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Guidelineson NeonatalSeizures
IRCCSAssociazioneOasi Maria SS.WHO Collaborating Centre
World HealthOrganization
Guidelineson NeonatalSeizures
WHO Department of Mental Healthand Substance Abuse
WHO Department of Maternal, Newborn,Child and Adolescent Health
OASI Department of Mental RetardationUnit of Neurology and ClinicalNeurophysiopathology
World HealthOrganization
IRCCSAssociazioneOasi Maria SS.WHO Collaborating Centre
_ _
WHO Library Cataloguing-in-Publication Data: 2011
Guidelines on neonatal seizures.
1.Seizures - diagnosis. 2.Seizures - prevention and control.3.Seizures - drug therapy. 4.Infant, Newborn, Diseases.5.Guidelines. I.World Health Organization.ISBN 978 92 4 154830 4 (NLM classification: WS 421)
© World Health Organization 2011
All rights reserved. Publications of the World Health Organization are available on the WHO web site(www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or fornoncommercial distribution – should be addressed to WHO Press through the WHO web site(http://www.who.int/about/licensing/copyright_form/en/index.html).
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Editing: Rosa Di Giorgio
Graphics: Leonardo Arangio
Printed in Italy - Villaggio Cristo Redentore srl, Troina EN - Tel. +39 0935 657813
_ _
TABLE OF CONTENTS
Abbreviations .......................................................................................................................................... 5
Executive summary ........................................................................................................................ 7
Introduction .............................................................................................................................................. 9
Scope of the guidelines and target audience ............................................ 10
Methodology .......................................................................................................................................... 11
Summary of questions and recommendations ........................................ 17
Annexes .......................................................................................................................................................... 35
Annex 1: List of contributors .............................................................................. 37
Annex 2: GRADE profiles and summary ofindividual studies .................................................................................... 41
References .................................................................................................................................................... 71
Appendix: Search strategy of the literature .................................................. 81
3
_ _
ABBREVIATIONS
AED antiepileptic drug
CI confidence interval
CNS central nervous system
CRD Centre for Reviews and Dissemination
CT computed tomography
DARE Database of Abstracts of Reviews of Effects
EEG electroencephalography
GDG Guideline Development Group
GRADE Grading of Recommendations Assessment, Development, and Evaluation
HIE hypoxic-ischaemic encephalopathy
IBE International Bureau for Epilepsy
ILAE International League Against Epilepsy
IMCI Integrated Management of Childhood Illness
IMPAC Integrated Management of Pregnancy and Childbirth
IRCCS Institute for Research on Mental Retardation and Brain Aging
ISRCTN International Standard Randomized Controlled Trial Number Register
MD mean difference
mRCT meta-register of randomized controlled trials
MRI magnetic resonance imaging
MRS magnetic resonance spectroscopy
NGO non-governmental organization
NLM National Library of Medicine
NPV negative predictive value
NS neonatal seizures
OR odds ratio
PPV positive predictive value
PT preterm
RCT randomized controlled trial
RR relative risk
US ultrasound
WHO World Health Organization
WMD weighted mean difference
5
_ _
EXECUTIVE SUMMARYNeonatal seizures represent one of the most frequent neurological events in newborninfants, often reflecting a variety of different pre-, peri-, or postnatal disorders of thecentral nervous system (CNS). They are also a common manifestation of metabolicabnormality in newborn period and often represent the first sign of neurological dys-function in neonates. They may be symptomatic or cryptogenic, herald subsequentepilepsy, can be associated with potential morbidity and mortality, and may be used asa factor in considering long-term prognosis. Despite the enormous clinical significanceof these events, many aspects of their management are not well supported with evi-dence-based recommendations.
In particular, rather few studies address issues related to the use of antiepilepticdrugs (AEDs), such as indications for acute therapy, selection of first-line and second-line agents, pharmacokinetics of commonly used AEDs, and duration of treatment afterthe seizures are controlled on AEDs for neonatal seizures (NS).
The Global Campaign Against Epilepsy, a World Health Organization (WHO) part-nership with the International League Against Epilepsy (ILAE) and the InternationalBureau of Epilepsy (IBE), in collaboration with the Institute for Research on MentalRetardation and Brain Aging (IRCCS) named Associazione Oasi Maria SS., a WHOCollaborating Centre for Training and Research in Neuroscience (WHO/CC), initiated aproject to develop evidence-based guidelines for the management of neonatal seizures.These guidelines are intended to be of use for neonatologists, paediatric neurologists,paediatricians, general practitioners, nurse practitioners, nurses and other health profes-sionals who may be in contact with infants experiencing seizures within the first 28 daysof life (age up to 44 weeks post-conception). The guidelines are framed so as to beapplied by health care providers practicing in a wide range of health care facilities, fromthose with limited resources to tertiary care centres.
The Guideline Development Group identified 11 research questions to be of highestpriority. Two of these questions were background questions on prevalence of neonatalseizures and predictors of prognosis of neonatal seizures. The remaining 9 questionsfocused on priority issues related to management of neonatal seizures. The Grading ofRecommendations Assessment, Development, and Evaluation (GRADE) approach wasused for grading the quality of evidence after adaptation to the relevant working area.The quality of the evidence for an outcome was graded as follows: high, moderate, lowor very low. After grading the available studies for each outcome, recommendationswere formulated on the basis of the summary and quality of evidence, balance betweenbenefits and harms, values and preferences of policy makers, health care providers andparents, feasibility and resource use; in addition, costs were analyzed to see whetherthey could be qualitatively justifiable by the benefits. The recommendations were grad-ed into two types: strong and weak. In some cases, the recommendations were context-specific which is indicated in the document as appropriate.
Table 1 lists the key recommendations of the guidelines:
7
_ _
8 No.
R
EC
OM
ME
ND
AT
ION
S S
tren
gth
Q
ua
lity
of
evid
ence
1.
Clin
ical
ly a
ppar
ent s
eizu
res
in th
e ne
onat
e sh
ould
be
trea
ted
if th
ey la
st m
ore
than
3 m
inut
es o
r ar
e br
ief s
eria
l sei
zure
s.
Stro
ng
Not
gra
ded
In
spe
cial
ized
car
e fa
cilit
ies
whe
re e
lect
roen
ceph
alog
raph
y is
ava
ilabl
e, a
ll el
ectr
ical
sei
zure
s, e
ven
in th
e ab
senc
e of
cli
nica
lly a
ppar
ent
seiz
ures
, sho
uld
also
be
trea
ted.
St
rong
, con
text
-spe
cific
N
ot g
rade
d
2.
In a
ll ne
onat
es w
ith
seiz
ures
, hyp
ogly
caem
ia s
houl
d be
rul
ed o
ut a
nd tr
eate
d if
pre
sent
bef
ore
anti
epile
ptic
dru
g tr
eatm
ent i
s co
nsid
ered
. St
rong
N
ot g
rade
d
If
faci
litie
s fo
r m
easu
ring
glu
cose
are
not
ava
ilabl
e, c
onsi
der
empi
rica
l tre
atm
ent w
ith
gluc
ose.
W
eak,
con
text
-spe
cific
If
ther
e ar
e cl
inic
al s
igns
sug
gest
ive
of a
ssoc
iate
d se
psis
or
men
ingi
tis,
cen
tral
ner
vous
sys
tem
infe
ctio
n sh
ould
be
rule
out
by
doin
g a
lum
bar
punc
ture
, and
trea
ted
if p
rese
nt w
ith
appr
opri
ate
anti
biot
ics.
St
rong
If
faci
litie
s fo
r lu
mba
r pu
nctu
re a
re n
ot a
vaila
ble,
con
side
r em
piri
cal t
reat
men
t wit
h an
tibi
otic
s fo
r ne
onat
es w
ith
clin
ical
sig
ns o
f sep
sis
or
men
ingi
tis.
W
eak,
con
text
-spe
cific
In
all
neon
ates
wit
h se
izur
es, s
erum
cal
cium
sho
uld
be m
easu
red
(if f
acili
ties
are
ava
ilabl
e) a
nd tr
eate
d if
hyp
ocal
caem
ia is
pre
sent
. St
rong
, con
text
-spe
cific
In
the
abse
nce
of h
ypog
lyca
emia
, men
ingi
tis, h
ypoc
alca
emia
or a
noth
er o
bvio
us u
nder
lyin
g et
iolo
gy su
ch a
s hy
poxi
c-is
chae
mic
enc
epha
lopa
thy,
in
trac
rani
al h
aem
orrh
age
or in
farc
tion,
pyr
idox
ine
trea
tmen
t may
be
cons
ider
ed b
efor
e an
tiep
ilept
ic d
rug
trea
tmen
t in
a sp
ecia
lized
cen
tre
whe
re th
is tr
eatm
ent i
s ava
ilabl
e.
Wea
k, c
onte
xt-s
peci
fic
3.Ph
enob
arbi
tal s
houl
d be
use
d as
the
firs
t-lin
e ag
ent f
or tr
eatm
ent o
f neo
nata
l sei
zure
s; p
heno
barb
ital
sho
uld
be m
ade
read
ily a
vaila
ble
in
all s
etti
ngs.
St
rong
V
ery
low
4.In
neo
nate
s w
ho c
onti
nue
to h
ave
seiz
ures
des
pite
adm
inis
teri
ng th
e m
axim
al to
lera
ted
dose
of p
heno
barb
ital
, eit
her
a be
nzod
iaze
pine
,
.
phen
ytoi
n or
lido
cain
e m
ay b
e us
ed a
s the
seco
nd-li
ne a
gent
for c
ontr
ol o
f sei
zure
s (us
e of
phe
nyto
in o
r lid
ocai
ne re
quir
es c
ardi
ac m
onito
ring
faci
litie
s).
Wea
k
Ver
y lo
w
5.In
neo
nate
s w
ith
norm
al n
euro
logi
cal e
xam
inat
ion
and/
or n
orm
al e
lect
roen
ceph
alog
raph
y, c
onsi
der
stop
ping
ant
iepi
lept
ic d
rugs
if
neon
ate
has
been
sei
zure
-fre
e fo
r >
72 h
ours
; the
dru
g(s)
sho
uld
be r
eins
titu
ted
in c
ase
of r
ecur
renc
e of
sei
zure
s.
Wea
k V
ery
low
6.
In n
eona
tes
in w
hom
sei
zure
con
trol
is a
chie
ved
wit
h a
sing
le a
ntie
pile
ptic
dru
g, th
e dr
ug c
an b
e di
scon
tinu
ed a
brup
tly
wit
hou
t any
ta
peri
ng o
f the
dos
es.
Wea
k
Not
gra
ded
In
neo
nate
s req
uiri
ng m
ore
than
one
ant
iepi
lept
ic d
rug
for
seiz
ure
cont
rol,
the
drug
s m
ay b
e st
oppe
d on
e by
one
, with
phe
noba
rbita
l bei
ng th
e la
st d
rug
to b
e w
ithdr
awn.
W
eak
7.
In th
e ab
senc
e of
clin
ical
sei
zure
s, n
eona
tes
wit
h hy
poxi
c-is
chae
mic
enc
epha
lopa
thy
need
not
to b
e gi
ven
pro
phyl
acti
c tr
eatm
ent w
ith
phen
obar
bita
l.
Stro
ng
Mod
erat
e
8.
Whe
re a
vaila
ble,
all
clin
ical
sei
zure
s in
the
neon
atal
per
iod
shou
ld b
e co
nfir
med
by
elec
troe
ncep
halo
grap
hy.
Stro
ng, c
onte
xt-s
peci
fic
Not
gra
ded
E
lect
roen
ceph
alog
raph
y sh
ould
not
be
perf
orm
ed fo
r th
e so
le p
urpo
se o
f det
erm
inin
g th
e et
iolo
gy in
neo
nate
s w
ith
clin
ical
sei
zure
s.
Stro
ng
9.
Rad
iolo
gica
l inv
esti
gati
ons
(ultr
asou
nd, c
ompu
ted
tom
ogra
phy
and
mag
neti
c re
sona
nce
imag
ing)
of t
he c
rani
um/h
ead
shou
ld n
ot b
e pe
rfor
med
to d
eter
min
e th
e pr
esen
ce o
r ab
senc
e of
clin
ical
sei
zure
s or
to e
valu
ate
the
effi
cacy
of t
reat
men
t wit
h an
tiep
ilept
ic d
rugs
in
neon
ates
.
Stro
ng
Not
gra
ded
R
adio
logi
cal i
nves
tigat
ions
may
be
done
as a
par
t of t
he c
ompr
ehen
sive
eva
luat
ion
of th
e et
iolo
gy o
f neo
nata
l sei
zure
s or
to d
eter
min
e pr
ogno
sis i
n ne
onat
es w
ith s
eizu
res.
W
eak,
con
text
-spe
cific
TAB
LE1-
KEY
REC
OM
MEN
DA
TIO
NS
OF
NEO
NA
TAL
SEIZ
UR
ESG
UID
ELIN
ES
_ _
INTRODUCTIONSeizures are a common occurrence in both term and preterm (PT) neonates. Despitetheir frequency and clinical significance, currently there are no clearly defined evidence-based guidelines to address major questions about their management. While diagnosisand management of seizures are often considered within the context of tertiary carehealth centres, seizures are a common manifestation in newborns presenting to the fullrange of health-care facilities. Therefore, there is a need for evidence-based guidelineswhich can be applied to different health-care facilities with varying resources and adapt-ed by health-care providers of all levels of expertise.
Neonatal seizures, one of the most frequent neurological events in newborn infants,reflect a variety of pre-, peri- or postnatal disorders of the central nervous system (CNS).These may range from benign, self-limited illnesses to severe, prolonged or life-threat-ening disorders. They are also a common manifestation of metabolic abnormality orinfection. Due to the increased availability of diagnostic tools, such as electroen-cephalography (EEG), video-EEG monitoring, and early neuroimaging to supplementclinical observation, the diagnosis of neonatal seizures may be established more accu-rately. It is also possible that incidence figures may have changed in recent times.Furthermore, higher incidence and prevalence rates of epilepsy have been found indeveloping countries, so it is conceivable that incidence and prevalence rates of neona-tal seizures could rather differ between developed and developing countries (Brown etal., 1972; Leveno et al., 1989; Okan et al., 1995; Garcias Da Silva et al., 2004; Sankaret al., 2007).
Some aspects of treatment of neonatal seizures have changed little over the last 50years. In newborns with seizures, it is indicated to initiate a early diagnostic work up todetermine the cause, depending upon the facilities available. Even though mostneonates who present with seizures are treated with antiepileptic drugs (AEDs), onlyvery few studies address the issues related to use of AEDs such as the first-line and sec-ond-line drugs, their pharmacokinetics, the duration of treatment, and the methods ofdiscontinuing treatment after achieving adequate control of seizures. In particular, thereis a lack of randomized controlled trials to validate a treatment algorithm of neonatalseizures. The AEDs used tend to be older generation drugs associated with the most sideeffects (Co et al., 2007). Moreover, clinical control of neonatal seizures using the twocommonly used AEDs - phenobarbital and phenytoin - is achieved in only 50 to 80% ofcases, with even less effect in the control of most neonatal electrical seizures (Painter etal., 1999; Boylan et al., 2002; Rennie et al., 2003; Boylan et al., 2004). Management ofneonatal seizures becomes even more difficult in resource-poor settings because of thelimited number of facilities available for diagnosis, treatment and monitoring.
Clinical and experimental data suggest a longer duration of seizures as being asso-ciated with greater difficulty in controlling them. Furthermore, seizures can have imme-diate and long-term adverse consequences on the immature and developing brain(Shany et al., 2007). Irrespective of immediate attempts to suppress the neonatalseizures with AEDs, the risk for subsequent neuro-developmental deficits and earlydeath is substantial. Newborn infants with seizures are at risk for death, whereas sur-vivors are at risk for neurological impairment, developmental delay, later epilepsy andcognitive impairment (Ronen et al., 2007). Hence, it is important to conduct systemat-ic review of the evidence to determine the optimal diagnosis and treatment regimens forthe management of neonatal seizures.
9
_ _
These guidelines have been produced in response to a request for guidance to manag-ing of neonatal seizures, with the hope of highlighting as well as resolving some of thecontroversies in this field, and to standardize practice.
All health workers involved in the care of the newborn infant are commonly con-fronted with the clinical problem of seizures in neonates. Despite the frequency of theseevents, that can be acute, symptomatic or herald subsequent epilepsy, no clear answersare currently available to major questions about their management nor are there evi-dence-based guidelines for the management of neonatal seizures.
However, the clinical concerns go beyond those raised by physician-specialists.Health-care providers with varying degrees of training have to face the issues of new-borns with seizures, irrespective of the level of resources available at the facility they areworking at. The lack of guidelines for care in these settings is also an important health-care problem to be addressed.
Accordingly, the Global Campaign Against Epilepsy, a World Health Organization(WHO) partnership with the International League Against Epilepsy (ILAE) and theInternational Bureau of Epilepsy (IBE), in collaboration with the Institute for Research onMental Retardation and Brain Aging (IRCCS) named Associazione Oasi Maria SS., aWHO Collaborating Centre for Training and Research in Neuroscience (WHO/CC), con-ducted systematic review of the literature to assist in developing evidence-based guide-lines for the management of neonatal seizures. The WHO Departments involved in thedevelopment of these guidelines included the Department of Mental Health andSubstance Abuse and the Department of Maternal, Newborn, Child and AdolescentHealth. The WHO/CC Associazione Oasi Maria SS. (IRCCS), based in Troina (EN), Italy,provided financial support for the development of guidelines and the organization of rel-evant meetings.
These guidelines are intended to be of use for neonatologists, paediatric neurolo-gists, paediatricians, general practitioners, nurse practitioners, nurses and all the otherhealth professionals that may be responsible for addressing problems of newborns withseizures occurring within the first 28 days of life (up to 44 weeks post-conception). Thedocument has been written so that it can be applied to care-givers practicing at a widerange of health care facilities: from those with limited resources to those functioning astertiary care centres.
10
SCOPE OF GUIDELINESAND TARGET AUDIENCE
_ _
METHODOLOGYThe Guideline Development Group (GDG) was convened to advise on the content andprocess, interpretation of evidence and to formulate and finalize the recommendations.It consisted of experts with multidisciplinary expertise and with an adequate regionaland gender representation. Multidisciplinary expertise that was sought included guide-line development methodology, neonatology, paediatrics, paediatric neurology, primarycare, public health and epidemiology. A list of GDG members is provided in Annex 1.
A conflict of interest declaration as per WHO rules was filled by all contributors. HelenCross (United Kingdom) reported receiving travel support for herself to attend meetings(£5000) and honoraria for educational activities (£5000 for herself plus the researchunit) from Eisai, UCB and Janssen Cilag (in total combined) and being on the advisoryboard of Eisai and UCB (£1000). Angelina Kakooza (Uganda) received internationalscholarship award in 2005 for a 6-week fellowship in Boston from the American EpilepsySociety as well as support from said Society to attend Society meetings in 2005 and2007. Hans Hartmann (Germany) reported owning company shares in Pfizer forUS$10000 and Novartis for US$15000. The other members of the GDG reported noconflict of interest. The declared conflicts of interest were reviewed by the technicalunits and discussed with the Director of the responsible unit. During the meeting, allmembers provided a verbal summary of their written declarations of interest. None ofthe declared interest by the GDG members were considered significant as to affect theproceedings of the GDG and for any further action to be taken.
At the first GDG meeting held in Troina, Sicily, Italy, on November 16-17, 2007, keyquestions requiring an answer were drafted. The scoping questions focused on contro-versial areas that needed to be covered or topics requiring changes in policy or prac-tice. In addition to the scoping questions, outcomes were identified for evidence reviewand making decisions and recommendations. These were rated as critical, important ornot important by the GDG members. Each of the questions deserved separate system-atic reviews, taking into consideration the critical and important outcomes. The per-formed systematic reviews were peer-reviewed by the GDG and also by external peer-reviewers.
The following questions were identified to be of the highest priority:
Background questions
• What is the prevalence of various causes of neonatal seizures in different geographi-cal regions of the world?
• Which clinical factors and diagnostic tests best predict the prognosis of neonatalseizures?
Questions directly related to management of neonatal seizures
1. Which newborn seizures require acute antiepileptic drug treatment?
2. What is the clinical efficacy of empirical treatment of newborns with seizures (prior tolaboratory tests) for hypoglycaemia, hypocalcaemia, and bacterial infection/meningitis?
3. Which is the preferred first-line antiepileptic drug for a newborn with seizures requir-ing treatment with antiepileptic drugs?
11
Declaration of conflictof interest
Formulating questionsand choosing outcomes
Priority questions
_ _
4. Which is the preferred second-line antiepileptic drug treatment for a newborn withseizures not responding to maximal tolerated dose of phenobarbital?
5. If a newborn has seizures and is controlled on current antiepileptic drug treatment,when should the medication be discontinued?
6. If a newborn has seizures and is controlled on current antiepileptic drug treatment,how should the medication be discontinued?
7. What is the effect of prophylactic treatment of at-risk neonates with hypoxic-ischaemic encephalopathy on mortality, recurrence of seizures and/or long-term neu-rological outcomes?
8. What is the value of electroencephalography in the management of a newborn withseizures?
9. What is the value of imaging of the cranium/head in diagnosis, evaluation of etiolo-gy, treatment, and prognosis of the newborn with seizures?
Selection of studies
We searched all published trials utilizing random or quasi-random patient allocation aswell as observational studies for useful information related to the priority questions.Recent review articles were also searched to ensure inclusion of specific references rele-vant to the question. For the question on epidemiology of neonatal seizures (NS), wealso referred to national chapters of International League Against Epilepsy (ILAE) – theinternational professional epilepsy non-governmental organization (NGO) – to get infor-mation on country-based databases and any prevalence studies on NS that may nothave been published in indexed journals.
Type of participants
Full-term neonates with clinical and/or electrographic seizures, commencing within thefirst 28 days of life and preterm neonates presenting with clinical and/or electroen-cephalograhic seizures commencing before a corrected age of 28 days (44 weeks post-conception).
Search strategy, data abstraction and synthesis of the evidence
Literature search was performed using all key words consecutively. The explored data-bases are enclosed in the Appendix. Studies were stratified according to type of inter-vention or exposure, study design, birth weight and gestational age where possible.Effects were expressed as relative risks (RR) or odds ratios (OR) for categorical data andas mean differences (MD) or weighted mean differences (WMD) for continuous datawherever possible. When available, results adjusted for potential confounders – partic-ularly for observational studies – were preferred to unadjusted results. When resultsadjusted for potential confounders were not available, unadjusted results were used. Allthe studies reporting on a critical outcome are summarized in the table of individualstudies (Annex 2).
12
Evidence retrievaland synthesis
_ _
We considered pooled effects for developing recommendations, wherever feasible.When results of three or more randomized controlled trials (RCTs) were available for anoutcome, and the overall quality of evidence using the Grading of RecommendationsAssessment, Development, and Evaluation (GRADE) approach was at least “low”,observational studies were not considered. However, when there were 2 or less RCTs foran outcome or the quality of evidence was “very low”, we pooled the effects from RCTswith those from available cohort and case-control studies. When pooled effects wereavailable from published systematic reviews and no new studies were identified, weused the published pooled effects. When considering new studies, we updated thepooled effects using “metan” command in Stata 11.0. The same was done when nopublished pooled effects were identified. For pooling, we used the author reportedadjusted effect sizes and confidence intervals as far as possible. We used random effectsmodels for meta-analysis either when important inconsistency in effects was found orrandom effects model was not unduly affected by small studies. When pooling of resultswas not possible, we used the range of effect sizes observed in the individual studies indeveloping recommendations.
All relevant reviews were summarized and the evidence was synthesized using theGRADE methodology where possible (Atkins et al., 2004). In case it was not possible toGRADE the evidence, a study-by-study table was developed to summarize and assessthe quality of the evidence. Annex 2 provides the evidence synthesis.
A few pragmatic instructions and adaptations to guide the application of GRADE weredeveloped to increase consistency by ensuring that the same background logic wasemployed in assessing the evidence for each scoping question. These instructions wereused to rate the five aspects considered in the quality assessment: (1) limitations (risk forbias); (2) inconsistency; (3) indirectness; (4) imprecision; (5) reporting bias. The qualityof the set of studies included – reporting results for an outcome – was graded as: high,moderate, low or very low. The interpretation of the above grades in these guidelines isthe following:
High: One can be sure that the intervention is beneficial, has no effect or is harmful.Results, including the magnitude of the pooled effect, are unlikely to change with newstudies.
Moderate: One can be reasonably sure that the intervention is beneficial, has no effect oris harmful. However, the magnitude of the pooled effect may change with new studies.
Low: Although it is likely, one cannot be sure the intervention is beneficial, has no effector is harmful. The magnitude of the pooled effect is uncertain and is likely to changewith new studies.
Very low: One cannot be certain about the effects of the intervention.
One of the difficulties in using GRADE is that the evidence base for an outcome mayinclude studies with varying methodological quality and sample size. We thereforeincluded the weight of the studies in the estimation of the pooled effect to make judg-ments about the quality of the set of included studies. The criteria used to grade thequality of evidence are shown in Table 2. We used a cut-off of 50% of total weight ofevidence for rating the study design, limitations in methods, and directness. For consis-tency, we used a cut-off of 75% of total weight.
Grading the qualityof evidence
13
_ _
Lim
itat
ion
s in
Met
hod
sB
ased
on
met
hods
of s
tudi
es w
ith
>50
%
of w
eigh
t of e
vide
nce
Des
ign
Bas
ed o
n de
sign
of
stud
ies
wit
h>
50%
of
wei
ght
of e
vide
nce
All
ocat
ion
co
nce
alm
ent
(the
two
com
para
ble
grou
ps a
nd lo
w
risk
of r
ever
se
caus
alit
y)
Bli
nd
ing
or
oth
er
app
roac
hes
to
red
uce
m
easu
rem
ent
bias
Los
s to
fo
llo
w-u
p
An
alys
is
inte
nti
on to
tr
eat;
clu
ster
ad
just
ed if
ap
pli
cabl
e (a
djus
ted
for
conf
ound
ing)
Pre
cisi
on
Bas
ed o
n 95
%C
I of
the
pool
edef
fect
siz
e
Con
sist
ency
Bas
ed o
n th
e di
rect
ion
of e
ffec
t siz
e of
>2
stud
ies
wit
h >
75%
of
wei
ght o
f evi
denc
e
Dir
ectn
ess
Bas
ed o
n di
rect
ness
of
stud
ies
wit
h >
50%
of
wei
ght o
f ev
iden
ce
Ove
rall
Qu
alit
y of
Evi
den
ce
Bas
ed o
n th
e sc
ore
tota
l in
colu
mns
on
the
left
If R
CT,
th
en =
0
If q
uasi
-RC
T,
then
= -
0.5
(If
obse
rvat
iona
l,th
en =
-1.
0)
If a
lloca
tion
co
ncea
lmen
t ad
equa
te,
then
= 0
If a
lloca
tion
co
ncea
lmen
t in
adeq
uate
/
unkn
own,
th
en =
-0.
5
Not
app
licab
le if
qu
asi-
rand
omiz
ed
(If o
bser
vati
onal
st
udie
s w
ith
impo
rtan
t ris
k of
se
lect
ion
bias
or
reve
rse
caus
alit
y,th
en =
-0.5
)
If b
lindi
ng to
in
terv
enti
on,
then
= 0
If “
obje
ctiv
e”
outc
ome,
th
en =
0
If o
utco
me
not
“obj
ecti
ve”
but
obse
rver
s bl
inde
d,
then
= 0
; if
not
, th
en =
-0.
5
If d
iffe
renc
e in
m
easu
rem
ent
proc
edur
es fo
r th
e tw
o co
mpa
riso
n gr
oups
, th
en =
-0.
5
If c
ohor
t fo
llow
ed u
p,
and
<20
% lo
st,
then
= 0
; if
not
, th
en =
-0.
5
If repr
esen
tati
ve
cros
s se
ctio
nal
surv
eys,
th
en =
0;
if n
ot,
then
= -
0.5
If in
tent
to tr
eat
anal
ysis
, th
en =
0;
if n
ot,
then
= -
0.5
If c
lust
er R
CT
and
anal
ysis
cl
uste
r-ad
just
ed,
then
= 0
; if
not
, th
en =
-0.
5
(If o
bser
vati
onal
st
udie
s ad
just
ed
for
conf
ound
ing
then
= o
, if
not,
then
= -0
.5)
If C
I do
es n
ot
incl
ude
“nul
l”, a
nd
both
CI
limit
s m
ean
mea
ning
ful b
enef
it
or u
nacc
epta
ble
harm
, th
en=
0
If C
I do
es n
ot
incl
ude
“nul
l”, b
ut C
Iw
ider
than
abo
ve,
then
= -
0.5
If C
I in
clud
es “
null”
, an
d bo
th C
I lim
its
excl
ude
mea
ning
ful
bene
fit o
r un
acce
ptab
le h
arm
, th
e n=
0
If C
I in
clud
es “
null”
, bu
t C
I w
ider
than
th
e ab
ove,
th
en=
-1.
0
If >
3 st
udie
s an
d po
oled
eff
ect i
ndic
ates
m
eani
ngfu
l ben
efit
or
unac
cept
able
har
m,
and
indi
vidu
al s
tudi
es
in th
e sa
me
dire
ctio
n as
poo
led
effe
ct,
then
= 0
, if
not
, th
en=
-1.
0
If >
3 st
udie
s an
d po
oled
eff
ect i
ndic
ates
no
eff
ect,
and
indi
vidu
al s
tudi
es a
lso
indi
cate
no
effe
ct,
then
= 0
, if
not
, th
en=
-1.
0
If o
nly
two
stud
ies
wit
h ef
fect
siz
es in
sa
me
dire
ctio
n, th
en =
-0
.5, i
f eff
ect s
izes
in
diff
eren
t dir
ecti
ons,
th
en=
-1.
0
If s
ingl
e st
udy,
th
en=
-1.
0
If p
opul
atio
n as
w
ell a
s in
terv
enti
on in
st
udie
s sa
me
as
thos
e of
inte
rest
, th
en =
0
If o
ne o
f the
two
diff
eren
t fro
m th
at
of in
tere
st ,
then
= -
0.5
If b
oth
diff
eren
t fr
om th
ose
of
inte
rest
, th
en =
-1.
0
If fi
nal s
core
= 0
or
-0.
5,
then
HIG
H
If fi
nal s
core
= -
1 or
-1.5
, th
en
MO
DE
RA
TE
If fi
nal s
core
= -
2 or
-2.5
, th
en L
OW
If fi
nal s
core
-3
, th
en V
ER
Y L
OW
14 TAB
LE2
- G
RA
DE
CR
ITER
IAFO
RA
SSES
SIN
GTH
EQ
UA
LITY
OF
EVID
ENC
E
_ _
The second GDG meeting was organized on March 6-8, 2009 to draft and finalize therecommendations. A two-step process was followed to draft the recommendations.First, the evidence was summarized and quality of evidence assessed for all the ques-tions. The GDG then considered the summary and quality of evidence, balance betweenbenefits and harms, values and preferences of policy-makers, health care providers andparents, feasibility and resource use; in addition, costs were analyzed to see whetherthey could be qualitatively justifiable by the benefits to formulate the recommendationfor all the questions, irrespective of the GRADE being u sed for assessing the quality ofevidence. On the basis of considerations on the balance between desirable and undesir-able effects, quality of evidence, values, preferences and feasibility issues, the GDGadditionally provided a judgment on the strength of each recommendation, to be cate-gorized as strong or weak. We anticipated that, in some circumstances, recommenda-tions may apply only if specific conditions are met. Indeed, they were context-specificrecommendations, as indicated for the recommendations where relevant.
The strength of a recommendation reflects the degree of confidence to the extentthat the desirable effects of adherence to a recommendation outweigh the undesirableeffects. Desirable effects can include beneficial health outcomes, less burden and sav-ings. Undesirable effects can include harms, more burden and higher costs. Burdens arethe demands of adhering to a recommendation that patients or caregivers (e.g. families)may dislike, such as having to undergo more frequent tests or opting for a treatmentthat may require a longer time for recovery.
Although the degree of confidence is a continuum, the GRADE system defines twocategories: strong and weak.
• A strong recommendation is one for which the panel is confident that the desir-able effects of adherence to a recommendation outweigh the undesirable effects.This can be either in favour of or against an intervention.
• A weak recommendation is one for which the panel concludes that the desirableeffects of adherence to a recommendation probably outweigh the undesirableeffects, but the panel is not confident about these trade-offs. Reasons for notbeing confident can include:
› absence of high quality evidence› presence of imprecise estimates of benefits or harms› uncertainty or variation in how different individuals value the outcomes› small benefits› the benefits may not be worth the costs (including the costs of implementing
the recommendation).
Despite the lack of a precise threshold between a strong and a weak recommenda-tion, the presence of important concerns about one or more of the above reasons makesa weak recommendation more likely. In addition, some of the recommendations werecontext-specific, i.e. some recommendations, be strong or weak, might not be appli-cable in all settings.
Implications of a strong recommendation are as follows:• For patients: most people in this situation would want the recommended course of
action and only a small proportion would not.• For clinicians: most patients should receive the recommended course of action.
Adherence to this recommendation is a reasonable measure for good quality care.• For policy makers: the recommendation can be adopted as a policy in most situa-
tions. Quality initiatives could use this recommendation to measure variations inquality.
Implications of a weak recommendation are as follows:• For patients: the majority of people in this situation would want the recommend-
ed course of action, but many would not.
Formulationof recommendations
15
_ _
• For clinicians: be prepared to help patients to make a decision that is consistentwith their own values.
• For policy makers: there is a need for substantial debate and involvement of stake-holders.
The scoping questions and outcomes as well as the evidence reviews were circulated forpeer-review to experts from different regions of the world. An audit was kept for all thecomments received from the external reviewers; comments were discussed and agreedupon by the GDG members.
During the meetings, the designated member of the GDG presented the systematicreview of the evidence, balance between benefits and harms, values and preferences,resource use and feasibility issues. All the above issues were discussed by the GDG foreach of the scoping questions. Agreement was reached by consensus. The “review bydate” was discussed by GDG members and it was decided that Department of MentalHealth and Substance Abuse will review the guidelines for any update required 5 yearsafter its publication.
A print and electronic version of the guidelines will be published for wider disseminationand easy access for the target audiences. In addition, the guidelines would be dissemi-nated by partners involved in its development through their networks. Articles based onthe guidelines would also be submitted to journals for its wider dissemination to scien-tific audience.
The guidelines will be field-tested in different health settings and by different cadresof health care providers before its implementation. Following the field test and any nec-essary revisions, guidelines will be considered for inclusion in the standard WHO train-ing materials, including the Integrated Management of Childhood Illness (IMCI), theIntegrated Management of Pregnancy and Childbirth (IMPAC), and Pocketbook forHospital Care for Children.
16
Consensus, externalreview and updating
Presentation,dissemination, andimplementation plan
_ _
19
What is the prevalence of variouscauses of neonatal seizures in differ-ent geographical regions of theworld?
BACKGROUND QUESTION
Salient findings
• Given the differences in characteristics of the underlying populations, study designs,study sites, and classification and definitions used, it is difficult to provide a single esti-mate of the prevalence of different disease conditions in neonates with seizures.
• Among neonates with seizures, the reported ranges of median prevalence are the fol-lowing: hypoxic-ischaemic encephalopathy (HIE): 38-48%; hypoglycaemia: 3-7.5%;hypocalcaemia: 2.3-9%; central nervous system (CNS) infections: 5.5-10.3% (seeTable 3).
• The prevalence of these four common etiologies do not appear to be differentbetween term and preterm neonates. Also, we did not find any rate differencesbetween the studies published before and after 1990.
• Studies have reported higher frequency of neonatal seizures (NS) in males than infemales as well as in Black rather than in White infants or infants from other ethnici-ties and in preterm babies (Bergman et al., 1983; Saliba et al., 1999; Saliba et al.,2001).
• Most of the studies were conducted in developed country settings, with only very fewstudies conducted in developing countries.
Prevalence of different etiologies in infants with neonatal seizures (%) Study population
Date of publicationof studies Hypoxic-ischaemic
encephalopathy Hypoglycaemia Hypocalcaemia Central Nervous
System Infections
<1990 48% (13 to 83) [3 studies]
5.5% (5 to 6.5) [3 studies]
9% (2.6 to 20) [3 studies]
10.3% (9.5 to 12) [2 studies]
Term neonates
>1990 38% [1 study]
- - 7.5% [1 study]
<1990 40% [1 study]
3%[1 study]
2.3% (1.5 to 3) [2 studies]
5.5% (5 to 6) [2 studies]
Preterm neonates
> - - - - 0991
<1990 42.5% (12.5 to 77) [16 studies]
6% (1 to 13) [7 studies]
6% (0.5 to 43) [10 studies]
10% (0.7 to 24) [14 studies]
Both term and preterm ORunknown gestation
>1990 40% (12 to 80) [10 studies]
7.5% (4 to 13) [2 studies]
5% (5 to 5) [2 studies]
8.5% (2 to 16) [8 studies]
Median (range); see Annex 2 for details of individual studies
Note: Data stratified by date of publication (before and after 1990) because of the availability of
better monitoring and diagnostic modalities that could help in easy identification of studies in the
latter period
TABLE 3 - PREVALENCE OF NEONATAL SEIZURES
_ _
Which clinical factors and diagnostictests best predict the prognosis ofneonatal seizures?
Summary of evidence – Salient findings
• Studies included in the review mainly provided a moderate level of evidence becauseof the limitations in study populations, study design, and insufficient duration of theclinical follow-up and sparse data. Also, lack of electroencephalography (EEG) confir-mation in some studies might influence the study results because of inclusion ofneonates with electro-clinical and clinical seizures of possible non-epileptic events. Allstudies, except for one, were conducted in developed countries, in settings wellequipped to accurately diagnose and monitor seizures and therapy, and to assess theoutcomes. Therefore, all the findings might not be applicable in settings with limitedresources (see Annex 2 for details of individual studies).
• In general, prognosis and outcomes of NS are determined by neurological examina-tion during infancy and later in life, long-term neurodevelopment, and presence of thepost-neonatal epilepsy. The most reliable early predictors of later neurological out-comes are the underlying etiology of the seizures and specific EEG backgroundpatterns.
• Multiple rather than single factors seem to be most accurate in predicting outcome.Nearly all variables relate to the degree of brain injury at the time of seizure occur-rence which, in turn, relates to etiology.
• The interictal EEG from one or serial recordings, the ictal EEG and findings on neu-roimaging are selected as most powerful methods for NS prognosis. Background EEGactivity is significantly and independently related to the neurodevelopment outcome.
• An abnormal neurological examination appears to be related to an adverse outcomeas well. Since this parameter is independent from any diagnostic equipment, it shouldbe a part of the follow-up plan for infants with neonatal seizures in any settings.
• As preterm neonates appear to have a higher risk for long-term adverse outcome thanterm infants with NS, they have to be followed more closely for abnormal neurologi-cal development.
• Different, standardized instruments are available for assessment of neurodevelopmentin infants; they could be adapted to the specific population. The age-appropriatenessand the quality of expertise are crucial for their quality and reliability.
• The effects of antiepileptic drugs (AEDs) on the immature and developing brain arenot clear. There is no convincing data that short-term or long-term therapies adverse-ly alter cognitive function. No study addressing this issue was found.
• Concerning the limitations of nonrandomized, cohort or observational studies, aprospective, multicentre, randomized placebo-controlled trial with long term clinicalfollow-up of neurological and cognitive outcomes is recommended. Instruments ofthe assessment should be adapted to the low-resource settings.
20
BACKGROUND QUESTION
_ _
Summary of evidence – Values and benefits
• In newborns with seizures, work-up should be initiated quickly to determine the cause,depending upon the facilities available. We did not identify any randomized controlledtrials or well conducted observational studies examining the effects of AED treatmentcompared with no treatment in infants with NS.
• There is some evidence from observational studies that serial, ongoing seizures aredetrimental to the developing brain; there is also some evidence that electrical seizuresmay be associated with worse outcome if not controlled.
• Though a significant clinical benefit has not been demonstrated in the past, the pos-sible benefits of treatment with AEDs outweigh possible harms with no evidence ofclinically relevant adverse effects of adequate and short term AED treatment.
Recommendation(s)
• Clinically apparent seizures in the neonate should be treated if they last more than 3minutes or are brief serial seizures (strong recommendation).
• In specialized care facilities where electroencephalography is available, all electricalseizures, even in the absence of clinically apparent seizures, should also be treated(strong, context-specific recommendation).
21
Which newborn seizures requireacute antiepileptic drug treatment?
QUESTION 1
QUESTIONS DIRECTLY RELATED TO MANAGEMENT OF NEONATAL SEIZURES
_ _
Summary of evidence – Values and benefits
• There is no evidence from trials to support or reject empirical treatment (prior to lab-oratory tests) for hypoglycaemia, hypocalcaemia and bacterial or viral infections.
• The prevalence of hypoglycaemia in neonates with seizures is 3-7.5% (Table 3).Hypoglycaemia can be deleterious and is associated with sequelae including epilepsy(Caraballo et al., 2004). A risk/benefit analysis of empirical treatment of hypogly-caemia is not available. The possible harm with treatment is the worsening of hyper-glycaemia in some neonates with HIE. Since blood glucose can easily be measured atlow cost, this should be performed before treatment.
• The prevalence of hypocalcaemia in neonates with seizures varies between differentstudies with a range of 2.3-9% (Table 3). The studies reporting high incidences werepublished in the 1970s (Keen & Lee, 1973, and Langevin, 1974). With better nutri-tional management, the incidence of hypocalcaemia may since have declined.However, the data available are not sufficient to prove this assumption. Measurementof blood calcium is possible in hospital settings without time delay, although less eas-ily available than measurement of blood sugar. When given intravenously, calciummay cause significant harm, i.e. asystole or skin necrosis. The benefit vs. harm ratio forempirical treatment of hypocalcaemia before laboratory tests cannot be assessed.
• Data on different etiologies of neonatal seizures are highly inconsistent (Table 3).There is not sufficient evidence to describe regional differences. The only availablestudy from an African country found a very high incidence of bacterial infections inneonates with seizures admitted to a hospital in Kenya (Idro et al., 2008). This studymay be biased because only infants referred to hospital were included. The authors didnot state whether the neonates showed other clinical signs of infection and gave noinformation about laboratory tests performed. Since oral treatment of neonatal sepsisor pyogenic meningitis is not considered as a standard therapy, empirical treatmentwould imply intravenous therapy.
• Congenital herpes simplex virus infection is a rare cause of NS. A population-basedcase-control study found an increased odds ratio of 2.9 for a history of vaginal deliv-ery/maternal herpes simplex infection in infants presenting with seizures within thefirst 72 hours of life (Hall et al., 2006). The authors did not state whether the neonatesshowed other clinical signs of infection. Since oral treatment of congenital herpes sim-plex virus infection is not considered as a standard therapy, empirical treatment wouldimply intravenous therapy. A benefit vs. harm ratio of such treatment cannot beassessed due to paucity of data.
• Pyridoxine dependent epilepsy is a rare disease with an incidence of about 1:396 000(Been et al., 2005) compared to the overall incidence of neonatal seizures between1:71 and 1:1000. Other treatable neonatal epileptic encephalopathies with metaboliccauses, such as pyridoxal-phosphate dependent epilepsy, probably are even less fre-quent. The diagnosis of pyridoxine dependent epilepsy can be established clinically bya positive response to treatment with pyridoxine. Failure to diagnose this conditionmay have deleterious effects on affected neonates, but delay in treatment of otherunderlying etiologies may also cause harm. A benefit vs. harm ratio of empirical treat-ment with pyridoxine cannot be calculated.
22
What is the clinical efficacy ofempirical treatment of newbornswith seizures (prior to laboratorytests) for hypoglycaemia,hypocalcaemia, and bacterialinfection/meningitis?
QUESTION 2
_ _
Recommendation(s)
• In all neonates with seizures, hypoglycaemia should be ruled out and treated if pres-ent, before anti-epileptic drug treatment is considered (strong recommendation).
• If facilities for measuring glucose are not available, consider empirical treatment withglucose (weak, context-specific recommendation).
• If there are clinical signs suggestive of associated sepsis or meningitis, central nervoussystem infection should be ruled out by doing a lumbar puncture, and treated if pres-ent with appropriate antibiotics (strong recommendation).
• If facilities for lumbar puncture are not available, consider empirical treatment withantibiotics for neonates with clinical signs of sepsis or meningitis (weak, context-spe-cific recommendation).
• In all neonates with seizures, serum calcium should be measured (if facilities are avail-able) and treated if hypocalcaemia is present (strong, context-specific recommendation).
• In the absence of hypoglycaemia, meningitis, hypocalcaemia or another obviousunderlying etiology, such as hypoxic-ischaemic encephalopathy, intracranial haemor-rhage or infarction, pyridoxine treatment may be considered before antiepileptic drugtreatment, in a specialized centre where this treatment is available (weak, context-spe-cific recommendation).
23
_ _
24
Summary of evidence – Values and benefits
• Commonly used first-line AEDs for treatment of NS are phenobarbital and phenytoin.
• There is very low quality evidence from a single randomized controlled trial (RCT) thatthe two drugs are equally effective (Table 4); it should, however, be noted that onlyabout 55% of newborns respond to either of the two medications.
• Phenobarbital is easier to administer with a one daily dose being sufficient followingattainment of therapeutic levels. Phenytoin has more severe adverse effects than phe-nobarbital including cardiac side effects and extravasation (although these have beenmitigated by the introduction of fosphenytoin). The therapeutic range of phenytoin isvery narrow and blood levels need to be measured to a greater degree than phenobarbital.
• Phenobarbital is also cheaper and more easily available than phenytoin.
Recommendation(s)
• Phenobarbital should be used as the first-line agent for treatment of neonatal seizures;phenobarbital should be made readily available in all settings (strong recommendation).
Which is the preferred first-lineantiepileptic drug for a newbornwith seizures requiring treatmentwith antiepileptic drugs?
QUESTION 3
OUTCOME No. of studies
Design Limitations in methods
Precision Consistency Generalizability/Directness
Overall Quality
ofEvidence
Pooled effect size (95% CI) or range of
effect sizes if pooling not
possible at all
Seizure control
1 RCT
(0)
Limitations in allocation of subjects and
blinding
(-1.0)
Effect not significant, with wide
CI
(-1.0)
Single study
(-1.0)
From developed country setting
(-0.5)
VERY LOW
(Total score =
-3.5)
RR 0.97 (0.54, 1.72)
See Annex 2 for detailed GRADE profiles and tables of individual studies
TABLE 4 - FIRST-LINE ANTIEPILEPTIC DRUGS FOR NEONATAL SEIZURES: GRADE PROFILE SUMMARY
_ _
25
Summary of evidence – Values and benefits
• We identified only one observational study that compared midazolam withphenytoin as the second-line AED. The quality of evidence was graded as verylow. There was a significant benefit in seizure control with midazolam as thesecond-line AED; there was, however, no benefit or harm in the long-term neu-rodevelopmental outcomes (Table 5).
• Two studies have examined the effects of lidocaine and benzodiazepines on seizurecontrol. The quality of evidence was very low. There was no difference between thetwo (Pooled RR: 1.78, 95% CI: 0.90 to 3.52). No significant effect was observed onthe long-term neurodevelopment either (Table 5).
• Compared to benzodiazepines, lidocaine has a narrow therapeutic range and alsorequires cardiac monitoring while being administered. Moreover, it may not be readi-ly available in all settings. On the other hand, benzodiazepines have a higher risk incausing respiratory depression. Phenytoin also requires cardiac monitoring duringadministration.
Recommendation(s)
• In neonates who continue to have seizures despite the administering of the maximaltolerated dose of phenobarbital, either a benzodiazepine or phenytoin or lidocainemay be used as the second-line agent for control of seizures, the use of phenytoin orlidocaine requiring cardiac monitoring facilities (weak recommendation).
Which is the preferred second-lineantiepileptic drug treatment for anewborn with seizures not respond-ing to maximal tolerated dose ofphenobarbital?
QUESTION 4
_ _
26
OU
TC
OM
E
No.
of
stu
die
s D
esig
n
Lim
itat
ion
s in
m
eth
ods
Pre
cisi
on
Con
sist
ency
Gen
eral
izab
ilit
y /
D
irec
tnes
s O
vera
ll
Qu
alit
y of
E
vid
ence
Poo
led
eff
ect
size
(95%
CI)
or
ran
ge o
f eff
ect
size
s if
poo
lin
g
not
pos
sibl
e
at
all
Ben
zod
iaze
pin
es v
s. P
hen
yto
in
Seiz
ure
co
ntr
ol
1 O
bser
vati
onal
(-1.
0)
Lim
itat
ions
in a
lloca
tion
of
sub
ject
s, b
lindi
ng,
and
anal
ysis
(-1.
5)
Eff
ect
sign
ific
ant;
low
er
limit
of C
I m
eani
ngfu
l
(0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed c
ount
ry
sett
ing
(-0.
5)
VE
RY
L
OW
(Tot
al s
core
=
-4.0
)
RR
2.1
3 (1
.48,
3.0
8)
Nor
mal
n
euro
-d
evel
opm
ent
(unt
il 1
yea
r)
1 O
bser
vati
onal
(-1.
0)
Lim
itat
ions
in a
lloca
tion
of
sub
ject
s, b
lindi
ng,
and
anal
ysis
(-1.
5)
Eff
ect n
ot
sign
ific
ant,
wit
h w
ide
CI
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed c
ount
ry
sett
ing
(-0.
5)
VE
RY
L
OW
(Tot
al s
core
=
-5.
0)
RR
1.1
5 (0
.62,
2.1
4)
Seiz
ure
co
ntr
ol
2
(1 R
CT
and
1 ob
serv
atio
nal)
Maj
orit
y of
ev
iden
ce fr
om
obse
rvat
iona
l
(-1.
0)
Lim
itat
ions
in a
lloca
tion
of
sub
ject
s, b
lindi
ng, a
nd
anal
ysis
(-1.
5)
Pool
ed e
ffec
t not
si
gnif
ican
t, w
ith
wid
e C
I (-1.
0)
Bot
h st
udie
s in
the
sam
e di
rect
ion
(0)
Bot
h fr
om d
evel
oped
co
untr
y se
ttin
gs
(-0.
5)
VE
RY
L
OW
(Tot
al s
core
=
-4.0
)
RR
1.7
8 (0
.90,
3.5
2)
Nor
mal
n
euro
-d
evel
opm
ent
2
(1 R
CT
and
1 ob
serv
atio
nal)
Maj
orit
y of
ev
iden
ce fr
om
obse
rvat
iona
l
(-1.
0)
Lim
itat
ions
in a
lloca
tion
of
sub
ject
s, b
lindi
ng,
and
anal
ysis
(-1.
5)
Pool
ed e
ffec
t not
si
gnif
ican
t, w
ith
wid
e C
I (-1.
0)
Onl
y 2
stud
ies,
bot
h in
opp
osit
e di
rect
ion
(-1.
0)
Bot
h fr
om d
evel
oped
co
untr
y se
ttin
gs
(-0.
5)
VE
RY
L
OW
(Tot
al s
core
=
-5.
0)
RR
1.2
0 (0
.36,
3.9
6)
Lid
ocai
ne
vs. B
enzo
diaz
epin
es
See
An
nex
2fo
r de
taile
d G
RA
DE
prof
iles
and
tabl
es o
f in
divi
dual
stu
dies
TAB
LE5
- SE
CO
ND-L
INE
AN
TIEP
ILEP
TIC
DR
UG
SFO
RN
EON
ATA
LSE
IZU
RES
: G
RA
DE
PRO
FILE
SUM
MA
RY
_ _
Summary of evidence – Values and benefits
• Evidence from observational studies suggests that a large proportion of neonates inwhom the seizure control is achieved and who have normal findings on neurologicalexamination, EEG, neuroimaging or combination thereof are at a low risk (< 10%) forrecurrence of seizures (Table 6). Normal neurological examination includes normalsensorium and ability to breastfeed, and absence of abnormal findings in formal neu-rological examination; normal EEG means absence of spikes and normal backgroundactivity.
• There is very low quality evidence for significant benefits in seizure recurrence and forno benefits or harms in other outcomes like epilepsy, cerebral palsy or developmentaldelay following stoppage of AEDs compared with continuing therapy in neonates(Table 6).
• Given the saving on costs for both parents and health care systems, policy-makers andhealth providers are likely to give a high value to stopping AEDs in the neonatal period.
• No information is available regarding the time interval between achieving seizure con-trol and discontinuing AEDs; the seizure-free interval suggested here (72 hours) islargely based on expert opinion.
Recommendation(s)
• In neonates with normal neurological examination and/or normal electroencephalog-raphy, consider stopping antiepileptic drugs if seizure-free for >72 hours; the drug(s)should be reinstituted in case of recurrence of seizures (weak recommendation).
27
If a newborn has seizures and is con-trolled on current antiepileptic drugtreatment, when should the medica-tion be discontinued?
QUESTION 5
_ _
28
OU
TC
OM
E
No.
of
stu
die
s D
esig
n
Lim
itat
ion
s in
met
hod
sP
reci
sion
C
onsi
sten
cyG
ener
aliz
abil
ity/
Dir
ectn
ess
Ove
rall
Qu
alit
y of
Evi
den
ce
Poo
led
eff
ect
size
(95
% C
I) o
rra
nge
of e
ffec
t si
zes
if p
ooli
ng
n
ot p
ossi
ble
at
all
Seiz
ure
recu
rren
ce3
All
obse
rvat
iona
l
(-1.
0)
Lim
itat
ions
in
sele
ctio
n of
sub
ject
s an
d an
alys
is
(-1.
0)
Pool
ed e
ffec
t si
gnif
ican
t but
upp
er
limit
of C
I in
the
‘nul
l’ ra
nge
(-0.
5)
All
stud
ies
in
the
sam
e di
rect
ion
(0)
All
from
dev
elop
ed
coun
try
sett
ing
(-0.
5)
VE
RY
LO
W
(Tot
al s
core
= -
3.0
)
RR
0.6
6 (0
.47,
0.9
3)
Ep
ilep
sy
in in
fan
cy
1 O
bser
vati
onal
(-1.
0)
Lim
itat
ions
in
sele
ctio
n of
sub
ject
s an
d an
alys
is
(-1.
0)
Eff
ect n
ot s
igni
fica
nt,
wit
h w
ide
CI
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0.
5)
VE
RY
LO
W
(Tot
al s
core
= -4
.5)
RR
0.5
4 (0
.25,
1.1
9)
Cer
ebra
l pal
sy
1O
bser
vati
onal
(-1.
0)
Lim
itat
ions
in
sele
ctio
n of
sub
ject
s an
d an
alys
is
(-1.
0)
Eff
ect n
ot s
igni
fica
nt,
wit
h w
ide
CI
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0.
5)
VE
RY
LO
W
(Tot
al s
core
= -4
.5)
RR
0.6
3 (0
.31,
1.2
7)
Dev
elop
men
tal
del
ay
1O
bser
vati
onal
(-1.
0)
Lim
itat
ions
in
sele
ctio
n of
sub
ject
s an
d an
alys
is
(-1.
0)
Eff
ect n
ot s
igni
fica
nt,
wit
h w
ide
CI
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0.
5)
VE
RY
LO
W
(Tot
al s
core
= -4
.5)
RR
0.9
1 (0
.64,
1.2
9)
See
An
nex
2fo
r de
taile
d G
RA
DE
prof
iles
and
tabl
es o
f in
divi
dual
stu
dies
TAB
LE6
- D
ISC
ON
TIN
UA
TIO
NO
FA
NTI
EPIL
EPTI
CD
RU
GS
INN
EON
ATA
LSE
IZU
RES
: G
RA
DE
PRO
FILE
SUM
MA
RY
_ _
Summary of evidence – Values and benefits
• There is no available data to suggest that gradual withdrawal of AEDs has effects onshort term outcome such as breakthrough seizures and mortality as well as on longterm outcomes, e.g. epilepsy or neurodevelopmental impairment.
• There is no data regarding the sequence of withdrawal of AEDs in the case of neonatewho has had seizures and is controlled on multiple AEDs.
• The current treatment practices with regard to the mode of discontinuing AED treat-ment appears to vary widely between different settings and countries.
• Due to paucity of data, the following recommendations were formulated based onexpert opinion.
Recommendation(s)
• In neonates in whom seizure control is achieved with a single antiepileptic drug, thedrug can be discontinued abruptly without any tapering of the doses (weak recom-mendation).
• In neonates requiring more than one antiepileptic drugs for seizure control, the drugsmay be stopped one by one, with phenobarbital being the last drug to be withdrawn(weak recommendation).
29
If a newborn has seizures and is con-trolled on current antiepileptic drugtreatment, how should the medica-tion be discontinued?
QUESTION 6
_ _
Summary of evidence – Values and benefits
• We identified two studies – one RCT and one observational – that evaluated the effectof prophylactic therapy on mortality in infants with HIE. The quality of evidence wasgraded as very low. There was no significant effect on mortality (pooled RR: 1.80,95% CI: 0.78 to 4.19). A 1.80 RR with wide confidence intervals means that we can-not entirely rule out a significant harm in mortality with prophylactic phenobarbitaltreatment (Table 7).
• We found two RCTs studies examining the effect of the prophylactic therapy on abnor-mal neurological outcome. One study reported the outcome at discharge, while theother reported the incidence at 3 years of age. The quality of evidence was graded asmoderate. The pooled effect was 56% (95% CI: 24% to 79%) reduction in the risk ofabnormal neurological outcome. The fact that the significant pooled effect essentiallycomes from a single study, however, decreases the confidence in this outcome (Table 7).
• We identified 4 studies - three RCTs and one observational - that looked at the effectof the above therapy on the incidence of seizures during the initial hospital stay. Thesestudies used different doses of phenobarbital (10 to 40 mg/kg). The quality of evi-dence was graded as very low. There was no difference in the risk of subsequentseizures (pooled RR: 0.84, 95% CI: 0.34 to 2.09; Table 7).
• There is a debate about adverse effects of AEDs on the developing brain but no evi-dence from clinical studies. No prophylactic therapy would avoid additional medica-tion and associated costs. Given these considerations and low-to-very low quality evi-dence for not significant benefits in important outcomes, policy-makers and healthproviders are unlikely to give a high value to prophylactic treatment with phenobarbital.
Recommendation(s)
• In the absence of clinical seizures, neonates with hypoxic-ischaemic encephalopathydo not need to be given prophylactic treatment with phenobarbital (strong recom-mendation).
30
What is the effect of prophylactictreatment of at-risk neonates withhypoxic-ischaemic encephalopathyon mortality, recurrence of seizuresand/or long-term neurological out-comes?
QUESTION 7
_ _
OU
TC
OM
E
No.
of
stu
die
s D
esig
n
Lim
itat
ion
s in
m
eth
ods
Pre
cisi
on
Con
sist
ency
G
ener
aliz
abil
ity
/D
irec
tnes
s O
vera
ll Q
ual
ity
of E
vid
ence
P
oole
d e
ffec
t si
ze
(95%
CI)
or
ran
ge
of e
ffec
t si
zes
if
poo
lin
g n
ot
pos
sibl
e a
t a
ll
Mor
tali
ty
(dur
ing
init
ial
hosp
ital
sta
y)
2(1
RC
T an
d 1
obse
rvat
iona
l)
Maj
orit
y of
ev
iden
ce fr
om
obse
rvat
iona
l st
udy
(-1.
0)
Lim
itat
ions
in
sele
ctio
n of
su
bjec
ts a
nd
anal
ysis
(-1.
0)
Pool
ed e
ffec
t not
si
gnif
ican
t, w
ith
wid
e C
I
(-1.
0)
Bot
h st
udie
s in
the
sam
e di
rect
ion
(0)
Bot
h st
udie
s fr
om
deve
lopi
ng
coun
try
sett
ings
(0)
VE
RY
LO
W
(Tot
al s
core
= -
3.0
)
RR
1.8
0 (0
.78,
4.1
9)
Abn
orm
al
neu
rolo
gica
l ou
tcom
e (a
t dis
char
ge in
1
stud
y, a
t 3 y
ears
in
the
othe
r)
2 R
CT
s
(0)
Lim
itat
ions
in
follo
w-u
p an
d an
alys
is
(-1.
0)
Pool
ed e
ffec
t si
gnif
ican
t and
lo
wer
lim
it o
f CI
mea
ning
ful
(0)
(-0.
5)
Maj
orit
y of
evi
denc
efr
om th
e st
udy
in
deve
lopi
ng c
ount
ry
sett
ing
(0)
MO
DE
RA
TE
(Tot
al s
core
= -
1.5)
RR
0.4
4 (0
.24,
0.7
9)
Inci
den
ce o
f se
izu
res
(in
the
init
ial
hosp
ital
sta
y)
4(3
RC
Ts
and
1 ob
serv
atio
nal)
Maj
orit
y of
ev
iden
ce fr
om
RC
Ts
(0)
Lim
itat
ions
in
allo
cati
on o
f su
bjec
ts, f
ollo
w-u
p,an
d an
alys
is
(-1.
5)
Pool
ed e
ffec
t not
si
gnif
ican
t, w
ith
wid
e C
I
(-1.
0)
(-1.
0)
Maj
orit
y of
evi
denc
efr
om s
tudi
es in
de
velo
ping
cou
ntry
se
ttin
gs
(0)
VE
RY
LO
W
(Tot
al s
core
= -
3.5)
RR
0.8
4 (0
.34,
2.0
9)
Ran
dom
-eff
ects
m
odel
Eff
ect s
ize
of s
tudi
esw
ith
<75
% o
f tot
al
wei
ght i
n th
e sa
me
dire
ctio
n as
poo
led
effe
ct
Onl
y 2
stud
ies,
effe
ct s
ize
of b
oth
in s
ame
dire
ctio
n
See
An
nex
2fo
r de
taile
d G
RA
DE
prof
iles
and
tabl
es o
f in
divi
dual
stu
dies
TAB
LE7
- PR
OPH
YLA
CTI
CTR
EATM
ENT
OF
AT-
RIS
KN
EON
ATE
SW
ITH
HY
POX
IC-I
SCH
AEM
ICEN
CEP
HA
LOPA
THY:
GR
AD
EPR
OFI
LESU
MM
AR
Y
31
_ _
32
Summary of evidence – Values and benefits
Prospective studies. Prospective cohort studies (Ronen et al., 2007; Tekgul et al.,2006; Ortibus et al., 1996; Pisani et al., 2008b; Plouin et al., 1981; Dreyfus-Brisac etal., 1981; Bye et al., 1997) have reported an association between NS and abnormalneurological outcome, morbidity, and mortality; similarly, Mizrahi & Kellaway (1987)and Rowe et al. (1985) noted that EEG characteristics can help determine etiology andoutcomes. One study (McBride et al., 2000) observed an association between theamount of electrographic seizure activity and subsequent mortality and morbidity ininfants at risk for seizures and in infants with perinatal asphyxia. Normal EEG in theneonatal period has been reported to have a sensitivity of 96% and a specificity of81% in predicting the absence of seizures in the first two years of life (Laroia et al.,1998); another study (Kerr et al., 1990) found that EEG can help predict persistence ofseizures. While some studies (Scarpa et al., 1983; Kumar et al., 2007; Bye & Flanagan,1995) noted that the use of EEG could help with anticonvulsant management, others(Connell et al., 1989) showed mixed results to this regard.
Retrospective studies. Several studies (Khan et al., 2008; Pisani et al., 2008a; Carrascosaet al., 1996) have reported an association between abnormal EEG findings and neurolog-ical outcome, including developmental delay, epilepsy and death. While one study (VanRooij et al., 2007) noted that the duration – but not background pattern – was associat-ed with neurodevelopmental outcome, other studies (Staudt, 1990; Domenech-Martinezet al., 2003) reported a good correlation between abnormal background activity andprognosis. Serial EEGs (Tharp et al., 1981) as well as EEG on the first day of life (Pezzaniet al., 1986) have also been reported to help determine long-term prognosis.
• EEG is the most accurate method for confirming that a clinical event is of epileptic ori-gin, which is consistent with values and preferences of accurate diagnosis. However,the standard method of diagnosis is the clinical recognition of neonatal seizures.
• The risk of performing an EEG on a neonate is minimal, predominantly related to tran-sient discomfort and scalp irritation.
• While performing EEG, certain factors need to be considered such as minimally accept-able standard for the equipment and facilities, minimal training requirements for EEGtechnicians and interpretation of EEG by a trained person.
• The cost for performing an EEG (purchase and instrumentation maintenance, purchaseof supplies, personnel) may overwhelm health care facilities with limited resources; netbenefits are context-specific. In general, the net benefits are worth the costs.
• The application of EEG to determine specific etiological factors is rather limited.Although there are some EEG patterns that may be specific for certain neonatal braindisorders, these conditions are very few, represent a small proportion of risk factorsand are no longer the critical diagnostic test for these disorders. Although the relativeharm of performing an EEG is negligible, there appears to be no benefit in performingthe EEG for this purpose alone when other more definitive testing is available (such asneuroimaging or infectious disease diagnostics).
• Although the sequence of response to AEDs has been described by observational stud-ies, the effect has not been quantified. Studies titrating AED therapy to elimination ofelectrographic seizures have not been performed. Where available, recording of EEGto assess the efficacy of treatment is consistent with values and preferences of limit-ing sequels of neonatal seizures. However, the net benefits are context-specific. Inresource-challenged health care centres where EEG is not available, response to treat-ment is best assessed by clinical observation.
What is the value of electroen-cephalography in the managementof a newborn with seizures?
QUESTION 8
_ _
• The purpose of recording EEG for prognosis determination is based upon the idea ofmaximizing infant potential through early intervention. While there may be enhancedaccuracy in the prediction of long-term outcome by utilizing EEG, serial recordingswould imply a cost to be borne both on families and health care systems for data thatmay not have immediate implications.
Recommendation(s)
• Where available, all clinical seizures in the neonatal period should be confirmed byelectroencephalography (strong, context-specific recommendation).
• Electroencephalography should not be performed for the sole purpose of determiningthe etiology in neonates with clinical seizures (strong recommendation).
33
_ _
Summary of evidence – Values and benefits
Ultrasound (US). One study (Malik et al., 2005) reported that in about 10% of infantswith NS an abnormal finding was found on head US, while another study (Alcover-Bloch et al., 2004) reported 43% of infants with abnormal head US.
Computed tomography (CT)/Magnetic Resonance Imaging (MRI). One studyreported that in term neonates with seizures MRI findings did not correlate with eitherclinical signs of perinatal distress or perinatal causes of cerebral injury (Rollins et al.,1994); similarly, another study noted that severity of seizures in newborns with perina-tal asphyxia is independently associated with brain injury and is not limited to damagedetectable by MRI (Miller et al., 2002).
US vs. CT/MRI. One retrospective study reported that about 43% of neonates withseizures had an abnormal head US, while only 31% had abnormal findings on CTand/or MRI (Rollins et al., 1994); another study (Mercuri et al., 1995) noted that 88%(14/16) of neonates with seizures had haemorrhage or ischaemia detected on MRI,with 11 of them detectable by US, and that MRI could detect ischaemic lesions earlierthan US.
• There are no data to support the use of neuroimaging in determining whether clinicalor electrographic seizures are present. However, it can be a useful tool in the diagno-sis of intracranial lesions that may be associated with NS.
• Each modality – US, CT or MRI – has its relative strengths and weakness in the diag-nosis of various intracranial disorders; their conduct does not support any values orpreferences when used in this way.
• These tests can be expensive and resource-consuming. In addition, the technologymay be difficult to maintain and operate in low-resource areas.
• There are no data supporting the use of neuroimaging to determine the efficacy ofAED treatment.
• There is low quality evidence that the findings of neuroimaging can be utilized as oneof several factors in determining long-term outcome; the benefit to conduct thesetests to assess prognosis is unclear, and related to the etiologic findings.
Recommendation(s)
• Radiological investigations (ultrasound, computed tomography and magnetic reso-nance imaging) of the cranium/head should not be performed to determine the pres-ence or absence of clinical seizures or to evaluate the efficacy of treatment withantiepileptic drugs in neonates (strong recommendation).
• They may be performed as part of the comprehensive evaluation of the etiology ofneonatal seizures or to determine prognosis in neonates with seizures (weak, context-specific recommendation).
34
What is the value of imaging of thecranium/head in diagnosis, evalua-tion of etiology, treatment, and prog-nosis of the newborn with seizures?
QUESTION 9
_ _
Ramesh K. AgarwalAssociate ProfessorWHO/CC for Training and Research in Newborn Care &ICMR Centre for Advanced Research in Newborn HealthNeonatal Health Knowledge Centre (NHKC) Division of Neonatology, Department of PaediatricsAll India Institute of Medical Sciences, New Delhi, India.
John Patrick T. CoDirector, Outpatient Quality and Safety, MassGeneral Hospital for Children Director, Graduate Medical Education, Partners HealthCare Assistant Professor of Paediatrics, Harvard Medical SchoolMGH Center for Child and Adolescent Health Research and Policy Boston, MA, USA
J Helen CrossProfessor, The Prince of Wales's Chair of Childhood EpilepsyChair ILAE Commission for Paediatrics 2005-2009UCL-Institute of Child HealthGreat Ormond Street Hospital for Children & National Centrefor Young People with EpilepsyHead of Neurosciences UnitLondon, Great Britain
Maurizio EliaHead of the WHO/CC for Training and Research on NeuroscienceDirector of the Unit of Neurology and NeurophysiologyDepartment of Mental RetardationIRCCS Associazione Oasi Maria SS. – ONLUSTroina (EN) – Italy
Renzo GuerriniProfessor and DirectorClinic of Paediatric Neurology Meyer University Hospital Florence, Italy
Hans HartmannConsultant Pediatric NeurologistDepartment of Pediatric Kidney, Liver and Metabolic Diseases Hannover Medical School Hannover, Germany
Nebojsa JovicProfessorClinic of Neurology and Psychiatry for Children and YouthFaculty of MedicineBelgrade, Serbia
Angelina M. KakoozaPresident, ILAE, Epilepsy Society Uganda (EPISOU)Treasurer, ILAE, Commission on African Affairs.Board Member, ILAE, Commission on Education. Lecturer, Department of Paediatrics & Child HealthMakerere University College of Health SciencesSchool of MedicineKampala, Uganda
37
Annex 1: List of contributors
In alphabetical order
GUIDELINEDEVELOPMENT GROUP
_ _
Eli M. MizrahiChair, Department of NeurologyProfessor of Neurology and PediatricsBaylor College of MedicineHouston, TX, USA
Emmanuel RaffoProfessorPaediatric NeurologyUniversité de Lorraine - INSERM U 94Hôpital d'Enfants - CHU de NancyNancy, France
Jo WilmshurstAssociate ProfessorDepartment of Paediatric NeurologyRed Cross Children's HospitalCape Town, South Africa
Elizabeta ZisovskaProfessor of Pediatrics Chief of the Department of Neonatology, Gynecology & Obstetric Clinic Skopje, Republic of Macedonia
Rajiv BahlMedical OfficerDepartment of Maternal, Newborn, Child and Adolescent HealthWorld Health OrganizationGeneva, Switzerland
Dr Tarun DuaMedical OfficerDepartment of Mental Health and Substance Abuse World Health OrganizationGeneva, Switzerland
José Manoel BertoloteProfessor, AISRAPGriffith University, AustraliaAssociate Professor,Faculdade de Medicina de Botucatu – UNESPBotucatu, Brazil
Bernardo Dalla BernardinaProfessorUnit of Child Neuropsychiatry University of VeronaVerona, Italy
Hanneke de BoerGlobal Campaign Against Epilepsy Coordinator Stichting Epilepsie Instellingen Nederland (SEIN, WHO CC for Research, Training andTreatment in Epilepsy)Senior Officer International ContactsHoofddorp, The Netherlands
38
WHO Secretariat
Other key contributors
_ _
Deborah HirtzProgram Director, Office of Clinical ResearchNational Institute of Neurological Disorders and StrokeNational Institutes of HealthRockville, MD, USA
Solomon L. MoshéPresident, International League Against EpilepsyCharles Frost Chair In Neurosurgery and NeurologyProfessor of Neurology, Neuroscience & PediatricsVice-Chair, Dept. of NeurologyDirector, Pediatric Neurology,Director, Clinical NeurophysiologyAlbert Einstein College of MedicineBronx, NY, USA
M Jeeva SankarMedical OfficerDepartment of Maternal, Newborn, Child and Adolescent HealthWorld Health OrganizationGeneva, Switzerland
Martin WeberMedical OfficerChild and Adolescent Health and Development WHO country officeJakarta, Indonesia
39
_ _
41
Annex 2: GRADE profiles and summary of individual studies
Note. GRADE could not be applied to epidemiological data
Study population
Study period
Hypoxic-ischaemic encephalopathy
Hypoglycaemia Hypocalcaemia CNS infection
Until 1990
Eriksson & Zetterström - 48% Rose & Lombroso - 13% Gunn & Cable - 83%
Range: 13 to 83% Median: 48%
Eriksson & Zetterström - 6.5% Rose & Lombroso - 5% Gunn & Cable - NA
Range: 5 to 6.5% Median: 5.5%
Eriksson & Zetterström - 2.6% Rose & Lombroso - 20% Gunn & Cable - 9%
Range: 2.6 to 20% Median: 9%
Eriksson & Zetterström - 12% Rose & Lombroso - 9.5% Gunn & Cable – NA
Range: 9.5 to 12% Median: 10.3%
Only full term neonates
Since 1990
Lien et al.- 38%
Range: NA Median: 38%
Lien et al. - NA Lien et al. - NA Lien et al. - 7.5%
Range: NA Median: 7.5%
Mixed (full term and preterm neonates) or not known
Until 1990
Craig - NA Schulte - 54% Keen & Lee - 12,5% (+ICH)Combes et al. - 77% (+ICH) Rossiter et al. - NA Dennis - 44% (including hypoglycaemia and hypocalcaemia) Andre et al. - 56% McInerny & Schubert - 33% Langevin - 57% Ellison et al. - 24% Holden et al. - NA Ment et al. - 32% Goldberg - 30 to 41% Bergman et al. - 59% Zalneraitis - 74% Tudehope et al. - 40%
Range: 12.5% to 77% Median: 42.5%
Craig - NA Schulte - NA Keen & Lee - 4% Combes et al. - NA Rossiter et al. - 13% Dennis - 12% Andre et al. - 1.4% McInerny & Schubert - 7% Langevin - NA Ellison et al. - NA Holden et al. - NA Ment et al. - NA Goldberg - 1 to 11% Bergman et al. - 5% Zalneraitis - NA Tudehope et al. - NA
Range: 1% to 13% Median: 6%
Craig 0.5% Schulte - NA Keen & Lee - 42% Combes et al. - 10% Rossiter et al. - NA Dennis - 14% (pure) Andre et al. - 2.8% McInerny & Schubert - 30% Langevin - 43% Ellison et al. - 2% Holden et al. - NA Ment et al. - NA Goldberg - 4 to 6% Bergman et al. - 1.5% Zalneraitis - NA Tudehope et al. - NA
Range: 0.5% to 43% Median: 6%
Craig - 6% Schulte - 7% Keen & Lee - 0.7% Combes et al. - 7% Rossiter et al. - 13% Dennis - NA Andre et al. - 24% McInerny & Schubert - 10% Langevin - NA Ellison et al. - 3% Holden et al. - 17% Ment et al. - 11% Goldberg - 4 to 5% Bergman et al. - 12%Zalneraitis - 13% Tudehope et al. - 11%
Range: 0.7% to 24% Median: 10%
Since 1990
Toet et al. - 80% Legido et al. - 35% Lanska & Lanska - 40% Ortibus et al. - 37% Ronen et al. - 40% Brunquell et al. - 49% Garcias da Silva et al. - 34% Bye et al. - 42% Idro et al. - 12%
Range: 12% to 80% Median: 40%
Toet et al. - NA Legido et al. - NA Lanska & Lanska - NA Ortibus et al. - NA Ronen et al. - 13% Brunquell et al. - NA Garcias da Silva et al. - NA Bye et al. - 4% Idro et al. - NA
Range: 4% to 13% Median: 8.5%
Toet et al. - NA Legido et al. - NA Lanska & Lanska - NA Ortibus et al. - NA Ronen et al. - 5% Brunquell et al. - NAGarcias da Silva et al. - NA Bye et al. - NA Idro et al. - 5%
Toet et al. - NA Legido et al. - 12.5% Lanska & Lanska - Ortibus et al. - 9% Ronen et al. - 8% Brunquell et al. - 2% Garcias da Silva et al. - 13% Bye et al. - 6% Idro et al. - 6%
Range: 2% to 13% Median: 8%
Until 1990
Seay & Bray - 87% (birthweight<2,5kg)
Range: 40% to 87% Median: 63.5 %
Watkins et al. - 40%
Seay & Bray - NA Watkins et al. - 3%
Range: NA Median: 3%
Seay & Bray - 3% Watkins et al. - 1.5%
Range: 1.5% to 3% Median: 2.3%
Seay & Bray - 6% Watkins et al. - 5%
Range: 5% to 6% Median: 5.5%
Preterm neonates or low birth weight
Since 1990
--- --- --- ---
NA= not available
Prevalence of variouscauses of neonatalseizures in differentgeographical regionsof the world
TABLE 1
_ _
Summary of individual studies
Note. GRADE criteria could not be applied to epidemiological data
Prospective studies. Ronen et al. (2007), Tekgul et al. (2006), Ortibus et al. (1996),Pisani et al. (2008b), Plouin et al. (1981), Dreyfus-Brisac et al. (1981) and Bye et al.(1997) conducted prospective cohort studies, noting an association between neonatalseizures and abnormal neurological outcome, morbidity, and mortality. Both Mizrahi &Kellaway (1987) and Rowe et al. (1985) noted that EEG characteristics can help deter-mine etiology and outcomes. McBride et al. (2000) noted an association between theamount of electrographic seizure activity and subsequent mortality and morbidity ininfants at risk for seizures and in infants with perinatal asphyxia. Similarly, Laroia et al.(1998) noted that a normal EEG in the neonatal period is associated with the absenceof seizures within the first two years of life, with a sensitivity of 0.96 and specificity of0.81. Kerr et al. (1990) found that EEGs can help predict persistence of seizures. Scarpaet al. (1983), Kumar et al. (2007) and Bye & Flanagan (1995) noted that use of EEGcould help with anticonvulsant management, while Connell et al. (1989) showedmixed results to this regard. Murray et al. (2008) noted that only one third of neonateswith electrographic seizures had clinical signs.
Retrospective studies. Khan et al. (2008), Pisani et al. (2008a) and Carrascosa et al.(1996) noted an association between abnormal EEG findings and neurological out-come, including developmental delay, epilepsy and death. Van Rooij et al. (2007)noted that duration, but not background pattern, was associated with neurodevelop-mental outcome. Tharp et al. (1981) noted that using serial EEGs (also in the neona-tal period) can help determine prognosis, including neurodevelopmental outcomes.Hosain et al. (2003) noted that EEG helped identify apnoeic seizures. Pezzani et al.(1986) noted that EEG on the first day of life can help assess the degree of brain injury.Radvanyi-Bouvet et al. (1985) noted that in premature infants EEG can be helpful inassessment and therapy of atypical seizures. Staudt (1990) noted a correlationbetween abnormal background activity and prognosis. Domenech-Martinez et al.(2003) noted that moderately to markedly abnormal background EEG activity had ahigh positive predictive value for abnormal outcomes and can be helpful in assessingresponse to therapy.
Value of electroencepha-lography in themanagement of anewborn with seizures
42
_ _
Stu
dy/
Co
un
try
Des
ign
Su
mm
ary
of s
tud
y Q
ual
ity
Sam
ple
size
C
omm
ents
AM
ER
ICA
S
Kha
n e
t al.,
200
8,
Braz
il R
etro
spec
tive
Sequ
entia
l EE
G c
an b
ette
r hel
p pr
edic
t neu
rolo
gica
l out
com
e (n
euro
deve
lopm
enta
l del
ay,
epile
psy,
dea
th)
Low
58
Th
is s
tudy
was
use
d to
sho
w t
he b
enef
it of
doi
ng s
eque
ntia
l EE
Gs,
with
the
ana
lysi
s lo
okin
g fo
ras
soci
atio
n be
twee
n ab
norm
al E
EG
s and
out
com
es.
Ron
en e
t al.,
200
7,
Cana
da
Pros
pect
ive
coho
rt
EEG
can
help
pre
dict
ne
urol
ogic
al o
utco
me
Low
82
Th
is st
udy
was
a lo
ng-t
erm
follo
w-u
p st
udy
with
chi
ldre
n w
ho h
ad s
eizu
res i
n th
e ne
onat
al p
erio
d,an
d lo
oked
for s
tatis
tical
ass
ocia
tion
betw
een
abno
rmal
EE
Gs a
nd o
utco
mes
.
Tekg
ul e
t al.,
200
6,
USA
Pr
ospe
ctiv
e EE
G is
pro
gnos
tic o
f ne
urod
evel
opm
enta
l out
com
e Lo
w
98
This
was
a s
hort
-ter
m (
1.5
year
s) f
ollo
w-u
p st
udy
that
tes
ted
for
stat
istic
al a
ssoc
iatio
n be
twee
nab
norm
al E
EG
s and
out
com
es.
Ort
ibus
et a
l., 19
96,
USA
Pr
ospe
ctiv
e EE
G is
a p
redi
ctor
of
neur
odev
elop
men
tal o
utco
me,
bu
t not
pos
tnat
al se
izur
es
Low
81
N
eona
tes
with
sei
zure
s fo
llow
ed fo
r 17
mon
ths
(on
aver
age)
; ana
lysi
s lo
oked
for
asso
ciat
ion
and
mul
tivar
iate
mod
els f
or p
redi
ctin
g se
izur
es a
nd o
utco
mes
.
Hos
ain
et a
l., 2
003,
U
SA
Ret
rosp
ectiv
e Co
ntin
uous
EEG
hel
ps
diag
nose
apn
oeic
seiz
ures
Lo
w
10
Six
patie
nts
had
nons
peci
fic fi
ndin
gs c
onsi
stin
g of
mul
tifoc
al in
teri
ctal
epi
lept
iform
act
ivity
with
no e
vent
cor
rela
tion.
Con
tinuo
us 2
4-72
-hou
r E
EG
was
per
form
ed i
n al
l pa
tient
s to
rul
e ou
tap
noei
c se
izur
es. I
ctal
EE
G s
how
ed h
igh
corr
elat
ion
with
the
apn
oeic
epi
sode
s, c
onfir
min
g th
edi
agno
sis o
f apn
oeic
seiz
ures
.
McB
ride
et a
l., 2
000,
U
SA
Pros
pect
ive
EEG
can
help
pre
dict
mor
talit
y an
d m
orbi
dity
M
oder
ate
68
Cont
rol g
roup
; the
occ
urre
nce
of E
S w
as c
orre
late
d w
ith m
icro
ceph
aly
(p =
0.0
4), s
ever
e CP
(p =
0.03
), an
d fa
ilure
to
thri
ve (
p =
0. 0
3). I
n th
e su
bgro
up o
f inf
ants
with
asp
hyxi
a, t
hose
with
ES
wer
e m
ore
likel
y to
die
of n
euro
logi
c ca
uses
(p =
0.0
2) a
nd h
ave
mic
roce
phal
y (p
= 0
.05)
or s
ever
eCP
(p =
0.0
4). A
dditi
onal
ly, t
hose
with
the
grea
test
num
ber
of e
lect
rogr
aphi
c se
izur
es w
ere
mor
elik
ely
to h
ave
thes
e se
vere
out
com
es.
Laro
ia e
t al.,
1998
, U
SA
Ret
rosp
ectiv
e an
d pr
ospe
ctiv
e,
coho
rt
Nor
mal
/im
mat
ure
EEG
pre
dict
s ab
senc
e of
seiz
ures
in th
e ne
xt
18-t
o-24
hou
rs w
ith 9
6%
sens
itivi
ty a
nd 8
1% sp
ecifi
city
Low
29
EE
G d
one
on a
t ris
k in
fant
s, n
one
of th
em a
lrea
dy h
ad e
ver h
ad a
seiz
ure.
Ker
r et a
l., 19
90,
USA
Pr
ospe
ctiv
e co
hort
EE
G ca
n he
lp p
redi
ct w
heth
er
seiz
ures
cont
inue
; use
of b
oth
shor
t-te
rm a
nd a
mbu
lato
ry
EEG
s can
resu
lt in
som
e in
crem
enta
l ben
efit
Low
13
Th
irte
en n
eona
tes
with
sei
zure
s oc
curr
ing
afte
r 7
days
of a
ge w
ere
eval
uate
d w
ith s
tand
ard
shor
t-te
rm E
EG
dur
ing
the
initi
al s
eizu
res
and
with
am
bula
tory
EE
G w
hen
each
infa
nt w
as w
ithin
37-
44 w
eeks
of
corr
ecte
d ag
e (i.
e. g
esta
tiona
l ag
e pl
us c
hron
olog
ic a
ge).
Eigh
t ou
t of
13
stan
dard
EEG
s, 10
out
of
13 a
mbu
lato
ry E
EG
s, a
nd 1
2 ou
t of
13
with
the
com
bine
d us
e of
bot
h st
anda
rdEE
Gs
and
ambu
lato
ry E
EG
s ac
cura
tely
pre
dict
ed t
he o
ccur
renc
e of
sei
zure
s at
3-4
mon
ths
ofco
rrec
ted
age.
Res
ults
with
sta
ndar
d E
EG
and
am
bula
tory
EEG
did
not
pro
duce
sig
nific
antly
diffe
rent
ou
tcom
es.
Com
bine
d an
alys
is
of
stan
dard
EE
G
and
ambu
lato
ry
EEG
pr
oduc
edsi
gnifi
cant
ly d
iffer
ent
resu
lts f
rom
tho
se c
alcu
late
d w
hen
the
two
EE
G t
ypes
wer
e an
alyz
edin
depe
nden
tly (
Z =
3.9
8, p
= le
ss t
han
0.00
1). F
indi
ngs
indi
cate
tha
t th
e us
e of
bot
h te
sts
may
impr
ove
the
abili
ty t
o pr
edic
t co
ntin
ued
seiz
ure
activ
ity i
n in
fant
s w
ith n
eona
tal s
eizu
res
whe
nco
mpa
red
to t
he u
se o
f ea
ch m
easu
re s
epar
atel
y. T
his
stud
y lo
oked
at
test
ing
stra
tegi
es f
orpr
edic
ting
cont
inua
nce
of se
izur
es, a
nd N
OT
its u
sefu
lnes
s in
curr
ent m
anag
emen
t.
Miz
rahi
&
Kel
law
ay, 1
987,
U
SA
Pros
pect
ive
coho
rt
Stud
y to
cha
ract
eriz
e an
d cl
assi
fy
neon
atal
seiz
ures
Lo
w
349
Stud
y lo
oked
at a
ssoc
iatio
n be
twee
n EE
G fi
ndin
gs a
nd c
linic
al sy
mpt
oms a
nd o
utco
mes
.
Row
e et
al.,
1985
, U
SA
Pros
pect
ive
coho
rt
EEG
can
help
pre
dict
out
com
e Lo
w
74
Follo
w-u
p of
chi
ldre
n w
ith a
mea
n ag
e of
33
mon
ths;
loo
ked
for
asso
ciat
ion
betw
een
EE
Gfin
ding
s and
out
com
es.
Thar
p et
al.,
1981
, U
SA
Ret
rosp
ectiv
e co
hort
EE
G ca
n he
lp d
eter
min
e pr
ogno
sis
Low
81
Pr
emat
ure
infa
nts;
inf
ants
who
se s
eria
l E
EG
s w
ere
norm
al d
urin
g th
e ne
onat
al p
erio
d w
ere
usua
lly n
orm
al a
t fol
low
-up
or s
uffe
red
from
min
or s
eque
lae
(NPV
: 100
%).
All
child
ren
who
had
a t le
ast
one
mar
kedl
y ab
norm
al E
EG
suf
fere
d fr
om s
ome
type
of n
euro
logi
cal s
eque
lae
or d
ied.
This
stud
y an
alyz
ed th
e va
lue
of se
rial
EE
Gs.
Sche
r et a
l., 19
93,
USA
R
etro
spec
tive
EEG
can
help
conf
irm
seiz
ures
Lo
w
92
This
stu
dy m
ainl
y co
mpa
red
diffe
ring
sei
zure
cha
ract
eriz
atio
n be
twee
n te
rm a
nd p
re-t
erm
infa
nts.
43TAB
LE2
_ _
Pisa
ni e
t al.,
200
8b,
Ital
y Pr
ospe
ctiv
e H
elpf
ul in
pro
gnos
is o
f de
velo
pmen
tal o
utco
me
Low
38
St
udy
look
ed fo
r as
soci
atio
n of
EE
G fi
ndin
gs w
ith
neur
odev
elop
men
tal o
utco
me.
Mur
ray
et a
l., 2
008
, Ir
elan
d Pr
ospe
ctiv
e O
nly
one
thir
d of
neo
nata
l EE
G
seiz
ures
dis
play
s cl
inic
al
man
ifest
atio
ns; v
ideo
EE
G u
sed
for
the
stud
y
Low
51
O
nly
one-
thir
d of
neo
nata
l E
EG
sei
zure
s di
spla
ys c
linic
al s
igns
on
sim
ulta
neou
s vi
deo
reco
rdin
gs.
Mor
eove
r, t
wo-
thir
ds o
f th
ese
clin
ical
man
ifest
atio
ns a
re u
nrec
ogni
zed,
or
mis
inte
rpre
ted
by e
xper
ienc
ed n
eona
tal
staf
f. In
the
rec
ogni
tion
and
man
agem
ent
ofne
onat
al s
eizu
res
clin
ical
dia
gnos
is a
lone
is n
ot e
noug
h.
Pisa
ni e
t al.,
200
8a,
Ital
y R
etro
spec
tive
co
hort
, pr
ospe
ctiv
e fo
llow
-up
EE
G c
an h
elp
pred
ict
neur
olog
ical
out
com
e Lo
w
51 p
re-t
erm
in
fant
s Se
vere
ly a
bnor
mal
bac
kgro
und
EEG
act
ivity
(O
R=8
.298
, 95
% C
I: 1.3
16-5
2.30
1, p=
0.02
4) w
ere
inde
pend
ent p
redi
ctor
s of
abn
orm
al o
utco
me.
Nin
e in
fant
s pr
esen
ted
post
-neo
nata
l epi
leps
y. S
ever
ely
abno
rmal
cer
ebra
l ul
tras
ound
sca
ns w
ere
pred
ictiv
e of
epi
leps
y (O
R=1
3.72
, 95%
CI:
1.959
-96.
149,
p=0.
008)
. Thi
s stu
dy u
sed
odds
ratio
to es
timat
e di
ffere
nces
in o
utco
mes
acc
ordi
ng to
EEG
resu
lts.
Van
Roo
ij et
al.,
200
7,
Net
herl
ands
Ret
rosp
ecti
ve
EE
G is
the
mai
n pr
edic
tor
of
neur
odev
elop
men
tal o
utco
me
Low
56
Th
e du
rati
on,
but
not
the
back
grou
nd p
atte
rn,
was
cor
rela
ted
wit
h ne
urod
evel
opm
enta
lou
tcom
e; th
is s
tudy
look
ed fo
r E
EG
cha
ract
eris
tics
that
wou
ld h
elp
pred
ict o
utco
me,
but
did
not l
ook
at th
e in
crem
enta
l ben
efit
of d
oing
EE
G v
s. n
ot d
oing
EE
G.
Pezz
ani e
t al.,
198
6,
Ital
y R
etro
spec
tive
EE
G in
the
first
day
of l
ife ca
n he
lp
asse
ss d
egre
e of
cere
bral
inju
ry
Low
80
St
udy
char
acte
rize
d E
EG
fin
ding
s as
soci
ated
wit
h un
favo
urab
le o
utco
me
(dea
th,
maj
orse
quel
ae).
Rad
vany
i-B
ouve
t et
al.,
198
5,
Fran
ce
Ret
rosp
ecti
ve
EE
G c
an b
e he
lpfu
l in
reco
gnit
ion
of a
typi
cal s
eizu
res
and
asse
ssm
ent o
f the
ef
fect
iven
ess
of th
erap
y
Low
50
pr
emat
ure
Coh
ort b
roke
n in
to s
ubgr
oups
acc
ordi
ng to
ges
tati
onal
age
at d
eliv
ery
sm
all s
ubgr
oups
.
Dom
enec
h-M
artin
ez
et a
l., 2
003,
Sp
ain
Ret
rosp
ecti
ve
EE
G is
hel
pful
in d
iagn
osin
g an
d as
sess
ing
resp
onse
to
trea
tmen
t
Low
74
In
fant
s w
ith
mod
erat
ely
and
mar
kedl
y ab
norm
al E
EG
s ba
ckgr
ound
sho
wed
unf
avou
rabl
eou
tcom
es in
72.
2% P
PV a
nd 1
00%
PPV
of c
ases
res
pect
ivel
y, w
hile
onl
y 15
.4%
(84
.6%
NPV
)ha
d no
rmal
or
light
ly a
bnor
mal
EE
Gs
back
grou
nd.
Car
rasc
osa
et a
l., 1
996,
Sp
ain
Ret
rosp
ecti
ve,
coho
rt
EE
G s
omew
hat h
elpf
ul to
pr
edic
t out
com
e, b
ut c
ause
of
seiz
ure
and
cere
bral
lesi
on m
ost
impo
rtan
t fac
tors
Low
25
I.
Diff
eren
ces
wer
e fo
und
betw
een
the
type
s of
sei
zure
s pr
esen
ted
(clo
nic,
foc
al t
onic
, myo
clon
ic,
subt
ile w
ith a
pnoe
a, n
o ob
viou
s se
izur
e) a
nd th
e pr
ogno
sis,
but
no
sign
ifica
nt r
esul
ts. N
euro
logi
cal
findi
ngs
betw
een
seiz
ures
: tho
se w
ho s
how
ed n
o ch
ange
in c
onsc
ious
ness
follo
win
g th
e co
nvul
sion
had
a be
tter
pro
gnos
is t
han
thos
e sh
owin
g ch
ange
s. T
he d
iffer
ence
was
sig
nific
ant
(P=0
.03)
.Po
st-c
ritic
EE
G p
atte
rn:
thos
e w
ith n
orm
al o
r fo
cal
EEG
wer
e gr
oupe
d to
geth
er v
s. t
hose
who
show
ed m
ultif
ocal
alte
ratio
ns, p
rese
nted
with
cha
nges
in th
e ba
sic
rhyt
hm, w
ere
paro
xysm
al o
r of
low
vol
tage
; th
e fir
st t
ype
of E
EG i
ndic
ated
the
bes
t pr
ogno
sis
(OR
=12.
0; I
C 95
%;
1.1-
159.
5;p=
0.2)
. R
adio
diag
nosi
s: t
hose
with
no
chan
ges
on U
S or
CT-
MR
I h
ad b
ette
r pr
ogno
ses
(p>0
.001
) tha
n th
ose
with
pat
holo
gica
l one
s. N
one
had
path
olog
ical
sequ
elae
(OR
=0.0
). II
. M
ulti
vari
ant
anal
ysis
: th
e fi
nal
met
hod
only
ret
aine
d th
e va
riab
le “
Rad
iodi
agno
sis”
,im
plyi
ng t
hat
the
othe
r va
riab
les
lost
sig
nific
ance
whe
n co
rrec
ted
for
asso
ciat
ion
wit
hR
adio
diag
nosi
s (p
< 0
.001
; OR
= 0
.0).
Stau
dt, 1
990,
G
erm
any
(Art
icle
in G
erm
an,
abst
ract
in E
nglis
h re
view
ed)
Ret
rosp
ecti
ve
coho
rt
EE
G c
an h
elp
pred
ict p
rogn
osis
Lo
w
29
A c
orre
lati
on c
ould
be
show
n be
twee
n po
or p
rogn
osis
and
sup
pres
sion
of
back
grou
ndac
tivi
ty c
onsi
stin
g in
ina
ctiv
ity,
bur
st-s
uppr
essi
on p
atte
rn o
r m
oder
ate
supp
ress
ion.
By
cont
rast
, a
norm
al o
r m
ildly
sup
pres
sed
EE
G c
orre
late
d w
ith
good
lon
g-te
rm p
rogn
osis
.Pa
roxy
smal
dis
char
ges
in t
he E
EG
wer
e he
lpfu
l in
dia
gnos
ing
seiz
ures
and
als
o fo
rpr
ogno
sis
of
cere
bral
co
nvul
sion
s la
ter
on.
US
and
EE
G
findi
ngs,
es
peci
ally
m
ildin
trac
rani
al h
aem
orrh
ages
and
inc
reas
ed p
eriv
entr
icul
ar e
chog
enic
ity,
had
les
s pr
ogno
stic
valu
e. T
hus
stud
y lo
oked
for
corr
elat
ion
of E
EG
find
ings
and
out
com
es.
Con
nell
et a
l., 1
989,
E
ngla
nd
Pros
pect
ive
coho
rt
Res
pons
e to
ant
icon
vuls
ants
no
t con
sist
entl
y se
en o
n E
EG
Lo
w
31
Bac
kgro
und
EE
G a
bnor
mal
ity
(as
an in
dex
of a
ssoc
iate
d ce
rebr
al d
ysfu
ncti
on)
was
a g
uide
to p
oten
tial
lac
k of
res
pons
e to
ant
icon
vuls
ant
drug
s; i
t w
as a
lso
pred
icti
ve o
f su
bseq
uent
clin
ical
out
com
e ir
resp
ecti
ve o
f tre
atm
ent.
Scar
pa e
t al.,
198
3,
Ital
y Pr
ospe
ctiv
e co
hort
E
EG
can
hel
p pl
an fo
r an
tico
nvul
sant
man
agem
ent;
th
e du
rati
on o
f per
sist
ence
of
EE
G a
bnor
mal
itie
s w
as th
e m
ost i
mpo
rtan
t fin
ding
for
plan
ning
the
mai
nten
ance
of
anti
conv
ulsa
nt tr
eatm
ent a
nd
its
disc
onti
nuat
ion
Low
55
E
EG
use
d fo
r ex
tend
ed p
erio
d of
tim
e, c
onse
quen
tly,
this
stu
dy w
as n
ot s
o us
eful
.
EU
RO
PE
44
_ _
45Plou
in e
t al.,
1981
, Fr
ance
(art
icle
in F
renc
h,
abst
ract
in E
nglis
h re
view
ed)
Pros
pect
ive
coho
rt
EE
G c
an h
elp
dete
rmin
e pr
ogno
sis
Low
43
N
inet
y pe
rcen
t ha
d fa
vour
able
out
com
e. I
n th
e ca
ses
wit
h un
favo
urab
le e
volu
tion
, th
efo
llow
ing
crit
eria
allo
wed
for
ear
ly p
oor
prog
nosi
s: a
ver
y ea
rly
onse
t of
the
sei
zure
s in
the
first
or
seco
nd d
ay o
f lif
e, t
he p
rese
nce
of t
onic
sei
zure
s an
d hy
pert
ony
betw
een
seiz
ures
,du
rati
on o
f se
izur
es l
onge
r th
an 4
day
s, E
EG
act
ivit
y in
the
fre
quen
cy o
f th
e al
pha
band
duri
ng t
he s
eizu
res,
a fl
at t
raci
ng a
fter
the
sei
zure
s, v
ery
disc
onti
nuou
s ac
tivi
ty b
etw
een
the
seiz
ures
and
, fin
ally
, the
rea
ppea
ranc
e of
sei
zure
s af
ter
a se
izur
e-fr
ee in
terv
al.
Dre
yfus
-Bri
sac
et a
l., 1
981
Fran
ce
(art
icle
in F
renc
h,
abst
ract
in E
nglis
h re
view
ed)
Pros
pect
ive
coho
rt
EE
G c
an h
elp
dete
rmin
e pr
ogno
sis
Low
12
1 Th
e ve
ry p
oor
prog
nosi
s of
an
abno
rmal
EE
G p
atte
rn o
f the
pre
mat
ure
new
born
, i.e
. an
EE
G la
ckin
g an
y pa
tter
n co
rres
pond
ing
to a
ny g
esta
tion
al a
ge, i
s de
mon
stra
ted
in th
is
stud
y. S
uch
EE
Gs
of v
ery
poor
pro
gnos
is w
ere
dete
cted
in 4
6 ca
ses.
The
y re
veal
the
degr
ee
of s
ever
ity
of th
e ce
rebr
al le
sion
s, E
EG
abn
orm
alit
ies
and
cere
bral
lesi
ons
vary
ing
wit
h ge
stat
iona
l age
. Thi
s st
udy
conf
irm
ed th
e re
lati
vely
mild
sev
erit
y of
isol
ated
con
vuls
ions
as
com
pare
d to
sta
tus
epile
ptic
us.
SO
UT
HE
AS
T A
SIA
K
umar
et a
l., 2
007,
In
dia
(ful
l tex
t art
icle
co
uld
not b
e re
trie
ved)
Pros
pect
ive
Abn
orm
al E
EG
wer
e fo
und
in
one-
thir
d of
chi
ldre
n w
ith
clin
ical
sei
zure
s
Low
90
A
bnor
mal
EE
Gs
wer
e fo
und
in o
ne-t
hird
of c
ases
out
of 6
0 E
EG
s do
ne in
90
infa
nts.
26.
7%of
infa
nts
wit
h pe
rina
tal a
sphy
xia
had
abno
rmal
EE
Gs
(8/3
0), w
hile
60%
wit
h H
IE-I
I ha
dab
norm
al d
isch
arge
s; b
ackg
roun
d ac
tivi
ty w
as s
uppr
esse
d in
66.
66%
EE
Gs
in i
nfan
ts w
ith
HIE
-III
.
WE
ST
ER
N P
AC
IFIC
B
ye e
t al.,
199
7,
Aus
tral
ia
Pros
pect
ive,
co
hort
E
EG
can
hel
p pr
edic
t sur
viva
l Lo
w
53
Abn
orm
al fi
ndin
gs fr
om b
rain
imag
ing
stud
ies
and
a nu
mbe
r of
inde
pend
ent e
lect
rogr
aphi
cse
izur
e fo
ci w
ere
corr
elat
ed w
ith
som
e as
pect
s of
the
out
com
es a
t 1
year
. N
ote
that
thi
s
Bye
& F
lana
gan,
stud
y lo
oked
for
asso
ciat
ion
betw
een
findi
ngs
and
outc
omes
.
1995
, A
ustr
alia
Pros
pect
ive
coho
rt
EE
G is
hel
pful
in d
iagn
osis
Lo
w
32
Thir
ty-t
wo
pati
ents
ha
d co
nfir
med
se
izur
es.
Aft
er
adm
inis
trat
ion
of
anti
conv
ulsa
nts,
clin
ical
obs
erva
tion
s id
enti
fied
seiz
ures
in
a m
ean
of 6
6% (
SD=
7.3%
) of
the
coh
ort.
A 6
0-m
in E
EG
aft
er e
ach
stag
e of
phe
noba
rbit
al t
hera
py w
ould
gua
rant
ee e
lect
rogr
aphi
c se
izur
eca
ptur
e in
a m
ean
of 7
6% (
SD=
10%
) of
the
coh
ort.
A 6
0-m
in E
EG
aft
er a
dditi
on o
fph
enyt
oin
wou
ld g
uara
ntee
cap
ture
in
50%
of
case
s. C
oncl
usio
ns:
EE
G w
ould
avo
idm
isdi
agno
ses
in
mos
t pa
tien
ts
wit
h am
bigu
ous
clin
ical
si
gns.
A
fter
an
tico
nvul
sant
infu
sion
s, E
EG
add
s su
bsta
ntia
l inf
orm
atio
n to
that
obt
aine
d fr
om c
linic
al o
bser
vati
ons.
Bye
& F
lana
gan
1995
, A
ustr
alia
Pros
pect
ive
coho
rt
EE
G c
an h
elp
dete
ct s
ubcl
inic
al
seiz
ures
and
res
pons
e to
th
erap
y
Low
32
Th
ere
was
evi
denc
e of
red
uced
clin
ical
feat
ures
aft
er s
eque
ntia
l AE
D in
fusi
ons.
_ _
Summary of individual studies
Note. GRADE criteria could not be applied to epidemiological data
Malik et al. (2005) noted that approximately 10% of neonates with seizures showed anabnormal finding on head ultrasound (US). Alcover-Bloch et al. (2004) noted retrospec-tively that approximately 43% of neonates with seizures had an abnormal head US,while 31% had abnormal findings on CT and/or MRI. Rollins et al. (1994) noted that interm neonates with seizures, MRI findings did not correlate with either clinical signs ofperinatal distress or perinatal causes of cerebral injury, while Krishnamoorthy et al.(2000) found that MRI helped identify seizure etiology. Miller et al. (2002) reported theseverity of seizures in newborns with perinatal asphyxia as being independently associ-ated with brain injury and not limited to damage detectable by MRI. Keeney et al.(1991) noted that in neonates prospectively determined to be at risk for neurologichandicap, US detected 79% of lesions demonstrated by MRI, whereas only 41% weredetected by CT. Mercuri et al. (1995) found that 88% (14/16) of neonates with seizureshad haemorrhage or ischaemia noted on MRI, with 11 of these detectable by US, andthat MRI could detect ischaemic lesions earlier than US.
Value of cranium/headimaging in the manage-ment of a newborn withseizures
46
_ _
Stu
dy
/Co
un
try
D
esi
gn
S
um
ma
ry o
f st
ud
y
Qu
ali
ty
Sa
mp
le
size
C
om
me
nts
AM
ER
ICA
S
Ro
llin
s e
t a
l.,
199
4,
US
A
Pro
spec
tiv
e M
RI
do
ne
in t
erm
neo
na
tes
wit
h s
eizu
res;
pre
sen
ce o
r p
att
ern
of
MR
I fi
nd
ing
s d
oes
n
ot
ap
pea
r to
co
rrel
ate
wit
h
clin
ica
l si
gn
s o
f p
erin
ata
l d
istr
ess
or
pre
sum
ed c
au
ses
of
per
ina
tal
cere
bra
l in
jury
Lo
w
15
Sm
all
sa
mp
le s
ize;
ba
sed
on
MR
I, f
ive
pa
tien
ts h
ad
fo
cal
isch
aem
ic i
nju
ry o
f th
ece
reb
ral
hem
isp
her
es a
nd
/or
ba
sal
ga
ng
lia
an
d b
rain
st
em
. S
ix p
ati
ents
ha
dd
iffu
se c
ereb
ral
oed
em
a:
of
thes
e, f
ive
ha
d b
asa
l g
an
gli
a o
edem
a;
on
e h
ad
bra
inst
em o
ede
ma
. O
ne
pa
tie
nt
ha
d s
up
erio
r sa
git
tal
sin
us
thro
mb
osi
s w
ith
ve
no
us
infa
rcts
. T
hre
e p
ati
en
ts
ha
d
no
rma
l M
RI
stu
die
s.
Th
ere
wa
s n
o
corr
ela
tio
nb
etw
een
ma
rker
s o
f p
erin
ata
l d
istr
ess
, ri
sk f
act
ors
fo
r se
izu
res,
an
d p
rese
nce
or
pa
tter
n o
f M
RI
fin
din
gs.
M
ille
r et
al.
, 2
00
2,
US
A
Pro
spec
tiv
e S
tru
ctu
ral
da
ma
ge
de
tect
ed b
yM
RI
do
es n
ot
com
ple
tely
a
cco
un
t fo
r b
rain
in
jury
ca
use
d b
y p
erin
ata
l a
sph
yxia
Lo
w
90
(o
nly
33
h
ad
sei
zure
s)
Th
is
stu
dy
loo
ked
a
t co
rrel
ati
on
o
f se
izu
res
wit
h
lact
ate
/ch
oli
ne
leve
ls
ind
iffe
ren
t p
art
s o
f th
e b
rain
.
Kri
shn
am
oo
rth
y et
al.
, 2
00
0,
US
A
Pro
spec
tiv
e C
T a
nd
MR
I d
on
e; s
ho
rt-t
erm
n
euro
log
ic o
utc
om
e co
rrel
ate
dw
ith
th
e ex
ten
t o
f in
jury
see
n
on
th
e in
itia
l d
iffu
sio
n-
wei
gh
ted
im
ag
ing
sca
ns
for
all
p
ati
ents
Lo
w
8
Infa
nts
fo
llo
wed
fo
r a
mea
n o
f 17
mo
nth
s; h
ead
CT
, co
nve
nti
on
al
MR
I a
nd
dif
fusi
on
-wei
gh
ted
im
ag
es w
ere
ob
tain
ed.
All
pa
tien
ts s
ho
we
d i
ncr
ea
sed
les
ion
con
spic
uit
y a
nd
b
ette
r d
efin
itio
n
of
lesi
on
ex
ten
t o
n
the
dif
fusi
on
-wei
gh
ted
ima
ges
co
mp
are
d
wit
h
the
CT
a
nd
T
2-w
eig
hte
d
MR
I.
Dif
fusi
on
-wei
gh
ted
ima
gin
g i
s u
sefu
l in
th
e ev
alu
ati
on
of
acu
te i
sch
ae
mic
bra
in i
nju
ry a
nd
sei
zure
etio
log
y in
neo
na
tes.
K
een
ey
et a
l.,
199
1,
US
A
Pro
spec
tiv
e N
ot
all
ch
ild
ren
in
th
e st
ud
y h
ad
sei
zure
s; M
RI
Lo
w
100
T
he
use
fuln
ess
of
this
stu
dy
is s
om
ewh
at
lim
ited
in
th
at
chil
dre
n w
ere
at
risk
fo
rp
oo
r o
utc
om
es,
no
t n
eces
sari
ly a
ll h
ad
a h
isto
ry o
f se
izu
res.
Ma
lik
et
al.
, 2
00
5,
Pa
kis
tan
P
rosp
ecti
ve
9.5
% w
ith
in
tra
cra
nia
l b
leed
, 1.
5%
hyd
roce
ph
alu
s, 1
% w
ith
b
rain
ma
lfo
rma
tio
ns
Lo
w
20
0
US
do
ne
in a
ll p
ati
en
ts,
CT
do
ne
in a
few
; th
is
stu
dy
aim
ed t
o i
den
tify
th
eet
iolo
gy
of
seiz
ure
s in
a c
oh
ort
of
pa
tie
nts
; fo
r th
is r
evie
w,
the
rele
van
ce w
as
tha
ta
pp
rox
ima
tely
10
% h
ad
a f
ind
ing
on
hea
d U
S.
Alc
ove
r-B
loch
et
al.
, 2
00
4,
Sp
ain
(art
icle
in
Sp
an
ish
, a
bst
ract
in
En
gli
sh
rev
iew
ed)
Ret
rosp
ecti
ve
Hea
d U
S w
as
ab
no
rma
l in
33
in
fan
ts,
CT
an
d/o
r M
RI
ab
no
rma
l in
24
Lo
w
77
T
his
stu
dy
aim
ed t
o i
de
nti
fy t
he
eti
olo
gy
of
seiz
ure
s in
a c
oh
ort
of
pa
tien
ts,
ah
igh
per
cen
tag
e o
f th
em s
ho
we
d a
n a
bn
orm
ali
ty o
n a
ra
dio
gra
ph
ic s
tud
y.
Ma
yna
rd &
Ga
rrel
, 19
83
, F
ran
ce
(art
icle
in
Fre
nch
, a
bst
ract
in
En
gli
sh
rev
iew
ed)
gnir
ud ser
uzies d
ah t
aht s
nro
bwe
n 0
2 ni s
gni
dnif
de
bircsed ,ezis el
pm
as lla
mS
0
2
wo
L e
no
d T
C ro
SU
evitce
psor
Pth
e fi
rst
da
ys o
f li
fe.
Mer
curi
et
al.
, 19
95
, E
ng
lan
d
Pro
spec
tiv
e U
S a
nd
MR
I d
on
e, M
RI
sup
ple
men
t fi
nd
ing
s fr
om
US
L
ow
16
F
ou
rtee
n o
f th
e in
fan
ts h
ad
ha
emo
rrh
ag
ic o
r is
cha
emic
les
ion
s o
n M
RI
an
dth
ese
wer
e d
etec
ted
by
ult
raso
un
d s
can
nin
g i
n 1
1. E
arl
y u
ltra
sou
nd
sca
nn
ing
det
ecte
d
ha
emo
rrh
ag
ic
lesi
on
s,
alt
ho
ug
h
isch
ae
mic
le
sio
ns
wer
e
oft
en
no
td
etec
ted
un
til
the
end
of
the
firs
t w
eek
of
life
. E
arl
y M
RS
, h
ow
eve
r, w
as
ab
le t
od
etec
t a
ll t
he
isc
ha
emic
les
ion
s.
Ru
fo-C
am
po
s et
al.
, 2
00
0,
Sp
ain
(art
icle
in
Sp
an
ish
, a
bst
ract
in
En
gli
sh
rev
iew
ed)
Ret
rosp
ecti
ve
Ha
emo
rrh
ag
es w
ere
the
seco
nd
mo
st c
om
mo
n e
tio
log
y
of
seiz
ure
s
Lo
w
60
S
tud
y in
vest
iga
ted
22
med
ica
l va
riab
les
rela
ted
to
th
e cl
inic
al
his
tory
, n
euro
logi
cal
exam
inat
ion
, n
euro
imag
ing
stu
die
s, E
EG
an
d d
rug
s u
sed
. A
bn
orm
ali
ties
wer
e fo
un
do
n t
he
init
ial
exam
inat
ion
in
83
.3%
of
the
case
s. H
ypo
xic-
isch
aem
ic s
ynd
rom
e w
asth
e co
mm
on
est
etio
log
y,
foll
ow
ed
by
hae
mo
rrh
ages
, m
eta
bo
lic
dis
ord
ers,
card
iop
ath
ies,
mal
form
atio
ns
an
d i
nfe
ctio
us
dis
ease
s.
Ku
ma
r et
al.
, 2
00
7,
Ind
ia
(fu
ll t
ext
art
icle
co
uld
no
t b
e re
trie
ved
)
Pro
spec
tiv
e U
S d
on
e, r
ela
tio
n t
o s
eizu
res
no
t d
esc
rib
ed i
n a
bst
ract
L
ow
9
0
-
EA
ST
ER
N M
ED
ITE
RR
AN
EA
N
EU
RO
PE
SO
UT
H-E
AS
T A
SIA
47TAB
LE3
_ _
Patients: neonates with seizures
Intervention (exposure): treatmentwith one or more antiepileptic drugs
Control (unexposed): care as usual
Outcomes: mortality, seizure control,and abnormal neurological outcome
48
Need for treatment withantiepileptic drugs inneonates with seizures
Inte
rven
tion
al a
nd
/or
obs
erva
tion
al s
tud
ies
wit
h c
ontr
ol g
rou
p
Stu
dy
ID
Des
ign
In
terv
enti
on(e
xpos
ed)
Con
trol
(u
nex
pos
ed)
Ou
tcom
e N
um
ber
(%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mbe
r (%
) in
con
tro
l (u
nex
pos
ed)
grou
p
Eff
ect
(95%
CI)
D
irec
tnes
s L
imit
atio
ns
Mill
er e
t al.,
200
2 Pr
ospe
ctiv
e co
hort
stu
dy
Rev
iew
ed
effe
ct o
f on
goin
g cl
inic
al
seiz
ures
on
brai
n w
ith
MR
S N=
33
Rev
iew
ed M
RS
in n
eona
tes
wit
hout
sei
zure
s
N=
57
Cha
nges
in
MR
S -
- D
emon
stra
ted
that
sig
nifi
cant
ly
mor
e ch
ange
s co
nsis
tent
wit
h br
ain
inju
ry o
ccur
w
ith
goin
g se
izur
es
Lim
ited
(s
uppo
rted
nee
dfo
r ce
ssat
ion
of
seiz
ures
)
-
McB
ride
et a
l.,
2000
Pr
ospe
ctiv
e co
hort
stu
dy
Ele
ctri
cal
seiz
ures
N=
40
No
elec
tric
al
seiz
ures
N=
28
Mor
talit
y:
Abn
orm
al
neur
olog
ical
ou
tcom
e:
10 (
25%
)
14 (
47%
)
1 (4
%)
4(21
%)
P<0.
05
i.e. s
eizu
res
refle
ct p
oor
outc
ome
Lim
ited
(i
ncre
ased
se
izur
e ac
tivi
ty
corr
elat
ed w
ith
wor
se o
utco
me)
Not
ra
ndom
ized
; ob
serv
er n
ot
blin
ded
Boy
lan
et a
l., 2
004
N
=27
(N5
: exc
lude
d)
RC
T fo
r se
cond
lin
e ag
ents
Ele
ctri
cal
seiz
ures
tr
eate
d w
ith
a se
cond
line
ag
ent N
=11
Neo
nate
s w
ith
elec
tric
al
seiz
ures
re
spon
ding
to
phen
obar
bita
l al
one
N=
11
Mor
talit
y:
Seiz
ure
cont
rol:
Abn
orm
al
neur
olog
ical
ou
tcom
e:
4 (3
6%)
3 ( 2
7%)
6 (5
5%)
4 (3
6%)
11 (1
00%
)
2 (1
8%
)
Poor
out
com
e w
ould
res
ult f
rom
a
failu
re to
gai
n co
ntro
l aft
er u
sing
seco
nd li
ne a
gent
s
Lim
ited
N
ot
rand
omiz
ed
to n
o tr
eatm
ent;
sm
all s
tudy
si
ze
TAB
LE4
_ _
49Obs
erva
tion
al s
tud
ies
wit
ho
ut c
ontr
ol g
rou
pSt
ud
y ID
D
esig
n
Stu
dy
pop
ula
tion
%
wit
h o
utc
ome
Dir
ectn
ess
Lim
itat
ion
s O
ther
com
men
ts
Toet
et a
l., 2
005
Pr
ospe
ctiv
e ob
serv
atio
nal
stud
y
Long
term
follo
w-u
p of
cl
inic
al a
nd e
lect
ro-
ence
phal
ogra
phic
sei
zure
s in
neo
nate
s w
ith
HIE
and
ot
her
insu
lts
(hae
mor
rhag
e, a
rter
ial
stro
ke)
N=
206
80/2
06 (
39%
) di
ed
41/1
26 (3
3%) h
ad a
bnor
mal
ne
urol
ogic
al o
utco
me
6/92
(7%
) w
ith
grad
e 2
HIE
de
velo
ped
epile
psy
Lim
ited
(d
oes
not a
nsw
er
whe
ther
trea
tmen
t m
odif
ies
the
outc
ome)
Cou
ld n
ot a
nsw
er w
heth
er
AE
Ds
wer
e ha
rmfu
l; no
t spe
cifi
ed if
spe
cifi
c A
ED
s re
gim
en u
sed
Impl
ied
earl
y co
ntro
l of
NS
(48h
rs)
– b
ette
r ou
tcom
e –
but
adm
itte
d m
ay r
efle
ct n
eona
tes
wit
h m
ilder
insu
lts
Dom
enec
h-M
arti
nez
et a
l., 2
003
(abs
trac
t onl
y;
artic
le in
Spa
nish
)
Ret
rosp
ecti
ve
obse
rvat
iona
l st
udy
Rev
iew
ed E
EG
pat
tern
of
neon
ates
wit
h N
S
N=
56
Whe
n m
ildly
abn
orm
al o
r no
rmal
E
EG
: 15.
4% a
bnor
mal
neu
rolo
gy
Whe
n m
oder
ate
EE
G
abno
rmal
itie
s: 7
5% a
bnor
mal
ne
urol
ogy
Whe
n m
arke
d ab
norm
al E
EG
: 10
0% a
bnor
mal
neu
rolo
gy
Lim
ited
(s
tudy
is m
ore
abou
t EE
G/N
S ty
pese
mio
logy
)
nehw taht dedulcno
C
E
EG
was
gro
ssly
ab
norm
al, t
he o
utco
me
was
poo
r
Agg
arw
al e
t al.,
199
8
(abs
trac
t onl
y)
Pros
pect
ive
obse
rvat
iona
l st
udy
Obs
erva
tion
of a
gro
up a
t ri
sk fo
r N
S, c
ompa
red
to
neur
odev
elop
men
t and
en
ceph
alop
athy
N=
38
15 a
bnor
mal
neu
rolo
gica
l out
com
e W
hen
mild
enc
epha
lopa
thy:
no
rmal
out
com
e W
hen
NS
in is
olat
ion:
nor
mal
ou
tcom
e
Lim
ited
– im
plie
d N
S in
isol
atio
n (n
orm
al n
euro
logy
an
d no
en
ceph
alop
athy
) –
do
not
aff
ect
outc
ome
Not
cle
ar w
hat t
he
defi
niti
on o
f sei
zure
s w
as
Hon
& B
ourc
hier
, 1 9
91
Pros
pect
ive
obse
rvat
iona
l st
udy
Look
ed a
t mar
kers
as
soci
ated
wit
h po
or
outc
ome
N=
65
27 d
ied
24 (6
3.2%
of s
urvi
vors
) nor
mal
5
(13.
2% o
f sur
vivo
rs)
had
seiz
ures
at
1 y
ear;
poo
r ou
tcom
e as
soci
ated
w
ith
low
bir
th w
eigh
t and
dur
atio
nof
init
ial s
eizu
res
Lim
ited
– a
ided
op
tim
al ti
me
to
trea
t
_ _
Lim
itat
ion
s of
stu
dies
O
UT
CO
ME
N
o. o
f st
udie
sD
esig
nA
lloca
tion
conc
ealm
ent
(the
two
grou
ps
com
para
ble
and
low
risk
of
reve
rse
caus
ality
)
Blin
ding
or
othe
r ap
proa
ches
to
redu
ce
mea
sure
men
tbi
as
Loss
to
follo
w-
up(<
20%
)
Ana
lysi
s In
tent
ion
to
trea
t; cl
uste
r adj
uste
d if
appl
icab
le
(adj
uste
d fo
r co
nfou
ndin
g)
Pre
cisi
onC
onsi
sten
cyG
ener
aliz
abili
ty/
Dir
ectn
ess
Ver
y la
rge
effe
ct
or d
ose
resp
onse
grad
ien
t
Ove
rall
Qua
lity
ofE
vide
nce
Poo
led
effe
ctsi
ze (9
5% C
I)or
ran
ge o
f ef
fect
siz
es
(whe
re
pool
ed e
ffec
tsi
ze n
ot
poss
ible
to
asce
rtai
n)
Seiz
ure
con
trol
(d
urin
g th
e in
itia
l ho
spit
al
stay
)
1 R
CT
(0)
Unc
lear
(-0.
5)
No
(inte
rven
tion/
obse
rver
s w
ere
not
blin
d)
(-0.
5)
Yes
(0)
Yes
(0)
Effe
ct n
ot
sign
ifica
nt,
with
wid
e CI
(-1.
0)
Sing
le st
udy
(-1.
0)
From
dev
elop
ed
coun
try
setti
ng
(-0.
5)
Nil
VE
RY
LOW
(Tot
al
scor
e =
-3.5
)
RR
0.9
7
(0.5
4, 1.
72)
50
Patients: neonates with seizuresrequiring treatment
Intervention (exposure): phenobarbi-tal as the first-line drug
Control (unexposed): any otherantiepileptic drug as the first-linemedication
First-line antiepilepticdrug for treatment ofneonatal seizures
TAB
LE5
- G
RA
DE
TAB
LE
_ _
Stu
dy
ID
D
esi
gn
Stu
dy
p
op
ula
tio
nA
llo
cati
on
co
nce
alm
ent
(gro
up
s co
mp
ara
ble
a
nd
re
ve
rse
ca
usa
lity
u
nli
ke
ly)
Bli
nd
ing
(l
ow
ris
k o
f m
ea
sure
me
nt
bia
s)
<2
0%
lo
ss t
o
foll
ow
-up
Inte
nti
on
to
tr
ea
t a
na
lysi
s (a
dju
ste
d
for
mo
st
po
ten
tia
l co
nfo
un
de
rs)
Ou
tco
me
m
ea
sure
me
nt
Nu
mb
er
(%)
inin
terv
enti
on
(e
xp
ose
d)
gro
up
Nu
mb
er
(%)
in c
on
tro
l (u
ne
xp
ose
d)
gro
up
Eff
ect
(9
5%
CI)
L
imit
ati
on
s/co
mm
en
ts
Pai
nte
r et
al.,
19
99
U
SA
RC
T
Neo
nat
es
wit
h E
EG
co
nfi
rmed
se
izu
res
Un
clea
r N
o
(nei
ther
in
terv
enti
on
n
or
ob
serv
ers
wer
e b
lin
ded
)
Yes
Y
es
Co
ntr
ol o
f el
ectr
ical
se
izu
res
13/3
0 (
43.
5%)
in in
fan
ts w
ho
re
ceiv
ed
ph
enob
arb
ital
as
fir
st-l
ine
dru
g
13/2
9 (
45%
) in
infa
nts
wh
o
rece
ived
p
hen
ytoi
n a
s fi
rst-
lin
e d
rug
RR
0.9
7 (0
.54
, 1.7
2)
Neo
nat
es
wh
ose
se
izu
res
wer
e n
ot
con
tro
lled
by
the
assi
gned
d
rug
wer
e th
en t
reat
ed
wit
h b
oth
d
rugs
Ob
serv
ati
on
al
stu
die
s w
ith
ou
t a
ny
co
ntr
ol
gro
up
(n
ot
co
nsi
de
red
fo
r G
RA
DE
)
Incl
ud
ed
fo
r G
RA
DE
Stu
dy
ID
D
esi
gn
S
tud
y p
op
ula
tio
n
% w
ith
o
utc
om
e
Dir
ec
tne
ss
Lim
ita
tio
ns
Oth
er
co
mm
en
ts
Alc
ove
r-B
loch
et
al.
, 2
00
4
Ret
rosp
ecti
ve
ob
serv
ati
on
al
stu
dy
Pre
term
an
d t
erm
n
eon
ate
s w
ith
sei
zure
s;
N=
25
8
81.
8%
L
imit
ed
(do
es n
ot
an
swer
if
ph
eno
ba
rbit
al
is b
ette
r th
an
o
t her
AE
Ds)
Ret
rosp
ecti
ve d
ata
fro
m a
sin
gle
ce
nte
r
No
co
ntr
ol
gro
up
Ba
rth
a e
t a
l.,
20
07
R
etro
spec
tive
o
bse
rva
tio
na
l st
ud
y
Pre
term
an
d t
erm
n
eon
ate
s w
ith
sei
zure
s;
N=
32
2
82
.0%
L
imit
ed
Ret
rosp
ecti
ve d
ata
No
co
ntr
ol
gro
up
Nu
nes
et
al.
,2
00
8
Pro
spec
tiv
e o
bse
rva
tio
na
l st
ud
y
Pre
term
an
d t
erm
n
eon
ate
s w
ith
sei
zure
s;
N=
101
62
.0%
L
imit
ed
- N
o c
on
tro
l gr
ou
p
Bo
yla
n e
t a
l.,
20
02
O
bse
rva
tio
na
l st
ud
y P
rete
rm a
nd
ter
m
neo
na
tes
wit
h s
eizu
res;
N
=14
28
.5%
L
imit
ed
- N
o c
on
tro
l g
rou
p
Bo
yla
n e
t a
l.,
20
04
O
bse
rva
tio
na
l st
ud
y P
rete
rm a
nd
ter
m
neo
na
tes
wit
h s
eizu
res;
N
=2
2
50
.0%
L
imit
ed
-
No
co
ntr
ol
gro
up
51OU
TCO
ME:
SEI
ZUR
EC
ON
TRO
L
_ _
52
Preferred second-lineantiepileptic drug fortreatment of neonatalseizures
Lim
itat
ion
s of
stu
die
s O
UT
CO
ME
N
. of
stu
die
sD
esig
n
Allo
cati
on
conc
ealm
ent
(the
two
grou
ps
com
para
ble
and
low
ris
k of
re
vers
e ca
usal
ity)
Blin
ding
or
othe
r ap
proa
ches
to
red
uce
mea
sure
-m
ent b
ias
Loss
to
follo
w-
up(<
20%
)
Ana
lysi
s in
tent
ion
to
trea
t; c
lust
er
adju
sted
if
appl
icab
le
(adj
uste
d fo
r co
nfou
ndin
g)
Pre
cisi
on
Con
sist
ency
G
ener
aliz
abil
ity/
Dir
ectn
ess
Ver
y L
arge
effe
ct
or d
ose
resp
onse
gr
adie
nt
Ove
rall
Q
ual
ity
ofE
vid
ence
Po
oled
eff
ect
size
(9
5% C
I)
or r
ange
of
effe
ct s
izes
(w
her
e p
oole
d e
ffec
t si
ze n
ot
pos
sib
le t
o as
cert
ain
)
Ben
zod
iaze
pin
es (
I) v
s. P
hen
yto
in (
C)
Seiz
ure
cont
rol
(dur
ing
the
init
ial h
ospi
tal
stay
)
1 O
bser
v-
atio
nal
(-1.
0)
No
(-0.
5)
Unc
lear
(-0.
5)
Yes
(0)
No
(-0.
5)
Effe
ct
signi
fican
t; lo
wer
limit
of
CI
mea
ning
ful
(0)
Sing
le
stud
y
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0.
5)
Nil
VE
RY
LOW
(Tot
al
scor
e =
- 4.0
)
RR
2.1
3 (1
.48,
3.0
8)
Nor
mal
neu
ro-
deve
lopm
ent
1 O
bser
v-at
iona
l
(-1.
0)
No
(-0.
5)
Unc
lear
(-0.
5)
Yes
(0)
No
(-0.
5)
Effe
ct n
ot
sign
ifica
nt,
with
wid
e C
I
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0.
5)
Nil
VE
RY
LOW
(Tot
al
scor
e =
- 5.0
)
RR
1.1
5 (0
.62,
2.1
4)
Lid
oca
ine
(I)
vs. B
enzo
dia
zep
ines
(C
)
Seiz
ure
cont
rol
2 (1
RC
T an
d 1
obse
rv-
atio
nal)
Maj
ority
of
evid
ence
fr
om
obse
rv-
atio
nal
(-1.
0)
Unc
lear
in b
oth
stud
ies
(-0.
5)
Unc
lear
in
both
stu
dies
(-0.
5)
Yes
in
both
st
udie
s
(0)
Maj
ority
of
evid
ence
fr
om th
e st
udy
with
“N
o”
(-0.
5)
Pool
ed e
ffect
no
t si
gnifi
cant
, w
ith w
ide
CI
(-1.
0)
Bot
h st
udie
s in
the
sam
e di
rect
ion
(0)
Bot
h fr
om
deve
lope
d co
untr
y se
ttin
gs
(-0.
5)
Nil
VE
RY
LOW
(Tot
al
scor
e =
-
4.0)
RR
1.7
8 (0
.90,
3.5
2)
Nor
mal
neu
ro-
deve
lopm
ent
2(1
RC
T an
d 1
obse
rv-
atio
nal)
Maj
ority
of
evid
ence
fr
om
obse
rv-
atio
nal
(-1.
0)
Unc
lear
in b
oth
stud
ies
(-0.
5)
Unc
lear
in
both
stu
dies
(-0.
5 )
Yes
in
both
st
udie
s
(0)
Maj
ority
of
evid
ence
fr
om th
e st
udy
with
“N
o”
(-0.
5)
Pool
ed e
ffect
no
t si
gnifi
cant
, w
ith w
ide
CI
(-1.
0)
Onl
y 2
stud
ies,
bot
h in
opp
osite
di
rect
ion
(-1.
0)
Bot
h fr
om
deve
lope
d co
untr
y se
ttin
gs
(-0.
5)
Nil
VE
RY
LOW
(Tot
al
scor
e =
- 5.0
)
RR
1.2
0 (0
.36,
3.9
6)
TAB
LE6
- G
RA
DE
TAB
LE
_ _
Stu
dy
ID
D
esi
gn
S
tud
y
po
pu
lati
on
A
llo
ca
tio
n
con
cea
lme
nt
(gro
up
s co
mp
ar
ab
le
an
d r
ev
ers
e
cau
sali
ty
un
lik
ely
)
Bli
nd
ing
(l
ow
ris
k o
fm
ea
sure
me
nt
bia
s)
<2
0%
lo
ss t
o
foll
ow
-u
p
Inte
nti
on
to
tr
ea
t a
na
lysi
s
(ad
just
ed
fo
r m
ost
p
ote
nti
al
con
fou
nd
ers
)
Ou
tco
me
m
ea
sure
me
nt
Nu
mb
er
(%)
in
inte
rve
nti
on
(e
xp
ose
d)
gro
up
Nu
mb
er
(%)
in c
on
tro
l (u
ne
xp
ose
d)
gro
up
Eff
ect
(9
5%
CI)
L
imit
ati
on
s/
com
me
nts
Ob
serv
ati
on
al
stu
die
s w
ith
ou
t a
ny
co
ntr
ol
gr
ou
p,
i.e
. o
nly
be
nzo
dia
zep
ine
tre
atm
en
t (n
ot
co
nsi
de
re
d f
or
GR
AD
E)
Inc
lud
ed
fo
r G
RA
DE
Stu
dy
ID
D
esi
gn
S
tud
y p
op
ula
tio
n
Nu
mb
er
(%)
wit
h
ou
tco
me
D
ire
ctn
ess
L
imit
ati
on
s O
the
r co
mm
en
ts
Stu
dy
ID
D
esi
gn
S
tud
y
po
pu
lati
on
A
llo
ca
tio
n
con
cea
lme
nt
(gro
up
s co
mp
ar
ab
le
an
d r
ev
ers
e
cau
sali
ty
un
lik
ely
)
Bli
nd
ing
(l
ow
ris
k o
f m
ea
sure
-m
en
t b
ias)
<2
0%
lo
ss t
o
foll
ow
-u
p
Inte
nti
on
to
tr
ea
t a
na
lysi
s
(ad
just
ed
fo
r m
ost
p
ote
nti
al
con
fou
nd
ers
)
Ou
tco
me
m
ea
sure
me
nt
Nu
mb
er
(%)
in
inte
rve
nti
on
(e
xp
ose
d)
gro
up
Nu
mb
er
(%)
in c
on
tro
l (u
ne
xp
ose
d)
gro
up
Eff
ect
(9
5%
CI)
L
imit
ati
on
s
Ca
stro
Co
nd
e et
al.
, 2
00
5,
Sp
ain
Ob
serv
ati
on
al
Ter
m n
eon
ate
s w
ho
ha
ve
even
aft
er
effe
ct s
ize
ma
xim
al
do
se o
f p
hen
ob
arb
ita
l
No
(m
ajo
rity
of
con
tro
ls w
ere
fro
m a
h
isto
rica
l co
ho
rt –
g
rou
ps
no
t co
mp
ara
ble
)
Un
clea
r (n
o
info
rma
tio
n
on
bli
nd
ing
o
f o
bse
rver
s)
Yes
N
o
Fa
vora
ble
re
spo
nse
to
tr
eatm
ent
(ba
sed
on
EE
G
crit
eria
)
9/9
(10
0%
) in
in
fan
ts w
ho
re
ceiv
ed
mid
azo
lam
as
seco
nd
-lin
e a
gen
t
17/3
6 (
47
%)
in i
nfa
nts
wh
o
rece
ived
p
hen
yto
in a
s se
con
d-l
ine
ag
ent
RR
2.1
3
(1.4
8,
3.0
8)
Fav
ora
ble
re
spo
nse
def
ined
as
no
mo
re t
han
2
ES
s o
f <
30
se
con
ds
du
rati
on
p
er/h
rec
ord
ing
mu
ltip
le d
oses
of
mid
azol
am b
ut
only
1 d
ose
of p
hen
ytoi
n
van
Leu
ven
et a
l., 2
00
4 O
bse
rva
tio
na
l st
ud
y T
erm
neo
na
tes
wit
h H
IE t
rea
ted
wit
h m
ida
zola
m
11/1
5 (
73
%)
Lim
ited
-
No
co
ntr
ol
gro
up
p
uor
g lort
noc
oN
-
detimi
L )
%0
01( 2
3/2
3
mal
oza
dim
htiw
detaert set
an
oeN
yd
uts la
noit
avresb
O
30
02 ,.l
a te u
H Sh
eth
et
al.
, 19
96
O
bse
rva
tio
na
l st
ud
y T
erm
an
d p
rete
rm n
eon
ate
s tr
eate
d w
ith
mid
azo
lam
6
/6 (
100
%)
Lim
ited
-
No
co
ntr
ol
gro
up
M
ayt
al
et a
l.,
19
91
Ob
serv
ati
on
al
stu
dy
Ter
m a
nd
pre
term
neo
na
tes
trea
ted
wit
h l
ora
zep
am
6/7
(8
6%
) L
imit
ed
- N
o c
on
tro
l g
rou
p
Ca
stro
Co
nd
e et
al.
, 2
00
5,
Sp
ain
Ob
serv
ati
on
al
Ter
m
neo
na
tes
wh
o
ha
ve e
lect
rica
l se
izu
res
even
a
fter
ma
xim
al
do
se o
f p
hen
ob
atb
ita
l
No
(m
ajo
rity
of
con
tro
ls w
ere
fro
m a
h
isto
rica
l co
ho
rt –
g
rou
ps
no
t co
mp
ara
ble
)
Un
clea
r (n
o
info
rma
tio
n o
n
bli
nd
ing
of
ob
serv
ers)
Yes
N
o
No
rma
l n
euro
-d
evel
op
men
t a
t 1
yea
r
7/9
(78
%)
in i
nfa
nts
wh
o
rece
ived
m
ida
zola
m a
s se
con
d-l
ine
ag
ent
15/3
6 (
42
%)
in i
nfa
nts
wh
o
rece
ived
p
hen
yto
in a
s se
con
d-l
ine
ag
ent
RR
1.1
5 (0
.62
, 2
.14
)
53
Patients: neonates with seizures thatare not controlled by the first-linetreatment (predominantly pheno-barbital)
Intervention (exposure): benzodi-azepines
Control (unexposed): phenytoin
Summary tables ofindividual studies
OU
TC
OM
EA):
SEI
ZU
RE
CO
NT
RO
L(B
OT
HC
LIN
ICA
LA
ND
ELEC
TR
OC
LIN
ICA
L)
OU
TC
OM
EB):
NO
RM
AL
NEU
RO
DEV
ELO
PM
ENT
1. B
ENZO
DIA
ZEPI
NES
VS.
PH
ENY
TOIN
_ _
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
rem
ent
bia
s)
<20
%
loss
to
foll
ow-
up
Inte
ntio
n to
tr
eat a
nal
ysis
(a
dju
sted
for
mos
t pot
enti
al
con
foun
ders
)
Out
com
e m
easu
rem
ent
Nu
mbe
r (%
) in
in
terv
enti
on
(exp
osed
) gr
oup
Nu
mb
er (
%)
in c
ontr
ol
(un
exp
osed
) gr
oup
Eff
ect
(95%
CI)
L
imit
atio
ns/
co
mm
ents
0/3
in n
eona
tes
who
re
ceiv
ed
mid
azol
am a
s se
cond
-lin
e dr
ug
RR
4.6
7 (0
.32,
68.
0)
Boy
lan
et a
l., 2
004
UK
RC
T*
(Wei
ght =
13
.0%
)
Term
neo
nate
s w
ho h
ave
elec
tric
al
seiz
ures
eve
n af
ter
max
imal
do
se o
f ph
enob
arbi
tal
Unc
lear
N
o Ye
s Ye
s C
ontr
ol o
f el
ectr
ical
se
izur
es
3/5
(60%
) in
neo
nate
s w
ho r
ecei
ved
ligno
cain
e as
se
cond
-lin
e dr
ug
0/3
in n
eona
tes
who
re
ceiv
ed
clon
azep
am a
s se
cond
-lin
e dr
ug
RR
4.6
7 (0
.32,
68.
0)
Clon
azep
am w
as
used
in th
ose i
nfan
ts
who
se p
aren
ts
refu
sed
to g
ive
cons
ent (
in th
e RCT
, au
thor
s co
mpa
red
ligno
cain
e and
m
idaz
olam
)
Favo
rabl
e res
pons
e de
fined
as n
o m
ore
than
2 el
ectr
ical
seizu
res o
f <30
sec
dura
tion
per h
our
reco
rdin
g
Shan
y et
al.,
200
7Is
rael
Ret
ro-
spec
tive
char
t re
view
(Wei
ght=
87
.0%
)
Infa
nts
born
at
or a
fter
36
wee
ks o
f ge
stat
ion
with
H
IE a
nd
seiz
ures
eve
n af
ter
first
-lin
e tr
eatm
ent w
ith
phen
obar
bita
l an
d di
azep
am
Unc
lear
(n
o in
form
atio
non
how
the
seco
nd-l
ine
agen
t was
ch
osen
)
Unc
lear
(r
etri
eved
from
th
e fil
es)
Yes
No
Con
trol
of
clin
ical
and
el
ectr
ical
se
izur
es
17/2
2 (7
7%)
4/8
(50%
) R
R 1
.54
(0.7
4, 3
.20)
* In
fant
s w
ho r
ecei
ved
clon
azep
am w
ere
not r
ando
miz
ed (s
ee L
imit
atio
ns/c
omm
ents
abo
ve)
Incl
ud
ed f
or G
RA
DE
54
Patients: neonates with seizures thatcannot be controlled by using thefirst-line treatment (predominantlyphenobarbital)
Intervention (exposure): lidocaine(lignocaine)
Control (unexposed): benzodiazepinesO
UT
CO
ME
A):
SEI
ZU
RE
CO
NT
RO
L( B
OT
HC
LIN
ICA
LA
ND
ELEC
TR
OC
LIN
ICA
L)
2. L
IDO
CA
INE
VS.
BEN
ZOD
IAZE
PIN
ES
_ _
Ob
serv
atio
nal
stu
die
s w
ith
out
any
con
trol
gro
up
, i.e
. on
ly b
enzo
dia
zep
ine
trea
tmen
t (n
ot c
onsi
der
ed f
or G
RA
DE
)
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
Nu
mb
er (
%)
wit
h o
utc
om
e D
irec
tnes
s L
imit
atio
ns
Oth
er c
omm
ents
lanoitavresbO
0991 ,.la te yeR
stud
y Te
rm a
nd p
rete
rm n
eona
tes
trea
ted
with
lido
cain
e;
N=
13
11/1
3 (8
5%)
Lim
ited
(doe
s no
t ans
wer
if m
idaz
olam
is
bett
er th
an p
heny
toin
)
- N
o co
ntro
l gro
up
Hel
lstr
om- W
esta
s et
al.,
198
8 O
bser
vatio
nal
stud
y N
eona
tes
trea
ted
with
lido
cain
e;
N=
46
42/4
6 (9
2%)
Lim
ited
- N
o co
ntro
l gro
up
Ou
tcom
e: b
) Nor
mal
neu
rode
velo
pmen
t
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
rem
ent
bia
s)
<20
%
loss
to
foll
ow-
up
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
rem
ent
Nu
mb
er (
%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mb
er (
%)
in c
ontr
ol
(un
exp
osed
) gr
oup
Eff
ect
(95%
CI)
Lim
itat
ion
s/
com
men
ts
Boy
lan
et a
l., 2
004
UK
RC
T
(Wei
ght =
15
.8%
)
Term
neo
nate
s w
ho h
ave
ES
even
aft
er
max
imal
dos
e of
ph
enob
arbi
tal
Unc
lear
N
o Ye
s Ye
s N
orm
al n
euro
-de
velo
pmen
t 0/
5 in
neo
nate
s w
ho r
ecei
ved
ligno
cain
e as
se
cond
-lin
e dr
ug
1/3
(33.
3%)
in n
eona
tes
who
rec
eive
d m
idaz
olam
as
seco
nd-l
ine
drug
RR
0.2
2 (0
.01,
4.
20)
Shan
y et
al.,
200
7 Is
rael
Ret
rosp
ectiv
e ch
art r
evie
w
(Wei
ght =
84
.2%
)
Infa
nts
born
at
or a
fter
36
wee
ks o
f ge
stat
ion
with
H
IE a
nd
seiz
ures
eve
n af
ter
first
-lin
e tr
eatm
ent w
ith
phen
obar
bita
l an
d di
azep
am
Unc
lear
) (n
o in
form
atio
n on
how
the
seco
nd-l
ine
agen
t was
ch
osen
)
Unc
lear
(r
etri
eved
from
th
e fil
es)
Yes
No
Nor
mal
neu
ro-
deve
lopm
ent
9/22
(41%
) 2/
8 (2
5%)
RR
1.6
4 (0
.44,
6.
01)
55OU
TC
OM
EB):
NO
RM
AL
NEU
RO
DEV
ELO
PM
ENT
_ _
Lim
itat
ion
s of
stu
die
s O
UT
CO
ME
N
o. o
f st
ud
ies
Des
ign
Allo
catio
n co
ncea
lmen
t (t
he tw
o gr
oups
co
mpa
rabl
e an
d lo
w ri
sk o
f re
vers
e ca
usal
ity)
Blin
ding
or
othe
r ap
proa
ches
to
redu
ce
mea
sure
men
tbi
as
Los
s to
fo
llow
-up
(<20
%)
Ana
lysi
s in
tent
ion
to
trea
t; c
lust
erad
just
ed if
ap
plic
able
(a
djus
ted
for
conf
ound
ing)
Pre
cisi
on
Con
sist
ency
G
ener
aliz
abil
ity/
Dir
ectn
ess
Ver
y la
rge
effe
ct o
r d
ose
resp
onse
gr
adie
nt
Ove
rall
Q
ual
ity
of
Evi
den
ce
Po
oled
ef
fect
siz
e (9
5% C
I)
OR
ra
nge
of
effe
ct s
izes
(w
her
e p
oole
d
effe
ct s
ize
not
p
ossi
ble
to
asce
rtai
n)
Seiz
ure
recu
rren
ce
(abo
ut u
p to
5
yrs
of a
ge in
on
e st
udy)
3 A
ll ob
serv
atio
nal
(-1.
0)
Maj
orit
y of
ev
iden
ce fr
om
stud
ies
wit
h “N
o”
(-0
.5)
Maj
orit
y of
ev
iden
ce
from
stu
dies
wit
h “Y
es”
(0)
Maj
orit
y of
ev
iden
ce
from
stu
dies
w
ith
“Y
es”
(0)
Maj
orit
y of
ev
iden
ce
from
stu
dies
w
ith
“No”
(-0
.5)
Pool
ed e
ffect
si
gnifi
cant
but
up
per l
imit
of
CI i
n th
e ‘n
ull’
rang
e
(-0
.5)
All
stud
ies
in
the
sam
e di
rect
ion
(0)
All
from
dev
elop
ed
coun
try
sett
ings
(-0
.5)
Nil
VE
RY
L
OW
(Tot
al
scor
e =
-
3.0
)
RR
0.6
6 (0
.47,
0.9
3)
Epi
leps
y la
ter
in li
fe
(abo
ut u
p to
5
yrs
of a
ge)
1 O
bser
vati
onal
(-1.
0)
Unc
lear
(-0
.5)
Yes
(0)
Yes
(0)
No
(-0
.5)
Eff
ect
not
sign
ific
ant,
w
ith
wid
e C
I
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0
.5)
Nil
VE
RY
L
OW
(Tot
al
scor
e =
-
4.5)
RR
0.5
4 (0
.25,
1.1
9)
Cer
ebra
l pal
sy
(abo
ut u
p to
5
yrs
of a
ge)
1O
bser
vati
onal
(-1.
0)
Unc
lear
(-0
.5)
Yes
(0)
Yes
(0)
No
(-0
.5)
Eff
ect
not
sign
ific
ant,
w
ith
wid
e C
I
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0
.5)
Nil
VE
RY
L
OW
(Tot
al
scor
e =
-
4.5)
RR
0.6
3 (0
.31,
1.2
7)
Dev
elop
men
tal
dela
y
(abo
ut u
p to
5
yrs
of a
ge)
1O
bser
vati
onal
(-1.
0)
Unc
lear
(-0
.5)
Yes
(0)
Yes
(0)
No
(-0
.5)
Eff
ect
not
sign
ific
ant,
w
ith
wid
e C
I
(-1.
0)
Sing
le s
tudy
(-1.
0)
From
dev
elop
ed
coun
try
sett
ing
(-0
.5)
Nil
VE
RY
L
OW
(Tot
al
scor
e =
-
4.5)
RR
0.9
1 (0
.64,
1.2
9)
56
Patients: neonates with seizures thatare not controlled by the first-linetreatment (predominantly phenobar-bital)
Intervention (exposure): stoppingantiepileptic drugs (at discharge)
Control (unexposed): continuingantiepileptic drugs after dischargefrom the hospital
When to stopantiepileptic drugs inneonates with seizures?
TAB
LE7
- G
RA
DE
TAB
LE
_ _
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
rem
ent
bia
s)
<20
%
loss
to
foll
ow-u
p
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
re-
men
t
Nu
mb
er (
%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mb
er (
%)
in c
ontr
ol
(un
exp
osed
)gr
oup
Eff
ect
(95%
CI)
Lim
itat
ion
s
Gui
llet
& K
won
, 20
07,
USA
Obs
erva
tiona
l G
esta
tion
>34
w
eeks
and
on
set o
f se
izur
es w
ithin
5
days
of b
irth
an
d re
solu
tion
wit
hin
7 da
ys
of o
nset
of
seiz
ures
Unc
lear
(r
isk
of r
ever
se
caus
ality
can
not
be r
uled
out
)
Yes
(dat
a ob
tain
ed
from
cha
rts)
Yes
No
Seiz
ure
recu
rren
ce
(aft
er
disc
harg
e)
22/9
9 (2
2.2%
) in
infa
nts
who
w
ere
disc
harg
ed
hom
e w
ithou
t an
ticon
vuls
ants
10/3
3 (3
0.3%
) in
infa
nts
who
w
ere
disc
harg
ed
hom
e w
ith
phen
obar
bita
l
RR
0.7
3 (0
.39,
1.
38)
Ret
rosp
ectiv
e ch
art r
evie
w;
deci
sion
to
cont
inue
AE
D
to th
e di
scre
tion
of
phys
icia
ns
Bar
tha
et a
l., 2
007,
U
SA
Obs
erva
tiona
l In
fant
s w
ith
adm
issi
on/
disc
harg
e di
agno
sis
of
NS
No
(gro
ups
not
com
para
ble)
Yes
(dat
a re
trie
ved
from
cha
rts)
Yes
<20
% lo
ss
to fo
llow
-up
No
Nee
d fo
r se
cond
an
ticon
vuls
ant
(for
con
tinui
ng
seiz
ures
)
20/7
8 (2
5.6%
) in
infa
nts
who
w
ere
disc
harg
ed
hom
e w
ithou
t an
ticon
vuls
ants
110/
298
(36.
9%)
in in
fant
s w
ho
wer
e di
scha
rged
ho
me
with
ph
enob
arbi
tal
RR
0.6
9 (0
.46,
1.
04)
Neo
nate
s w
ho
wer
e co
ntin
ued
on
AE
D h
ad
eith
er c
linic
al
or e
lect
rica
l se
izur
es a
t di
scha
rge
Hel
lstr
om-W
esta
s
et a
l., 1
988,
Sw
eden
Obs
erva
tiona
l
Seiz
ure
recu
rren
ce
2/34
(5.9
%)
1/2
(50%
) R
R 0
.12
(0.0
2,
0.81
)
57OU
TC
OM
EA):
REC
UR
REN
CE
OF
SEIZ
UR
ESA
FTER
DIS
CH
AR
GE
_ _
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
rem
ent
bia
s)
<20
%
loss
to
foll
ow-
up
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
re-
men
t
Nu
mb
er (
%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mb
er (
%)
inco
ntr
ol
(un
exp
osed
) gr
oup
Eff
ect
(95%
CI)
L
imit
atio
ns
Gui
llet
& K
won
, 20
07
USA
Obs
erva
tiona
l G
esta
tion
>34
w
eeks
and
on
set o
f se
izur
es w
ithin
5
days
of b
irth
an
d re
solu
tion
wit
hin
7 da
ys
of o
nset
of
seiz
ures
Unc
lear
(r
isk
of r
ever
se
caus
ality
can
not
be r
uled
out
)
Yes
(dat
a ob
tain
ed
from
cha
rts)
Yes
No
Epi
leps
y un
til a
m
ean
age
of
abou
t 5 y
ears
13/9
9 (1
3.1%
) in
infa
nts
who
w
ere
disc
harg
ed
hom
e w
ithou
t an
ticon
vuls
ants
8/33
(24.
2%)
in in
fant
s w
ho
wer
e di
scha
rged
ho
me
with
ph
enob
arbi
tal
RR
0.5
4 (0
.25,
1.1
9)
Ret
ros-
pect
ive
char
t re
view
; de
cisi
on to
co
ntin
ue
AE
D to
the
disc
retio
n of
ph
ysic
ians
Ou
tcom
e: c
) C
ereb
ral p
alsy
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
rem
ent
bia
s)
<20
%
loss
to
foll
ow-
up
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
re-
men
t
Nu
mb
er (
%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mb
er (
%)
inco
ntr
ol
(un
exp
osed
) gr
oup
Eff
ect
(95%
CI)
L
imit
atio
ns
Gui
llet
& K
won
, 200
7 U
SA
Obs
erv-
atio
nal
Ges
tatio
n >
34
wee
ks a
nd
onse
t of
seiz
ures
with
in
5 da
ys o
f bir
th
and
reso
lutio
n w
ithi
n 7
days
of
ons
et o
f se
izur
es
Unc
lear
(r
isk
of r
ever
se
caus
ality
can
not
be r
uled
out
)
Yes
(dat
a ob
tain
ed
from
cha
rts)
Yes
No
Cer
ebra
l pal
sy
17/9
9 (1
7.2%
) in
infa
nts
who
w
ere
disc
harg
ed
hom
e w
ithou
t an
ticon
vuls
ants
9/33
(27.
3%)
in in
fant
s w
ho
wer
e di
scha
rged
ho
me
with
ph
enob
arbi
tal
RR
0.6
3 (0
.31,
1.2
7)
Ret
ros-
pect
ive
char
t re
view
; de
cisi
on to
co
ntin
ue
AE
D to
the
disc
retio
n of
ph
ysic
ians
58 OU
TC
OM
EB):
EP
ILEP
SYIN
LAT
ERLI
FE
OU
TC
OM
EC):
CER
EBR
AL
PA
LSY
_ _
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
rem
ent
bia
s)
<20
%
loss
to
foll
ow-
up
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
rem
ent
Nu
mb
er (
%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mb
er (
%)
in c
ontr
ol
(un
exp
osed
) gr
oup
Eff
ect
(95%
CI)
L
imit
atio
ns
Gui
llet
& K
won
,200
7 U
SA
Obs
erva
tiona
l G
esta
tion
>34
w
eeks
and
on
set o
f se
izur
es w
ithin
5 da
ys o
f bir
th
and
reso
lutio
n w
ithin
7 d
ays
of o
nset
of
seiz
ures
Unc
lear
(r
isk
of r
ever
se
caus
ality
can
not
be r
uled
out
)
Yes
(dat
a ob
tain
ed
from
cha
rts)
Yes
No
Dev
elop
men
tal
dela
y 52
/99
(52.
5%)
in in
fant
s w
ho
wer
e di
scha
rged
ho
me
with
out
antic
onvu
lsan
ts
19/3
3 (5
7.6%
) in
infa
nts
who
w
ere
disc
harg
ed
hom
e w
ith
phen
obar
bita
l
RR
0.9
1 (0
.64,
1.
29)
Ret
rosp
ectiv
e ch
art r
evie
w;
deci
sion
to
cont
inue
A
ED
to th
e di
scre
tion
of
phys
icia
ns
59OU
TC
OM
ED
): D
EVEL
OP
MEN
TA
LD
ELA
Y
_ _
We did not identify any studies – either RCTs or observational – that compared differ-ent regimens of stopping AEDs.
60
How to stop antiepilep-tic drugs in neonateswith seizures?
_ _
Lim
itat
ion
s of
stu
die
s O
UT
CO
ME
N
o. o
f st
ud
ies
Des
ign
Allo
cati
on
conc
ealm
ent
(the
two
grou
ps
com
para
ble
and
low
ris
k of
rev
erse
ca
usal
ity)
Blin
ding
or
othe
r ap
proa
ches
to
red
uce
mea
sure
-m
ent b
ias
Loss
to
follo
w-u
p (<
20%
)
Ana
lysi
s in
tent
ion
to
trea
t; c
lust
er
adju
sted
if
appl
icab
le
(adj
uste
d fo
r co
nfou
ndin
g)
Pre
cisi
on
Con
sist
ency
Gen
eral
izab
ilit
y/
Dir
ectn
ess
Ver
y la
rge
effe
ct o
r d
ose
resp
onse
gr
adie
nt
Ove
rall
Q
ual
ity
of
Evi
den
ce
Po
oled
eff
ect
size
(9
5% C
I)
OR
ran
ge o
f ef
fect
siz
es
(wh
ere
poo
led
eff
ect
size
not
p
ossi
ble
to
asce
rtai
n)
Mor
talit
y
(dur
ing
init
ial
hosp
ital
st
ay)
2(1
RC
T an
d 1
obse
rv-
atio
nal)
Maj
ority
of
evid
ence
fr
om
obse
rv-
atio
nal
stud
y
(-1.
0)
Maj
ority
of
evid
ence
from
stud
ies
with
“N
o”
(-0.
5)
Yes
in b
oth
stud
ies
(0)
Maj
ority
of
ev
iden
ce
from
st
udie
s w
ith
“Yes
”
(0)
No
(-0.
5)
Pool
ed
effe
ct n
ot
sign
ifica
nt,
with
wid
e C
I
(-1.
0)
Bot
h st
udie
s in
the
sam
e di
rect
ion
(0)
Bot
h st
udie
s fr
om
deve
lopi
ng c
ount
ry
sett
ings
(0)
V
ER
Y LO
W
(Tot
al s
core
=
-3.0
)
RR
1.8
0 (0
.78,
4.1
9)
Abn
orm
al
neur
olog
ical
ou
tcom
e
(at d
isch
arge
in
1 s
tudy
, at
3 ye
ars
in
the
othe
r)
2 R
CTs
(0)
Yes
in b
oth
stud
ies
(0)
Maj
ority
of
evid
ence
fr
om s
tudi
es
with
“Ye
s”
(0)
No
for
both
st
udie
s
(-0.
5)
No
for
both
st
udie
s
(-0.
5)
Pool
ed
effe
ct
sign
ifica
nt
and
low
er
limit
of C
I m
eani
ngfu
l
(0)
Onl
y 2
stud
ies,
ES
of
both
in th
e sa
me
dire
ctio
n
(-0.
5)
Maj
ority
of
evid
ence
from
the
stud
y in
de
velo
ping
cou
ntry
se
ttin
gs
(0)
M
OD
ER
ATE
(Tot
al s
core
=
-1.5
)
RR
0.4
4 (0
.24,
0.7
9)
Inci
denc
e of
se
izur
es
(in
the
init
ial
hosp
ital
st
ay)
4(3
RC
Ts
and
1 ob
serv
-at
iona
l)
Maj
ority
of
evid
ence
fr
om R
CTs
(0)
Maj
ority
of
evid
ence
from
stud
ies
with
“Y
es”
(0)
Maj
orit
y of
ev
iden
ce
from
stu
dies
w
ith
“No”
(-0.
5)
Maj
ority
of
ev
iden
ce
from
st
udie
s w
ith
“No”
(-
0.5)
Maj
ority
of
evid
ence
fr
om s
tudi
es
wit
h “N
o”
(-0.
5)
Pool
ed
effe
ct n
ot
sign
ifica
nt,
with
wid
e C
I
(-1.
0)
ES
of s
tudi
es
with
<75
% o
f to
tal w
eigh
t in
the
sam
e di
rect
ion
as
pool
ed e
ffect
(-
1.0)
Maj
orit
y of
ev
iden
ce fr
om
stud
ies
in
deve
lopi
ng c
ount
ry
sett
ings
(0)
V
ER
Y LO
W
(Tot
al s
core
=
-3.5
)
RR
0.8
4 (0
.34,
2.0
9)
Ran
dom
-eff
ects
m
odel
Patients: neonates with hypoxic-ischaemic encephalopathy (but yet todevelop seizures)
Intervention (exposure): prophylactictreatment with phenobarbital or otherantiepileptic drugs
Control (unexposed): no prophylaxis
Prophylactic treatmentwith phenobarbital inneonates withhypoxic-ischaemicencephalopathy
61TAB
LE8
- G
RA
DE
TAB
LE
_ _
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
re-
men
t b
ias)
<20
%
loss
to
foll
ow-
up
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
-re
men
t
Nu
mb
er (
%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mb
er
(%)
in
con
trol
(u
nex
pose
d)gr
oup
Eff
ect
(95%
CI)
L
imit
atio
ns
Sing
h et
al.,
200
5 In
dia
RC
T
(Wei
ght =
41
.6%
)
Ges
tatio
n >
34
wee
ks w
ith
low
Apg
ar,
feta
l dis
tres
s an
d fe
atur
es
of H
IE th
e fir
st 6
hou
rs
afte
r bi
rth
Yes
Yes
(no
info
rmat
ion
but “
hard
”
outc
ome)
No
(25%
loss
) N
o (p
ost-
rand
omiz
atio
n ex
clus
ions
)
Unt
il di
scha
rge
5/25
(20%
) in
infa
nts
who
re
ceiv
ed
intr
aven
ous
phen
obar
bita
l at
20
mg/
kg
3/20
(15%
) in
infa
nts
who
did
not
re
ceiv
e an
y pr
ophy
laxi
s
RR
1.3
3 (0
.36,
4.
92)
-
Aja
yi e
t al.,
199
8 N
iger
ia
Ret
rosp
ectiv
e ch
art r
evie
w
(Wei
ght =
58
.4%
)
Term
ne
onat
es w
ith
Apg
ar s
core
s <
5 at
one
and
fiv
e m
inut
es
No
(hig
her
num
ber
of in
fant
s in
ex
pose
d gr
oup
had
low
Apg
ar
scor
es; r
isk
of
reve
rse
caus
ality
can
not
be r
uled
out
en
tirel
y)
Yes
(fro
m th
e re
cord
s)
Yes
No
(onl
y pa
rtia
lly
adju
sted
)
Unt
il di
scha
rge
7/57
(12%
) in
infa
nts
who
re
ceiv
ed
intr
aven
ous
phen
obar
bita
l at
10
mg/
kg
5/91
(5.5
%)
in in
fant
s w
ho d
id n
ot
rece
ive
any
prop
hyla
xis
RR
2.2
4 (0
.74,
6.7
1)
The
2 gr
oups
of
infa
nts
wer
e m
anag
ed b
y 2
diffe
rent
co
nsul
tant
s (t
o gi
ve p
roph
ylax
is
or n
ot d
ecid
ed b
y th
e co
nsul
tant
);
used
a s
mal
ler
do
se o
f ph
enob
arbi
tal
62 OU
TC
OM
EA):
MO
RT
ALI
TY
_ _
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
rem
ent
bia
s)
<20
%
loss
to
foll
ow-
up
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
re-
men
t
Nu
mb
er (
%)
inin
terv
enti
on
(exp
osed
) gr
oup
Nu
mb
er (
%)
in c
ontr
ol
(un
exp
osed
) gr
oup
Eff
ect
(95%
CI)
L
imit
atio
ns
Sing
h et
al.,
200
5 In
dia
RC
T
(Wei
ght =
52
.5%
)
Ges
tatio
n >
34
wee
ks w
ith lo
w
Apg
ar, f
etal
dis
tres
s an
d fe
atur
es o
f HIE
th
e fir
st 6
hou
rs
afte
r bi
rth
Yes
Yes
(no
blin
d in
terv
entio
n;
blin
d ob
serv
ers)
No
(25%
lo
ss to
fo
llow
-up
)
No
(pos
t-ra
ndom
izat
ion
excl
usio
ns)
Abn
orm
al
neur
olog
ical
ou
tcom
e at
di
scha
rge
6/20
(30%
) in
infa
nts
who
re
ceiv
ed
intr
aven
ous
phen
obar
bita
l at
20
mg/
kg
9/17
(53%
) in
infa
nts
who
di
d no
t rec
eive
an
y pr
ophy
laxi
s
RR
0.5
6 (0
.25,
1.
28)
No
sign
ifica
nt
diffe
renc
e in
th
e ou
tcom
e al
so
at 3
mon
ths
(R
R 0
.36,
C
I 0.1
1, 1
.2)
Hal
l et a
l., 1
998
USA
R
CT
(Wei
ght =
47
.5%
)
Term
or
post
-ter
m
neon
ates
with
se
vere
bir
th
asph
yxia
Yes
Unc
lear
(n
o bl
ind
inte
rven
tion;
no
info
rmat
ion
on
blin
ding
of
obse
rver
s)
No
(22.
5%
loss
to
follo
w-
up)
No
(pos
t-ra
ndom
izat
ion
excl
usio
ns)
Abn
orm
al
neur
olog
ical
ou
tcom
e at
3
year
s
4/15
(27%
) in
infa
nts
who
re
ceiv
ed
intr
aven
ous
phen
obar
bita
l at
40
mg/
kg
13/1
6 (8
1%)
in in
fant
s w
ho
did
not r
ecei
ve
any
prop
hyla
xis
RR
0.3
3 (0
.14,
0.
78)
The
effe
ct o
f pr
ophy
lact
ic
trea
tmen
t w
as
sign
ifica
nt
even
aft
er
step
wis
e lo
gist
ic
regr
essi
on
(onl
y P
valu
es
give
n)
63OU
TC
OM
EB):
AB
NO
RM
AL
NEU
RO
LOG
ICA
LO
UT
CO
ME
_ _
Stu
dy
ID
Des
ign
S
tud
y p
opu
lati
on
A
lloc
atio
n
con
ceal
men
t (g
rou
ps
com
par
able
an
d r
ever
se
cau
sali
ty
un
like
ly)
Bli
nd
ing
(low
ris
k of
m
easu
re-
men
t b
ias)
<20
%
loss
to
foll
ow-
up
Inte
nti
on t
o tr
eat
anal
ysis
(a
dju
sted
for
m
ost
pot
enti
al
con
fou
nd
ers)
Ou
tcom
e m
easu
rem
ent
Nu
mb
er (
%)
in
inte
rven
tion
(e
xpos
ed)
grou
p
Nu
mb
er (
%)
in c
ontr
ol
(un
exp
osed
) gr
oup
Eff
ect
(95%
CI)
L
imit
atio
ns
Sing
h et
al.,
200
5 In
dia
RC
T
(Wei
ght =
19
.2%
)
Ges
tatio
n >
34 w
eeks
w
ith
low
A
pgar
, fet
al
dist
ress
and
fe
atur
es o
f H
IE th
e fir
st
6 ho
urs
afte
r bi
rth
Yes
No
(no
blin
d in
terv
entio
n an
d ou
tcom
e no
t “ha
rd”)
No
(25%
loss
) N
o (p
ost-
rand
omiz
atio
n ex
clus
ions
)
Seiz
ures
dur
ing
init
ial s
tay
2/25
(8%
) in
infa
nts
who
re
ceiv
ed
intr
aven
ous
phen
obar
bita
l at
20
mg/
kg
8/20
(40%
) in
infa
nts
who
di
d no
t rec
eive
an
y pr
ophy
laxi
s
RR
0.2
0 (0
.05,
0.
84)
Var
gas-
Ori
gel
et a
l., 2
004
Mex
ico
RC
T
(Wei
ght =
20
.4%
)
Se
izur
es d
urin
g in
itia
l sta
y 4/
37 (1
0.8%
) in
infa
nts
who
re
ceiv
ed
intr
aven
ous
phen
obar
bita
l at
40
mg/
kg
4/36
(11.
1%)
in in
fant
s w
ho
did
not r
ecei
ve
any
prop
hyla
xis
RR
0.9
7 (0
.26,
3.
60)
Hal
l et a
l., 1
998
USA
R
CT
(Wei
ght =
32
.7%
)
Term
or
post
-te
rm
neon
ates
w
ith s
ever
e bi
rth
asph
yxia
Yes
Unc
lear
(n
o bl
ind
inte
rven
tion;
no
info
rmat
ion
on b
lindi
ng o
f ob
serv
ers)
No
(22.
5%
loss
)
No
(pos
t-ra
ndom
izat
ion
excl
usio
ns)
Seiz
ures
dur
ing
init
ial s
tay
9/15
(60
%)
in in
fant
s w
ho
rece
ived
in
trav
enou
s ph
enob
arbi
tal
at 4
0 m
g/kg
14/1
6 (8
7.5%
) in
infa
nts
who
di
d no
t rec
eive
an
y pr
ophy
laxi
s
RR
0.6
9 (0
.44,
1.0
8)
Aja
yi e
t al.,
199
8 N
iger
ia
Ret
ro-
spec
tive
char
t re
view
(Wei
ght =
27
.7%
)
Term
ne
o nat
es
with
Apg
ar
scor
es <
5 at
on
e an
d fiv
e m
inut
es
No
(hig
her
num
ber
of in
fant
s in
ex
pose
d gr
oup
had
low
Apg
ar
scor
es)
Yes
(fro
m th
e re
cord
s)
Yes
No
(onl
y pa
rtia
lly
adju
sted
)
Unt
il di
scha
rge
13/5
7 (2
3%)
in in
fant
s w
ho
rece
ived
in
trav
enou
s ph
enob
arbi
tal
at 1
0 m
g/kg
8/91
(9%
) in
infa
nts
who
di
d no
t rec
eive
an
y pr
ophy
laxi
s
RR
2.5
9 (1
.15,
5.8
7)
Adj
uste
d O
R 1
.8
(0.7
, 4.7
)
The
2 gr
oups
of
infa
nts
wer
e m
anag
ed b
y 2
diffe
rent
co
nsul
tant
s;
used
a s
mal
ler
dose
of
phen
obar
bita
l
64 OU
TC
OM
EC):
INC
IDEN
CE
OF
SEIZ
UR
ESD
UR
ING
INIT
IAL
HO
SPIT
AL
STA
Y
_ _
Summary of evidence
Empirical treatment of hypoglycaemiaHypoglycaemia can be deleterious and is associated with sequelae including epilepsy(Caraballo et al., 2004). A risk/benefit analysis of empirical treatment is not available.Possible risks include worsening of hyperglycaemia in neonates with HIE, which is themost frequent etiological factor associated with NS. Since blood glucose can easily bemeasured at low cost, this should be performed before treatment.
Empirical treatment of hypocalcaemiaThe incidence/prevalence of hypocalcaemia in neonates with seizures is highly variable.Studies that have found a very high incidence were published in the 1970s (Keen et al.,1973; Langevin,1974). With better nutritional management, the incidence of hypocal-caemia may ever since have declined. However, the data available are not sufficient toprove this assumption. Measurement of blood calcium is possible in hospital settingswithout time delay though less easily available than measurement of blood sugar. Whengiven intravenously, calcium may cause significant harm, i.e. asystoly or skin necrosis.The benefit vs. harm ratio of empirical treatment of hypocalcaemia before laboratorytests cannot be assessed.
Empirical antibiotic treatmentData on different etiologies of neonatal seizures are highly inconsistent. There is not suf-ficient evidence to describe regional differences. However, in the only available studyfrom an African country, Idro and colleagues recently found a very high incidence ofbacterial infections in neonates with seizures admitted at a hospital in Kenya (Idro et al.,2008). This study may be biased because only neonates referring to the hospital wereincluded. Authors do not state whether the neonates showed other clinical signs ofinfection and give no information about laboratory tests performed. Since oral treatmentof neonatal sepsis or pyogenic meningitis is not considered as a standard therapy, empir-ical treatment implies intravenous therapy.
Empirical antiviral treatmentCongenital herpes simplex virus infection is a rare cause of NS. In their population-basedcase-control study, Hall et al. found an increased odds ratio of 2.92 for a history of vagi-nal delivery/maternal herpes simplex infection in neonates presenting with seizureswithin the first 72 hours of life (Hall et al., 2006). The authors do not state whether theneonates showed other clinical signs of infection. Since oral treatment of congenital her-pes simplex virus infection is not considered as a standard therapy, empirical treatmentimplies intravenous therapy. A benefit vs. harm ratio cannot be assessed due to paucityof data.
Empirical pyridoxine treatmentPyridoxine dependent epilepsy is a rare disease with an incidence of definite and prob-able cases of 1:396,000 (Been et al., 2005) compared to the overall incidence of NSbetween 1:71 to 1:1000. Other treatable neonatal epileptic encephalopathies withmetabolic causes, such as pyridoxal-phosphate dependent epilepsy probably are evenless frequent; only case reports and small series of patients have been published and anincidence cannot be calculated. Diagnosis of pyridoxine dependent epilepsy can beestablished clinically by a positive response to treatment with pyridoxine. Failure to diag-nose this condition may have deleterious effects on affected neonates, but delay intreatment of other underlying etiologies may also cause harm. A benefit vs. harm ratiocannot be calculated.
No controlled trials were identifiedand therefore GRADE could not beapplied
Empirical treatment forhypoglycaemia,hypocalcaemia andinfections with seizures
65
_ _
Stu
dy
ID
Des
ign
O
utc
ome
Nu
mbe
r (%
) in
ex
pos
ed g
rou
p
Nu
mbe
r (%
) in
co
ntr
ol g
rou
p
Eff
ect
(95%
CI)
D
irec
tnes
sL
imit
atio
ns
stu
dy
Labr
ecqu
e e
t al.,
198
4 R
etro
spec
tive
coh
ort
Seiz
ure
recu
rren
ce
2/43
(4.
6%)
4/7(
57.1
%)
RR
0.0
8 (0
.02
to 0
.36)
Ye
s O
bser
vati
onal
Bro
d et
al.,
198
8 R
etro
spec
tive
coh
ort
Seiz
ure
recu
rren
ce
0/10
5/
14 (3
5.7%
) R
R 0
.12
(0.0
1, 2
.02)
Ye
s O
bser
vati
onal
stu
dy
Ghe
rpel
li et
al.,
199
2 R
etro
spec
tive
coh
ort
Seiz
ure
recu
rren
ce
0/11
7/
12 (
58.3
%)
RR
0.0
7 (0
, 1.3
6)
Yes
Obs
erva
tion
al s
tudy
Stu
dy
ID
Des
ign
O
utc
ome
Nu
mbe
r (%
) in
ex
pos
ed g
rou
p
Nu
mbe
r (%
) in
co
ntr
ol g
rou
p
Eff
ect
(95%
CI)
D
irec
tnes
sL
imit
atio
ns
Scar
pa e
t al.,
198
3
Ret
rosp
ecti
ve c
ohor
t Se
izur
e re
curr
ence
4/
43
8/8
RR
0.0
9 (0
.04
to 0
.24)
Ye
s O
bser
vati
onal
stu
dy
Bro
d et
al .
, 198
8 R
etro
spec
tive
coh
ort
Seiz
ure
recu
rren
ce
4/22
5/
8 R
R 0
.29
(0.1
0 to
0.8
2)
Yes
Obs
erva
tion
al s
tudy
B
rod
et a
l., 1
988
Ret
rosp
ecti
ve c
ohor
t Se
izur
e re
curr
ence
1/
10
4/5
RR
0.1
3 (0
.02
to 0
.84)
) Ye
s O
bser
vati
onal
stu
dy
Cla
ncy
& L
egid
o, 1
991
Ret
rosp
ecti
ve c
ohor
t Se
izur
e re
curr
ence
2/
8 13
/19
RR
0.3
7 (0
.11
to 1
.26)
Ye
s O
bser
vati
onal
stu
dy
Ghe
rpel
li et
al.,
199
2 R
etro
spec
tive
coh
ort
Seiz
ure
recu
rren
ce
2/18
5/
5 R
R 0
.11
(0.0
3 to
0.4
1)
Yes
Obs
erva
tion
al s
tudy
66
Outcome: recurrence of seizures
Patients: neonates with seizures thatare controlled by one or moreantiepileptic drugs
Exposed group: infants with the saidpredictor in neonatal period/at dis-charge
Unexposed group: infants withabnormal neurological examination inneonatal period/at discharge
Predicting the prognosisin neonates withseizures
TAB
LE9
- O
UT
CO
ME
A)
REC
UR
REN
CE
OF
SEIZ
UR
ES
PRED
ICTO
R1:
NO
RM
AL
NEU
RO
LOG
ICA
LEX
AM
INA
TIO
NIN
NEO
NA
TAL
PER
IOD/A
TD
ISC
HA
RG
E
PRED
ICTO
R2:
NO
RM
AL
EEG
INN
EON
ATA
LPE
RIO
D/A
TD
ISC
HA
RG
E
_ _
Stu
dy
ID
Des
ign
O
utc
ome
Nu
mbe
r (%
) in
ex
pos
ed g
rou
p
Nu
mbe
r (%
) in
co
ntr
ol g
rou
p
Eff
ect
(95%
CI)
D
irec
tnes
sL
imit
atio
ns
Ghe
rpel
li et
al.,
199
2
Ret
rosp
ecti
ve c
ohor
t Se
izur
e re
curr
ence
1/1
1 4/
7 R
R 0
.16
(0.0
2 to
1.1
5)
Yes
Obs
erva
tion
al s
tudy
Stu
dy
ID
Des
ign
O
utc
ome
Nu
mbe
r (%
) in
ex
pos
ed g
rou
p
Nu
mbe
r (%
) in
co
ntr
ol g
rou
p
Eff
ect
(95%
CI)
D
irec
tnes
sL
imit
atio
ns
Ghe
rpel
li et
al.,
199
2
Ret
rosp
ecti
ve c
ohor
t Se
izur
e re
curr
ence
1/1
1 4/
7 R
R 0
.16
(0.0
2 to
1.1
5)
Yes
Obs
erva
tion
al s
tudy
67PRED
ICTO
R3:
NO
RM
AL
CR
AN
IAL
US
INN
EON
ATA
LPE
RIO
D/A
TD
ISC
HA
RG
E
PRED
ICTO
R4:
STA
TUS
OF
MU
LTIP
LEPA
RA
MET
ERS
(ELE
CTR
OEN
CEP
HA
LOG
RA
PHY,
NEU
RO
LOG
ICA
LEX
AM
INA
TIO
N, N
EUR
OIM
AG
ING,
RES
OLU
TIO
NO
FU
ND
ERLY
ING
CO
ND
ITIO
N, E
TC.)
INN
EON
ATA
LPE
RIO
D/A
TD
ISC
HA
RG
E
_ _
Stu
dy
Met
hod
s P
red
icto
r O
utc
ome
Des
ign
of
stu
dy
Con
sist
ency
D
irec
tnes
s L
imit
atio
ns
of s
tud
y
Legi
do e
t al.,
19
91
Coh
ort,
retr
ospe
ctiv
e st
udy
N=
40
Dev
elop
men
tal a
sses
smen
t Fa
vour
able
out
com
e (n
orm
al
deve
lopm
ent)
, unf
avou
rabl
e (d
eath
, ep
ileps
y, d
evel
opm
enta
l del
ay,
cere
bral
pal
sy);
follo
w-u
p ra
nged
fr
om 5
to 5
6 m
onth
s
mod
erat
e In
cons
iste
nt in
te
rms
of b
rain
m
atur
ity
limite
d Se
nsiti
vity
of c
linic
al r
ecog
niti
on
of N
S w
as lo
w (2
1%);
siz
e of
su
bgro
ups
with
diff
eren
t et
iolo
gies
is s
mal
l to
have
st
atis
tical
pow
er
Ort
ibus
et a
l.,
1996
C
ohor
t stu
dy,
pros
pect
ive
anal
ysis
N
=81
EE
G m
onito
ring
(ict
al, i
nter
icta
l re
cord
s, b
ackg
roun
d ac
tivity
, ne
gativ
e an
d po
sitiv
e sh
arp
wav
es,
inte
rict
al n
euro
logi
cal e
xam
inat
ion:
no
rmal
, mod
erat
ely
abno
rmal
, se
vere
ly a
bnor
mal
; neu
roim
agin
g st
udie
s (c
rani
al U
S, C
T, M
RI)
; de
velo
pmen
tal a
sses
smen
t
Long
term
out
com
e: fa
vour
able
, un
favo
urab
le (n
orm
al, m
ildly
ab
norm
al, s
ever
ely
abno
rmal
);
deve
lopm
ent o
f pos
t-ne
onat
al
epile
psy
good
go
od
usef
ul
No
vide
o-E
EG
rec
ordi
ngs
wer
e pe
rfor
med
; lac
k of
mon
itori
ng
may
res
ult i
n m
isse
d ne
onat
es
with
bri
ef o
r ra
re s
eizu
res
Tem
ple
et a
l.,
1995
C
ohor
t stu
dy,
retr
ospe
ctiv
e an
alys
is
N=
22
Neu
rops
ycho
logi
cal a
sses
smen
t of
inte
llige
nce,
spe
lling
, mem
ory,
soc
ial
adju
stm
ent
appl
ied
at a
ge 6
and
ag
es 1
8-19
yea
rs
Long
term
cog
nitiv
e ou
tcom
e:
cogn
itive
dec
line
(spe
cific
lear
ning
di
sabi
litie
s), n
orm
al d
evel
opm
ent
epyt ,ytireves g to
n italer sliated oN
etaredo
m etaredo
man
d E
EG
con
firm
atio
n of
NS
Boy
lan
et a
l.,
1999
C
ohor
t stu
dy,
pros
pect
ive
anal
ysis
N
=24
Vid
eo-E
EG
17
pts
with
ele
ctro
grap
hic/
clin
ical
se
izur
es,
7 pt
s cl
inic
al-o
nly
seiz
ures
Bac
kgro
und
EE
G a
bnor
mal
in a
ll bu
t on
e, r
evea
led
poor
ne
urod
evel
opm
enta
l out
com
e
mod
erat
e In
cons
iste
ncy
in
term
s of
bra
in
mat
urity
and
in
type
of s
eizu
res
mod
erat
e It
is n
ot c
lear
that
clin
ical
se
izur
es a
lone
wer
e of
epi
lept
ic
natu
re; e
lect
rogr
aphi
c se
izur
es
alon
e w
ere
not s
epar
atel
y st
udie
d
McB
ride
et a
l.,
2000
Obs
erva
tiona
l pr
ospe
ctiv
e st
udy
with
co
ntro
l gro
up
N=
68
Out
com
e co
hort
of n
eona
tes
with
an
d w
ithou
t neo
nata
l sei
zure
s ba
sed
on id
enti
ficat
ion
of e
lect
rogr
aphi
c se
izur
es
Am
ount
of e
lect
rogr
aphi
c se
izur
e ac
tivity
cor
rela
ted
with
sub
sequ
ent
mor
talit
y an
d m
orbi
dity
good
go
od
Iden
tifie
d ne
ed to
tr
eat a
ll se
izur
es w
ith
quite
goo
d ev
iden
ce
to im
prov
e ou
tcom
e
Nee
d ra
ndom
ized
blin
ded
com
pari
son
stud
y to
ass
ess
this
68
Predicting the prognosisin infants with neonatalseizures
OU
TC
OM
EB):
OT
HER
OU
TC
OM
ES
_ _
Stu
dy
Met
hod
s P
red
icto
r O
utc
ome
Des
ign
of
stu
dy
Con
sist
ency
D
irec
tnes
s L
imit
atio
ns
of s
tud
y
Tekg
ul e
t al.,
20
06
Coh
ort s
tudy
, re
tros
pect
ive
anal
ysis
N
=89
Neu
rolo
gica
l exa
min
atio
n an
d ne
urod
evel
opm
enta
l tes
ting
afte
r di
scha
rge
and
at 1
2 to
18
mon
ths
Prog
nost
ic v
alue
of s
eizu
re
etio
logy
, neu
rolo
gica
l ex
amin
atio
n, E
EG
and
ne
uroi
mag
ing
good
go
od
usef
ul
Ret
rosp
ectiv
e, n
o co
ntro
l gr
oup.
Out
com
e w
as li
mite
d to
the
earl
y ps
ycho
mot
or
deve
lopm
ent (
18 m
onth
s)
Ron
en e
t al.,
20
07
Popu
latio
n-ba
sed
stud
y, p
rosp
ectiv
e co
hort
stu
dy, c
linic
al
follo
w-u
p N
=82
/90
Prog
nost
ic v
alue
of s
eizu
re ty
pe,
gest
atio
nal a
ge a
t del
iver
y, b
irth
w
eigh
t, N
S et
iolo
gy, n
eona
tal E
EG
an
d nu
mbe
r of
AE
D
Long
term
out
com
e:
favo
urab
le w
ith n
orm
al
neur
olog
ical
and
cog
niti
ve
stat
us, p
oor,
(phy
sica
l di
sabi
lity,
cog
niti
ve
impa
irm
ent,
lear
ning
di
sabi
lity,
pos
t-ne
onat
al
epile
psy)
good
In
cons
iste
ncy
in te
rms
of b
rain
mat
urity
(b
oth
pret
erm
and
full
term
new
born
s in
clud
ed) a
nd in
term
of
type
of s
eizu
res
very
use
ful
Imag
ing
findi
ngs
not
co
nsid
ered
as
sepa
rate
pr
ogno
stic
fact
or. I
nclu
ded
infa
nts
with
gen
eral
ized
m
yocl
onic
eve
nts
with
out
EE
G c
onfir
mat
ion
Pisa
ni e
t al.,
20
07
Coh
ort,
pros
pect
ive
stud
y N
=10
6
Eva
luat
ion
of s
tatu
s ep
ilept
icus
and
re
curr
ent
NS
for
neur
olog
ical
ou
tcom
e, a
sses
sed
at 2
4 m
onth
s of
co
rrec
ted
age.
Impa
ct o
f clin
ical
fa
ctor
s (g
esta
tiona
l age
, bir
th
wei
ght,
cere
bral
ultr
asou
nd
findi
ngs)
. Gen
eral
dev
elop
men
t was
as
sess
ed u
sing
Gri
ffith
’s M
enta
l de
velo
pmen
t Sca
le
Gen
eral
dev
elop
men
t: n
orm
al
or a
bnor
mal
; ne
urod
evel
opm
enta
l out
com
e w
as c
lass
ified
as
favo
urab
le o
r ad
vers
e (d
eath
, cer
ebra
l pal
sy,
deve
lopm
enta
l del
ay,
epile
psy,
blin
dnes
s or
de
afne
ss)
mod
erat
e In
cons
iste
ncy
in te
rms
of b
rain
mat
urity
(b
oth
pret
erm
and
full
term
new
born
s in
clud
ed) a
nd in
term
of
type
of s
eizu
res
Doe
sn’t
real
ly a
nsw
er
ques
tion,
but
impl
ied
cont
rol o
f sta
tus
and
repe
ated
neo
nata
l se
izur
es c
ould
ref
lect
be
tter
out
com
e
All
stud
ied
subj
ects
had
sy
mpt
omat
ic N
S, w
hich
us
ually
ref
lect
s se
vere
acu
te
or c
hron
ic n
euro
logi
cal
inju
ry; t
he h
igh
perc
enta
ge
of u
nfav
oura
ble
outc
ome
may
be
resu
lt of
sev
ere
CN
S in
volv
emen
t
Iype
et a
l.,
2008
Pr
ospe
ctiv
e co
hort
st
udy,
clin
ical
fo
llow
-up
over
2-8
m
onth
s
Prog
nost
ic v
alue
of N
S et
iolo
gy, E
EG
(n
orm
al v
s. in
teri
ctal
dis
char
ges)
, ge
stat
iona
l age
at d
eliv
ery,
bir
th
we i
ght
Favo
urab
le o
r po
or in
term
s of
mor
talit
y, n
euro
logi
cal
stat
us a
nd p
ost-
neon
atal
ep
ileps
y
mod
erat
e In
cons
iste
ncy
in te
rms
of b
rain
mat
urity
typ
e of
sei
zure
s, a
nd E
EG
co
nfir
mat
ion
Use
ful f
or th
e pr
edic
tion
of e
arly
ps
ycho
mot
or
deve
lopm
ent i
n ne
wbo
rn fr
om th
e se
ttin
g in
a
deve
lopi
ng c
ount
ry
Seiz
ures
wer
e re
cogn
ized
ra
ther
clin
ical
ly th
an b
y E
EG
, sho
rt fo
llow
-up
(2-8
m
onth
s) is
insu
ffici
ent f
or
diag
nosi
s of
mild
mot
or a
nd
cogn
itive
def
icit
s an
d la
ter
onse
t of e
pile
psy
Pisa
ni e
t al.,
20
08a
Pros
pect
ive
coho
rt
stud
y, c
linic
al
follo
w-u
p ov
er 2
-8
mon
ths
N=
51
Ris
k fa
ctor
s, e
tiolo
gy a
nd ty
pe o
f NS,
E
EG
act
ivity
, cer
ebra
l US
sca
ns
Favo
urab
le o
r po
or in
term
s of
mor
talit
y, n
euro
logi
cal
impa
irm
ent a
nd p
ost-
neon
atal
epi
leps
y
mod
erat
e m
oder
ate
Use
ful f
or e
arly
ps
ycho
mot
or
deve
lopm
ent i
n pr
eter
m b
abie
s of
di
ffere
nt d
egre
e of
br
ain
imm
atur
ity
It is
diff
icul
t to
dist
ingu
ish
the
effe
cts
of N
S on
im
mat
ure
brai
n fr
om
influ
ence
of i
mm
atur
ity p
er
se. T
he lo
ng te
rm
prog
nost
ic c
ompo
nent
was
m
issi
ng
69
_ _
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Khan RL et al. (2008). Predictive value of sequential electroencephalogram (EEG) inneonates with seizures and its relation to neurological outcome. Journal of ChildNeurology, 23:144-50.
Kohelet D et al. (2004). Israel Neonatal Network. Risk factors for neonatal seizures invery low birthweight infants: population-based survey. Journal of Child Neurology,19:123-8.
Krishnamoorthy KS et al. (2000). Diffusion-weighted imaging in neonatal cerebralinfarction: clinical utility and follow-up. Journal of Child Neurology, 15:592-602.
Kumar A, Gupta A, Talukdar B (2007). Clinico-etiological and EEG profile of neonatalseizures. Indian Journal of Pediatrics, 74:33-7.
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Search methods for identification of studies
The following databases were searched:a) Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library,
Issue 3, 2008: http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME?CRETRY=1&SRETRY=0)
b) MEDLINE any date (http://www.ncbi.nlm.nih.gov/sites/entrez)c) Cabi Global Health database (http://www.cabi.org/home.asp)d) National Library of Medicine (NLM) Gateway (http://gateway.nlm.nih.gov/gw/Cmd)e) Centre for Reviews and Dissemination (CRD); web site: http://www.crd.york.ac.uk/
crdweb/ (DARE: Database of Abstracts of Reviews of Effects plus NHS) f) International registers of ongoing clinical trials ISRCTN (http://www.controlled-
trials.com/isrctn/)g) Embase (http://www.embase.com/)h) Ovid MEDLINE database (http://gateway.ovid.com/autologin.html). Studies from
1950 to end of week 3 Nov 2008i) Abstracts of annual meetings of Society of Pediatric Academic Societies 2000-2008
(http://www.abstracts2view.com/pasall)j) A bibliographic database of Indian biomedical journals (http://indmed.nic.in/)k) Manual search of abstracts of annual meetings of National Neonatology Forum of Indial) Wiley Inter Science journals database was searchedm) National Guidelines Clearinghouse was searched matching some of the keywordsn) Hand search within the International journals and Congress/Conference proceedings,
and reference lists of the retrieved papers/studies (http://www.who.int/hinari/en/)
Search terms
The electronic search strategy involved keywords, using the search fields of abstract,MeSH subject heading, exploded subject heading, subject heading word, text word andtitle. The following key words were used:
• seizures • outcomes • septicaemia• convulsions • EEG • pyridoxine• newborn • predicting factors • prognosis• neonate • phenytoin • neurodevelopment• treatment • phenobarbital • long-term• anticonvulsant drugs • midazolam • diagnostic tests• neuro* examination • diazepam• clinic*examination • lidocaine/lignocaine• hypocalcaemia • term• meningitis • preterm• herpes simplex • hypoglycaemia
Moreover, combinations of the above terms were used, employing the search fields ofabstract, MeSH subject heading, exploded subject heading, subject heading word, textword and title.
Limits
Human, English, Clinical Trial, Meta Analysis, Practice Guideline, Randomised ControlledTrial, Review, Comparative study, Consensus Development Conference, NIH, ControlledClinical trial, English abstract and Multicenter study. And combinations with these key words.Limitations: Clinical trial Due to the paucity of documents retrieved with the above mentioned limitations, thesearch was repeated several times excluding some of the limitations. 83
Search strategyof the literature
_ _
a) Cochrane Central Register of Controlled Trials
CENTRAL, The Cochrane Library, Issue 3, 2008 (http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/HOME?CRETRY=1&SRETRY=0), Cochrane Controlled Trials Registry SearchDate: Issue 3, 2008newborn, seizures, treatment and anticonvulsants.The search retrieved 52 titles: 10 Cochrane reviews, one other review and 41 clinical tri-als.
b) MEDLINE any date (http://www.ncbi.nlm.nih.gov/sites/entrez)
Search Number 1Limits: Humans, Clinical Trial, Randomized Controlled Trial, Systematic review,Newborn: birth-1 month
Search Most Recent Queries Time Result#15 Search (#3) AND (#14) Limits: Humans, 14:31:51 243
Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#14 Search convulsions Limits: Humans, Clinical Trial, 14:30:51 861Randomized Controlled Trial, Review, Newborn:birth-1 month
#13 Search ((#1) AND (#7)) AND (#6) Limits: Humans, 14:28:51 12Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#12 Search (#1) AND (#7) Limits: Humans, 14:28:27 17Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#11 Search (((#1) AND ) AND (#2)) AND (#5) Limits: 14:27:41 18Humans, Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#10 Search (#1) AND (#4) Limits: Humans, 14:26:56 58Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#9 Search (#1) AND (#3) Limits: Humans, 14:26:28 56Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#8 Search (#1) AND (#2) Limits: Humans, 14:24:04 114Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#7 Search phenytoin Limits: Humans, Clinical Trial, 14:19:57 22Randomized Controlled Trial,Newborn: birth-1 month
#6 Search phenobarbital Limits: Humans, Clinical Trial, 14:19:48 129Randomized Controlled Trial,Newborn: birth-1 month
#5 Search barbiturates Limits: Humans, Clinical Trial, 14:19:38 153Randomized Controlled Trial,Newborn: birth-1 month
#4 Search antiepileptic drugs Limits: Humans, 14:19:19 316Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#3 Search anticonvulsants Limits: Humans, 14:19:06 314Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month84
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#2 Search treatment Limits: Humans, Clinical Trial, 14:18:51 10427Randomized Controlled Trial,Newborn: birth-1 month
#1 Search seizures Limits: Humans, Clinical Trial, 14:18:28 147Randomized Controlled Trial,Newborn: birth-1 month
Search Number 2 (Repeated search in MEDLINE)Limits: Humans, Clinical Trial, Randomized Controlled Trial, Review, Newborn: birth-1 month
Search Most Recent Queries Time Result#18 Search (#3) AND (#14) Limits: Humans, 03:15:51 243
Clinical Trial, Randomized Controlled Trial,Newborn: birth-1 month
#17 Search convulsions Limits: Humans, 03:14:51 861Clinical Trial, Randomized Controlled Trial,Review, Newborn: birth-1 month
#16 Search (#3) AND (#6) Limits: Humans, 03:09:51 50Clinical Trial, Randomized Controlled Trial,Review, Newborn: birth-1 month
#15 Search (#12) AND (#11) AND (#6) AND (#4) 03:04:57 3Limits: Humans, Clinical Trial, RandomizedControlled Trial, Review, Newborn: birth-1 month
#14 Search (#1) AND (#11) AND (#5) Limits: Humans, 03:02:41 7Clinical Trial, Randomized Controlled Trial, Review,Newborn: birth-1 month
#13 Search midazolam Limits: Humans, Clinical Trial, 03:02:07 70Randomized Controlled Trial, Review,Newborn: birth-1 month
#12 Search phenytoin Limits: Humans, Clinical Trial, 03:02:00 129Randomized Controlled Trial, Review,Newborn: birth-1 month
#11 Search phenobarbital Limits: Humans, Clinical Trial, 03:01:48 322Randomized Controlled Trial, Review,Newborn: birth-1 month
#10 Search (#1) ) AND (#4) AND (#6) Limits: Humans, 02:55:10 39Clinical Trial, Randomized Controlled Trial, Review,Newborn: birth-1 month
#9 Search (#3) AND (#6) Limits: Humans, Clinical Trial, 02:53:54 50Randomized Controlled Trial, Review,Newborn: birth-1 month
#8 Search (#1) AND (#3) AND (#5) Limits: Humans, 02:52:46 7Clinical Trial, Randomized Controlled Trial, Review,Newborn: birth-1 month
#7 Search (#1) AND (#2) AND (#6) Limits: Humans, 02:53:23 19Clinical Trial, Randomized Controlled Trial, Review,Newborn: birth-1 month
#6 Search duration Limits: Humans, Clinical Trial, 02:49:55 2159Randomized Controlled Trial, Review,Newborn: birth-1 month
#5 Search discharge Limits: Humans, Clinical Trial, 02:49:35 1078Randomized Controlled Trial, Review,Newborn: birth-1 month
#4 Search treatment Limits: Humans, Clinical Trial, 02:49:29 33688Randomized Controlled Trial, Review,Newborn: birth-1 month 85
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#3 Search antiepileptic drugs Limits: Humans, 02:49:20 919Clinical Trial, Randomized Controlled Trial, Review,Newborn: birth-1 month
#2 Search anticonvulsants Limits: Humans, Clinical Trial, 02:49:09 902Randomized Controlled Trial, Review,Newborn: birth-1 month
#1 Search seizures Limits: Humans, Clinical Trial, 02:48:59 792Randomized Controlled Trial, Review,Newborn: birth-1 month
Search Number 3 (in PubMed)Limits: Humans, All Infant: birth-23 months
Search Most Recent Queries Time Result#14 Search (#2) AND (#3) AND (#13) AND (#6) 11:12:14 22
Limits: Humans, All Infant: birth-23 months#13 Search antiepileptic drugs Limits: Humans, 11:11:43 6698
All Infant: birth-23 months#12 Search (#2) AND (#3) AND (#7) AND (#6) 11:05:28 14
Limits: Humans, All Infant: birth-23 months#11 Search (#2) AND (#3) AND (#5) Limits: Humans, 11:04:13 22
All Infant: birth-23 months#10 Search treatment Limits: Humans, 11:02:49 337306
All Infant: birth-23 months#9 Search (phenytoin) AND (#2) AND (#3) 11:01:35 4
AND (#4)) AND (#6) Limits: Humans,All Infant: birth-23 months
#8 Search phenytoin Limits: Humans, 11:01:13 949All Infant: birth-23 months
#7 Search phenobarbital Limits: Humans, 11:01:04 1733All Infant: birth-23 months
#6 Search discharge Limits: Humans, 11:00:49 7849All Infant: birth-23 months
#5 Search anticonvulsants AND discharge Limits: 11:00:38 79Humans, All Infant: birth-23 months
#4 Search anticonvulsants Limits: Humans, 11:00:29 6550All Infant: birth-23 months
#3 Search newborn Limits: Humans, 11:00:19 400680All Infant: birth-23 months
#2 Search seizures Limits: Humans, 11:00:06 10597All Infant: birth-23 months
#1 Search Limits: Humans, 10:59:52 725448All Infant: birth-23 months
Date 08/11/2008, 13/11/2008 and 28/11/2008: Initially, the search was limited to clinical tri-als. However, only few papers were retrieved, most of which had to be excluded on the basisof the title. Therefore, the search was repeated without limit and 346 titles were retrieved.
Search Most Recent Queries Time Result#6 Search pyridoxine neonate seizure 12:12:10 120#5 Search neonate seizure meningitis clinical 12:11:18 91#3 Search septicemia neonate seizure clinical 12:09:55 58#2 Search hypocalcemia neonate seizure clinical 12:09:22 30#1 Search hypoglycemia neonate seizure clinical 12:08:45 47
Search Most Recent Queries Time Results#1 Search neonate seizure herpes 05:25:01 6086
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c) Cabi Global Health database (http://www.cabi.org/home.asp)
1 Neonatal screening for glutaryl-CoA dehydrogenase deficiency.Lindner, M., Kölker, S., Schulze, A., Christensen, E. Greenberg, C. R., Hoffmann, G. F./ Journal of Inherited Metabolic Disease, 2004, Vol. 27, No. 6, pp. 851-859, 18 ref.
[Added:20050209]
2 Adverse effects of early phenobarbital administration in termnewborns with perinatal asphyxia.Ajayi, O. A., Oyaniyi, O. T., Chike-Obi, U. D. / Tropical Medicine and InternationalHealth, 1998, Vol. 3, No. 7, pp. 592-595, 13 ref.
[Added:19981205]
3 Phenylketonuria: contemporary screening and diagnosis.Mabry, C. C. / Annals of Clinical and Laboratory Science, 1990, Vol. 20, No. 6, pp.392-397, 18 ref.
[Added:19920829]
d) Search in NLM Gateway 1 (http://gateway.nlm.nih.gov/gw/Cmd)
Search History Clear History
NLM Gateway Search 1Number Search Items Found Actions#25 Search: newborn and convulsions and 195 View Results
anticonvulsants and Diazepam Delete#24 Search: newborn and convulsions and 48 View Results
anticonvulsants and Lidocaine Delete#23 Search: newborn and convulsions and 0 View Results
anticonvulsants and phenorbarbitone Delete#22 Search: newborn and convulsions and 226 View Results
anticonvulsants and phenytoin Delete#21 Search: (newborn and seizures and term and 62 View Results
treatment and Diazepam) and Phenytoin Delete#20 Search: (newborn and seizures and preterm 14 View Results
and treatment) and Clinic* examination Delete#19 Search: (newborn and seizures and preterm 7 View Results
and treatment) and Neuro* examination Delete#18 Search: (newborn and seizures and preterm and 0 View Results
treatment and phenytoin) and Neuro* examination Delete#17 Search: (newborn and seizures and preterm and 0 View Results
treatment and phenytoin) and Clinic* examination Delete#16 Search: (neonates and convulsions and term and 386 View Results
treatment) and Diazepam Delete#15 Search: (neonates and convulsions and term and 120 View Results
treatment) and Lidocaine Delete#14 Search: (neonates and convulsions and 0 View Results
term and treatment) and Phenorbarbitone Delete#13 Search: (neonates and convulsions and term 131 View Results
and treatment) and Phenytoin Delete#12 Search: (neonates and convulsions and preterm 33 View Results
and treatment) and Diazepam Delete 87
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#11 Search: (neonates and convulsions and 7 View Resultspreterm and treatment) and Lidocaine Delete
#10 Search: (neonates and convulsions and 0 View Resultspreterm and treatment) and Phenorbarbitone Delete
#9 Search: (neonates and convulsions and 14 View Resultspreterm and treatment) and Phenytoin Delete
#8 Search: (newborn and seizures and term and 102 View Resultstreatment) and Phenytoin Delete
#7 Search: (newborn and seizures and term and 0 View Resultstreatment) and Phenorbarbital Delete
#6 Search: (newborn and seizures and 0 View Resultsterm and treatment) and Phenorbarbitone Delete
#5 Search: (newborn and seizures and term 101 View Resultsand treatment) and Lidocaine Delete
#4 Search: (newborn and seizures and term and 305 View Resultstreatment) and Diazepam Delete
#3 Search: (newborn and seizures and preterm and 24 View Resultstreatment) and Diazepam Delete
#2 Search: (newborn and seizures and preterm and 5 View Resultstreatment) and Lidocaine Delete
#1 Search: (newborn and seizures and preterm and 0 View Resultstreatment) and phenorbarbital Delete
NLM Gateway search 2Clinical trials 18 titles retrieved
Number Search Items Found Actions#8 Search: perinatal and seizures and 18 View Results
anticonvulsants and discharge Delete#7 Search: neonatal and seizures and 66 View Results
anticonvulsants and discharge Delete#6 Search: newborn and seizures and 55 View Results
anticonvulsants and discharge Delete#5 Search: newborn and seizures and 275 View Results
phenytoin Delete#4 Search: newborn and seizures and 682 View Results
phenobarbital Delete#3 Search: seizures and newborn and 1100 View Results
antiepileptic drugs Delete#2 Search: seizures and newborn 2968 View Results
and therapy Delete#1 Search: seizures and newborn and 1070 View Results
anticonvulsants Delete
04. 11. 2008Search in NLM Gateway (http://gateway.nlm.nih.gov/gw/Cmd)Neonatal seizures and prognosis Summary: 1148 records foundNeonatal seizures and prognosis, clinical trials, reviews Summary: 57 records found
06.11.2008Neonatal seizures and prognostic factors Summary: 69 records foundNeonatal seizures and prognostic factors, clinical trials Summary: 9 records foundNeonatal seizures and prognostic tests Summary: 27 records foundNeonatal seizures and prognostic tests, clinical trials Summary: 10 records found105 Items. were selected88
_ _
e) Centre for Reviews and Dissemination - CRD(http://www.crd.york.ac.uk/crdweb/)
CRD (Centre for Review and Dissemination) consisting of DARE: Database of Abstractsof Reviews of Effects, Structured abstracts of quality-assessed reviews and NationalInstitute for Health research (NHS)
Search history Matching records#1 neonatal seizures AND prognosis 0
RESTRICT YR 1990 2008#2 neonatal seizures AND prognosis AND factors 0
AND tests RESTRICT YR 1970 2008
Search history Matching records#1 newborn AND seizures AND treatment 6
RESTRICT YR 1998 2008
f) International registers of ongoing clinical trials ISRCTN(http://www.controlled-trials.com/isrctn/)
Internet-based trials registers were searched for ongoing trials. The registers searchedwere: Trials Central (www.trialscentral.org) which is a database of clinical trials registersthat gives access to Current Controlled Trials, made up of two registers, ISRCTN (a data-base of randomized controlled trials with an international randomized controlled trialnumber) and mRCT (metaRegister of controlled trials), a database combining registersof ongoing randomized controlled trials in all areas of healthcare. Trials Central also linksto the Australasian Perinatal Trials Registry.
These registers were searched using keywords neonate and seizure.
International registers of ongoing clinical trials ISRCTNhttp://www.controlled trials.com/isrctn/
89
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90
Internet-based trials registers (10.11.2008 and 30.09.2008) were searched twice forongoing trials. These registers were searched using keywords neonatal and seizures;neonatal seizures and prognosis.
01 Effectiveness of sucrose analgesia in reducing pain responses in infants bornto diabetic and non-diabetic mothers: A randomized controlled trial Date assigned: 15 August 2005
02 Levetiracetam (Keppra®) in neonates: safety of intravenous levetiracetam forneonates with seizures Date assigned: 11 April 2007
03 Minimizing needle poke pain in newborn infants with a pain relieving creamand sugar water Date assigned: 23 August 2007
04 Effect of timing of cord clamping on postnatal packed red blood cells valueand clinical outcome in term newborns: a randomised controlled trial Date assigned: 02 March 2005
These registers were searched using keywords neonatal and seizures; neonatal andseizure and 7 trials retrieved:
01 Effectiveness of sucrose analgesia in reducing pain responses in infants bornto diabetic and non-diabetic mothers: A randomized controlled trialDate assigned: 15 August 2005
02 Levetiracetam (Keppra®) in neonates: safety of intravenous levetiracetam forneonates with seizures Date assigned: 11 April 2007
03 Minimizing needle poke pain in newborn infants with a pain relieving creamand sugar waterDate assigned: 23 August 2007
04 Effect of timing of cord clamping on postnatal packed red blood cells valueand clinical outcome in term newborns: a randomised controlled trialDate assigned: 02 March 2005
05 Efficacy of zinc (given as an adjunct) in the treatment of severe and verysevere pneumonia in hospitalised children 2 to 24 months of age Date assigned: 23 April 2007
30.09.2008 / 10.11.2008
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06 The effect of treatment of neonatal electrographic seizures, detected with thecontinuous cerebral function monitoring, with respect to occurrence of post-neonatal epilepsy and neurodevelopmental outcome.Date assigned: 20 December 2005
07 Whole body hypothermia for the treatment of perinatal asphyxialencephalopathy Date assigned: 21 September 2000
Some of the titles were overlapped during the combined search.
g) Embase (http://www.embase.com/)
h) Ovid MEDLINE database (http://gateway.ovid.com/autologin.html).Studies from 1950 to end of week 3 November 2008Search History saved as “Neonatal seizures 1”
Search History (13 searches) (Click to expand) (Click to close)
Searches Results Search Type Display#1 (neonate and seizures and phenobarbital).mp. 24 Advanced Display
[mp=title, original title, abstract, name ofsubstance word, subject heading word]
#2 limit 1 to (abstracts and english language 22 Advanced Displayand humans)
#3 (neonate and seizures and phenytoin).mp. 15 Advanced Display[mp=title, original title, abstract, name ofsubstance word, subject heading word]
#4 (neonate and seizures and lidocaine).mp. 4 Advanced Display[mp=title, original title, abstract, name ofsubstance word, subject heading word]
#5 (neonate and seizures and diazepam).mp. 6 Advanced Display[mp=title, original title, abstract, name ofsubstance word, subject heading word]
#6 (newborn and phenobarbital and 257 Advanced Displayanticonvulsants).mp. [mp=title, original title,abstract, name of substance word, subject heading word]
#7 limit 6 to (abstracts and english language 160 Advanced Displayand humans)
#8 (newborn and phenytoin and anticonvulsants). 252 Advanced Displaymp. [mp=title, original title, abstract, name ofsubstance word, subject heading word]
#9 limit 8 to (abstracts and english language 146 Advanced Displayand humans)
#10 (newborn and midazolam and anticonvulsants). 26 Advanced Displaymp. [mp=title, original title, abstract, name ofsubstance word, subject heading word]
#11 (newborn and diazepam and anticonvulsants). 80 Advanced Displaymp. [mp=title, original title, abstract, name ofsubstance word, subject heading word]
#12 limit 11 to (abstracts and english language 41 Advanced Displayand humans)
#13 (newborn and lidocaine and anticonvulsants). 22 Advanced Displaymp. [mp=title, original title, abstract, name ofsubstance word, subject heading word]
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Ovid EEGDatabase: Ovid MEDLINE(R) 1950 to Present with Daily Update
Search Strategy:1 seizures/ or seizures, febrile/ (35556)2 seizure$1.ti,ab. (61915)3 1 or 2 (77985)4 exp Infant, Newborn/ (429018)5 3 and 4 (5098)6 (newborn or neonat$2).ti,ab. (207340)7 3 and 6 (3452)8 7 or 5 (6211)9 exp Electroencephalography/ (108506)10 (Electroencephalogra$3 or eeg$1).ti,ab. (53047)11 10 or 9 (117394)12 8 and 11 (1604)13 limit 12 to yr=”1980 - 2008” (1376)14 from 13 keep 2 (1)15 seizures/di or seizures, febrile/di (3153)16 2 and di.fs. (14424)17 16 or 15 (15441)18 13 and 17 (733)19 13 not 18 (643)20 (outcome$1 or utility or value).ti,ab. (937651)21 19 and 20 (157)22 21 or 18 (890)23 from 22 keep 1-500 (500)24 from 22 keep 501-890 (390)
OVID ultrasoundDatabase: Ovid MEDLINE(R) 1950 to Present with Daily Update
Search Strategy: 1 seizures/ or seizures, febrile/ (35556)2 seizure$1.ti,ab. (61915)3 1 or 2 (77985)4 exp Infant, Newborn/ (429018)5 3 and 4 (5098)6 (newborn or neonat$2).ti,ab. (207340)7 3 and 6 (3452)8 7 or 5 (6211)9 exp Electroencephalography/ (108506)10 (Electroencephalogra$3 or eeg$1).ti,ab. (53047)11 10 or 9 (117394)12 8 and 11 (1604)13 limit 12 to yr=”1980 - 2008” (1376)14 from 13 keep 2 (1)15 seizures/di or seizures, febrile/di (3153)16 2 and di.fs. (14424)17 16 or 15 (15441)18 13 and 17 (733)19 13 not 18 (643)20 (outcome$1 or utility or value).ti,ab. (937651)21 19 and 20 (157)22 21 or 18 (890)23 from 22 keep 1-500 (500)
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24 from 22 keep 501-890 (390)25 Magnetic Resonance Imaging/ (190329)26 25 or mri.ti,ab. (210510)27 26 and 17 (3891)28 limit 27 to yr=”1980 - 2008” (3891)29 8 and 17 (1816)30 26 and 29 (353)31 from 30 keep 1-353 (353)32 Tomography, X-Ray Computed/ (210791)33 32 or ct.ti,ab. (267531)34 33 and 29 (249)35 from 34 keep 1-249 (249)36 Ultrasonography/ or Ultrasonography, Doppler, Transcranial/ (63182)37 ultrasound.ti,ab. (98222)38 36 or 37 (140891)39 38 and 29 (64)40 limit 39 to yr=”1980 - 2008” (64)41 from 40 keep 1-64 (64)
OVID CTOvid Technologies, Inc. Email Service
Search for: 33 and 29Results: 1-249Database: Ovid MEDLINE(R) 1950 to Present with Daily Update
Search Strategy:1 seizures/ or seizures, febrile/ (35556)2 seizure$1.ti,ab. (61915)3 1 or 2 (77985)4 exp Infant, Newborn/ (429018)5 3 and 4 (5098)6 (newborn or neonat$2).ti,ab. (207340)7 3 and 6 (3452)8 7 or 5 (6211)9 exp Electroencephalography/ (108506)10 (Electroencephalogra$3 or eeg$1).ti,ab. (53047)11 10 or 9 (117394)12 8 and 11 (1604)13 limit 12 to yr=”1980 - 2008” (1376)14 from 13 keep 2 (1)15 seizures/di or seizures, febrile/di (3153)16 2 and di.fs. (14424)17 16 or 15 (15441)18 13 and 17 (733)19 13 not 18 (643)20 (outcome$1 or utility or value).ti,ab. (937651)21 19 and 20 (157)22 21 or 18 (890)23 from 22 keep 1-500 (500)24 from 22 keep 501-890 (390)25 Magnetic Resonance Imaging/ (190329)26 25 or mri.ti,ab. (210510)27 26 and 17 (3891)28 limit 27 to yr=”1980 - 2008” (3891)29 8 and 17 (1816) 93
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30 26 and 29 (353)31 from 30 keep 1-353 (353)32 Tomography, X-Ray Computed/ (210791)33 32 or ct.ti,ab. (267531)34 33 and 29 (249)35 from 34 keep 1-249 (249)
OVID MRIDatabase: Ovid MEDLINE(R) 1950 to Present with Daily Update
Search strategy:1 seizures/ or seizures, febrile/ (35556)2 seizure$1.ti,ab. (61915)3 1 or 2 (77985)4 exp Infant, Newborn/ (429018)5 3 and 4 (5098)6 (newborn or neonat$2).ti,ab. (207340)7 3 and 6 (3452)8 7 or 5 (6211)9 exp Electroencephalography/ (108506)10 (Electroencephalogra$3 or eeg$1).ti,ab. (53047)11 10 or 9 (117394)12 8 and 11 (1604)13 limit 12 to yr=”1980 - 2008” (1376)14 from 13 keep 2 (1)15 seizures/di or seizures, febrile/di (3153)16 2 and di.fs. (14424)17 16 or 15 (15441)18 13 and 17 (733)19 13 not 18 (643)20 (outcome$1 or utility or value).ti,ab. (937651)21 19 and 20 (157)22 21 or 18 (890)23 from 22 keep 1-500 (500)24 from 22 keep 501-890 (390)25 Magnetic Resonance Imaging/ (190329)26 25 or mri.ti,ab. (210510)27 26 and 17 (3891)28 limit 27 to yr=”1980 - 2008” (3891)29 8 and 17 (1816)30 26 and 29 (353)31 from 30 keep 1-353 (353)
i) Abstracts of Annual meetings of Society of Pediatric Academic Societies2000-2008 (http://www.abstracts2view.com/pasall)
j) A Bibliographic database of Indian biomedical journals (http://indmed.nic.in/)
k) Manual search of abstracts of annual meetings of National Neonatology Forumof India.
l) Wiley Inter Science database was searched.There were 37 results for: “Prognosis of neonatal seizures in AllFields, in all subjects, in product type Journals”
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m) National Guideline Clearinghouse was search using wordassociations: “neonatal seizure treatment”; “neonate seizure treatment”; “newbornseizure treatment”; “neonatal seizure drug”; “neonate seizure drug”; “newborn seizuredrug”; “neonatal convulsions treatment”; “neonate convulsions treatment”; “newbornconvulsions treatment”; “neonatal convulsions drug”; “neonate convulsions drug”;“newborn convulsions drug”.
n) Additional manual search was also done with standard Internet browser crossing.
The words: neonatal, seizures, treatment and guidelines to eventually identify otherssites of interest.
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