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Abstract and Introduction

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 specific 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 year.
[1]
It is important to
recognise encephalitis because specific treatments given early can improve the outcome in
certain cases
[2]

Despite being uncommon, the symptoms and signs with which children with encephalitis present
are often non-specific. For this reason, many children are initiated on treatment for encephalitis
even if they do not really have a significant likelihood of having the syndrome. Conversely, a
recent study has shown that the management of children with encephalitis is haphazard and could
be improved.
[4]
Paediatricians should therefore have a safe and robust management plan for
children who present with suspected encephalitis.
Definition of Encephalitis
Encephalitis means inflammation 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
microorganisms) or those caused by other inflammatory pathologies (see Box 2 and Box 3 ). In
many cases, a cause is not identified 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 confirmation (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 inflammation, such as inflammatory cells in the cerebrospinal fluid
(CSF) or changes on brain imaging suggestive of inflammation. 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)
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 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
inflammatory 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 influenza 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.
Epidemiology
The epidemiology of encephalitis is not well defined due to the lack of a standard case definition
and variations in diagnostic criteria. There are also significant 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
notification 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 viruses
[15 16]
). There are more
patients with immunocompromise due to primary immunodeficiency, HIV infection, treatment
for cancer (both transplantation and chemotherapy) or treatment with immunomodulatory agents
for rheumatological and inflammatory 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 specific 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.
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 identified 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).
Presentation of Encephalitis
Classically, children present with a brief 'flu-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 or experience a seizure.
[20]
Children who are immunocompromised may have a
more subacute presentation.
Features in the History That May Give Important Clues
It is important to ask some specific questions when considering the aetiology of encephalitis in a
child; this includes a detailed vaccination and travel history (see Table 1 and Table 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 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 andBox 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.
mportant 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 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 anti-
NMDA 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 findings in a child with encephalitis include signs
of meningism (bulging fontanelle in a young infant and nuchal rigidity or positive Kernig's 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 flexion 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
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 Box 1and Box 2 . Recently, encephalitis
caused by newly identified 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 influence 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 identified 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 identified in the series were VZV
followed by adenovirus, which were found in 21% and 4% of cases, respectively. Other viral
causes of encephalitis in England include CMV, EBV, measles virus, mumps virus and
enterovirus.
[5 19]
A more recent prospective study of causes of encephalitis in England identified
203 patients over a period of 2 years. The main aetiologies were HSV (19%), VZV (5%)
andMycobacterium tuberculosis (5%). However, 75 (37%) had unknown causes and 42 patients
(21%) had acute immune-mediated encephalitis.
[5]
In France a prospective study of infectious
encephalitis confirmed 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 35 000
50 000 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 specific bacterium,
with M tuberculosisaffecting 15% and L monocytogenes affecting 10% of cases.
[25]
M
pneumoniae is another important pathogen identified in 517% of cases of encephalitis.
[35 36]
It is
however, rarely found in the CSF and is usually identified 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 identified 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 andCoccidioides immitis were the main fungal pathogens
identified in a total of three patients.
A Eurosurveillance report on meningitis and encephalitis identified 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 figures from the Health Protection Agency reported
that 60% of cases of encephalitis/meningitis have no known aetiology.
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 non-
infectious 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 figure 1). The
following investigations should be performed routinely:

(Enlarge Image)
Figure 1.
Guideline for the investigation of unexplained acute encephalopathy.
full blood count and film
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-specific
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. Specific clinical findings should direct sampling
from other sites, such as a nasopharynx, urine, stool and throat. A viral throat swab may allow
identification of respiratory viruses, measles or enteroviruses (culture, PCR or
immunofluorescence), while a nasopharyngeal aspirate can be used to detect respiratory viruses
(influenza A, parainfluenza, 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 immunofluorescence 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 identification of infection with HSV,
VZV, CMV, EBV, RSV, adenovirus, influenza A and B virus, parainfluenza and enteroviruses,
rotavirus, M pneumoniaeand arboviruses. Serological cross-reactivity among the flaviviruses
(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.
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 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
specific 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 identification 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 amplification of specific 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 Group
[40]
described a study of CSF specimens from patients with biopsy-
confirmed or negative herpes simplex encephalitis (HSE) disease. This study defined the
sensitivity and specificity 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 confirmed HSV
encephalitis the initial CSF HSV PCR is negative, particularly in the first 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 non-infectious 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 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 pressure
[43]
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.
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 non-
infectious 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 figure 1). The
following investigations should be performed routinely:

(Enlarge Image)
Figure 1.
Guideline for the investigation of unexplained acute encephalopathy.
full blood count and film
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-specific
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. Specific clinical findings should direct sampling
from other sites, such as a nasopharynx, urine, stool and throat. A viral throat swab may allow
identification of respiratory viruses, measles or enteroviruses (culture, PCR or
immunofluorescence), while a nasopharyngeal aspirate can be used to detect respiratory viruses
(influenza A, parainfluenza, 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 immunofluorescence 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 identification of infection with HSV,
VZV, CMV, EBV, RSV, adenovirus, influenza A and B virus, parainfluenza and enteroviruses,
rotavirus, M pneumoniaeand arboviruses. Serological cross-reactivity among the flaviviruses
(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.
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 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
specific 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 identification 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 amplification of specific 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 Group
[40]
described a study of CSF specimens from patients with biopsy-
confirmed or negative herpes simplex encephalitis (HSE) disease. This study defined the
sensitivity and specificity 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 confirmed HSV
encephalitis the initial CSF HSV PCR is negative, particularly in the first 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 non-infectious 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 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 pressure
[43]
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.
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 non-
specific 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 slow-wave
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.
Management
Children with encephalitis are often in hospital for several weeks due to the length of intravenous
treatment required, 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 find 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 difficulties) as the child gets older,
especially following HSE.
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 figure 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 first
opportunity.
In the UK, empirical antiviral therapy for viral encephalitis is mainly limited to treatment of
herpes viruses, especially HSV, except in the flu 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 significant neurological impairment.
Given the non-specific 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 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 difficult 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 first 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 definitive 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
influenzae 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.
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 specific 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 difficult.
[52]
There is no place for the use of oral
aciclovir as poor CSF concentrations are achieved.
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 influenza A or B. Treatment guidelines are based on studies that examined the clinical
course of flu. 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 flu 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
doxycycline
[33]
for all children.
Other Treatable Conditions
Many of the infectious agents that can cause encephalitis are rarely seen in clinical practice.
However several of them have specific treatment options for what may be life-threatening or
damaging conditions (see Box 3 on figure 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 specific 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 first
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
findings 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 first line
treatment to children 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]

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) identified 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 specific 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.
Conclusion
Encephalitis remains an uncommon acute neurological syndrome in paediatric practice with an
estimated annual incidence rate in England of 2.8 per 100 000.
[19]
Encephalitis can be the result
of direct infection or para/postinfectious and immune-mediated causes. Surveillance of
encephalitis remains inadequate with significant under-reporting. The majority of cases of
encephalitis in Europe have no known aetiology, with HSV being the most commonly identified
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 define 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).
http://www.medscape.com/viewarticle/757590_14

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