Acta Pdiatrica ISSN 0803-5253

REVIEW ARTICLE

Systematic review of neonatal seizure management strategies provides

guidance on anti-epileptic treatment
Lena Hellstrom-Westas (lena.westas@kbh.uu.se)1, Geraldine Boylan2, Johan 
Agren1
1.Department of Womens and Childrens Health, Uppsala University, Uppsala, Sweden
2.Department of Paediatrics & Child Health, University College Cork, Cork, Ireland

Keywords ABSTRACT
Anti-epileptic drugs, Electroencephalogram, There is a lack of scientific evidence to support the best management of neonatal seizures.
Newborn, Phenobarbital, Status epilepticus
Current strategies for neonatal seizure management were investigated by analysis of all
Correspondence surveys published during the time period 20002012. Methods for seizure diagnosis and
m-Westas, Department of Womens and
L Hellstro
Childrens Health, Uppsala University Hospital,
availability of electroencephalogram (EEG), including monitoring, varied. Phenobarbital was
SE-751 85 Uppsala, Sweden. the drug of first choice, and the use of off-label drugs and treatment times varied.
Tel: +46-18-611 00 00 | Conclusion: We conclude that there is an urgent need for more evidence-based studies
Fax: +46-18-6115833 |
Email: lena.westas@kbh.uu.se
to guide neonatal seizure management.

Received
21 April 2014; revised 11 July 2014;
accepted 19 September 2014.

DOI:10.1111/apa.12812

Hellstrom-Westas L, Boylan GB,  Agren J. Results from multiple

surveys on seizure management can guide future
development of neonatal anti-epileptic treatment strategies.
Acta Paediatrica 2014; Stockholm. ISSN
The copyright line for this article was changed on 7 May 2015
after original online publication.

INTRODUCTION During the last decade, the management of neonatal

Seizures in newborn infants are often caused by, or associ-
ated with, other severe neonatal conditions such as
hypoxiaischaemia, cerebral haemorrhage, metabolic dis-
turbance and infection. Seizures may also be attributed to
syndromes, malformations or more rarely primary epilepsy
(1,2). Newborn infants with seizures represent a high-risk
population with increased mortality and risk for neurolog-
ical handicaps and epilepsy in survivors (3).
The clinical presentation of neonatal seizures may be very
vague, and many are indeed entirely subclinical (4). Hence,
clinical recognition of neonatal seizures is unreliable (5).
Correct identification of seizures is enhanced by the use of
electroencephalogram (EEG) or amplitude-integrated EEG
(aEEG) monitoring of high-risk infants (57). EEG monitors
using the aEEG trend and limited-channel EEG (aEEG/
EEG) are now standard in many neonatal intensive care
units (NICUs).
seizures has undergone major changes in several aspects.
The increased use of aEEG/EEG monitoring combined with
an increased awareness of the inherent difficulties of
diagnosing neonatal seizures by clinical observation only
Key notes
 Scientific evidence to support the best management of
neonatal seizures is scarce.
 Methods for seizure diagnosis differ, as does the
availability of amplitude-integrated EEG (aEEG) and
EEG. Anti-epileptic treatment varies, and there is no
data on long-term effects.
 There is an urgent need for more evidence-based data
to guide neonatal seizure management in term and
preterm infants.

2014 The Authors. Acta Pdiatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Pdiatrica 2015 104, pp. 123129 123
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Review of neonatal seizure management m-Westas et al.
Hellstro

has led to the increased likelihood of accurate seizure

diagnoses. Consequently, an increased number of neonatal
seizures are diagnosed. However, as many babies have both
clinical and subclinical seizures, the actual number of
babies with diagnosed seizures may not have changed (7,8).
A major limitation in the management of infants with
diagnosed seizures is the lack of evidence-based treatment
once seizures are diagnosed. Only a few randomised
controlled studies comparing anti-epileptic treatment strat-
egies in relation to effect on electrographic seizure activity
have been performed. A Cochrane review (9) published in
2004 reported on anticonvulsant treatment for neonates; it
only included two studies (10,11). Another Cochrane report
reviewed the effects of anticonvulsants on mortality and
morbidity in term infants after perinatal asphyxia (1214).
To our knowledge, no major progress has occurred in
neonatal anti-epileptic drug treatment; that is, no rando-
mised controlled trials primarily assessing anti-epileptic
drugs have been completed since the publication of these
reports. There is an abundance of both older and more
recent nonrandomised observational reports on the effects
of various anti-epileptic drugs. Many of these studies are
lacking simultaneous EEG recording, and it is therefore
impossible to draw any conclusions regarding their true
efficacy on electrographic seizure activity. Due to the lack
of any evidence base for the treatment of neonatal seizures,
the recommended management is largely dependent on
expert opinions, consensus and tradition.
The problem of neonatal seizure management is signif-
icant. Relatively recent data from the United States, Canada
and unpublished data from Sweden indicate that the overall
seizure incidence is around 23/1000 live born infants (1,2).
Data from low- and middle-income countries are scarce,
but the seizure incidence is believed to be higher; a recent
estimate from Kenya demonstrated a neonatal seizure
incidence more than 10 times higher than that in North
America and Sweden (39.5/1000 live births) (15). Unfortu-
nately, there is very little available data on the prevalence of
neonatal seizures in Europe, although quite large variations
can be expected as indicated by a report on perinatal data
published in 2008 (www.europeristat.com). In the Euro-
Peristat project, perinatal data collected in 2004 from 25 EU
countries demonstrated large variations in neonatal and
infant mortality as well as in the incidence of preterm birth.
The aim of this study was to investigate current strategies
for neonatal seizure management, especially the diagnosis
and treatment of neonatal seizures, by an analysis of surveys
published during the time period 20002012.
Figure 1 Search strategy using MeSH terms, number of references within
brackets.
We also searched PubMed for eligible studies, published
in all languages, with the following terms in combination
with Newborn AND Seizure: Management, Treatment,
Anticonvulsant treatment, EEG, EEG monitoring, AND
Survey, Figure 2. We also searched PubMed for the
following terms in combinations (not shown): Newborn,
neonatal, brain, seizure, diagnosis, aEEG, monitoring,
management, anti-epileptic, drug, treatment, anticonvul-
sive, survey, questionnaire.
In all searches that rendered <1500 references, all
citations and selected abstracts were assessed for relevance.
Finally, we also searched all reference lists of the selected
studies on surveys (below), for further studies on neonatal
seizure management.
RESULTS
Altogether 17 studies (repeatedly found in the multiple
research criteria combinations above and by all three search
strategies) presenting surveys on neonatal seizure manage-
ment (diagnosis and treatment) were considered relevant.
Fourteen of these were published during the review period
while two were published earlier, in 1982 and 1993,
respectively (16,17). One study included a survey of man-
agement practices of hypoxicischaemic encephalopathy,
published in 1988 (18). The three older references were not
included in the comparisons because they reflect neonatal
seizure management 2030 years ago.
Tables 13 present summaries of the 14 studies that were
considered relevant for this review of surveys on current

METHOD
PubMed was searched in November 2012 using three
search strategies. First, we searched PubMed using the
MeSH terms: Infant, Newborn AND Seizures/diagnosis;
Infant, Newborn AND Seizures/therapy; Infant, New-
born AND Seizures/drug therapy; Infant, Newborn Figure 2 Terms used for PubMed search, number of references within
AND Seizures/prevention and control; Infant, Newborn brackets.
AND Seizures/epidemiology, Figure 1.

124 2014 The Authors. Acta Pdiatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Pdiatrica 2015 104, pp. 123129
 m-Westas et al.
Hellstro Review of neonatal seizure management

neonatal seizure management. Some of the studies are

Sz diagnosis/monitoring
quoted in more than one table. Table 1 shows data from six

Preterm 34/53.5%
aEEG/EEG and/or EEG

at-risk newborns:
studies that included methods for seizure diagnosis, mainly

Term: 33/66.5
aEEG/EEG and EEG (1924). Table 2 presents data from
seven studies, five of which are surveys to professionals or
institutions while two studies contain data on administered
anti-epileptic treatment in newborn infants retrieved from
large databases covering multiple institutions (20,22,24
29). Table 3 displays views on neonatal seizure manage-

100% had access to aEEG/EEG and/or EEG

Available to 92%,

Recommended aEEG or EEG after asphyxia:

90% had access to aEEG/EEG and/or EEG

would be used

ment among neonatologists as compared to paediatric

Preterm 58%
Term 58.2%
Sz diagnosis:
neurologists, retrieved from four studies (20,22,3032).
by 59%
EEG

DISCUSSION
This literature search of current practices in neonatal
Neonatologists 70.5%

Level 3 NICU: 87%

Level 2 NICU: 33% seizure management rendered 14 surveys of diagnostic
Neurologists 40%
Available to 76%,

aEEG availability:

procedures and anti-epileptic treatments, mainly completed

would be used

by neonatologists and paediatric neurologists from Western

by 62%
aEEG/EEG

Europe, USA, Canada, Australia and New Zealand.

It is clear that the use of aEEG/EEG and EEG monitor-
ing for seizure diagnosis is high in the responding NICUs.
However, in some studies, the results mainly reflect practice
Denmark, France, Germany,

in larger academic units. When level II NICUs were also

Ireland, Italy, Netherlands,
59% Europe, 26% USA

included in one survey, the number of units with access to

aEEG/EEG monitoring was significantly lower (23). The
Spain, Sweden, UK

Europe, Canada
USA (75%), UK,

increased use of aEEG/EEG and EEG monitoring is also

New Zealand

supported by the increasing number of scientific publica-

Australia and

tions using or assessing these methods (5,7). It has recently

Country

been shown that use of aEEG/EEG monitoring is associ-

Israel

UK

ated with significantly shorter time to seizure diagnosis in

encephalopathic infants and fewer infants with a seizure
diagnose without aEEG/EEG or EEG verification, but not
66/112 (59%)
94/152 (62%)

36/55 (65%)

13/20 (65%)

with an increased use of anti-epileptic drugs (6). Although

estimated
400500
Responders

214/214

193 of an

the number of detected seizures increases when continuous

(100%)

aEEG/EEG or EEG monitoring is used, the overall number

210

of infants with a seizure diagnosis is perhaps not increased

because many infants have both clinical and subclinical
Paediatric/Neonatologist (69%),

seizures (8,9). Only two relatively small randomised con-

All listed neonatologists (2005)

Paediatric/Neurologists (15%)
Neonatologists at 20 European

trolled trials have investigated whether the use of contin-

Senior nurses at all NICUs

neurocritical care (19%)

uous aEEG/EEG monitoring is associated with less seizure

Neonatologists (25%),

Neonatal neurologist/
Table 1 Surveys assessing methods for diagnosis of neonatal seizures

Neurologists (56%),

burden, one of the studies also used a seizure event detector

University hospitals

(33,34). Both studies demonstrated nonsignificant trends

Neonatologists

towards fewer seizures when aEEG/EEG was used to

Neurologists

in the UK

detect and guide administration of anti-epileptic drugs.

Subjects

Neonatologists seem to be keener than paediatric neurol-

ogists in monitoring high-risk infants before seizures are
diagnosed (20).
Phenobarbital is the preferred first drug of choice for
scenario (neonatal encephalopathy)

acute treatment of neonatal seizures, both among neona-

Postal questionnaire with a case

tologists and paediatric neurologists. When this treatment

Ponnusamy et al. 2010 (23).
Study and study characteristics

fails, neonatologists seem to initially favour higher doses of

Bassan et al. 2008 (20).
Questionnaire 20 items

Boylan et al. 2010 (21).

Vento et al. 2010 (22).

Web-based survey; 23
Glass et al. 2012 (24).

phenobarbital while paediatric neurologists generally prefer

Filan et al. 2007 (19).

to use other anti-epileptic medications and also more

Web-based survey

Telephone survey

multiple choice,

frequently off-label drugs such as levetiracetam and topira-

mate. The second choice anti-epileptic drug for neonatal
seizures is phenytoin. This is understandable as one of the
Survey

few randomised controlled trials available compared phe-

nobarbital with phenytoin, initially as a first-line medication

2014 The Authors. Acta Pdiatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Pdiatrica 2015 104, pp. 123129 125
 126
Table 2 Surveys investigating preferred, or actually administered, anti-epileptic drug treatment of neonatal seizures
Study Subjects Country 1st AED 2nd AED 3rd AED Prophylactic AED
Review of neonatal seizure management

Wheless et al. 2005 (25). Paediatric neurologists USA Benzodiazepine/ Lorazepam Fosphenytoin Infant with NE, mean
33 questions, 645 treatment (epileptologists), 39/41 (95%) Phenobarbital (SD) 8. 2 (5.5) weeks
options, scenarios
Bartha et al. 2007 (26). Infants with seizure diagnosis, USA (5 NICUs) Phenobarbital 82% Lorazepam 9% Phenytoin 2% 75%
Administered AED, database all gestational ages (n = 480)
Silverstein & Ferriero 2008 (27). Paediatric neurologists at 2007 71% USA, Levetiracetam 47%, topiramate 55%
Off-label use of AED, survey Annual Child Neurology 20% Canada, Levetiracetam and/or topiramate 73%
Society meeting, 55 replies 9% other
Blume et al. 2009 (28). Infants with seizure diagnose USA (31 states) Phenobarbital 76% Phenytoin 16% Benzodiazepines 67% (day prior
Administered AED, database (ICD-9 779.0, 345.19), to discharge)
all gestational ages (n = 6099)
Vento et al. 2010 (22). Neonatologists at European 10 European countries, Phenobarbital 100% 85% midazolam, 85% lidocaine,
Questionnaire with 3 parts university hospitals, 13/20 (65%) see table 1 7.5% clonazepam, 7.5% lidocaine/phenyl,
(diagnosis, treatment) 7.5% phenytoin 7.5% midazolam/diaz
Koppelstatter et al. 2011 (29). German University Hospitals, Germany 45.7% used levetiracetam;
Levetiracetam use, survey 35/36 (97.2%) 20% used levetiracetam in preterms
Glass et al. 2012 (24). Neonatologists (24.9%), USA (75%), UK, Preterm: Phenobarbital Preterm: Preterm:
Web survey, 23 multiple choice Paediatric neurologists (55.9%), Europe, Canada 72.2%, Lorazepam 21.9% Phenytoin 40.6%, Phenytoin 35.2%,
Neonatal neurologist/neurocritical care Phenobarbital 26.2% Levetiracetam 21%
(19.2%), 193/400500 (~45%) Term: Term: Term:
Phenobarbital 70.9%, Phenytoin 42.8%, Phenytoin 34.9%,
Lorazepam 23.1% Phenobarbital 27.2% Levetiracetam 18.9%

AED = Anti-epileptic drug; ICD-9 = International Classification of Diseases, version 9; NE = Neonatal encephalopathy; NICU = Neonatal intensive care unit.
Hellstro
m-Westas et al.

2014 The Authors. Acta Pdiatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Pdiatrica 2015 104, pp. 123129
 m-Westas et al.
Hellstro Review of neonatal seizure management

and then with a crossover design as add-on treatment to the

72% no reply
Duration of AED

Median 12 w
other drug (9). The two drugs were comparable as first-line

Median 8 w

3 months:
treatments, and the combined efficacy of both drugs was

HIE/IVH:

81.4%
94.8%
86.2%
91.3%
3 mo

53%
more than 60%. Benzodiazepines and lidocaine are other
drugs commonly used for anti-epileptic treatment. Although
these drugs were only compared in a small randomised
controlled trial (10), they are commonly used and several
Prophylactic AED

Seldom/never:
Rarely/never:
observational studies have investigated their acute effects
No: 89%
No: 56%

2% 8%
and pharmacokinetics (35). Two studies investigated neo-

72.9%
10.5%
36.2%
21.7%
natologists and paediatric neurologists preferred treat-
ments of seizures in preterm infants, which were very
similar to that of term infants (24,32).
Benzodiazepines 69.2%,

Benzodiazepines 71.4%,

Most neonatal seizures are entirely subclinical. Although

some experimental data indicate that subclinical seizures
Phenytoin 14.5%

Phenytoin 14.3%

may also be detrimental for brain function, clinical data

54.3%
68.4%
32.8%
43.5%
supporting these findings are scarce. During the last decade,
an ongoing debate has been whether subclinical seizures
Lidocaine
Lidocaine
Lidocaine
Lidocaine
3rd AED

should be treated or not, not least in the light of possible

adverse effects of anti-epileptic drugs on brain development
(36). Bassan et al. addressed this dilemma; when asking
whether neonatal electrographic seizures could be harmful
Phenobarbital 12.5%

Phenobarbital 14.7%
Phenytoin 85,3.1%,

for the brain, 38% of paediatric neurologists and 34% of

77.1%
84.2%
67.2%
69.6%
Phenytoin 78.1%,

neonatologists said yes, while 47% and 43%, respectively,

replied that they did not know (20). Forty per cent of the
Table 3 Anti-epileptic drugs (AED) used by neonatologists as compared to paediatric neurologists. Figures are numbers and percentages

Midazolam
Midazolam
Midazolam
Midazolam
Phenytoin
Phenytoin

paediatric neurologists and 38% of the neonatologists

2nd AED

would treat electrographic seizures, while 30% and 35%

would not and the remaining said they did not know. It is
our impression that these figures reflect much of the overall
debate regarding treatment of subclinical neonatal seizures
Benzodiazepines 11.4%

Benzodiazepines 10.9%
Phenobarbital 87.5%,

Phenobarbital 85.7%,

85.7%

86.2%
78.2%
100%

(37).
Phenobarbital 97%
Phenobarbital 94%

Prophylactic anti-epileptic treatment has traditionally

Phenobarbital
Phenobarbital
Phenobarbital
Phenobarbital

been administered to many infants with neonatal seizures.

The risk for postnatal epilepsy after neonatal seizures is
1st AED

generally considered to be 1015%, but has been as high as

3035% in some studies (3). In two observational studies
using aEEG/EEG monitoring and also treating subclinical
seizures, postnatal epilepsy rates were 8.3% and 9.4%, that
Paediatric neurologists 118/609 (20.7%)

Paediatric neurologists 61/128: (47.6%)

is lower than in many comparable studies, thus indicating

Paediatric neurologists 18/45 (38%)

Paediatric neurologists 36/55 (65%)

that treatment of subclinical seizures may be associated

Neonatologists 125/579 (23.1%)

Neonatologists 73/150 (48.7%)

with lower risk for postnatal epilepsy (7,38). Another

Neonatologists 89/142 (63%)

Neonatologists 66/112 (59%)

retrospective study indicated that prophylactic treatment

+ residents 19/46 (41.3%)

+ residents 23/40 (57.5%)

did not change outcomes, although it cannot be certain that

infants receiving prophylaxis were otherwise similar to
infants not treated (39). Overall, neonatologists seem to
advocate shorter anti-epileptic treatment duration than
paediatric neurologists (20,32). This difference could be due
Responders

to the fact that paediatric neurologists are more often

consulted in infants with more severe and/or refractory
seizures. Furthermore, clinical and experimental data
indicate that long-term use of some of the more common
m et al. 2012 (32).
47 items, 7 scenarios. USA
Australia and New Zealand

Guillet & Kwon 2008 (31).

National survey, randomly

anti-epileptic drugs may be associated with adverse side

Carmo & Barr 2005 (30).

Questionnaire, 20 items.

Questionnaire, 20 items,
Bassan et al. 2008 (20).

effects on the central nervous system.

Case: infant with NE.

5 scenarios. Sweden
selected specialists,

During the last decade, several new effective anti-epilep-

Study characteristics

tic medications have been introduced for paediatric and

adult use. Some of them have also been used off-label in
neonates, for example levetiracetam and topiramate. A few
Wickstro
Israel

small nonrandomised observational studies report the

effects and side effects of these drugs, which are more

2014 The Authors. Acta Pdiatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Pdiatrica 2015 104, pp. 123129 127
Review of neonatal seizure management
frequently used by paediatric neurologists than by neona-
tologists.
A major limitation for this overview is the relatively low
response rate in the original surveys, which makes general
comparisons and conclusions difficult. However, as many
of the surveys came to similar conclusions, it is likely that
the results are valid. Another limitation is the comparisons
between studies that did not have exactly the same research
questions. To make the comparisons, some replies had to be
categorised and simplified, and of course some of the details
of the original studies are then lost.
The current study identifies some key questions for future
studies. The first is the identification and epidemiology of
seizures in high-risk infants. Seizures, often entirely sub-
clinical, are common in high-risk newborn infants. Unless
continuous aEEG/EEG or EEG monitoring is routinely
used in the NICU, seizures in some infants will be
undetected. Recent data, using aEEG/EEG monitoring,
indicate that the seizure prevalence in extremely preterm
infants may be very high (40,41). A majority of these
seizures were brief and subclinical, and consequently, most
of these infants did not receive anti-epileptic treatment
because the seizures were not detected during the initial
course. The seizures were associated with intraventricular
haemorrhages and early morbidity but there was no clear
association with long-term outcome indicating that anti-
epileptic treatment may not be necessary for these seizures
(41,42). Another key issue is the need for randomised trials
investigating the efficacy of commonly used anti-epileptic
drugs on electrographic seizure activity, and in long-term
outcome.
In conclusion, there is an urgent need for more evidence-
based knowledge to guide neonatal seizure management,
especially with regard to anticonvulsive treatment including
long-term effects of acute and prophylactic anti-epileptic
drug treatment (43). Survivors of neonatal seizures are at
high risk for adverse neurodevelopmental outcome and
epilepsy; more effective management may improve their
long-term prognosis and quality of life (44). In addition,
important concerns regarding adverse effects of the phar-
macological treatment per se must be addressed. There is
still very little evidence available to guide decisions on the
most effective and safe anti-epileptic treatment strategies in
newborn infants of different gestational ages. Most of the
current knowledge on neonatal seizures, such as inci-
dences, risk factors and treatment strategies comes from
Western Europe, North America, Australia and New Zea-
land. Consequently, a survey of current views and thera-
peutic strategies in other parts of the world is warranted.
ACKNOWLEDGEMENTS
The research leading to these results has received funding
from the European Communitys Seventh Framework
Programme (FP7/2007-2013) under grant agreement no
241479. We thank the staff of the Medical library at
Uppsala University Hospital for kind assistance with the
literature search.
128 2014 The Authors. Acta Pdiatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Pdiatrica 2015 104, pp. 123129
m-Westas et al.
Hellstro
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