SUPPLEMENT ARTICLE

Summary Proceedings From the Neurology Group on

Neonatal Seizures
Robert R. Clancy, MD

Division of Neurology, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

The author has indicated he has no financial relationships relevant to this article to disclose.

ABSTRACT
One of the highest risk periods for seizures during the human life span is the first
month of life. Most neonatal seizures are triggered by acute illness such as
www.pediatrics.org/cgi/doi/10.1542/
hypoxic-ischemic encephalopathy, stroke, or infection; rarely are they triggered by peds.2005-0620D
epilepsy per se. Seizures are the most common and important sign of acute doi:10.1542/peds.2005-0620D
neonatal encephalopathy, are a major risk for death or subsequent neurologic
The views presented in this article do not
disability, and by themselves may contribute to an adverse neurodevelopmental necessarily reflect those of the Food and
outcome. Customary clinical practice includes visual monitoring of high-risk ne- Drug Administration (FDA). This article
reflects discussions of designing clinical
onates for seizures, performance of a routine electroencephalogram (EEG) for trials in newborns and should not be
suspicious clinical seizure activity, and empirical treatment with phenobarbital. construed as an agreement or guidance
from the FDA. Drug development and
Presently, however, there are no data that have unequivocally demonstrated the clinical-trial design must be discussed with
efficacy of barbiturates in the treatment of neonatal seizures. The neurology group the relevant review division within the
recognizes an important need for randomized, placebo-controlled, ethically ac- FDA.

ceptable trials of phenobarbital efficacy and safety in the treatment of neonatal Key Words
EEG, seizures, congenital heart disease,
seizures. After exploring 3 possible frameworks for clinical trials of phenobarbital neonatal seizures, phenobarbital
in the treatment of neonatal seizures, the neurology group ultimately focused on Abbreviations
a multicenter, placebo-controlled, electroencephalographer-blinded study of phe- HIE— hypoxic-ischemic encephalopathy
EEG— electroencephalogram
nobarbital versus placebo in a homogeneous group of newborns who are at high ENS— electroencephalographically
risk of developing early subclinical electroencephalographically detected neonatal detected neonatal seizure
seizures. Continuous video-EEG monitoring would establish the presence and ECMO— extracorporeal membrane
oxygenation
number of seizures. Criteria for escape from the study to treatment are clearly
Accepted for publication Oct 17, 2005
defined. The proposed study could provide the first concrete evidence of treatment Address correspondence to Robert R. Clancy,
efficacy because (1) it examines a homogeneous patient population, (2) the MD, Division of Neurology, University of
Pennsylvania School of Medicine, Children’s
recognition and quantification of seizures rests solely on the gold standard of Hospital of Philadelphia, 324 S 34th St,
seizure detection (EEG), and (3) the dosing of phenobarbital is matched specifi- Philadelphia, PA 19104. E-mail: clancy@email.
chop.edu
cally to the phenobarbital-binding characteristics of the individual treated. This
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
study would affirm or refute the common practice of phenobarbital as the first-line Online, 1098-4275); published in the public
treatment of neonatal seizures. domain by the American Academy of
Pediatrics

PEDIATRICS Volume 117, Number 3, March 2006 S23

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T HE NEUROLOGY GROUP began its task by considering
the areas of neonatal neurology that might be ap-
propriate for consideration of large-scale, formal, ran-
domized, controlled treatment trials. There are several
important scenarios in neonatal neurology in which
physicians must choose to offer or withhold treatment
on the basis of scant or uncontrolled data. Topics con-
sidered included the efficacy and safety of anticoagula-
tion for sinovenous thromboses or arterial ischemic
strokes,1 activated tissue plasminogen for embolic
strokes, and serial lumbar punctures or acetazolamide
for posthemorrhagic hydrocephalus. However, none of
these important topics seemed ready for large-scale clin-
ical trials. As a consequence, the neurology group chose
2 conditions deemed sufficiently common, potent, and
with adequate existing scientific bases to begin formal
clinical studies: neonatal seizures and hypoxic-ischemic
encephalopathy (HIE).
NEONATAL-SEIZURES TREATMENT TRIAL
Background
Seizures occur in 1% to 5% of infants during the first
month of life (the neonatal period), which is one of the
highest-risk periods for seizures during the human life
span.2–5 Most neonatal seizures are triggered by an acute
illness such as HIE, stroke, or infection; rarely are they
triggered by epilepsy per se. Seizures are the most com-
mon and important sign of acute neonatal encephalop-
athy6 and are well recognized as a major risk factor for
death or subsequent neurologic disability.7–11 Growing
evidence from research in newborn animal models sup-
ports the view that neonatal seizures by themselves con-
tribute to an adverse neurodevelopmental outcome.12,13
However, evidence in human newborns is scant,14 and
designing clinical studies to demonstrate injury from
neonatal seizures is difficult, because they are con-
founded by the magnitude of the inciting insult.
Customary clinical practice includes visual monitor-
ing of high-risk neonates for seizures, performance of a
routine electroencephalogram (EEG) for suspicious clin-
ical seizure activity, and empirical treatment with phe-
nobarbital. There presently are no data that have dem-
onstrated unequivocally the efficacy of barbiturates in
the treatment of neonatal seizures. Goldberg et al15 re-
ported a randomized, controlled study of thiopental ad-
ministered soon after perinatal asphyxia. Seizures were
diagnosed on clinical grounds and occurred in 76% of
the treated infants and 73% of the placebo-treated con-
trols. Hall et al16 reported the results of a neuroprotection
trial that administered high-dose phenobarbital after
perinatal asphyxia. The group that received phenobar-
bital had a lower recurrence of seizures than did the
placebo group, but the difference was not statistically
significant. Connell et al17 reported the response to an-
tiepileptic drugs of electrographically detected neonatal
S24 CLANCY
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seizures that were discovered during continuous EEG
monitoring in 31 acutely ill neonates. Only 2 infants
showed a complete cessation of both clinical and EEG-
detected seizures, and 6 infants had an equivocal elec-
troclinical response. Clinical cessation of seizures oc-
curred in 13 infants, although their electrographically
detected neonatal seizures persisted. The remaining 10
infants had the persistence of both clinical and EEG-
detected seizures. Bye and Flanagan18 and Boylan et al19
also reported a mixed response of electroclinical seizures
to phenobarbital treatment. Painter et al20 compared
the relative response of electrographically detected neo-
natal seizures to either phenobarbital or phenytoin,
which were administered in a randomized fashion. Ces-
sation of electrographically detected neonatal seizures
occurred in 43% of the phenobarbital-treated group and
in 45% of the phenytoin-treated group. However, be-
cause there was not a placebo control arm of the study,
absolute efficacy could not be determined. The most
recent study of the treatment of neonatal seizures in-
cluded a standard administration of phenobarbital at a
dose of 40 mg/kg and video-EEG monitoring, but there
was no control group. Of 22 infants, 11 (50%) had a
cessation of seizures, and the choice of a second-line
drug in the nonresponders was randomized to ligno-
caine or benzodiazepines.19 Finally, Evans and Levene21
state in their Cochrane review of the treatment of neo-
natal seizures that “at the present time, anticonvulsant
therapy administered in the immediate period following
perinatal asphyxia cannot be recommended for routine
clinical practice, other than in the treatment of pro-
longed or frequent clinical seizures.” In summary, there
is a pressing need for randomized, placebo-controlled,
ethically acceptable trials of phenobarbital efficacy and
safety in the treatment of neonatal seizures.
Potential Clinical-Trial Frameworks
Before the Newborn Drug Development Initiative Work-
shop I, the neurology group explored 3 possible frame-
works for clinical trials of phenobarbital in the treatment
of neonatal seizures. The neurology group ultimately
focused on an electroencephalographer-blinded study
of phenobarbital versus placebo in a homogeneous
group of newborns who are at high risk to develop early
subclinical electroencephalographically detected neona-
tal seizures (ENSs). Anticipatory video-EEG monitoring
or early phenobarbital treatment is not customary clin-
ical care. Potential patient populations included those
who had experienced HIE, extracorporeal membrane
oxygenation (ECMO),22 or newborn heart surgery for
serious congenital heart defects.23 This last group was
selected to develop a working protocol because contem-
porary data were available in the congenital heart de-
fects population in which ⬃11% develop postoperative
ENSs that usually are subclinical.24 Because subclinical
ENSs would not be diagnosed and treated if infants were
not participating in the study, they could be studied
ethically, at least for a few hours, by using either phe-
nobarbital or placebo to assess seizure reduction. The
occurrence of clinical seizures or electrographically de-
tected status epilepticus would constitute escape criteria.
The neurology group initially proposed to use a com-
monly used definition of efficacy for seizure-reducing
drugs (ie, a 50% reduction of seizures in at least half of
the treated patients, adjusted for the controls). Sample-
size estimates varied on the basis of the threshold values
chosen for study entry, determined by preliminary da-
ta.24 For example, if at least 10 ENSs in a 3-hour pre-
treatment baseline were required to enter the phenobar-
bital treatment study, it was estimated that 46 patients
(23 treated with phenobarbital and 23 treated with pla-
cebo) would be needed for enrollment. After additional
discussion, however, the neurology group decided that
in this specific clinical context, the definition of efficacy
should be a total cessation of seizures, not merely a 50%
reduction. This alteration reduces the number of subjects
required for enrollment.
Clinical-Trial–Design Issues
The neurology group reported the following conclusions
about the study-design issues.
Clinical End Points
Clinical end points for treatment of ENSs are notoriously
elusive but are still important to clinicians.25 The custom-
ary clinical practice is to visually monitor high-risk ne-
onates for the emergence of clinical seizures, perform
routine EEG examinations when suspicious clinical ac-
tivity appears, and empirically treat with phenobarbital.
Video-EEG monitoring allows examination of the tradi-
tional end point of treatment (ie, cessation of clinical
seizures) and ENSs. Although EEG-detected seizure end
points are believed to be more objective,26 there are no
data that demonstrate interobserver agreement; how-
ever, disputes can be adjudicated posthoc. In summary,
the neurology group decided that ENSs should be the
primary efficacy end point rather than clinical seizures.
Selection of the First Drug To Study
The neurology group agreed that phenobarbital should
be the first drug studied on the basis of the following
considerations.
● Phenobarbital is the traditional agent selected to treat
neonatal seizures and is used worldwide.
● The best scientific data that exist in animals are based
on phenobarbital.
● Adequate safety data exist. However, preadministra-
tion testing would need to include an in vitro binding
study to determine the dose.20,27 This study is needed
because the portion of phenobarbital that is unbound,
and thus available to enter the brain and produce the
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desired effects, is highly variable. The neurology group
concluded that the goal of treatment is a free (“un-
bound”) level of ⬃25 mg/L, which has been shown to
be safe in neonates.20 This level corresponds to a load-
ing dose of ⬃35 to 45 mg/kg per dose. The neurology
group hopes that participating clinicians will accept
this dose, which exceeds the often-cited clinical con-
vention of 20 mg/kg loading dose.
● An efficacy trial of phenobarbital would have an im-
mediate impact on understanding the therapeutic
value of phenytoin, because a comparative study
showed that total cessation of seizures is the same
whether an infant is randomly assigned first to phe-
nobarbital or to phenytoin.20
● Evidence is insufficient to recommend the primary
study of benzodiazepines and other putative antiepi-
leptic drugs; these drugs must await secondary confir-
mation in circumstances of primary treatment failure.
Exclusion of Preterm Infants
The underlying causes of seizures in preterm infants are
not as well understood as those for term infants. The
preterm group is etiologically heterogeneous, and no
consensus exists for an epileptic basis of paroxysmal
clinical “seizures” (variable occurrence of electrographi-
cally detected seizures). Theoretically, ␥-aminobutyric
acid (GABAergic) drugs, paradoxically, may depolarize
neurons and lower the seizure threshold in very low
birth weight neonates,28 although this effect is not sup-
ported by typical clinical observations. As a conse-
quence, the neurology group concluded that this inau-
gural phenobarbital study should focus on neonates of
ⱖ37 weeks’ conceptional age.
Generalizability of Phenobarbital-Treatment–Trial Results
The neurology group acknowledged that great care must
be exercised in applying the results of the proposed
study to other neonatal-seizure populations. The neu-
rology group considered the proposed clinical scenario of
the phenobarbital-treatment trial as an example of early
and mild seizures, albeit triggered by an acute stress in
the form of serious congenital heart defects that require
early heart surgery. It is possible that seizures might
respond to phenobarbital differently in other circum-
stances such as for severe HIE, in the premature infant,
or in those infants whose seizures arise from develop-
mental abnormalities such as tuberous sclerosis.
Proposed Clinical-Trial Framework
The neurology group had sought a randomized, con-
trolled trial study design that would be sensitive to and
respectful of customary clinical practices. After examin-
ing 3 different study designs, the neurology group pro-
posed a phenobarbital-efficacy trial for ENSs (see Fig 1)
that would include the elements described in Table 1.
SUPPLEMENT S25
FIGURE 1
Phenobarbital (PB) efficacy trial for ENSs. Rx indicates phenobarbital administration.
Ethical Considerations
Seizures are common in newborn infants who are ex-
posed to serious conditions such as HIE, ECMO, and
TABLE 1 Framework for the Study of Phenobarbital Treatment of
ENSs
Type of study Multicenter, placebo-controlled, electroencephalographer-
blinded study of phenobarbital vs placebo
Study population A homogeneous population of term infants (ⱖ37 wk
conceptional age) at high risk for ENSs (eg, congenital
heart disease surgery, HIE, or ECMO); potential study
populations with conditions other than congenital
heart disease would need extensive preliminary data
and individual study
Enrollment Preoperative enrollment for infants undergoing congenital
heart disease surgery
Monitoring Continuous video-EEG monitoring to establish the
presence and number of seizures
Entry criteria Two or more ENSs in a 3-h pretreatment baseline period
Intervention The study would include the following 2 arms, with
phenobarbital administered and adjusted to achieve
a free-phenobarbital level of ⬃25 mg/L
Phenobarbital (early treatment)
Placebo (and later treatment with phenobarbital)
End point Cessation of EEG-detected seizures, adjusted for the
controls
Escape criteria Criteria for escape from the study to treatment would
include
Presence of clinical seizures (specifically defined as focal
clonic, focal tonic, or sustained eye deviation) verified
by EEG
Electrographically detected status epilepticus that will
need to be defined in the protocol (no formal
definition of electrographic status exists)
Secondary The neurology group needs to determine the secondary
treatment treatment protocol for initial drug failure
protocol
Follow-up Careful neurodevelopmental follow-up to 8 y of age; there
was consensus that it will not be possible to
demonstrate subtle adverse effects of phenobarbital
administration per se on long-term outcomes
S26 CLANCY
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newborn heart surgery, and many are not accompanied
by visible clinical seizure activity.11,29 The opportunity to
detect early subclinical ENSs is only possible in an inves-
tigational environment that includes continuous video-
EEG monitoring on all at-risk subjects. Thus, it is very
likely that those infants who participate in this study will
have their ENSs detected and the initiation of specific
treatment much earlier than those infants who do not
participate in the study. The determination of the free-
phenobarbital– binding capacity improves the accuracy
of phenobarbital dosing, is not a part of routine clinical
care, and improves the likelihood of seizure cessation if
phenobarbital is indeed an efficacious drug. It is likely
that infants in the placebo group, who are given the
appropriate dose of phenobarbital after the first 3 hours,
would still have received treatment for their seizures
earlier than if they had not participated in the study. It is
unlikely that those infants who do not participate in the
study would reach that point of therapy sooner than
those infants who do participate.
The contemporary treatment of neonatal seizures is
hampered by the absence of even a single randomized,
controlled efficacy study of phenobarbital or any other
antiepileptic drug.21 Although it is customary in the care
of newborns with seizures to use phenobarbital or other
traditional antiepileptic drugs, evidence of efficacy has
never been established. The proposed study could pro-
vide the first concrete evidence of treatment efficacy
because (1) it examines a homogeneous patient popula-
tion (those with seizures provoked by acquired central
nervous system stressors such as HIE, ECMO, or new-
born heart surgery), (2) the recognition and quantifica-
tion of seizures rests solely on the gold standard of
seizure detection (the EEG), and (3) the dosing of phe-
nobarbital is specifically matched to the phenobarbital-
binding characteristics of the individual treated. In the
contemporary treatment of neonatal seizures, physicians
around the world most commonly choose phenobarbital
as the first line of treatment. This study would be the first
to affirm or refute this practice.
FUTURE DIRECTIONS
The neurology group agreed that the next steps should
include the following:
● Obtain preliminary data in other groups at high risk
for ENSs (eg, infants in the HIE hypothermia trial and
infants who have undergone ECMO therapy) and de-
scribing the incidence of ENSs and the number of
seizures per hour.
● Explore a range of sample-size estimates based on
different values for specific entry criteria such as the
number of pretreatment seizures that must occur in
the baseline period.
● Consider adding an additional study arm to include a
benzodiazepine drug.
● Consider alternative approaches for premature infants
with ENSs.
ACKNOWLEDGMENTS
I gratefully acknowledge financial and administrative
support from the National Institutes of Health and the
Food and Drug Administration.
My thanks go to Donna Ferriero, MD, for helpful
comments.
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SUPPLEMENT S27
 Summary Proceedings From the Neurology Group on Neonatal Seizures
Robert R. Clancy
Pediatrics 2006;117;S23
DOI: 10.1542/peds.2005-0620D
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2006 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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 Summary Proceedings From the Neurology Group on Neonatal Seizures
Robert R. Clancy
Pediatrics 2006;117;S23
DOI: 10.1542/peds.2005-0620D

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/117/Supplement_1/S23.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2006 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Dalhousie University on June 23, 2015