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

Encephalopathy in children: an approach to

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

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 4 CT of the head showing subdural blood with a bright

cerebellum in a child with non-accidental head injury.

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.
Figure 5 (A) CT of the head with contrast showing swollen brain
with loss of grey/white matter differentiation. (B) Brain MRI (axial T2
by planning investigations based on a differential diagnosis. fast spin echo) showing diffuse high signal in the basal ganglia in the
Below we set out investigations that are indicated for each of same patient as figure 5A.
the causative categories listed in box 1.
encephalomyelitis (ADEM) is long and pointers in the his-
Infection/parainfection tory, and results from throat/stool/urine samples will allow
Inflammatory markers would be expected to be raised in men- targeted testing of the CSF.1 In certain children (eg, patients
ingitis and cerebral abscesses. One should not be reassured who are immunocompromised) fungal causes will need to be
by unremarkable values when there is good clinical suspicion looked for.
of central nervous system infection. Blood cultures and viral EEG can also be helpful in diagnosing encephalitis. There is
serology (including mycoplasma and Borrelia) are useful, as is usually generalised or focal slowing. The classically described
blood PCR for suspected viruses. Viral throat, urine and stool focal temporal changes and periodic lateralising epileptiform
samples can also help identify a precipitant. In demyelinating discharges are no longer thought to be pathognomonic of her-
conditions, it would also be important to send blood oligoclo- pes simplex virus encephalitis.11
nal bands (paired with cerebrospinal fluid (CSF)). Aquaporin Neuroimaging is not necessary in straightforward menin-
4 antibodies are becoming increasingly useful but are not as gitis at presentation but may be required if the child does
sensitive for neuromyelitis optica as in adults 5. Their presence not improve as expected. CT pre/post contrast can diagnose
however can imply a risk of relapse.6 Lumbar puncture (LP) is complications of meningitis (eg, hydrocephalus, abscess,
the gold standard for diagnosis and should be performed as infarction) (figure 1) but in suspected encephalitis and demy-
soon as is safe.7–10 Microscopy, culture and sensitivity, pro- elinating conditions MRI is more sensitive. (fi gure 2A,B)
tein and glucose should be sent in addition to viral samples. MRI is also superior when parainfectious cerebellitis is
The list of viruses causing encephalitis/acute demyelinating suspected.

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Review

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
Figure 6 MRI of the brain showing right middle cerebral artery blood and CSF studies for lactate and glucose can be use-
infarct. 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
Autoimmune
LP. Taking blood for karyotyping and DNA for storage is
It has become clear that autoantibodies are associated with
also appropriate.
encephalitis, particularly limbic encephalitis,12–15 with prom-
ising treatment options with immunomodulatory therapies.
N-methyl- D -aspartate (NMDA) receptor antibodies, voltage Toxins
gated potassium channel antibodies and glutamic acid decar- The history will hopefully give some clues but urine for toxi-
boxylase antibodies have all been implicated in children with cology should be obtained as soon as possible. Blood should
limbic encephalitis and should be considered in children pre- also be taken for paracetamol and salicylate levels, and a heavy
senting with memory disturbance, affective change and sei- metal screen where poisoning could be a possibility. Drug lev-
zures or movement disorders. Testing for these antibodies can els of anticonvulsants in known epileptic children should be
be performed on blood. NMDA receptor antibody encephali- tested in situations of acute deterioration in conscious level, as
tis is associated with ovarian teratomas and any girl in whom toxicity may be the cause.
this is a suspected diagnosis should have a pelvic ultrasound. An MRI scan can be useful and show particular patterns of
MRI of the brain may show changes in the limbic region and brain injury with particular drugs. Discussion with a neurora-
it may be this that fi rst prompts further investigation with diologist is advised.
antibody testing.
Hashimoto’s encephalopathy is a rare cause of encephalopa- Metabolic
thy in children but needs to be considered and thyroid func- This is a broad category and children with suspected metabolic
tion tests as well as thyroid autoantibodies are simple tests disease are at risk of being overinvestigated while missing the
that should be performed in unexplained encephalopathy.16 one crucial investigation necessary for diagnosis. Blood, urine
(figure 3A,B). and CSF results are important in many cases and ammonia,
lactate, venous blood gas, plasma amino acid, urine organic
Trauma and amino acid and sometimes CSF lactate, glucose and amino
Neuroimaging is the pivotal investigation. Non-contrast CT acid tests should be done acutely. Beyond this, discussion with
is often sufficient, identifying bleeds, cerebral contusion and a metabolic specialist or neurologist is advised.
in some case showing hypoxic-ischaemic damage. In non- MRI is also an important diagnostic tool in metabolic dis-
accidental injury there are characteristically subdural bleeds ease, and again it is outside the scope of this review to cover
of differing appearances on CT and MR, fractures and evi- this in detail. When metabolic disease is suspected it is impor-
dence of hypoxic-ischaemic damage. (figure 4) Bleeding for tant to consider the use of spectroscopy. Metabolic causes of
which there is no obvious causes can also raise the possibil- encephalopathy can be suspected when there are symmetrical
ity of metabolic disease such as glutaric aciduria type 1 and changes in white or grey matter or both on MRI and magnetic
Menke’s. Organic and amino acids, copper and caeruoplasmin resonance spectroscopy shows a lactate peak.
and in some cases a skin biopsy may be necessary. Basic inves- Endocrine causes should also be addressed in this category
tigations such as full blood count, clotting and liver function and blood glucose, blood gas and urine dipstick tests will

4 of 7 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 vascular tree, most conveniently performed with MRI with
will point to adrenal insufficiency. magnetic resonance angiography (MRA)20 (figure 6). MRI is
also the follow-up imaging modality of choice. 21 A full blood
Hypertensive count and clotting investigation are needed and the erythro-
This diagnosis is largely made on initial observations. The cyte sedimentation rate and an autoimmune screen are help-
underlying cause (eg, haemolytic uraemic syndrome, Henoch– ful in looking for vasculitic causes. Homocysteine, cholesterol
Scohlein purpura) should be investigated by renal function, and triglyceride levels should be checked and prothrombotic
urinalysis, renal ultrasound cardiac echo and endocrine inves- states should also be looked for, in the family history and
tigations (eg, cortisol, renin, aldosterone, catecholamines). 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
Hypoxic/ischaemic
is also indicated where a cause for infarction is not clearly
Hypoxic-ischaemic damage secondary to trauma, prolonged
demonstrated.
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 Haemorrhage
hours of injury, although there is often an optimum timing for This is normally secondary to trauma but may be spontane-
scanning. If the child survives, repeat imaging when myelina- ous in children with abnormal clotting/platelets or in children
tion is complete (after 2 years of age) is recommended to look at with arteriovenous malformations (AVM). Platelet count and
the permanent changes once acute oedema and haemorrhage clotting screen are essential. Specific factor assays can be dis-
have resolved. In such children LFTs, urea and electrolyte, clot- cussed with a paediatric haematologist. In the fi rst instance CT
ting and urine dipstick tests are essential to look for evidence will show most haemorrhages but underlying AVM may need
of multiorgan damage. to be considered with MRI/MRA, CT angiography or catheter
In children with stroke the fi rst investigation is usually CT, angiography. AVM are often not visible until the acute bleed
which reliably detects haemorrhagic causes of stroke. Studies has resolved or been neurosurgically managed 22 and therefore
have shown however that CT alone will miss a large num- delayed angiographic imaging may be advised.
ber of acute ischaemic stroke cases20 (CT detection in 10%
compared to MRI detection in 46%). Brain imaging is rec- Malignancy
ommended within 24 h of onset of symptoms suggestive of Brain tumours may present with encephalopathy. Children
ischaemic stroke, along with imaging of the cervicocranial with known brain tumours can also become encephalopathic

Davies E, Connolly DJ, Mordekar SR. Arch Dis Child (2011). doi: 10.1136/adc.2011.300998 5 of 7
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as a result of raised intracranial pressure, tumour spread, or Specific management

chemotherapeutic agents. Imaging is the fi rst line investiga- It is outside the scope of this article to detail the specific treat-
tion. CT will detect many tumours and in an emergency is ment of each individual cause of encephalopathy but table 1
useful at showing hydrocephalus, cerebral oedema and hae- lists some specific treatments and supportive care. Some of
morrhage. Most paediatric brain tumours are in the midline these can be started soon after presentation but some should
and therefore midline shift, a marker of cerebral mass effect, be reserved until discussion with a specialist.
may not be clearly evident. MRI may be useful for surgical
planning or for smaller lesions or tumours in specific sites. Rehabilitation
Once imaging has suggested a tumour then more detailed Following acute management the rehabilitation phase is also
neuro-oncological investigations and management need to be an extremely important part of management and should not
planned with specialist teams. Basic full blood count, clotting, be overlooked. Involvement of the hospital multidisciplinary
group and save/crossmatch, full electrolyte investigations are team should be instigated as soon as possible. Consideration
certainly needed and pituitary function tests should be consid- should be given to education and psychological input for the
ered dependent on the site of the tumour. child as well as family support as there may be a huge change
to individual and family circumstances.
MANAGEMENT
Emergency management
In the fi rst instance a child with altered mental state needs SUMMARY
to be managed with good emergency care, irrespective of the The encephalopathic child is a paediatric emergency that can
cause. This undoubtedly improves outcome. Consideration present a diagnostic conundrum, and carries with it significant
needs to be given to use of a paediatric intensive care unit morbidity and mortality. Good management can limit the
(PICU) care if there is a suggestion of an unstable airway or extent of longer-term damage. It is important that all clini-
organ support is required. cians who may be involved with children with altered mental
Management of raised intracranial pressure is important state use a systematic approach that allows them to form a
and neuroprotective strategies include nursing with head in differential diagnosis, instigate useful and appropriate inves-
midline, 20° up and maintaining normocapnea. tigations and initiate good emergency care. Clinicians also
Treatment of raised intracranial pressure can involve use need to consider specific treatments for individual diagnoses.
of hyperosmolar substances. Evidence for use of mannitol This review has described such an approach, starting with the
in children is mainly extrapolated from adult studies and patient’s presentation rather than a specific diagnosis and pull-
there is emerging but non-conclusive evidence that hyper- ing together biochemical, metabolic, microbiological, neuro-
tonic saline is more effective than mannitol. 23–25 To date radiological and electrophysiological investigations, based on
use of either in traumatic brain injury with life threatening recent available evidence. It therefore provides a review of cur-
intracranial pressure is supported by the literature as is use rent clinical practice.
in the intensive care setting where intracranial monitoring
Competing interests None.
is occurring. For other situations individual judgement is
required. Provenance and peer review Commissioned; externally peer reviewed.
The use of steroids in bacterial meningitis reduces hear-
ing loss and neurological sequelae in Haemophilus influenzae
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Davies E, Connolly DJ, Mordekar SR. Arch Dis Child (2011). doi: 10.1136/adc.2011.300998 7 of 7
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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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