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ADC Online First, published on December 27, 2011 as 10.1136/adc.2011.300998
Review

Encephalopathy in children: an approach to

1Department of Paediatric
Neurology, Sheffield Children’s
Hospital, NHS Foundation
Trust, Sheffield, UK
2Department of Paediatric
Neuroradiology, Sheffield
Children’s Hospital, NHS
Foundation Trust, Sheffield, UK
Correspondence to
Santosh R Mordekar,
Department of Paediatric
Neurology, Sheffield Children’s
Hospital, NHS Foundation
Trust, Ryegate Children’s
Centre, Tapton Crescent Road,
Sheffield, S10 5DD, UK;
santosh.mordekar@sch.nhs.uk
Received 7 September 2011
Accepted 23 November 2011
assessment and management
Emily Davies,1 Daniel J Connolly,2 Santosh R Mordekar1
ABSTRACT
Childhood encephalopathy is an uncommon but
significant paediatric presentation and is associated
with significant mortality and long-term morbidity in
survivors. By definition it is a somewhat non-specific
presentation with a wide differential diagnosis and long
list of possible investigations. Choice of investigation,
including neuroimaging modality, can be a daunting
prospect for the clinician faced with the encephalopathic
child and it is important to select appropriately for a
high diagnostic yield. Initial management centres on
good emergency care irrespective of cause. More
specific therapies however vary enormously, and
appropriate treatment is important and influences
outcome. Evidence exists for mana©gement of many of
the individual conditions causing encephalopathy. This
review aims to outline a clinical approach to selecting
investigations to identify a specific cause and provides
an overview of the treatment for the commoner causes
of encephalopathy that a general paediatrician may
reasonably expect to be faced with.
INTRODUCTION
The encephalopathic child is a paediatric emer-
gency and presents a considerable challenge. The
child may present acutely to general paediatri-
cians and emergency medicine specialists but cer-
tain specialities (eg, neurology, hepatology) may
see subacute presentations. Encephalopathy is not
a diagnosis but a descriptive term for a syndrome
of global brain dysfunction with a wide differ-
ential. Morbidity and mortality in these chil-
dren remains high but prompt recognition of the
encephalopathic state and appropriate and timely
investigations will help identify treatable causes
and can minimise further neurological impair-
ment. In this overview we present a structured
approach to assessing, investigating and manag-
ing such children. We do not include neonatal
encephalopathy in this review.
There is inevitably some overlap with the child
with encephalitis, on which a helpful review has
recently been published,1 but it is important to
recognise encephalopathy as a different clinical
entity to encephalitis.
PRESENTATION
A child can present with encephalopathy at any
age. There may be an acute or more insidious
onset. The child may have previously been neu-
rologically intact, or they may present with an
encephalopathic crisis on the background of long-
standing neurological impairment. The defi ning
feature is an altered mental state and the parent/
carer’s assessment of such children is crucial, par-
ticularly for the paediatrician seeing the child for
the fi rst time.
Depending on the age of the child there may
be a change in personality or behaviour, deterio-
ration in cognitive functioning, developmental
regression/stasis, reduction in conscious level and
specific localising features such as seizures, ataxia,
tremor or other focal motor signs. There may also
be systemic features such as fever, vomiting, leth-
argy, loss of appetite and headache.
CAUSES OF ENCEPHALOPATHY
The differential is wide and best considered system-
atically. Box 1 lists the causes we feel should be con-
sidered in the general paediatric acute setting.
CLINICAL ASSESSMENT
In any child with reduced conscious level the
ABC approach (airway, breathing and circula-
tion) is the appropriate fi rst line assessment. Once
airway protection, respiratory adequacy and cir-
culatory sufficiency are established then more
detailed assessment of the neurological status can
be performed. It is important to obtain a history
from someone who knows the child well. Salient
points are the child’s pre-existing neurological
status, development and medical history, as well
as birth history. The timing and nature of the
deterioration, any recent febrile illnesses, symp-
toms of headache, vomiting and/or diarrhoea and
a history of seizures should be sought. A history
of travel or contact with animals or insects is also
important. Questions to assess the likelihood of
drug/toxin ingestion, including prescribed drugs/
chemotherapeutic agents are necessary and need
broaching sensitively. A history of trauma is
normally obvious but it is important to ask spe-
cifically about any minor, seemingly insignificant
head or neck trauma (carotid artery dissection can
be a cause of stroke in children). A family history
of neurological, metabolic, vascular or haemato-
logical disease is important, as is a history of early
childhood or infant deaths. Parental consanguin-
ity is also relevant. The social history may or may
not give clues when considering the possibility of
non-accidental injury and the housing situation is
important when thinking about lead poisoning.
Formal examination of the encephalopathic
child is difficult. Opportunistic examination and
observation is a key. Watching if and how the
child communicates, whether they are visually
alert, and their pattern and quality of movement
can tell you more than a formal examination in a

Copyright Article
Davies E, Connolly DJ,author (orArch
Mordekar SR. their employer)
Dis Child 2011. Produced by BMJ Publishing Group Ltd (& RCPCH) under 1licence.
(2011). doi: 10.1136/adc.2011.300998 of 7
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Review

Box 1 Causes of encephalopathy Box 2 Initial investigations in a child with

encephalopathy

Infection and parainfectious Capillary glucose and laboratory glucose

Meningitis Blood gas
Encephalitis Urea and electrolytes
Intracerebral abscess Liver function tests
Systemic infection leading to altered mental state Ammonia
Acute disseminated encephalomyelitis Full blood count and film
Autoimmune Blood cultures
N-methyl-D-aspartate receptor antibody encephalitis Plasma to save (1–2 ml)
Voltage gated potassium antibody encephalitis Serum to save (1–2 ml)
Hashimoto’s encephalopathy Urine dipstick
Trauma Urine to save (10 ml)
Accidental
Non-accidental
Seizure related
Non-convulsive status
Post ictal
Epileptic encephalopathy
Toxins
Drugs (therapeutic and recreational)
Heavy metal poisoning
Carbon monoxide
Metabolic
Uraemia
Hyperammonaemia
Hyper/hypoglycaemia
Lactic acidosis
Liver failure
Leucoencephaloapathies, for example, mitochondrial
disorders, organic acidopathies
Hypertensive
Renal disease
Cardiac disease Figure 1 CT of the head with contrast. Hydrocephalus, marked
Hypoxic/ischaemic periventricular low attenuation with effacement of surface sulci
Neonatal hypoxic-ischaemic encephalopathy consistent with ventriculitis in a child with meningitis.
Near drowning
Near miss sudden infant death syndrome INVESTIGATIONS
Following prolonged resuscitation/cardiorespiratory arrest Investigations should be undertaken to identify a cause
Vascular (stroke, venous thrombosis, migraine) that is treatable, but identifying a cause that is not treat-
Haemorrhage able is also important. Families are keen to have an expla-
Traumatic nation for their child’s condition, this allows a more
informed prognosis to be given and stops further unneces-
Spontaneous (eg, arteriovascular malformation,
sary investigations.
coagulopathy) There is no one list of investigations for the encephalopathic
Malignancy child as these should be tailored to the history and investi-
Primary brain tumour gation. Recent evidence-based guidelines do, however, state
Metastatic disease a list of investigations (box 2)2 that should be undertaken at
presentation in children with reduced conscious level to iden-
tify an immediately treatable cause. Two further stages of
combative child. Assessment of orientation and memory can investigation are suggested if initial tests are unrevealing. A
be made with simple questions. A more detailed neurological review paper from 2001 gives an extensive list of investiga-
examination may give vital clues as to the underlying diag- tions for children with non-traumatic coma3 and the recent
nosis and the cardiovascular, respiratory and gastrointestinal review paper on encephalitis in children details investigations
examinations should not be overlooked. when this is the cause of encephalopathy.1 Diagnostic imaging
A set of basic observations (temperature, heart rate, respira- plays a pivotal role in establishing a diagnosis in the enceph-
tory rate, blood pressure and saturations) should be carried alopathic child.4
out as soon as possible. A bedside blood glucose measurement Here, we propose a clinical approach that incorporates
is crucial. these second line investigations and neuroimaging strategies,

2 of 7 Davies E, Connolly DJ, Mordekar SR. Arch Dis Child (2011). doi: 10.1136/adc.2011.300998
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Figure 2 (A) Brain MRI (coronal T2 fluid attenuation inversion
recovery (FLAIR)) showing bilateral multiple foci signal chance
consistent with acute demyelinating encephalomyelitis (ADEM). (B)
Brain MRI (axial fast spin echo) showing bilateral multiple foci T2
signal change with enhancement consistent with ADEM.
Figure 3 (A) Brain MRI (coronal T2 fluid attenuation inversion
recovery (FLAIR)) showing high T2 signal in the hippocampi bilaterally
in a child with limbic encephalitis. (B) Brain MRI (coronal T2 HiRes)
showing high signal in the hippocampi bilaterally in the same child as
figure 3A.
by planning investigations based on a differential diagnosis.
Below we set out investigations that are indicated for each of
the causative categories listed in box 1.
Infection/parainfection
Inflammatory markers would be expected to be raised in men-
ingitis and cerebral abscesses. One should not be reassured
by unremarkable values when there is good clinical suspicion
of central nervous system infection. Blood cultures and viral
serology (including mycoplasma and Borrelia) are useful, as is
blood PCR for suspected viruses. Viral throat, urine and stool
samples can also help identify a precipitant. In demyelinating
conditions, it would also be important to send blood oligoclo-
nal bands (paired with cerebrospinal fluid (CSF)). Aquaporin
4 antibodies are becoming increasingly useful but are not as
sensitive for neuromyelitis optica as in adults 5. Their presence
however can imply a risk of relapse.6 Lumbar puncture (LP) is
the gold standard for diagnosis and should be performed as
soon as is safe.7–10 Microscopy, culture and sensitivity, pro-
tein and glucose should be sent in addition to viral samples.
The list of viruses causing encephalitis/acute demyelinating
Davies E, Connolly DJ, Mordekar SR. Arch Dis Child (2011). doi: 10.1136/adc.2011.300998
Review
Figure 4 CT of the head showing subdural blood with a bright
cerebellum in a child with non-accidental head injury.
Figure 5 (A) CT of the head with contrast showing swollen brain
with loss of grey/white matter differentiation. (B) Brain MRI (axial T2
fast spin echo) showing diffuse high signal in the basal ganglia in the
same patient as figure 5A.
encephalomyelitis (ADEM) is long and pointers in the his-
tory, and results from throat/stool/urine samples will allow
targeted testing of the CSF.1 In certain children (eg, patients
who are immunocompromised) fungal causes will need to be
looked for.
EEG can also be helpful in diagnosing encephalitis. There is
usually generalised or focal slowing. The classically described
focal temporal changes and periodic lateralising epileptiform
discharges are no longer thought to be pathognomonic of her-
pes simplex virus encephalitis.11
Neuroimaging is not necessary in straightforward menin-
gitis at presentation but may be required if the child does
not improve as expected. CT pre/post contrast can diagnose
complications of meningitis (eg, hydrocephalus, abscess,
infarction) (figure 1) but in suspected encephalitis and demy-
elinating conditions MRI is more sensitive. (fi gure 2A,B)
MRI is also superior when parainfectious cerebellitis is
suspected.
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Review
Figure 6 MRI of the brain showing right middle cerebral artery
infarct.
Autoimmune
It has become clear that autoantibodies are associated with
encephalitis, particularly limbic encephalitis,12–15 with prom-
ising treatment options with immunomodulatory therapies.
N-methyl- D -aspartate (NMDA) receptor antibodies, voltage
gated potassium channel antibodies and glutamic acid decar-
boxylase antibodies have all been implicated in children with
limbic encephalitis and should be considered in children pre-
senting with memory disturbance, affective change and sei-
zures or movement disorders. Testing for these antibodies can
be performed on blood. NMDA receptor antibody encephali-
tis is associated with ovarian teratomas and any girl in whom
this is a suspected diagnosis should have a pelvic ultrasound.
MRI of the brain may show changes in the limbic region and
it may be this that fi rst prompts further investigation with
antibody testing.
Hashimoto’s encephalopathy is a rare cause of encephalopa-
thy in children but needs to be considered and thyroid func-
tion tests as well as thyroid autoantibodies are simple tests
that should be performed in unexplained encephalopathy.16
(figure 3A,B).
Trauma
Neuroimaging is the pivotal investigation. Non-contrast CT
is often sufficient, identifying bleeds, cerebral contusion and
in some case showing hypoxic-ischaemic damage. In non-
accidental injury there are characteristically subdural bleeds
of differing appearances on CT and MR, fractures and evi-
dence of hypoxic-ischaemic damage. (figure 4) Bleeding for
which there is no obvious causes can also raise the possibil-
ity of metabolic disease such as glutaric aciduria type 1 and
Menke’s. Organic and amino acids, copper and caeruoplasmin
and in some cases a skin biopsy may be necessary. Basic inves-
tigations such as full blood count, clotting and liver function
4 of 7
tests (LFTs) are also needed and crossmatching blood should
be considered. MRI is more sensitive at detecting subtle
hypoxic-ischaemic changes and may be useful in determining
the extent of irreversible brain injury. Rarely, infection can
produce subdural fluid collection with secondary haemor-
rhage and parenchymal injury. Infl ammatory markers, blood
and CSF analysis may be required to exclude infection for
medicolegal purposes. (figure 5A,B).
Seizure related
Seizure activity can be a primary cause of encephalopathy or
can be a consequence of another diagnosis and is important
to recognise promptly. Several studies have linked outcome
to seizure activity in patients with encephalopathy of various
causes.17–19
No investigation may be necessary in a child with known
epilepsy who is encephalopathic following a prolonged
seizure/seizure cluster but recovers as expected. EEG how-
ever can help diagnose seizure activity when it is difficult
clinically (eg, non-convulsive status (NCS), electrical sta-
tus epilepticus in sleep). It can also help classify epileptic
encephalopathies. In newly presenting epileptic encephal-
opathies there are a number of other investigations indicated
and seeking the advice of a paediatric neurologist is advised.
It is beyond the scope of this review to detail investigation
of epileptic encephalopathy. Having said that, paired fasting
blood and CSF studies for lactate and glucose can be use-
ful and given that LP may be performed before consultation
with a paediatric neurologist, ensuring these samples are
taken with a sample to save may avoid the need for repeat
LP. Taking blood for karyotyping and DNA for storage is
also appropriate.
Toxins
The history will hopefully give some clues but urine for toxi-
cology should be obtained as soon as possible. Blood should
also be taken for paracetamol and salicylate levels, and a heavy
metal screen where poisoning could be a possibility. Drug lev-
els of anticonvulsants in known epileptic children should be
tested in situations of acute deterioration in conscious level, as
toxicity may be the cause.
An MRI scan can be useful and show particular patterns of
brain injury with particular drugs. Discussion with a neurora-
diologist is advised.
Metabolic
This is a broad category and children with suspected metabolic
disease are at risk of being overinvestigated while missing the
one crucial investigation necessary for diagnosis. Blood, urine
and CSF results are important in many cases and ammonia,
lactate, venous blood gas, plasma amino acid, urine organic
and amino acid and sometimes CSF lactate, glucose and amino
acid tests should be done acutely. Beyond this, discussion with
a metabolic specialist or neurologist is advised.
MRI is also an important diagnostic tool in metabolic dis-
ease, and again it is outside the scope of this review to cover
this in detail. When metabolic disease is suspected it is impor-
tant to consider the use of spectroscopy. Metabolic causes of
encephalopathy can be suspected when there are symmetrical
changes in white or grey matter or both on MRI and magnetic
resonance spectroscopy shows a lactate peak.
Endocrine causes should also be addressed in this category
and blood glucose, blood gas and urine dipstick tests will
Davies E, Connolly DJ, Mordekar SR. Arch Dis Child (2011). doi: 10.1136/adc.2011.300998
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Review

Table 1 Specific management of encephalopathy

Cause Treatment

Infection Cefotaxime/aciclovir/clarithromycin
Parainfectious/demyelination Steroids (prednisolone, methylprednisolone)
Immunoglobulins
Autoimmune Steroids
Immunoglobulins
Plasmapheresis
Immunosuppressants
Trauma Neuroprotective strategies
Neurosurgery
Seizures Advanced paediatric life support protocol for status epilepticus
Steroids/clobazam for non-convulsive status
Toxins Organ support: for example, intubation, antiarrthymics, management of hypo/hypertension, correction of electrolyte, acid–base and
clotting derangement, management of hypo/hyperthermia, treatment of seizures
Activated charcoal (may not be possible if reduced Glasgow Coma Score)
Haemodialysis
Specific antidotes (seek advice from Poisons Information Service)
Metabolic Dietary restriction
Clearance of toxic metabolites (dialysis, sodium phenylbutyrate, sodium benzoate, carnitine, glycine)
Specific enzyme/amino acids supplementation for example, thiamine, biotin, arginine, citrulline
Specific drugs (seek advice from metabolic specialist)
Hypertensive Antihypertensives (eg, labetalol, sodium nitroprusside)
Hypoxic-ischaemic Anticoagulation for arterial dissection, venous thrombosis
Aspirin for arterial ischaemic stroke (secondary prevention)
Haemorrhage Correction of clotting abnormalities
Platelet replacement
Immunoglobulins to be considered in idiopathic thrombocytopenic purpura
Neurosurgery
Malignancy Steroids
Neurosurgery
Chemotherapy/radiotherapy

identify diabetic ketoacidosis and blood and urine electrolytes
will point to adrenal insufficiency.
Hypertensive
This diagnosis is largely made on initial observations. The
underlying cause (eg, haemolytic uraemic syndrome, Henoch–
Scohlein purpura) should be investigated by renal function,
urinalysis, renal ultrasound cardiac echo and endocrine inves-
tigations (eg, cortisol, renin, aldosterone, catecholamines).
Hypoxic/ischaemic
Hypoxic-ischaemic damage secondary to trauma, prolonged
resuscitation or multiorgan failure may be suggested on initial
CT by loss of grey/white matter differentiation. MRI is more
sensitive at detecting damage and can show changes within
hours of injury, although there is often an optimum timing for
scanning. If the child survives, repeat imaging when myelina-
tion is complete (after 2 years of age) is recommended to look at
the permanent changes once acute oedema and haemorrhage
have resolved. In such children LFTs, urea and electrolyte, clot-
ting and urine dipstick tests are essential to look for evidence
of multiorgan damage.
In children with stroke the fi rst investigation is usually CT,
which reliably detects haemorrhagic causes of stroke. Studies
have shown however that CT alone will miss a large num-
ber of acute ischaemic stroke cases20 (CT detection in 10%
compared to MRI detection in 46%). Brain imaging is rec-
ommended within 24 h of onset of symptoms suggestive of
ischaemic stroke, along with imaging of the cervicocranial
vascular tree, most conveniently performed with MRI with
magnetic resonance angiography (MRA)20 (figure 6). MRI is
also the follow-up imaging modality of choice. 21 A full blood
count and clotting investigation are needed and the erythro-
cyte sedimentation rate and an autoimmune screen are help-
ful in looking for vasculitic causes. Homocysteine, cholesterol
and triglyceride levels should be checked and prothrombotic
states should also be looked for, in the family history and
by checking protein C, protein S, factor V Leiden, anti-phos-
pholipid and anti-cardioplipin antibodies. Discussion with
haematologists is advised at this stage. An echocardiogram
is also indicated where a cause for infarction is not clearly
demonstrated.
Haemorrhage
This is normally secondary to trauma but may be spontane-
ous in children with abnormal clotting/platelets or in children
with arteriovenous malformations (AVM). Platelet count and
clotting screen are essential. Specific factor assays can be dis-
cussed with a paediatric haematologist. In the fi rst instance CT
will show most haemorrhages but underlying AVM may need
to be considered with MRI/MRA, CT angiography or catheter
angiography. AVM are often not visible until the acute bleed
has resolved or been neurosurgically managed 22 and therefore
delayed angiographic imaging may be advised.
Malignancy
Brain tumours may present with encephalopathy. Children
with known brain tumours can also become encephalopathic

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as a result of raised intracranial pressure, tumour spread, or
chemotherapeutic agents. Imaging is the fi rst line investiga-
tion. CT will detect many tumours and in an emergency is
useful at showing hydrocephalus, cerebral oedema and hae-
morrhage. Most paediatric brain tumours are in the midline
and therefore midline shift, a marker of cerebral mass effect,
may not be clearly evident. MRI may be useful for surgical
planning or for smaller lesions or tumours in specific sites.
Once imaging has suggested a tumour then more detailed
neuro-oncological investigations and management need to be
planned with specialist teams. Basic full blood count, clotting,
group and save/crossmatch, full electrolyte investigations are
certainly needed and pituitary function tests should be consid-
ered dependent on the site of the tumour.
MANAGEMENT
Emergency management
In the fi rst instance a child with altered mental state needs
to be managed with good emergency care, irrespective of the
cause. This undoubtedly improves outcome. Consideration
needs to be given to use of a paediatric intensive care unit
(PICU) care if there is a suggestion of an unstable airway or
organ support is required.
Management of raised intracranial pressure is important
and neuroprotective strategies include nursing with head in
midline, 20° up and maintaining normocapnea.
Treatment of raised intracranial pressure can involve use
of hyperosmolar substances. Evidence for use of mannitol
in children is mainly extrapolated from adult studies and
there is emerging but non-conclusive evidence that hyper-
tonic saline is more effective than mannitol. 23–25 To date
use of either in traumatic brain injury with life threatening
intracranial pressure is supported by the literature as is use
in the intensive care setting where intracranial monitoring
is occurring. For other situations individual judgement is
required.
The use of steroids in bacterial meningitis reduces hear-
ing loss and neurological sequelae in Haemophilus influenzae
meningitis but does not affect mortality26 and, if used, should
be given with or within 4 h of the fi rst dose of antibiotics.10
Dexamethasone can be helpful for cerebral oedema associated
with intracranial mass lesions. Treatment of acutely reversible
causes such as hypoglycaemia and electrolyte disturbances
should be promptly recognised and treated, although care
should be taken not to correct some electrolyte disturbances
too rapidly. Management of the child with diabetic ketoacido-
sis is a prime example and there are national guidelines that
should be followed. 27 28 Seizures should be treated by follow-
ing the Advanced Paediatric Life Support guideline for status
epilepticus. 29
Where metabolic disease is suspected emergency treat-
ment is crucial to prevent further damage and the fi rst step
is stopping feeds and starting intravenous dextrose. If hyper-
ammonaemia is present, sodium benzoate, sodium phenyl-
butyrate and arginine intravenously will help reduce plasma
ammonia levels and discussion with the local dialysis unit/
PICU is required. 30
In many circumstances it is appropriate to initiate antimicro-
bial treatment acutely, particularly if there is any suggestion of
fever or prodromal illness. Cefotaxime is the appropriate fi rst
line antibiotic, with the addition of aciclovir where there is
a reasonable suspicion of herpes encephalitis. Mycoplasma is
another treatable organism so addition of a macrolide should
be considered.
6 of 7
Specific management
It is outside the scope of this article to detail the specific treat-
ment of each individual cause of encephalopathy but table 1
lists some specific treatments and supportive care. Some of
these can be started soon after presentation but some should
be reserved until discussion with a specialist.
Rehabilitation
Following acute management the rehabilitation phase is also
an extremely important part of management and should not
be overlooked. Involvement of the hospital multidisciplinary
team should be instigated as soon as possible. Consideration
should be given to education and psychological input for the
child as well as family support as there may be a huge change
to individual and family circumstances.
SUMMARY
The encephalopathic child is a paediatric emergency that can
present a diagnostic conundrum, and carries with it significant
morbidity and mortality. Good management can limit the
extent of longer-term damage. It is important that all clini-
cians who may be involved with children with altered mental
state use a systematic approach that allows them to form a
differential diagnosis, instigate useful and appropriate inves-
tigations and initiate good emergency care. Clinicians also
need to consider specific treatments for individual diagnoses.
This review has described such an approach, starting with the
patient’s presentation rather than a specific diagnosis and pull-
ing together biochemical, metabolic, microbiological, neuro-
radiological and electrophysiological investigations, based on
recent available evidence. It therefore provides a review of cur-
rent clinical practice.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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Encephalopathy in children: an approach to

assessment and management
Emily Davies, Daniel J Connolly and Santosh R Mordekar

Arch Dis Child published online December 27, 2011

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