 1). The use of online resources such as the Centers for Disease Control or WHO may guide on likely infectious agents and any recent changes in disease prevalence.

FEATURES IN THE HISTORY THAT MAY GIVE IMPORTANT CLUES

It is important to ask some specic questions when considering the aetiology of encephalitis in a child; this includes a detailed vaccination and travel history (see tables 1 and 2). The family should be asked about a history of a rash in the child or their contacts. This may be present in those with chickenpox (VZV), slapped cheek syndrome (parvovirus), hand, foot and mouth disease (enterovirus), roseola (HHV-6), or meningococcal or streptococcal infection. The history of the presence of a cold sore or stomatitis (caused by HSV type 1) may be relevant, but more often a child with HSV encephalitis does not have any obvious perioral lesions.11 Parotitis, abdominal pain (pancreatitis) or testicular pain (orchitis) may be present in those with Table 3 Aetiologies of encephalitis
Mailles and Stahl25 France, 2007 (n=253 adults and children) 131 identiable causes HSV VZV Mycoplasma tuberculosis Staphylococcus spp. Listeria CMV EBV Tick-borne encephalitis Enterovirus HIV JC virus Toscana virus Lyme disease Mycoplasma pneumoniae Rickettsia conorii Pseudomonas spp. Streptococci Neisseria meningitidis Toxoplasma gondii Coxiella burnetti Enterococcus faecium Francisella tularensis Legionella pneumophila Inuenza A Haemophilus inuenzae (non-typable) WNV Dengue virus JEV Cryptococcus neoformans Measles Adenoviruses HHV-6 Powassan virus Streptococcus pneumoniae Parvovirus Dual infection Immune mediated 55 (42%) 20 (15.2%) 20 (15.2%) 13 (10%) 3 (2.3%) 3 (2.3%) 3 (2.3%) 2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%) 1 (0.8%) 1 (0.8%) 1 (0.8%) 1 (0.8%) 1 (0.8%) 1 (0.8%) Kolski et al26 Canada, 19941995 (n=145 adults and children) 20 identiable causes 4 (20%) 1 (5%) 2 (10%)* 11 (55%) 2 (20%) 2 (20%) 1 (5%)

IMPORTANT EXAMINATION FINDINGS IN A CHILD WITH ENCEPHALITIS

Some children may have a clinical picture of a brainstem or rhombo-encephalitis and could have features of abnormal

Galanakis et al27 Greece, 20052007 (n=42 children) 24 identiable causes 3 (12.5%) 3 (12.5%) 1 (4.2%) 1 (4.2%) 1 (4.2%) 1 (4.2%) 6 (25%) 1 (4.2%) 1 (4.2%) 2 (8.3%) 2 (8.3%) 1 (4.2%)

Lee et al28 Taiwan, 20002001 (n=124 adults and children) 79 identiable causes 45 (57%) 16 (20%) 10 (12.6%) 8 (10%) 1 (1.3%) 1 (1.3%) 5 (6.3%)

Granerod et al5 England, 20052006 (n=203 adults and children) 128 identiable causes 38 (19%) 10 (5%) 10 (5%) 1 (0.5%) 1 (0.5%) 3 (1%) 1 (0.5%) 1 (0.5%) 1 (0.5%) 4 (2%) 2 (1%) 2 (1%) 1 (0.5%) 1 (0.5%) 2 (1%) 1 (0.5%) 1 (0.5%) 3 (1%) 3 (1%) 42 (21%)

Srey et al29 Cambodia, 19992000 (n=52 children) 52 identiable causes 1 (1.9%) 1 (1.9%) 3 (5.8%) 4 (7.6%) 15 (28.9%) 28 (53.8%)

*2 had M pneumoniae identied. 1 had HHV-6 identi ed. Dual ndings: 1 Cryptococcus spp. and VZV; 1 Mycobacterium tuberculosis and T gondii; 1 M tuberculosis and HIV. Dual ndings: 1 JEV and alphavirus; 12 non- avivirus and non-alphavirus; 15 avivirus and alphavirus (inconclusive). CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpes virus 6; HSV, herpes simplex virus; JEV, Japanese encephalitis virus; LCMV, lymphocytic choriomeningitis virus; WNV, West Nile virus; VZV, varicella zoster virus.

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brainstem function including lower cranial neuropathies. Infective agents to consider with this clinical presentation include enteroviruses, listeria and tuberculosis (TB). Rarely, children with encephalitis may have a movement disorder including chorea or other dyskinesias. For these children, it is important to consider viruses known to have a predilection for basal ganglia infection including arboviruses such as Japanese encephalitis or WNV. Movement disorders and psychiatric features are also a feature of the newly described antiNMDA receptor antibody encephalitis.6 Limbic encephalitis is very rare in children but has been reported in association with voltage-gated potassium channel antibodies and paraneoplastic conditions. 21 These children may have memory problems, altered sleep patterns and other psychiatric features. 21 In more general terms, important examination ndings in a child with encephalitis include signs of meningism (bulging fontanelle in a young infant and nuchal rigidity or positive Kernigs sign in older children). However, these signs are not always present in children with meningitis or encephalitis and their presence or absence should not be used to rule encephalitis in or out. 22 It is also important to rapidly assess the level of coma and to look for abnormal neurological signs suggestive of raised intracranial pressure including a low or falling coma score, raised blood pressure, bradycardia, abnormal pupil responses, abnormal exion or extension to a painful stimulus (decerebrate and decorticate positioning), altered breathing patterns and papilloedema. 23 Children with encephalitis can have subtle seizures which it is important to recognise. Failure to control seizures can lead to raised intracranial pressure, an increase in metabolic activity, acidosis and vasodilation, which can further increase pressure. Features of seizures may include tonic eye deviation, nystagmus, or subtle clonic movements of the face or limbs or any paroxysmal alteration in heart rate or other observations. 24 England include CMV, EBV, measles virus, mumps virus and enterovirus. 5 19 A more recent prospective study of causes of encephalitis in England identi ed 203 patients over a period of 2 years. The main aetiologies were HSV (19%), VZV (5%) and Mycobacterium tuberculosis (5%). However, 75 (37%) had unknown causes and 42 patients (21%) had acute immunemediated encephalitis. 5 In France a prospective study of infectious encephalitis con rmed HSV as the leading cause of viral encephalitis (42% of cases), followed by VZV (15% of cases), 25 whereas in Finland VZV is the leading cause of encephalitis in children. 32 In addition to these common pathogens, arthropod-borne viruses can cause encephalitis. In Northern and Eastern Europe, Central European tick-borne encephalitis is the most frequently detected agent, whereas in the USA, WNV is the second most common cause of encephalitis. 33 JEV is the leading cause of viral encephalitis in Asia with an estimated 35 00050 000 cases and 15 000 deaths reported annually. 34 It is a seasonal disease, with most cases occurring in temperate areas from June to September. Bacteria associated with encephalitis across Europe are predominantly M tuberculosis, Listeria monocytogenes and Mycoplasma pneumoniae, as well as Borrelia and Rickettsia species.12 In France, 30% of cases of encephalitis were attributed to infection with a specic bacterium, with M tuberculosis affecting 15% and L monocytogenes affecting 10% of cases. 25 M pneumoniae is another important pathogen identied in 517% of cases of encephalitis. 35 36 It is however, rarely found in the CSF and is usually identied serologically. Parasites and fungi are rare causes of encephalitis, and usually affect immunocompromised patients. They have been reported to account for 3% and 1% of cases, respectively, in a prospective study of 1570 patients with encephalitis over a period of 7 years. 37 Balamuthia mandrillaris and Baylisascaris procyonis were identied as the two parasitic aetiological agents. The infections due to B procyonis all occurred in children who had a CSF and peripheral eosinophilia. Cryptococcus neoformans and Coccidioides immitis were the main fungal pathogens identied in a total of three patients. A Eurosurveillance report on meningitis and encephalitis identied C neoformans as the main fungal pathogen and Acanthamoeba species, Toxoplasma gondii and Naegleria species as the predominant parasitic pathogens.12 These variations in the geographical distribution of disease and vectors provide clues to help the clinician target appropriate investigations to identify a possible aetiological agent. However, despite use of a wide range of investigations, the aetiology of encephalitis remains unknown in approximately one third of cases. 5 Recent gures from the Health Protection Agency reported that 60% of cases of encephalitis/meningitis have no known aetiology. 5 12

AETIOLOGY OF ENCEPHALITIS
While a direct viral infection is the most common cause of encephalitis, the syndrome may be caused by other infectious agents and also by non-infectious aetiologies. The differential diagnosis and mimics of viral encephalitis are listed in boxes 1 and 2. Recently, encephalitis caused by newly identied autoantibodies has been described, which may be either a parainfectious or postinfectious phenomenon or a paraneoplastic condition. 5 6 Many viruses are reported as causes of encephalitis, and there is considerable geographical and seasonal variation as to which pathogens predominate. In addition, new viruses are constantly emerging and spreading, largely as a result of changes in the distribution of their vectors (eg, the WNV outbreak mentioned previously 31). It seems likely that environmental factors including climate change and an increase in international travel, can inuence the emergence of viral outbreaks. A list of the viral causes of encephalitis in children is shown in box 1. Globally, the most common viral cause of sporadic encephalitis in adults and children is HSV (see table 3), the causative organism in 22% of cases of viral encephalitis with an aetiology identied in England from 1990 to 1998.19 Of these cases of herpes encephalitis, 19% occurred in children and 4.8% in neonates. The next most common viruses identied in the series were VZV followed by adenovirus, which were found in 21% and 4% of cases, respectively. Other viral causes of encephalitis in
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LABORATORY INVESTIGATION Baseline investigations

The emphasis on initial testing in a child presenting with signs and symptoms suggestive of encephalitis should be directed at (1) making an early diagnosis of treatable alternative noninfectious causes of this clinical syndrome and (2) seeking an infectious aetiology and treating the complications of such an infection. Testing for infectious agents should be guided by the history particularly of immunocompromise, immunisation status and travel (see gure 1). The following investigations should be performed routinely:
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full blood count and lm urea and electrolytes liver function tests capillary glucose, laboratory blood glucose blood gas (arterial or capillary or venous) lactate urinalysis (dipstick at bedside) for ketones, glucose, protein, nitrites and leucocytes plasma ammonia (taken from a venous or arterial sample) blood culture 12 ml of plasma to be separated, frozen and saved for later analysis if required 12 ml of plain serum to be saved for later analysis if required 10 ml of urine to be saved. The full blood count may show lymphocytosis in viral encephalitis. Other non-speci c abnormalities could include renal dysfunction (often hyponatraemia thought to be secondary to dehydration or inappropriate antidiuretic hormone secretion), raised hepatic enzymes (EBV, CMV, mitochondrial disorders, some drugs), raised amylase (mumps), abnormal coagulation and hypoglycaemia. In the presence of a disturbed level of consciousness respiratory acidosis may be present, but the presence of metabolic acidosis may point to a metabolic disorder, in which case an ammonia, lactate and plasma amino acids are important for the differential diagnosis. Further guidance on baseline investigations is given in the RCPCH Decreased Conscious Level guideline. 8

Microbiology and virology investigations

Blood cultures may identify bacteria or fungi. Specic clinical ndings should direct sampling from other sites, such as a nasopharynx, urine, stool and throat. A viral throat swab may allow identication of respiratory viruses, measles or enteroviruses (culture, PCR or immunouorescence), while a nasopharyngeal aspirate can be used to detect respiratory viruses (inuenza A, parainuenza, adenoviruses and respiratory syncytial virus (RSV)) using PCR, antigen detection or culture. Chlamydophila pneumoniae and M pneumoniae can also be detected in throat swabs using PCR. Stool samples may reveal infection with enteroviruses, mumps virus or measles viruses through PCR or culture. If vesicles are present, a viral swab should be taken from the vesicle for detection of VZV or HSV by immunouorescence or PCR. Skin biopsies of other lesions may be considered. Urine can be cultured for CMV, mumps or measles virus. Serological testing may be useful in identifying some causes of encephalitis. Serum and CSF IgM antibodies or a rising IgG concentration may allow identication of infection with HSV, VZV, CMV, EBV, RSV, adenovirus, inuenza A and B virus, parainuenza and enteroviruses, rotavirus, M pneumoniae and arboviruses. Serological cross-reactivity among the aviviruses (Japanese encephalitis, St. Louis encephalitis, WNV) complicates diagnosis. 38 Convalescent serology should be obtained a minimum of 3 weeks after the onset of the clinical illness to demonstrate rising antibody levels.

unless contraindications exist as documented in the RCPCH Reduced Consciousness Guideline.8 CSF should be sent for the following investigations in all children with suspected encephalitis: To the microbiology laboratory for microscopy, culture and sensitivity analysis To the virology laboratory for PCR for HSV types 1 and 2 and VZV; a sample should be stored for possible analysis in the future after discussion with a virologist To biochemistry laboratory for glucose (with paired plasma sample), lactate and oligoclonal bands (with paired serum sample). Any remaining sample should be stored. Further tests may be needed in the future, including specic pathogen antibody testing or testing for autoimmune antibodies. In viral encephalitis, evaluation of the CSF may reveal a mononuclear pleocytosis and moderately elevated protein level, or the CSF red blood cell count may be raised (haemorrhagic encephalitis). The presence of eosinophils suggests infection with helminths, but is also seen with toxoplasma infection, Rickettsiae rickettsii and infection with M pneumoniae. 33 A decreased CSF glucose concentration suggests a bacterial, fungal or protozoal aetiology. Of note, up to 10% of patients with viral encephalitis will have a completely normal CSF, especially if the LP is done in the early stages of the illness. 39 The gold standard for the diagnosis of encephalitis is identication of the infectious agent in brain tissue (rarely used now) or the CSF. Since encephalitis is a brain infection, CSF may be negative, especially in the early stages of the disease. For virus detection, isolation in cell culture has now been replaced by amplication of specic nucleic acid from CSF or brain by PCR (HSV types 1 and 2, VZV, HHV-6 and HHV-7, CMV, EBV, enteroviruses, respiratory viruses, HIV and C pneumoniae). In 1995, a report from the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group40 described a study of CSF specimens from patients with biopsy-con rmed or negative herpes simplex encephalitis (HSE) disease. This study de ned the sensitivity and specicity of HSV DNA PCR to be 94% and 98%, respectively. Real-time PCR has also been studied in patients with HSE. The viral load in the CSF correlated directly with clinical outcome; the quantity of virus correlated with the levels of consciousness, presence of CT/MRI lesions and a poor neurological outcome.41 It is now well recognised that in a proportion of children with subsequently con rmed HSV encephalitis the initial CSF HSV PCR is negative, particularly in the rst days of the disease. These false negative results are thought to be related to the absence of HSV or only very low titres of the virus in the CSF at the onset of the encephalitic process.42 In such cases, a second LP and HSV PCR testing should be considered and aciclovir continued if there is clinical evidence of encephalitis (a positive PCR may become negative after initiation of aciclovir therapy).

Neuroimaging
Neuroimaging is a key part of the investigation of a child presenting with a syndrome suggestive of encephalitis. In addition to providing direct evidence of brain involvement from an infectious process, it is the key to excluding many of the noninfectious alternative diagnoses (eg, ADEM, vascular events, abscesses or collections or other space occupying lesions). While MRI is the investigation of choice, it is often not available at
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CSF analysis
The use of lumbar puncture (LP) in children with suspected CNS infections has declined recently, most likely as a result of uncertainty over contraindications. However, CSF analysis is very useful in this group of children and should be undertaken
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Candidiasis Parasites Cerebral malaria Sporadic causes of viral encephalitis (not geographically restricted) listed by group Herpes viruses Herpes simplex virus type 1 and 2, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpes virus 6 and 7 Enteroviruses Coxsackieviruses, echoviruses, enteroviruses 70 and 71, parechovirus, poliovirus Paramyxoviruses Measles virus, mumps virus Other (rarer causes) Flu viruses, adenovirus, parvovirus, lymphocytic choreomeningitis virus, rubella virus Geographically restricted causes of encephalitis (mostly arthropod-borne*) The Americas West Nile, La Crosse, St Louis, dengue, rabies Europe/Middle East Tick-borne encephalitis, West Nile, rabies Africa West Nile, Rift Valley fever virus, Crimean-Congo haemorrhagic fever, dengue, rabies Asia Japanese encephalitis, West Nile, dengue, Murray valley encephalitis, rabies, Nipah Australasia Murray valley encephalitis, Japanese encephalitis *All viruses are arthropod-borne, except for rabies and Nipah virus. Toxoplasmosis Cysticercosis Rickettsiae Typhus Q fever Erlichiosis Cat scratch disease Para/postinfectious causes GuillainBarr syndrome* ADEM* Systemic viral illnesses with complex febrile convulsions Non-infectious diseases Vasculitic Systemic lupus erythematosus Polyarteritis nodosa ANCA associated vasculitis Neoplastic Primary brain tumour Brain metastases Paraneoplastic limbic encephalitis Metabolic Diabetic ketoacidosis and coma Hepatic encephalopathy Hypertensive encephalopathy Haemolytic uraemic syndrome Hypoglycaemia Box 2 Diseases mimicking viral meningoencephalitis in children (modi ed from Solomon and Whitley 30) Central nervous system infections Bacteria Bacterial meningitis Tuberculous meningitis Brain abscess Typhoid fever Parameningeal infection Lyme disease Leptospirosis Mycoplasma pneumoniae Listeria monocytogenes Brucellosis Subacute bacterial endocarditis (emboli) Fungi Cryptococcus Coccidiomycosis Histoplasmosis Reyes syndrome Mitochondrial encephalopathy Toxic encephalopathy (drugs, alcohol) Other Drug reactions Subarachnoid and subdural haemorrhage Venous sinus thrombosis and infarction Ischaemic cerebrovascular accidents Epileptic encephalopathy or non-convulsive status epilepticus Functional illness NMDAR, encephalitis Voltage gated K channel limbic encephalitis *GuillainBarr syndrome and ADEM may follow viral or bacterial infections or vaccinations. Very rare in children. ADEM, acute disseminated encephalomyelitis; ANCA, antineutrophil cytoplasmic antibodies; NMDAR, N-methyl-Daspartate antibody receptor.
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Box 1 Causes of acute viral encephalitis (modi ed from Solomon and Whitley 30)

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presentation. Most children presenting with encephalopathy and a fever (or a history of a febrile illness) will have a CT scan initially, preferably with contrast, particularly to look for lesions needing immediate management (eg, if there are clinical signs suggestive of herniation or a space occupying lesion). The CT scan cannot be used to rule out raised intracranial pressure43 and clinical signs must be used. The CT may be normal in both infectious and non-infectious causes of encephalitis, but patients with HSV encephalitis often have changes in the fronto-temporal regions with loss of the normal gyral pattern and later hypodensity. The MRI is more sensitive and diffusion weighted imaging can be especially useful.44 MRI is not usually available as a front-line investigation, especially in the district general hospital. In young children, a general anaesthetic is usually needed for the procedure and this can also provide an opportunity to undertake an LP if it has not already been done. and the length of recovery requiring rehabilitation in many cases. Some children will need transfer to a paediatric intensive care unit (ICU) in the early stages of their illness and they will often require ongoing care in a centre that can offer a multidisciplinary neurorehabilitation programme. Supportive measures that should be considered for all children include the treatment of immediate complications such as reduced consciousness, seizures and raised intracranial pressure, circulatory support and treatment of aspiration pneumonias.45 After emergency management, issues such as feeding and the prevention of ICU complications (including venous thrombosis and critical illness neuropathy) should be considered. During convalescence, consideration should be given to physical, psychological and educational rehabilitation. Centres differ in their ability to offer these services across the country. Treatment for longer term complications including epilepsy, spasticity and dystonia should be available. Parents and children will nd information about charities that offer support to those who have suffered an acute brain injury useful including the Encephalitis Society, Headway and the Child Brain Injury Trust. Referral to a community paediatrician or child psychiatry team may be needed for behavioural problems or other neurocognitive sequelae. Long term follow-up is essential as different problems may emerge (such as memory difculties) as the child gets older, especially following HSE.

EEG
The EEG can be a useful investigation of encephalitis, as a pointer to diagnosis and for evaluation for seizure activity. EEG is a sensitive indicator of cerebral dysfunction showing nonspecic diffuse high amplitude slow waves of encephalopathy. It may also demonstrate focal seizure activity which may have either no motor component or only subtle clinical features. The EEG may be of value in children with HSV encephalitis if the typical pattern of periodic lateralising epileptiform discharges are seen arising from the temporal lobe with slowwave complexes occurring at intervals of 23 s. These were once thought to be pathognomonic of HSV encephalitis, but it is now recognised they can be seen in other disorders including space occupying lesions.

EMPIRIC TREATMENT
Treatment should be guided according to likely aetiology. Usually at the time of clinical presentation the pathogen is uncertain and therefore broad-spectrum antimicrobials and antiviral treatment should be initiated pending the results of diagnostic studies (see gure 1). Factors that are most likely to modify the approach to empiric treatment are a history of travel or immunocompromise and these areas of the history need to be actively sought at the rst opportunity.

MANAGEMENT
Children with encephalitis are often in hospital for several weeks due to the length of intravenous treatment required,

Box 3

Aciclovir treatment in children

When to start aciclovir in children with suspected herpes simplex virus (HSV) encephalitis Aciclovir should be started in all patients with clinical features suggestive of encephalitis as soon as possible, pending the results of diagnostic studies The diagnosis of herpes simplex encephalitis (HSE) should be considered in any patient with a progressively deteriorating level of consciousness with fever, focal seizures or focal neurological abnormalities in the absence of any other cause When to stop aciclovir in children treated for suspected HSV encephalitis If there is no ongoing clinical suspicion of HSE (a denitive alternative diagnosis becomes apparent, or it seems very unlikely that the patient has viral encephalitis) Aciclovir may be stopped if a negative CSF HSV PCR is obtained at >72 h following onset of neurological symptoms AND there is a low clinical suspicion of HSE (eg, a clinical recovery and normal level of consciousness, normal neuroimaging and <5 cells/mm3 in CSF)1 When NOT to start aciclovir in children with neurological symptoms/signs Child with simple febrile convulsions Seizures without documented fever or history of fever (unless immunocompromised) Other obvious cause for symptoms, eg, blocked VP shunt, child with epilepsy (who has an increase in seizures with a febrile illness), acute head injury, drug overdose CSF and clinical picture are highly suggestive of bacterial meningitis When NOT to stop aciclovir in children treated for suspected HSV encephalitis Negative CSF HSV PCR but other features consistent with HSE (particularly if CSF and MRI ndings are abnormal and consistent with the diagnosis) CSF pleocytosis can be absent and false negative HSV PCR results can occur, particularly early on in the illness (see text)
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In the UK, empirical antiviral therapy for viral encephalitis is mainly limited to treatment of herpes viruses, especially HSV, except in the u season when oseltamivir may be considered. In early studies comparing aciclovir and vidarabine for the treatment of HSV encephalitis, it was shown that 6 months after therapy aciclovir decreased mortality to 19% as compared to a mortality of 55% in the vidarabine treated group. 2 However, despite treatment with aciclovir, two thirds of patients are left with signicant neurological impairment. Given the non-specic presentation of encephalitis due to HSV infection and the poor prognosis in cases where therapy is commenced late, most clinicians have a low threshold for

Figure 1 Guideline for the investigation of unexplained acute encephalopathy.

Continued

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Figure 1 Continued

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starting aciclovir in suspected cases of encephalitis (see When to start aciclovir in box 3). Since most children with a similar presentation who are started on antiviral treatment will not have HSV infection, the decision to stop treatment is perhaps one of the most difcult faced by clinicians. Aciclovir should not be stopped if a negative CSF HSV PCR is obtained but other features are consistent with HSE. False negative PCR results can occur, particularly in the rst 3 days of illness. In such patients the LP should be repeated because it may be positive 2448 h later and, even if negative again, treatment continued for at least 10 days if there are other compatible features. However, if a de nitive alternative diagnosis has become apparent, or it seems very unlikely that the patient has viral encephalitis, then it is reasonable to stop the aciclovir earlier. Empirical treatment with broad spectrum antibiotics should include a third generation cephalosporin such as ceftriaxone, to cover Streptococcus pneumoniae, Haemophilus inuenzae and Neisseria meningitidis infections in addition to ampicillin or amoxicillin to cover L monocytogenes.46 Some have recommended the addition of azithromycin in the empirical treatment to cover infection caused by Mycoplasma, but the role of antibiotic therapy for mycoplasma encephalitis remains unclear. 37

Varicella zoster virus

Aciclovir is also effective against varicella zoster virus (VZV). No randomised controlled trial has been performed to establish the dose or duration of treatment, but on the basis of a few case series 53 aciclovir at a dose of 10 mg/kg every 8 h is recommended for 1014 days treatment.

Flu
There are no randomised controlled trials and very few data regarding treatment of encephalitis caused by inuenza A or B. Treatment guidelines are based on studies that examined the clinical course of u. A 5-day treatment course of oseltamivir in children with respiratory symptoms was associated with a median reduction in clinical illness of 36 h and a reduction in fever of 25 h compared with placebo recipients. 54 The current recommendation for treatment of u virus encephalitis is treatment with oseltamivir for a period of 5 days. 33

M pneumoniae
Antibiotic therapy has been temporally associated with clinical improvement in some cases of M pneumoniae encephalitis, however complete recovery has also been reported without any antibiotic treatment and the role of antibiotic therapy remains unclear. 55 Current guidelines indicate that it is reasonable to consider empiric antibiotic therapy with azithromycin or doxycycline33 for all children.

SPECIFIC THERAPY HSV

Aciclovir is the treatment of choice for encephalitis caused by HSV. Studies in the 1990s in neonates suggested that aciclovir, as a selective and specic inhibitor of viral replication, is superior to vidarabine.47 However in these trials, morbidity remained high and there was a high rate of disease progression during treatment and relapse following cessation of treatment. More recent studies have shown that high dose aciclovir (60 mg/kg/day intravenously) given for 21 days for HSV encephalitis in neonates reduces the rates of relapse and improves neurological outcome.48 However, there are no published randomised controlled trials in older children examining treatment dose and duration of aciclovir to treat herpes encephalitis, but studies are ongoing. In adults and children over 12 years of age, the current recommended treatment regime is 10 mg/kg every 8 h of intravenous aciclovir (30 mg/kg/day) for 1421 days in immunocompetent patients and 21 days in immunosuppressed patients.33 49 The British National Formulary for children states that children aged 3 months to 12 years should receive 500 mg/m 2 every 8 h of intravenous aciclovir. Rates of relapse of herpes encephalitis have been reported to be as high as 26% but do not occur if treatment is given for longer than 14 days and at doses greater than or equal to 30 mg/kg/day. 50 For this reason, some experts recommend using higher doses and longer duration at all ages while the outcome of further evaluation is awaited. We recommend 3 weeks duration for all proven or strongly suspected cases. A negative CSF PCR result at the end of treatment is associated with a better outcome and antiviral therapy should be continued in the context of a positive PCR. 51 Valaciclovir (valene ester of aciclovir which is converted to aciclovir after absorption) has good bioavailability and can in certain circumstances be used to treat HSV encephalitis. It is recommended that it should only be used after at least 10 days of intravenous aciclovir and when ongoing intravenous treatment is proving difcult. 52 There is no place for the use of oral aciclovir as poor CSF concentrations are achieved.
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Other treatable conditions

Many of the infectious agents that can cause encephalitis are rarely seen in clinical practice. However several of them have specic treatment options for what may be life-threatening or damaging conditions (see box 3 on gure 1) including CMV, measles, Cryptococcus, TB and Bartonella henselae. Most of these agents would be seen mainly in those who have travelled, are unimmunised or immunocompromised or who have had specic exposures (to TB, animals). It is therefore highly important to elicit these features of the history at an early stage and direct investigations for these agents appropriately and in a timely manner (ie, at the same time as rst line investigations if the history warrants).

IMMUNOMODULATORY TREATMENT
At the current time, steroids are not generally given to children with a strong suspicion of or proven viral encephalitis and their role in raised intracranial pressure is controversial. A study of 45 adults with HSV encephalitis found that lack of corticosteroid administration was a predictor of poor outcome and an accompanying editorial made a strong case for further research in this area. 56 57 A randomised controlled trial of the use of steroids in adults with HSE is currently underway in Europe and the UK. Expert opinion in adults would also suggest a course of corticosteroids in VZV reactivation encephalitis particularly if large vessel vasculitis is thought to be a strong component (imaging ndings consistent with stroke). The recommended adult dose is 6080 mg once daily for 35 days. It may be reasonable to consider this in children with the same clinical picture, and an equivalent dose would be 2 mg/kg/day of prednisolone for 35 days (maximum 60 mg). 58 Expert neurology advice should be sought for these patients with VZV reactivation encephalitis. Steroids are the mainstay of treatment for children with ADEM and are usually given as rst line treatment to children
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with an antibody-mediated encephalitis. 59 The ideal management in the longer term for children with antibody-mediated encephalitis is currently unknown as only a few case reports and series have been reported so far. Treatment with intravenous immunoglobulin, plasma exchange and other immunosuppressants, including cyclophosphamide and azathioprine, has been used.6 60 aetiology, with HSV being the most commonly identied pathogen. Despite treatment with aciclovir, morbidity remains high. There are very few randomised controlled trials looking at treatment of encephalitis and there are few data on long-term outcomes. Consequently, there are many unanswered questions about the ideal management and treatment of encephalitis. Continued surveillance of encephalitis in Europe and collaboration between clinicians, epidemiologists and microbiologists could help de ne diagnostic criteria, develop and validate treatment guidelines and provide information on long-term sequelae. The new National Institute for Health Research funded study of encephalitis in the UK due to start in 2011 will hopefully address some of these questions (http://www.liv. ac.uk/neuroscience/brain-infections).
Acknowledgements The authors would like to thank Dr Katie Jeffries, Consultant Virologist, John Radcliffe Hospital, Oxford, and Dr Mike Pike, Consultant Paediatric Neurologist, John Radcliffe Hospital, Oxford, for their help in the development of the guideline for the investigation of unexplained acute encephalopathy (gure 1). AJP is a Jenner Investigator and James Martin Senior fellow and DK is funded by the NIHR Oxford Biomedical Research Centre. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed. Contributors The article was commissioned by Patrick Cartlidge from AJP from the Department of Paediatrics, University of Oxford. The article was written by CT with collaboration from RK and AR of the Alder Hey Childrens Hospital in Liverpool and DK from the University of Oxford, Childrens Hospital.

PROGNOSIS
The literature on long-term outcome and prognosis following encephalitis is limited to a few studies. HSV encephalitis in neonates and children remains the most widely studied as it continues to be associated with poor long-term neurological outcomes despite appropriate therapy. Long-term morbidity rates are quoted as 30% in adults and up to 67% in children with HSV encephalitis.61 62 Patients younger than 3 years of age are more likely to develop severe sequelae or to die of HSV infection than older patients.61 A prospective study of 27 children examined predictors of adverse outcome in HSV encephalitis. A Glasgow coma score of less than 6 and disease that was present for more than 4 days prior to starting treatment were predictors of poor outcome. 52 At 2 years after treatment, 30% of aciclovir recipients were judged to be normal or mildly impaired, 9% had moderate sequelae, and 53% were dead or severely impaired. The results from a more recent 12-year prospective study of children with HSV encephalitis demonstrated that neurological sequelae occurred in 63% of cases, including seizures in 44% and developmental delay in 25%. There were, however, no deaths in this study group.63 The 10-year viral encephalitis surveillance study in England (19891998) identied that in children the overall case-death rate was 2.3 per 100 cases, of which 1.9 per 100 cases were herpes encephalitis and 2.1 per 100 cases were viral encephalitis without a specic diagnosis.19 A retrospective study of 93 children admitted to hospital in Stockholm, Sweden between 2000 and 2004, demonstrated that 60% of patients had sequelae at discharge from hospital. 64 Some of these were mild symptoms such as fatigue, but in 24% of cases symptoms included cognitive impairment, dysphasia, motor impairment, ataxia or epilepsy. All children with RSV encephalitis made a full recovery, however 66% of children with enterovirus encephalitis had ataxia, fatigue and personality change and 60% of children with VZV encephalitis had ataxia. Cognitive impairment was present in both cases of HSV encephalitis and the two children with EBV encephalitis had problems with ataxia and cognitive impairment with one child having epilepsy. Predictors of adverse outcomes were focal neurology at the time of presentation, with 84% having symptoms at discharge, and encephalopathy. Seizures at presentation were not predictive of symptoms at discharge. Pleocytosis in the CSF and abnormalities on neuroimaging were also predictive of persistent sequelae.

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