Pediatr Drugs (2013) 15:9–18
DOI 10.1007/s40272-012-0005-1
THERAPY IN PRACTICE
Clinical Management of Seizures in Newborns
Diagnosis and Treatment
Linda G. M. van Rooij • Marcel P. H. van den Broek •
Carin M. A. Rademaker • Linda S. de Vries
Published online: 19 January 2013
Ó Springer International Publishing Switzerland 2013
Abstract Neonatal seizures can be classified as tonic,
clonic, myoclonic, and subtle. A clinical diagnosis is not
easy as seizures are usually subtle in neonates. In the
majority of newborn infants seizures are subclinical. On the
other hand, not all abnormal movements identified by cli-
nicians as clinical seizures are accompanied by electroen-
cephalographic seizure discharges in the EEG. Precise
incidence is difficult to delineate and depends on study
population and criteria used for diagnosis of seizures.
Controversy exists as to whether neonatal seizures them-
selves cause damage to the developing brain, or if the
damage is primarily due to the underlying cause of the
seizures. As a result of this controversy there is ongoing
discussion whether all seizures (both clinical and subclin-
ical) should be treated. In addition, when (sub)clinical
seizures are treated, there is no consensus about the most
appropriate treatment for neonatal seizures and how to
assess the efficacy of treatment.
Current therapeutic options to treat neonatal seizures
(i.e. primarily first-generation antiepileptic drugs [AEDs])
are relatively ineffective. In practice, phenobarbital still
remains the drug of first choice for EEG confirmed or
suspected seizures. Benzodiazepines are also used in
(phenobarbital) refractory cases. Several (small) studies
indicate that lidocaine is an effective drug for refractory
L. G. M. van Rooij (&)  L. S. de Vries
Department of Neonatology, KE 04.123.1, Wilhelmina
Children’s Hospital, University Medical Centre Utrecht,
PO Box 85090, 3508 AB Utrecht, The Netherlands
e-mail: l.g.m.vanrooij@umcutrecht.nl
M. P. H. van den Broek  C. M. A. Rademaker
Department of Clinical Pharmacy, Wilhelmina Children’s
Hospital, University Medical Centre Utrecht, Utrecht,
The Netherlands
seizures as second- or third-line treatment. Although data
are scarce, some AEDs with a wide acceptance in adult and
pediatric neurology practice are being used to treat neo-
natal seizures (i.e. second-generation AEDs). These drugs
are chemically different from all first-generation AEDs and
they have an effect on other pathways so they provide new
pharmacological targets for controlling seizures in new-
borns. Levetiracetam, topiramate, felbamate, bumetanide,
lamotrigine and vigabatrin are examples of these second-
generation AEDs.
There is an urgent need for prospective, randomized,
controlled trials to assess the efficacy and safety of these
second-generation AEDs in neonates.
The aim of this review is to provide an overview of the
current knowledge of diagnosis, the effect on brain injury,
and the treatment of neonatal seizures.
1 Introduction
Seizures occur more often during the neonatal period than
at any other time of life [1]. The most common etiology of
neonatal seizures is hypoxic-ischemic encephalopathy
(HIE) due to perinatal asphyxia. In the population-based
study by Ronen et al., 42 % of neonatal seizures were seen
following HIE [2]. Other important causes include intra-
cranial hemorrhage and stroke, infections of the central
nervous system, congenital malformations, inborn errors of
metabolism, transient metabolic disturbances, maternal
drug abuse or rare neonatal epilepsy syndromes (benign
familial neonatal-infantile seizures or fifth-day seizures) [1,
2]. When seizures persist in spite of administration of
different antiepileptic drugs (AEDs) one should always
consider pyridoxine-dependent epilepsy or pyridoxine
phosphate oxidase deficiency as possible causes, and a
10
therapeutic trial with oral pyridoxal 50 -phosphate in addi-
tion to pyridoxine needs to be undertaken [3, 4].
Precise incidence is difficult to delineate and depends on
the study population and criteria used for diagnosis of
seizures. In studies from the US, an incidence of 0.15–3.5
per 1000 live births has been reported [2, 5, 6]. Clinical
recognition of seizures in newborns is not always
straightforward because of a highly variable clinical
expression [1]. Since the use of prolonged (video-) EEG
registration it is known that a substantial part of electro-
graphic neonatal seizure patterns are not accompanied by
clinical signs, especially following treatment with AEDs
[7–10].
Controversy exists as to whether neonatal seizures
themselves cause damage to the developing brain, or if the
damage is primarily due to the underlying cause of the
seizures.
As a result of this controversy there is ongoing discus-
sion whether all seizures (both clinical and subclinical)
should be treated. When (sub)clinical seizures are treated,
there is no consensus about the most appropriate treatment
for neonatal seizures and how to assess the efficacy of
treatment.
In this review, an overview is given of the current
knowledge of the diagnosis, the effect on brain injury, and
the treatment of neonatal seizures with the most frequently
used AEDs (phenobarbital, midazolam, lorazepam, clona-
zepam, phenytoin, and lidocaine) in clinical practice, and
some relatively new upcoming AEDs (levetiracetam,
topiramate, felbamate, bumetanide, lamotrigine, and viga-
batrin) [11–13].
2 Diagnosis
Neonatal seizures can be classified as tonic, clonic, myo-
clonic, and subtle [14]. A clinical diagnosis is not easy as
seizures tend to be subtle in neonates, including blinking,
eye deviation, chewing, or apnea. In some cases clinical
recognition is not even possible; for example, when the
infant is given drugs for muscle paralysis while being
ventilated [1]. On the other hand, not all abnormal move-
ments identified by clinicians as clinical seizures are
accompanied by electroencephalographic seizure dis-
charges in the EEG. These movements have been described
by Mizrahi and Kellaway as ‘motor automatisms’ of
uncertain origin [9]. They may reflect ‘brainstem release
phenomena’ or may be seizure discharges in deep cerebral
structures, which are not transmitted to surface EEG
electrodes because of the immature synaptogenesis and
cortical projections [9, 15]. In view of this clinical com-
plexity it is argued that the diagnosis of neonatal seizures
should not be based on clinical observation alone. On the
L. G. M. van Rooij et al.
other hand, Mizrahi and Kellaway described in their study,
over 20 years ago, that around two-thirds of clinical seizure
events were not accompanied by seizure patterns in the
EEG [9]. Other studies confirmed this poor correlation
between the clinical and electrographic manifestations of
neonatal seizures. Another problem that is common in the
newborn with neonatal seizure is ‘electroclinical dissocia-
tion’ or ‘uncoupling’, which means that clinical seizures
decrease or disappear while electroencephalographic sei-
zure patterns continue or even increase [7, 8, 10, 16]. Only
the EEG can confirm the epileptic nature of neurologically
suspected movements and is considered essential for the
evaluation and confirmation of neonatal seizures. It is
known that electrographic neonatal seizure patterns are
strikingly different from seizure patterns in older infants
and adults. Typically, they start focally and evolve in
amplitude, duration, and waveform morphology. The focal
onset of neonatal seizures is regardless of whether the brain
injury is diffuse or more localized. They commonly extend
from their place of origin, recruiting nearby areas and even
remote locations of the contralateral hemisphere [17–19].
Patrizi et al. reported that in full-term infants focal onset of
seizures is more common and that in preterm infants sei-
zures start with a more regional onset [21]. They also
showed that there is no clear relationship between etiology
and location of onset or morphology of the discharges [21].
A recent study by Shellhaas and Clancy reported that 78 %
of individual seizures appear in the C3–C4 channel [22].
Nowadays, the most commonly used diagnostic criteria for
electrographic seizure patterns in the neonatal EEG are ‘‘a
sudden, repetitive, evolving and stereotyped ictal pattern
with a clear beginning, middle and ending and a minimum
duration of 5–10 seconds’’. However, shorter durations of
only a few seconds of epileptiform patterns have also been
described to be associated with an adverse outcome [23–
27]. In a recent study, Murray et al. found that with detailed
review of continuous video-EEG monitoring, only 34 % of
electrographic seizures had evident clinical signs [28].
They also reported that only 27 % of the seizures which
had clinical features were recognized by medical and
nursing staff and that there was an overdiagnosis of clinical
seizures of 73 %. Thus, the requisite to diagnose and
evaluate treatment of neonatal seizures will be a continuous
video-EEG registration. Prolonged video-EEG recordings
are available, but this is not applicable in the clinical set-
ting in most hospitals and, therefore, at present are mainly
used for research applications. Prolonged video-EEG reg-
istration requires regular attendance of technicians and a
trained clinical neurophysiologist for correct interpretation
of the neonatal EEG. Hence there is a need for alternative
methods of continuous brain monitoring for daily care in
the neonatal intensive care units (NICUs). With the use of
amplitude integrated EEG (aEEG), a simplified and
Clinical Management of Seizures in Newborns
practical tool was introduced in many NICUs. The aEEG
method was first applied in the original Cerebral Function
Monitor, developed by Maynard et al. [29]. The aEEG
records a single-channel EEG from two parietal electrodes
(corresponding to P3–P4 according to the international
10–20 system for electrode placement). The EEG signal is
filtered (suppresses activity below 2 Hz and above 15 Hz),
rectified, smoothed, and time-compressed. The signal is
displayed on a semi-logarithmic scale at slow speed (6 cm/h)
at the cot side [30, 31]. Published papers on aEEG in neo-
nates include both clinical and experimental studies [32]. A
recent meta-analysis reported that aEEG is suitable for very
early prediction of outcome after perinatal asphyxia [33].
The presence of seizures and the effect of treatment in infants
at risk can also be monitored by aEEG [34–37]. As a result of
the widespread use of this method, new digital aEEG
equipment has been developed, which allows us to study
more channels with simultaneous display of the original
EEG signal. Several automatic seizure detection algorithms
have also been developed to improve seizure detection using
aEEG [37–39].
However, there is concern about the accuracy of aEEG
in seizure detection. A study by Rennie et al. reported poor
sensitivity and specificity for diagnosis of seizures with
aEEG [40]. They used inexperienced observers and the
aEEG traces were recorded at different speeds and there
was no access to the raw EEG. Others focused on patient
identification, rather than individual seizure pattern rec-
ognition, and showed that about 80 % of patients with
seizures were correctly detected with aEEG [35, 41]. As a
result of the technique used in aEEG, it is clear that focal,
brief, or low amplitude seizures are difficult to detect [22,
35, 41]. Shellhaas et al. recently reported that aEEG alone
has significant limitations in the detection and quantifica-
tion of neonatal seizures [42]. They found a mean seizure
detection rate of 40.3 % among 125 recordings with sei-
zures. A limitation of their study was the very short dura-
tion of the aEEG recording, and the observers once again
had no access to the raw EEG, which is nowadays obsolete
and not realistic as everybody does have access to digital
equipment. In a recent study, Shah et al. showed that the
2-channel aEEG in combination with the raw EEG signal
detected 78 % of electrical seizure patterns [37]. Therefore,
users of aEEG must be aware that not all seizures will be
detected, but aEEG is a sensitive method to identify an
important proportion of neonatal electrographic seizure
patterns. Further development of seizure detection algo-
rithms is likely to contribute to increased accuracy of sei-
zure detection [38]. This accuracy of seizure detection is of
great importance as more evidence has become available
from animal studies that seizures may impair brain devel-
opment and lead to long-term deficits in learning, memory,
and behavior [43]. Although data in humans are scarce,
11
recent studies suggest an adverse effect of both clinical and
subclinical neonatal seizures on neurodevelopmental out-
come. Neonatal seizures have been reported to predispose
to later problems with regard to cognition, behavior and
development of postneonatal epilepsy [44, 45]. In a first,
multicenter, randomized, controlled trial, full-term infants
with moderate to severe HIE and subclinical seizures were
assigned randomly to either treating clinical seizures and
subclinical seizure patterns (group A) or to blinding the
aEEG registration and only treat clinical seizures (group
B). Although the groups were small there was a trend for a
shorter median duration of seizure patterns in group A
compared with group B. Another important observation in
this study was that a significant correlation was found
between the duration of seizure patterns and the severity of
brain injury in the blinded group, as well as in the whole
group [46].
In recent years, hypothermia has become a standard
treatment for term infants with moderate to severe HIE, to
improve outcome. However, there are limited data
regarding seizure occurrence during therapeutic hypother-
mia. Wusthoff et al. reported an incidence of 65 %, in
which 46 % of the infants had subclinical seizures [47].
They also found that the range of time to seizure onset was
wide. A recent study by Glass et al. reported an incidence
of 30 %, and several AEDs were required to control the
seizures [48].
3 Treatment
As a consequence of the growing body of evidence that
neonatal seizures per se contribute to adverse neurodevel-
opmental outcome, clinicians are more focused on treat-
ment of neonatal seizures. The question, however, still
remains how aggressively neonatal seizures should be
treated. Unfortunately, data from randomized controlled
trials to support the choice of anticonvulsants are limited,
and no definite recommendations based on available data
can be made [12]. However, European NICUs have a
similar therapeutic approach for the first-, second- and
third-line anticonvulsants [13]. First-generation, older
AEDs are still the drugs of first (and second/third) choice
because of extensive clinical experience, despite their
limited clinical effectiveness.
3.1 First-Generation Antiepileptic Drugs (AEDs)
Traditional mechanisms of AEDs comprise an inhibitory
effect on the glutamatergic pathway, enhanced c-amino-
butyric acid (GABA) inhibition, or an influence on neu-
ronal ion homeostasis. However, in the developing brain,
neuronal apoptosis can be triggered by blockade of
12
N-methyl-D-aspartate (NMDA) receptors or (excessive)
activation of GABAA-receptors. First-generation AEDs,
such as phenobarbital and benzodiazepines, exert their
effect by stimulation of GABA. Bittigau et al. showed that
these AEDs may cause apoptotic neurodegeneration in the
developing rat brain at plasma concentrations relevant for
seizure control in humans [49–51].
3.1.1 Phenobarbital
In practice, phenobarbital still remains the drug of first
choice for confirmed or suspected seizures [52–54]. The
choice for phenobarbital can be explained by its good
safety profile, although there is evidence that phenobarbital
itself may impair neurodevelopmental outcome and
increase neuronal apoptosis. Glier and colleagues observed
that neuronal apoptosis increased with phenobarbital doses
of 40 mg/kg and more in rats [55]. Nevertheless, there are
limited studies that demonstrate good efficacy of pheno-
barbital. Seizure response rates after loading doses of
15–20 mg/kg are reported to range from 33 to 40 %. With
rapid sequential loading doses, up to a total dose of 40 mg/
kg, the responsiveness could be improved to 77 % [56–58].
Responsiveness under hypothermia might even be higher
than under normothermia [115].
It has been suggested that early posthypoxia-ischemia
administration of phenobarbital may augment the neuro-
protective efficacy of therapeutic hypothermia in newborns
as well as in a neonatal rodent model [59, 115].
Painter et al. reported the effect of phenobarbital com-
pared with phenytoin. In 43 % of the phenobarbital-treated
group, seizures were controlled compared with 45 % in the
phenytoin-treated group. Addition of the other drug, when
seizures were not controlled with the first drug, did not
significantly improve seizure control [16].
Although phenytoin (or its less alkaline prodrug fos-
phenytoin) is not inferior to phenobarbital, it has some
clinically relevant disadvantages such as a dose-dependent
rate of elimination, which makes dose adjustment com-
plicated (i.e. non-linear pharmacokinetics), risk of
increased central nervous system toxicity (due to increased
free drug fraction) in case of renal impairment and hypo-
albuminemia, risk of hypotension and cardiac arrhythmias
if administered too fast, and risk of adverse local reactions
at the injection site of the high alkalinity of the parenteral
formulation. Moreover, fosphenytoin is not available in
some countries in Southern Europe [13].
Phenobarbital can be administered as an intravenous
loading dose of 20 mg/kg, followed by a 10–20 mg/kg if
required. The loading dose can be divided in two equal
dosages when the neonate is not ventilated, but this will
postpone the time window until a therapeutic concentration
will be reached. Since phenobarbital has a long half-life in
L. G. M. van Rooij et al.
neonates (e.g. 140 hours in asphyxiated neonates) [60],
rapid maintenance doses (2.5–5 mg/kg/day) are not needed
in these patients after administration of a sufficient loading
dose. Dosing under neonatal hypothermia does not require
dose adjustment for phenobarbital [115].
Therapeutic drug monitoring (TDM; therapeutic win-
dow 20–40 mg/L) is recommended in case of seizures and
to prevent drug accumulation or ineffectiveness during
maintenance dosages since the half-life has wide ranges in
newborns. The effectiveness was found to plateau at a
serum concentration of 40 mg/L and a further increase
to [50 mg/L induced sedation and compromised neuro-
logic assessment [56].
3.1.2 Benzodiazepines
Benzodiazepines (particularly midazolam, clonazepam,
and lorazepam [11, 13]) are also used in (phenobarbital)
refractory cases, with an efficacy reported from 0 to 100 %
[61, 62], with two studies reporting responses of 67 % and
80 %, respectively [63, 64]. Midazolam, one of the most
lipophilic benzodiazepines, readily crosses the blood-brain
barrier and has a very rapid onset of action. Less lipophilic
benzodiazepines, such as lorazepam, have a less rapid
onset but do have a favourable less-rapid redistribution
from the central nervous system that reduces the risk of
symptoms of withdrawal after dose cessation.
Midazolam is short-acting and has a more rapid onset of
action. A disadvantage can be its metabolic pathway because
pharmacologically active (glucuronidated) metabolites are
formed. Drug-drug interactions or renal impairment could
cause undesired accumulation of these metabolites. In con-
trast, the metabolites of clonazepam and lorazepam are
pharmacologically inactive. Benzodiazepine dosing regi-
mens are displayed in Table 1.
Although no therapeutic window has been established
for seizure control or adverse effects, TDM can be applied
in clinical practice to monitor undesired drug accumulation
during continuous infusion.
Table 1 Benzodiazepine dosing regimens
Benzodiazepine Loading dose Maintenance dose
Midazolam (IV) [65] 0.05 mg/kg in 0.15–0.5 mg/kg/ha
10 min
Lorazepam (IV) [11] 0.05–0.1 mg/kg None, loading dose may be
in 5 min repeated if necessary
Clonazepam (IV) [66] 0.1 mg/kg 0.01 mg/kg, 3–5 dosages
bolus
IV intravenous
a
Increase dosing with steps of 0.05 mg/kg/h until a dosage of 0.3 mg/kg/
h, with a maximum of 0.5 mg/kg/h
Clinical Management of Seizures in Newborns
3.1.3 Lidocaine
Although not widely used, several (small) studies indicate
that lidocaine is an effective drug for refractory seizures as
second- or third-line treatment. The response rate varies
from 70 to 92 % during normothermia and hypothermia
[62–64, 67–70, 116]. The physicochemical properties of
lidocaine enable passage of the blood-brain barrier, and in
the central nervous system it acts as a depressant. Adverse
cardiac effects, such as ventricular tachycardia or fibrilla-
tion, should be closely monitored but are not frequently
observed [70–72]. A renewed bodyweight-based dosing
regimen allows lower cumulative dosages which will fur-
ther reduce the risk of the occurrence of adverse cardiac
effects
During therapeutic hypothermia, lidocaine dosing
should be reduced. Lowered body temperature may alter
pharmacokinetic and pharmacodynamic profiles with, in
case of lidocaine, increased risk of (cardiac) toxicity due to
decreased lidocaine clearance [73]. To account for
deceased clearance under hypothermia, a dosing regimen
has been developed based on population pharmacokinetics;
an initial bolus loading dose of 2 mg/kg is given followed
by consecutive continuous infusions of 6 mg/kg/h (for 3.5
hour), 3 mg/kg/h (for 12 hours), 1.5 mg/kg/h (for 12 hours)
for patients with bodyweight 2.0–2.5 kg, or for patients
with bodyweights 2.5–4.5 kg an initial bolus loading dose
of 2 mg/kg is given followed by consecutive continuous
infusions of 7 mg/kg/h (for 3.5 hours), 3.5 mg/kg/h (for
12 hours), 1.75 mg/kg/h (for 12 hours), before stopping
[116]. With this regimen, no cardiac arrhythmias have been
observed in the hypothermic infants.
TDM is advised in case of (suspected) cardiac toxicity
or persisting seizures. Based on observations and extensive
clinical expertise, the suspected threshold for cardio- and
neurotoxic adverse effects in neonates is [9 mg/L.
Lidocaine should not be given to patients with con-
genital heart disease or to patients who have already
received phenytoin.
3.2 Second-Generation AEDs
Unfortunately, (a combination of) first-generation AEDs
are not always effective enough for seizure control in
certain neonates. Second-generation AEDs, such as lev-
etiracetam, topiramate, felbamate, bumetanide, and lamo-
trigine are chemically different from all first-generation
AEDs and have an effect on other pathways. These drugs
provide promising new pharmacological targets for con-
trolling seizures in newborns. Although data are scarce,
these drugs, with a wide acceptance in adult and pediatric
neurology practice, are already being used to treat neonatal
13
seizures [74]. Efficacy and safety of these second-genera-
tion drugs should be established in the neonatal population.
Second-generation AEDs are assumed to have no or less
pro-apoptotic properties at therapeutic doses. For leveti-
racetam and topiramate, this was observed in an in vivo rat
model [55, 75].
3.2.1 Levetiracetam
Despite limited experience and data on its safety and effi-
cacy in newborns, levetiracetam seems to be an effective
and well-tolerated adjunctive antiepileptic agent for seizure
control in neonates and infants [20, 76]. Levetiracetam
binds to the vesicular protein synaptic vesicle protein 2A
(SV2A) via vesicular entry in neurons, and reduces pre-
synaptic neurotransmitter release [77].
Controversy exists as to whether levetiracetam exerts its
effect via (indirect) modulation of GABAAergic or via a
non-GABAergic pathway [78, 79]. Potentiation of the
effect of the benzodiazepine diazepam has been observed
by Mazarati and colleagues [80].
In older children and adults it has shown to exert broad-
spectrum action since various seizure types have shown a
response [76]. The rapid onset of action, presence of an
intravenous formulation and good tolerability of a possible
loading dose do make levetiracetam a suitable therapeutic
option for treatment of status epilepticus. Since it is elim-
inated by the kidneys, dosages should be reduced in case of
impaired renal function. There are no known clinically
relevant drug-drug interactions with levetiracetam.
Khan et al. observed that 86 % of neonates treated with
levetiracetam intravenously for seizures with different
types and aetiologies had complete seizure cessation at 1
hour [20]. In this study, 20 out of 22 neonates (91 %)
received a 50 mg/kg loading dose. The other two received
a dose of 10 and 20 mg/kg, respectively. Overall, 86 % of
all patients received levetiracetam because of seizures that
were refractory to one or more first-generation AEDs
(phenobarbital, fosphenytoin, lorazepam, and midazolam).
Although one patient exhibited increased irritability, no
immediate adverse effects were evident during or after
infusions [20].
As well as in clinical observations, (neuronal) safety
also has been confirmed in an in vivo animal model. In P8
rats, doses of up to 100 mg/kg of levetiracetam were found
not to be more neurotoxic (in terms of inducing neuronal
apoptosis) than their controls, as observed by Manthey et al
[75]. Levetiracetam can be dosed intravenously as a load-
ing dose (20–50 mg/kg) followed by an initial maintenance
dose of 5 mg/kg, which may be increased if required. With
a median half-life of about 9 hours in term neonates, a
twice-daily dosing schedule seems to be advisable [81].
14
TDM could become a future option. In adults, a thera-
peutic range of 5–25 mg/L (or even up to 46 mg/L) is used,
although there is some evidence that the clinical effect may
not be related to the concentration in plasma. TDM could
be advised in case of ineffectiveness, impaired renal
function or (suspected) toxicity.
3.2.2 Topiramate
Topiramate is a second-generation AED that enhances
GABA activity, inhibits kainate-mediated conductance at
glutamate receptors, and modifies Na?- and Ca2?-depen-
dent action potentials [82]. It appears to be an AED with
neuroprotective properties in animal models, and was
found to improve cognitive function [83, 84].
In a small, retrospective, cohort study in neonates,
administration of topiramate resulted in ‘apparent reduc-
tion or no further seizures’ in four out of six neonates with
seizures refractory to phenobarbital despite plasma con-
centrations of 34–42 mg/L. However, a randomized, con-
trolled trial suggested oral topiramate (in doses up to
25 mg/kg/day) may not be effective as add-on AED for
infants between 1 month and 2 years of age [85, 86].
In a questionnaire, adverse effects were recognized
more frequently in topiramate-treated infants than in lev-
etiracetam-treated neonates. The main reported adverse
effects included metabolic acidosis and irritability or
feeding problems [74].
Currently, there is limited data about dosing and efficacy
of topiramate in neonates. There is some published expe-
rience with topiramate dosing during therapeutic hypo-
thermia [87, 88]. Because topiramate dosages for neonatal
seizures are not yet established, TDM-guided dosing is
recommended. A therapeutic range for the antiepileptic
effect of topiramate, established in adults, is 5–20 mg/L
[89]. A disadvantage of topiramate is that a parenteral
formulation is not yet available since the onset of effect
depends on the speed of oral drug absorption.
3.2.3 Felbamate
Felbamate, which is chemically unrelated to topiramate,
inhibits the NMDA receptor and potentiates GABAergic
action by interacting with the strychnine insensitive glycine
recognition site of the NMDA receptor [90]. In an in vivo
animal model of incomplete cerebral ischemia and hypoxia
in 7-day-old rat pups, felbamate showed a neuroprotective
effect [91].
Since felbamate is only available as oral preparations,
rapid absorption and distribution is required in order to
obtain a fast and adequate drug level in the brain. Laroia
et al. concluded that due to slow absorption, oral felbamate
is unsuitable to reach adequate neuroprotective levels in a
L. G. M. van Rooij et al.
timely fashion in infants with HIE [92]. A limitation of this
finding is that it is based on a study with only four indi-
viduals. In addition, in animal models no linear relationship
between oral drug dosages and drug peak concentrations
have been observed, which may be due to incomplete
absorption of the drug at the relatively high dosages [93,
94]. This disproportional absorption phenomenon has not
been described in humans.
Potential dose-independent fatal adverse effects (aplas-
tic anemia and acute liver failure) can be caused by fel-
bamate and limit its use. These risks for toxicity should be
evaluated before starting treatment [95]. Moreover, ade-
quate dosages for neonatal seizure control have not been
published.
Peak blood levels of 70–120 mg/L are associated with
neuroprotection against selective hypoxic-ischemic neuro-
nal necrosis. Based on the relative lack of clinical experi-
ence with felbamate and on possible disproportional
absorption, felbamate administration to neonates should be
avoided or at least restricted. If felbamate is administered,
TDM-guided dosing is recommended. In addition, blood
chemistry should be closely monitored.
3.2.4 Bumetanide
In cases of persistent refractory seizures, the loop-
diuretic bumetanide may occasionally be used in clinical
practice in the near future. It inhibits the Na(?)-K(?)-
2Cl(-) co-transporters NKCC1 and KCC2 but has a
500-fold greater affinity for NKCC1 than for KCC2 [96].
It is registered as a diuretic because of its inhibition of
NKCC1 in the thick ascending loop of Henle in neph-
rons, but in neonatal rat pups this inhibition of NKCC1
in cortical neurons resulted in a depression of epilepti-
form activity. The drug seems to pass the blood-brain
barrier and the antiepileptic effect was observed in
dosages that have been tested in human neonates for
diuresis studies [97–99]. Bumetanide dosages for neo-
natal seizure control are currently under investigation in
a prospective multicentre study.
NKCC1 inhibition causes an elevation of intracellular
chloride. The effectiveness of NKCC1 inhibition is sup-
ported by the hypothesis that GABA is an excitatory neu-
rotransmitter in immature cortical neurons [98, 99]. In
mature neurons of adults, KCC2 is more expressed than
NKCC1, but in immature neurons of neonates NKCC1 is
more expressed than KCC2. Therefore, in immature neo-
natal neurons the baseline intracellular chloride concen-
tration is higher than in mature adult neurons. Activation of
GABA in immature neurons results in a chloride efflux
causing synaptic excitation [100].
The strength of GABAergic neurotransmission depends
on the intraneuronal chloride concentration. NKCC1 is
Clinical Management of Seizures in Newborns
responsible for a chloride (Cl-) flux into the cell (influx),
and KCC2 is responsible for a flux out of the cell (efflux).
High intracellular chloride concentrations result in mem-
brane hyperpolarization, and low intracellular chloride
concentrations result in membrane depolarization, which
causes excitation [98, 100].
Hypothetically, low intracellular chloride concentra-
tions in immature neurons can be the cause of their
relatively low effectiveness in neonatal convulsions since
barbiturates and benzodiazepines activate GABAergic
neurotransmission, [98]. Bumetanide has been found to
augment phenobarbital effectiveness (seizure frequency
and duration decreased) in hippocampal rat slices [101].
3.2.5 Lamotrigine
Lamotrigine is an AED that acts at voltage-dependent
sodium channels, stabilizing the neuronal membrane and
inhibiting the release of glutamate and aspartate [102].
Lamotrigine is only available as an oral preparation.
In children, lamotrigine has been demonstrated to be
effective as adjunctive therapy for the generalized seizures
associated with Lennox-Gastaut syndrome, adjunctive
therapy of partial seizures, and monotherapy of absence
seizures [103]. Evidence of clinical application of lamo-
trigine in neonates and its efficacy in these patients is very
limited. In one published case report, the introduction of
lamotrigine (4.4 mg/kg as a single daily dose) as add-on
therapy was followed by rapid and sustained control of
seizures in a neonate [104].
Lamotrigine is well tolerated in children. Results from
placebo-controlled, add-on trials showed that 85 % of
lamotrigine recipients experienced an adverse event com-
pared with 83 % of placebo recipients. Skin rash associated
with hospitalization and the discontinuation of the study
drug was reported more frequently by lamotrigine recipi-
ents than by placebo recipients, and more frequently by
children than by adults. The incidence of rash may be
reduced with proper initial dosing and dose escalation
[105].
Although clear relationships between lamotrigine
plasma concentration and pharmacologic response have not
been demonstrated, TDM-guided dosing would be recom-
mendable because of the limited experience in neonates.
For (adult) patients with refractory seizures, Morris and
colleagues advise a therapeutic window of 3–14 mg/L
[106].
Due to necessary dose escalation steps, lamotrigine is
not indicated for the rapid treatment of neonatal seizures.
Based on the relative lack of clinical experience, lamotri-
gine administration to neonates should be avoided or at
least restricted. If lamotrigine is administered, TDM-gui-
ded dosing is recommended.
15
3.2.6 Vigabatrin
Vigabatrin is a selective enzyme-activated irreversible
inhibitor of GABA transaminase [107]. It is given as a
racemic mixture, of which only the S(?) isomer has
pharmacological activity [108]. Vigabatrin is only avail-
able as an oral preparation. It is indicated in infants
(1 month to 2 years) as monotherapy for infantile spasms.
In the literature, vigabatrin has been shown to be effective
in resistant neonatal seizures in two patients [109].
In contrast to the other mentioned AEDs, vigabatrin is
predominantly eliminated by the kidneys in its unaltered
form. In patients with renal impairment the dose should be
decreased. No direct relationship between plasma concen-
tration and effect have been established for vigabatrin,
implying that dose adjustments should be based more on
clinical response than on plasma drug concentration [110].
However, TDM-guided dosing can be recommended in
patients with renal impairment.
Peripheral vision loss is an adverse effect that has been
reported as altered visual acuity, color discrimination, or
contrast sensitivity [111]. In a large, multinational analysis,
the prevalence of vigabatrin-induced vision loss was
approximately 15 % in children [112]. A study performed by
Jammoul et al. indicates that vigabatrin generates a taurine
deficiency responsible for its retinal phototoxicity [111].
Other adverse effects recorded in children (drowsiness,
constipation, fatigue and apathy) are generally transient,
being observed during the dose-modification phase and
disappearing either spontaneously or on reduction of the
vigabatrin dose [113].
To assess this risk of vision loss, the European Medi-
cines Agency has recommended visual field testing at
baseline and at 6 months. However, in neonates visual field
testing is not possible; visual field testing in infants is
possible from 3 months of age [114]. Based on the lack of
evidence and the risk of vision loss, which cannot be tested
in neonates, vigabatrin should not be used as an option to
treat neonatal convulsions.
4 Conclusion
Neonatal seizures are a common problem in the neonatal
period. Although progress has been made in the diagnosis
and treatment of neonatal seizures, there are still questions
that remain unanswered. Antiepileptic drugs that are cur-
rently used to treat neonatal seizures are relatively inef-
fective, but the effectiveness appears to improve under
hypothermia therapy. Although data are scarce, some
AEDs with a wide acceptance in adult and pediatric neu-
rology practice are being used to treat neonatal seizures.
There is an urgent need for prospective, randomized,
16
controlled trials to determine the efficacy and safety of
these second-generation AEDs in neonates.
Acknowledgements Linda van Rooij and Marcel van den Broek
contributed equally to this article. No sources of funding were used to
assist in the preparation of this review. The authors have no conflicts
of interest that are directly relevant to the content of this review.
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