Guidelines on Neonatal Seizures - WHO

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

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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

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_ _

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

_ _

Summary of questions

and recommendations

_ _

_ _

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

_ _


• 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


• 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


• 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

_ _


• 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

_ _


• 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

_ _


• 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


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

_ _


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

_ _

Annexes

_ _

_ _

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%


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%


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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_ _

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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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Appendix:

Search strategy of the literature

_ _

_ _

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

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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




#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



#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

_ _

#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

_ _

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]


#8 (newborn and phenytoin and anticonvulsants). 252 Advanced Displaymp. [mp=title, original title, abstract, name ofsubstance word, subject heading word]


#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]


#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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Date post:	03-Oct-2021
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Guidelines on Neonatal Seizures - WHO

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