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Education & Practice Online First, published on March 30, 2015 as 10.1136/archdischild-2014-306388
REVIEW

Neonatal seizures—part two:

Aetiology of acute symptomatic
seizures, treatments and the
neonatal epilepsy syndromes
Anthony R Hart,1,2 Elizabeth L Pilling,2 James J P Alix3

1
Department of Paediatric and
Neonatal Neurology, Sheffield
Children’s Hospital NHS
Foundation Trust, Ryegate
Children’s Centre, Sheffield,
South Yorkshire, UK
2
Department of Neonatology,
Sheffield Teaching Hospitals NHS
Foundation Trust, Sheffield, UK
3
Department of Clinical
Neurophysiology, Sheffield
Teaching Hospitals NHS
Foundation Trust, Royal
Hallamshire Hospital, Sheffield,
UK
Correspondence to
Dr Anthony Hart, Department of
Paediatric and Neonatal
Neurology, Sheffield Children’s
Hospital NHS Foundation Trust,
Ryegate Children’s Centre,
Tapton Crescent Road, Sheffield,
South Yorkshire S10 5DD, UK;
anthony.hart@sch.nhs.uk
Received 11 March 2014
Revised 10 December 2014
Accepted 25 February 2015
▸ http://dx.doi.org/10.1136/
edpract-2014-306385
To cite: Hart AR, Pilling EL,
Alix JJP. Arch Dis Child Educ
Pract Ed Published Online
First: [ please include Day
Month Year] doi:10.1136/
archdischild-2014-306388
ABSTRACT
Most neonatal epileptic seizures are provoked by
an underlying condition or problem—‘acute
symptomatic seizures’. However, a few neonatal
epilepsy syndromes exist, and these are defined
by the constellation of seizure types, EEG
findings and family history seen. Making an
accurate diagnosis of an epilepsy syndrome can
help direct investigations, treatment options and
provide prognostic information. This article
discusses the investigative approach and
treatments for neonatal epileptic seizures,
including the neonatal epilepsy syndromes.
INTRODUCTION
Once a clinician has diagnosed neonatal
epileptic seizures and defined the seizure
type, the next step is to decide whether
they are acute symptomatic seizures or
part of an epileptic syndrome. Most neo-
natal epileptic seizures are acute symp-
tomatic;1 however, a small number of
neonatal epilepsy syndromes exist.
Diagnosing neonatal epilepsy syndromes
helps the formulation of investigation
plans, choice of antiepileptic drugs and
the duration of treatment. Prognostic
information can also be gathered. This
article reviews neonatal acute symptom-
atic seizures and epilepsy syndromes,
with a particular focus on aetiologies,
investigations and treatments.
ACUTE SYMPTOMATIC SEIZURES
Acute symptomatic seizures occur at the
time of, or near to, either a systemic or
brain insult, including metabolic derange-
ments.2 The timing of seizure onset may
help to determine the possible aetiology.3
Table 1 summarises the typical causes of
neonatal seizures by their time of appear-
ance and includes the neonatal epilepsy
syndromes for comparison. Other infor-
mation gained from family, antenatal,
birth and postnatal histories can also help
determine aetiology. Hypoxic ischaemic
encephalopathy (HIE) is the commonest
cause of neonatal acute symptomatic sei-
zures.1 Clinicians should also be aware
that fetuses with metabolic or neuro-
logical disorders may decompensate
during labour and delivery and experi-
ence seizures. Thus, beware assuming all
encephalopathic neonates with seizures
have HIE.
Where the history, examination and
initial screen for acute symptomatic sei-
zures do not reveal a cause, further inves-
tigations may be warranted. We suggest
some investigations in table 2. A few
points on investigations are worth noting:
serum glucose samples should be taken
before the lumbar puncture (LP) to help
identify glucose transporter type 1 defi-
ciency syndrome, where a low cerebro-
spinal fluid (CSF) glucose (below
2.2 mmol/L) or CSF:plasma ratio (<0.45)
is noted in the absence of infection.4 If
the serum samples are taken after the LP,
the plasma glucose will be falsely high
because of the stress response and the
ratio will subsequently be meaningless.
The LP will then need to be repeated.
Similarly, if an LP is being undertaken in
a neonate with seizures, then paired CSF
and plasma amino acids should be con-
sidered to look for glycine or serine
encephalopathies. This may also prevent
the need to repeat the LP at a later date.
Investigations for vitamin-responsive epi-
lepsies and a therapeutic trial of vitamins
should be given for refractory neonatal sei-
zures where no other cause is known. The
recommended doses are given in table 3.

Hart AR, et al. Arch Dis Child Educ Pract Ed 2015;0:1–7. doi:10.1136/archdischild-2014-306388 1
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Review

Table 1 Aetiology by predominant time of onset

Time of onset Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 and beyond

Seizure aetiology Structural, developmental brain abnormalities

Intrauterine (congenital) infection
Pyridoxine dependent/pyridoxal phosphate responsive epilepsy
Perinatal asphyxia
Sepsis
Hypoglycaemia
Perinatal stroke
Maternal drug withdrawal
Periventricular haemorrhage
Perinatal trauma
Hypoglycaemia
Benign familial neonatal convulsions
Hypocalcaemia
Aminoacidopathies
Galactosaemia
Ketotic and non-ketotic hyperglycinaemia
Follinic acid-responsive seizures
Glucose transporter type 1 deficiency
Ohtahara
Early myoclonic epilepsy
Benign neonatal seizures
Migrating partial seizures of infancy
Adapted from Appleton and Gibbs.3

Pyridoxine can be given intravenously but may cause recommendations advised starting enteral pyridoxal
apnoea, so careful observation is required. Pyridoxine phosphate first because it treated both conditions.5 6
was not traditionally thought to treat pyridoxal However, recent cases have highlighted cases in which
phosphate-dependent seizures, and thus pyridoxal phosphate worsened, and pyridoxine
improved, seizures in individuals with mutations in the
pyridoxal phosphate (PNPO) gene.7 This has confused
Table 2 Suggested investigations useful in determining the matters considerably, and the authors’ practice is now to
cause of neonatal seizures try two doses of intravenous pyridoxine first and then
swiftly move on to enteral pyridoxal phosphate where
Approach Possible investigations
no response is seen. In an ideal world, investigations
Initial screen (for acute Liver function test would be completed quickly and then treatment subse-
symptomatic seizures) Renal function test quently instigated with minimum delay. Given the diffi-
Calcium and magnesium culties in achieving this, together with risk of the
Glucose
Blood cultures possible deterioration in a neonate’s condition, we rec-
Lumbar puncture ommend vitamin treatments be instigated immediately
Urine culture and investigations completed as soon as possible. Biotin
Cranial ultrasound/magnetic resonance and follinic acid (calcium follinate) should be com-
imaging
menced at the same time as the B vitamins and
Possible second-line Electroencephalography
investigations Lactate
Acylcarnitines Table 3 Recommended doses for vitamin-responsive epilepsy in
Ammonia
neonates
Urate
Biotinidase Drug/condition Dose
Copper, caeruloplasmin and hair analysis
Plasma and urine amino acids Biotin 5 mg orally/NGT twice a day, can increase up to
Urine organic acids 10 mg twice a day
Paired cerebrospinal fluid (CSF) and plasma
amino acids (includes glycine and serine) Follinic acid 5 mg orally/NGT twice a day
Paired CSF and plasma glucose and lactate Pyridoxine 100 mg intravenous trial dose (if positive, can be
(if not done already for glucose transporter given orally 15 mg/kg/day in divided doses to a
type 1 deficiency syndrome) maximum of 500 mg)
Urine alpha aminoadipic semialdehyde
(αAASA) (or plasma/CSF pipecolic acid Pyridoxal Surtees: 10 mg/kg/dose 2 h apart orally as trial
if not available) phosphate Baxter: 50 mg/kg/day in divided doses for 2 weeks*
Urine sulfites Adapted from references 5 and 6. *Authors’ current practice.
Congenital infection screen NGT, nasogastric tube.

2 Hart AR, et al. Arch Dis Child Educ Pract Ed 2015;0:1–7. doi:10.1136/archdischild-2014-306388
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subsequently stopped when investigations rule these
conditions out.6
THE NEONATAL EPILEPSY SYNDROMES
The neonatal epileptic syndromes include
▸ benign neonatal seizures (fifth day fits)
▸ benign neonatal familial seizures
▸ early infantile epileptic encephalopathy (EIEE) (Ohtahara
syndrome)
▸ early myoclonic epileptic encephalopathy (EMEE)
▸ migrating partial seizures of infancy
A summary of the neonatal epilepsy syndromes,
including EEG findings, is found in table 4.
Benign neonatal seizures are colloquially called fifth
day fits. They are characterised by unilateral, bilateral
or migrating clonic movements of limbs and face
lasting minutes and occurring in clusters or status epi-
lepticus.8 The seizures may also be associated with
apnoea.9 They are not associated with a family
history, so this epilepsy syndrome is often a diagnosis
of exclusion after other causes of acute symptomatic
seizures prove negative (table 2), the seizures have dis-
appeared and the baby looks well. The acute manage-
ment of acute seizures may be with phenobarbital,
benzodiazepines and/or phenytoin. Long-term treat-
ments are not necessary as the seizures disappear
within a day.8 9
Benign familial neonatal seizures are frequent, short
tonic seizures with posturing, apnoea, vocalisations, eye
movement abnormalities and autonomic changes. Focal
or generalised clonic seizures can also be seen alongside
the tonic seizures, but pure clonic seizures are rare.10
The key to the diagnosis is the seizure type, timing of
onset and the family history. The latter may not be
known in the acute phase, leading to neonates being
investigated for acute symptomatic causes (table 2). The
acute treatment is with phenobarbital, benzodiazepines
and/or phenytoin. Regular preventative medication
should be considered where seizures are frequent, and
options include carbamazepine, sodium valproate or
levetiracetam.
Early infantile epileptic encephalopathy (Ohtahara
syndrome) is an uncommon epileptic syndrome with
poor prognosis. Onset of seizures may occur in utero
or postnatally. Tonic seizures and epileptic spasms,
occurring in isolation or clusters, are the commonest
seizures and may be symmetrical or asymmetrical.
They classically occur in both the awake and sleep
states and are associated with bursts on the EEG with
suppression between them lasting typically 3–5 s, but
sometimes longer.11
Developmental brain abnormalities are the com-
monest cause,11 some of which may only be demon-
strated at postmortem.12 13 A number of gene
mutations are also associated with Ohtahara syn-
drome, including in the STXBP1, ARX and SCN2A
genes.14 Investigations will include MRI, consider-
ation of metabolic investigations (table 2) and a
Hart AR, et al. Arch Dis Child Educ Pract Ed 2015;0:1–7. doi:10.1136/archdischild-2014-306388
Review
review by the genetics team. There are no consistently
effective treatments: vigabatrin may help to some
degree15 and a therapeutic trial of vitamins should be
tried.16 17 Chloral hydrate, an old-fashioned drug
now used for sedation but with antiepileptic proper-
ties, has also helped in an isolated case.18 Where a
surgically resectable lesion is present, epilepsy surgery
can stop or reduce seizures.19 Where no surgically
resectable lesion is present, the prognosis is poor.
Early myoclonic encephalopathy (EME) is similar to
Ohtahara syndrome, but the predominant seizure type
is myoclonic, rather than tonic, seizures. The epileptic
seizures may come in clusters or occur continuously.
Seizure onset is shortly after birth. The EEG shows
burst suppression, which is more apparent in sleep
than wakefulness, in contrast to Ohtahara syndrome
where the pattern is continuous.11
There are many causes of EME. Autosomal-
recessive genetic and metabolic aetiologies are most
common, with structural lesions less prevalent than
Ohtahara syndrome.11 The investigative approach will
initially involve metabolic tests and neuroimaging
(table 2). No medications are consistently effective.
Vigabatrin may worsen and the ketogenic diet
improve seizure frequency caused by non-ketotic
hyperglycinaemia.20 21 We advocate trying vitamins
early. The prognosis is poor.
Migrating partial seizures in infancy is an epileptic
syndrome usually presenting later in infancy, which can
be seen in the neonatal period. The seizures are focal
clonic and/or tonic and may be associated with auto-
nomic features (table 4). They may migrate from one
region of the body and EEG to another. The cause is
unknown, but genetic aetiologies exist including in the
KCNT1 potassium ion channel.22 The vast majority of
antiepileptic drugs are ineffectual.23 24 Stiripentol and
clobazam, and possibly also levetiracetam, have been
described to gain complete control of seizures when
given together,24 25 but did not improve the EEG abnor-
malities.24 Potassium bromide has gained complete
control in one patient26 but not in others.23 Rufinamide
has reduced seizure frequency by 50% in 2 of 5
patients,27 and acetazolamide has gained complete
control of apnoeic seizures.23 Quinidine has been used
successfully in one child.28 We have had success with a
combination of phenytoin, levetiracetam and acetazola-
mide, with seizures recurring when any of the three
drugs was withdrawn or phenytoin levels fell. A thera-
peutic trial of vitamins should be attempted early. The
ketogenic diet has also not been effective in published
cases,24 although we have cases that have responded.
Investigations for the aetiology of the neonatal epilepsy
syndromes
The investigations will depend on the clinical picture.
For example, a child who presents on day 5 in status
epileptics is likely to have a septic screen and possible
neuroimaging. But if the seizures quickly respond to
3
4
Table 4 A summary of the clinical features of the neonatal epilepsy syndromes
Neonatal epilepsy Axis 1 (ictal phemenology—what
syndrome you see) Axis 2 (seizure types) EEG findings Axis 4 (aetiology) Treatment Axis 5 (prognosis/disability)
Review

36
Benign neonatal Rhythmical jerking of the arms and legs. Focal, multifocal, Non-specific including: Unknown Intravenous Good.
9
seizures Sometimes facial involvement on days hemiconvulsive clonic seizures Interictal: benzodiazepine, Seizures abate8
4–6 of life8 9 ▸ Theta pointu alternants phenytoin acutely
▸ Multifocal abnormalities None in long term
▸ Discontinuous EEG
pattern
Ictal:
▸ Rhythmical spike/slow
waves in rolandic regions
Benign familial neonatal Short, frequent stiffenings with apnoea Tonic seizures with autonomic Non-specific including:10 36 Autosomal-dominant Intravenous Good.
seizures or crying. May have desaturation or features. Less frequently Interictal: channelopathy (strong benzodiazepine, Seizures abate by 6 months
bradycardia10 37 clonic seizures alongside tonic ▸ Normal family history). phenytoin acutely usually. 14% have longer-term
seizures ▸ Discontinuous OMIM: 608217 May require long-term seizures.
▸ Focal or multifocal OMIM: 121200 treatment Developmental outcome good36 37
abnormalities OMIM: 121201
▸ Theta pointu alternants Rare autosomal-recessive
Ictal: OMIM: 269720
▸ Flattening of EEG trace
initially
▸ Then bilateral, asymmetric
spike and sharp waves
Early infantile epileptic Sick baby. Seizures before or after birth Focal or generalised tonic Burst suppression in wake Structural brain None effective Dire if no surgically resectable
encephalopathy (average day 10). Tonic stiffening in seizures with autonomic and sleep states11 abnormalities most Consider vitamins, lesion. Half die within weeks.
(Ohtahara syndrome) clusters with desaturation, sometimes features. common.11–13 vigabatrin, ketogenic Survivors invariably have
due to diaphragmatic splinting11 Less common—focal clonic Genetic abnormalities14 diet15–17 neurological/learning difficulties
seizures Epilepsy surgery19 and epilepsy including West and
Lennox Gastaut syndromes11
Early myoclonic epilepsy Sick baby. Myoclonic seizures Burst suppression more Genetic causes, metabolic None effective. Dire. More than half die within
(EME) Rapid jerks of limbs, face and trunk. Also, focal clonic, autonomic apparent in sleep than wake aetiologies most common11 Consider vitamins and weeks or months.
May come in clusters but not and tonic seizures state11 ketogenic diet20 Survivors invariably have
rhythmical11 neurological/learning difficulties
and epilepsy11
Migrating partial Usually presents in infancy, rarely in Focal tonic, focal clonic and Interictal: Genetic aetiology most Consider vitamins Dire. Long-term neurological,
seizures of infancy neonatal period. autonomic seizures. ▸ Slow activity alternating likely22 For apnoea—try developmental difficulties and
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Frequent tonic deviation of eyes and Migrating seizures sides acetazolamide epilepsy
head to the side with eye lid jerking, ▸ Multifocal spikes Others: Death usually within a few years
and stiffening and clonic jerking of Ictal: ▸ Stiripentol and of life25
limbs. May have autonomic features. ▸ Rhythmical theta and clobazam
Seizures move around the body22 36 alpha discharges ▸ Potassium bromide
multifocally and migrating ▸ Levetiracetam
to different brain areas ▸ Rufinamide
▸ Several seizures occurring ▸ Quinidine
independently in different ▸ Ketogenic diet23–28
regions of brain36

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Review

Figure 1 Suggested algorithm for the treatment of neonatal epileptic seizures. BD, twice a day.

treatment and the baby looks otherwise well, further
investigations may not be warranted once the epilepsy
syndrome is diagnosed. In contrast, the investigations
for Ohtahara syndrome and EMEE will be more
extensive, including metabolic investigations, neuroi-
maging and genetic testing.
TREATMENTS OF NEONATAL EPILEPTIC SEIZURES
Acute epileptic seizures
No nationally agreed guidelines exist on the acute
treatment of neonatal seizures. Phenobarbital is used
as first-line treatment in many neonatal units. Animal
experiments have noted it is associated with neuronal

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apoptosis in rats, as are benzodiazepines.29
Phenobarbital also causes electroclinical dissociation
in human neonates30 and is implicated in reduced
cognitive and memory abilities in young children
when given long term.31 32 On the other hand, early
administration in neonatal HIE may improve
outcome.30 Without good evidence that other antiepi-
leptic drugs are better and safer, it seems logical to
retain phenobarbital for first-line use (figure 1).
Phenytoin has the same efficacy as phenobarbital,
but therapeutic-level monitoring is required and it has
a worse side effect profile.30 In our centre, phenytoin
is not used in neonates requiring inotropic support
because it causes hypotension and cardiac arrhyth-
mias. Benzodiazepines or lidocaine may also be of
use. Midazolam can suppress the conscious level and
respiratory drive, leading to ventilation and, in our
experience, hypotension. Lidocaine can cause arrhyth-
mias, and we try to avoid this in neonates who have
had phenytoin.
Newer antiepileptic drugs, such as topiramate and
lamotrigine, are also being used in small numbers of
neonates, but data on their effectiveness are limited.30
Levetiracetam is being used increasingly, particularly
because of its intravenous and enteral preparations
and data showing loading doses are safe and effective
with minimal side effects.33 34 However, the correct
loading dose is not known with studies varying from
10 to 50 mg/kg.34 35 Disagreement also exists about
whether maintenance doses should be given twice or
three times a day.35
The epilepsy syndromes
The treatment of the neonatal epilepsy syndromes will
be guided by the specific syndrome. For example,
there is no need for long-term therapy in benign neo-
natal seizures, but in migrating partial seizures of
infancy, for example, you may elect to try a trial of
vitamins, acetazolamide for seizures with apnoea, and
a combination of levetiracetam, stiripentol and cloba-
zam for other seizure types. We would strongly advise
consulting expert neurological advice in situations
where a complex epilepsy syndrome is considered.
CONCLUSION
Most neonatal epileptic seizures are acute symptom-
atic, resulting from conditions like HIE. Investigations
should be targeted, depending on what the differential
diagnoses are following a full history and examin-
ation. Little evidence exists on which antiepileptic
drugs are most effective for acute symptomatic sei-
zures or have the least short-term and long-term side
effects. No national consensus exists on the correct
pathway to treat neonatal seizures.
A limited number of neonatal epileptic syndromes
exist, some with good and some with dire prognosis.
A careful history, noting the seizure type and EEG
pattern, help to identify these syndromes. Where a
6 Hart AR, et al. Arch Dis Child Educ Pract Ed 2015;0:1–7. doi:10.1136/archdischild-2014-306388
benign syndrome is found, treatment for status epilep-
ticus or frequent seizure clusters can be instituted, fol-
lowed by a rapid withdrawal of medication. For the
more severe syndromes, few treatment options are
likely to be effective and prognosis is poor if no surgi-
cally resectable lesion is found. Vitamin-responsive
seizures should always be considered early in refrac-
tory neonatal seizures and specialist advice sought.
Contributors ARH performed the literature review and wrote
the article, providing neonatal and neurological viewpoints.
JJPA reviewed and edited the article, particularly with reference
to neurophysiology data. ELP reviewed the article and provided
comments from a neonatal perspective.
Competing interests None.
Provenance and peer review Not commissioned; externally
peer reviewed.
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Neonatal seizures−−part two: Aetiology of

acute symptomatic seizures, treatments and
the neonatal epilepsy syndromes
Anthony R Hart, Elizabeth L Pilling and James J P Alix

Arch Dis Child Educ Pract Ed published online March 30, 2015

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Collections Epilepsy and seizures (33)
Child health (288)

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