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Clin Perinatol. 2014 March ; 41(1): 177–190. doi:10.1016/j.clp.2013.10.004.

Neonatal Seizures: Advances in Mechanisms and Management

Hannah C. Glass, MDCM, MAS
Departments of Neurology and Pediatrics University of California, San Francisco, United States of
America

Synopsis
Seizures occur in approximately 1–5 per 1,000 live births, and are among the most common
neurologic conditions managed by a neonatal neurocritical care service. There are several, age-
specific factors that are particular to the developing brain, which influence excitability and seizure
generation, response to medications, and impact of seizures on brain structure and function.
Neonatal seizures are often associated with serious underlying brain injury such as hypoxia-
ischemia, stroke or hemorrhage. Conventional, prolonged, continuous video-electroencephalogram
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(cEEG) is the gold standard for detecting seizures, whereas amplitude-integrated EEG (aEEG) is a
convenient and useful bedside tool. Evaluation of neonatal seizures involves a thorough search for
the etiology of the seizures, and includes detailed clinical history, routine chemistries,
neuroimaging (and preferably magnetic resonance imaging, MRI), and specialized testing such as
screening for inborn errors of metabolism if no structural cause is identified and seizures persist
after correction of transient metabolic deficits. Expert opinion supports rapid medical treatment to
abolish electrographic seizures, however the relative risk versus benefit for aggressive medical
treatment of neonatal seizures is not known. While there is increasing evidence to support a
harmful effect of seizures on the developing brain, there is also evidence that commonly used
medications are potentially neurotoxic in animal models. Newer agents appear less harmful, but
data are lacking regarding optimal dosing and efficacy.

Keywords
Brain Injury; Developmental disability; Infant; newborn; Electroencephalography; Epilepsy;
Magnetic Resonance Imaging; Neurocritical Care; Seizures
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Introduction
Neonates are at especially high risk for seizures as compared to other age groups [1]. The
high risk for seizures - and especially acute symptomatic seizures - is likely multifactorial,
and due to both the relative excitability of the developing neonatal brain, as well as the high

© 2013 Elsevier Inc. All rights reserved.

Address correspondence to: Hannah C. Glass, MDCM, MAS, Associate Professor Neurology & Pediatrics, Co-Director Neuro-
Intensive Care Nursery, Neonatal Neurology Training Program Director, 505 Parnassus Avenue, M793, Box 0114, San Francisco, CA
94143-0114, [email protected].
Financial Disclosure:
Nothing to disclose
Disclosures
None
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 Glass Page 2

risk for brain injury due to global hypoxia-ischemia, stroke and intracranial hemorrhage [2].
The estimated rate of seizures in term newborns is said to be approximately 1–5 per 1,000
live births [3–5]. However, population-based studies do not take into account the low
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diagnostic accuracy of diagnosis by clinical observation alone [6, 7], and gold standard
continuous, prolonged video-electroencephalogram (cEEG) monitoring is not widely
available enough to make population-based predictions, therefore the true incidence remains
unknown.

The differential diagnosis for neonatal seizures is broad, and includes both structural-
metabolic, and genetic causes (Box 1). Seizures that arise from an acute symptomatic cause
such as hypoxic-ischemic encephalopathy, transient metabolic disturbance, infection, stroke,
or intracranial hemorrhage, are much more common than neonatal onset epilepsies, which
may be due to malformation, prior injury or genetic causes. Rare conditions such as inborn
errors of metabolism, vitamin-responsive epilepsies and neonatal epilepsy syndromes must
be considered in the setting of refractory seizures [8, 9].

Box 1
Etiology of neonatal seizures

Differential Diagnosis of Acute Symptomatic Seizures

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Global hypoxia-ischemia (hypoxic-ischemic encephalopathy, HIE)

Focal hypoxia-ischemia
Arterial stroke
Venous stroke
Intracranial hemorrhage
Intraventricular
Parenchymal
Subarachnoid
Subdural
Transient metabolic deficit
Hypoglycemia
Hypocalcemia and hypomagnesemia
Hyponatremia
Acute infection
Differential Diagnosis of Neonatal Onset Epilepsy
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Brain malformation
Intrauterine injury or congenital infection
Inborn error of metabolism and vitamin-responsive epilepsies
Neonatal Onset Epilepsy Syndromes
Benign familial neonatal seizures (eg., KCNQ2, KCNQ3)
Neonatal epileptic encephalopathies
Early myoclonic epilepsy
Early infantile epileptic encephalopathy (Ohtahara syndrome)

Neonatal seizures carry a high risk for early death. Among survivors, motor and cognitive
disabilities, as well as epilepsy are common [10]. The outcome depends largely on the
underlying disease process and severity of underlying brain injury. The impact of the
seizures themselves is not known, though studies in animal models suggest that seizures can

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alter brain development, leading to deficits in learning, memory and behavior (reviewed in
[11]).
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Pathophysiology
There are several, age-specific factors that are particular to the neonatal brain that lead to
enhanced excitability and seizure generation, poor response to conventional medications,
and adverse impact on brain development (see [12] for an excellent review).

Enhanced excitability of the neonatal brain

There are numerous mechanisms that render the immature brain hyperexcitable as compared
to the adult brain [12, 13]. First, the neonatal period is a time of physiologic, use-dependent
synaptogenesis, and both synapse and dendritic spine density are at their peak [14, 15].
Second, glutamatergic neurons - the primary excitatory mechanism of both the developing
and adult brain - are over-abundant, and their receptors are configured with subunits that
allow relative hyper-excitability [16, 17]. Third, gamma-amino-butyric acid (GABA) – the
primary inhibitory mechanism of the adult brain – can exert a paradoxical excitatory action
in the developing brain due to the preponderance of the NKCC1, and delayed expression of
the KCC2 chloride co-transporters, which leads to a high intracellular chloride
concentration, and depolarization in response to GABAergic agents [18–20].
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Anticonvulsants and the developing brain

Immature development of the excitatory and inhibitory neurotransmitter systems leads to a
lack of good targets for conventional anti-seizure medications, which makes neonatal
seizures particularly difficult to treat. The immature brain may be resistant to medications
that act as GABA agonists, not only as a result of the paradoxical chloride gradient as
discussed above, but also due to overall lower receptor expression, and an immature subunit
composition that is less sensitive to benzodiazepines than the adult brain [12, 13].

Seizures and early brain development

While early work with animal models demonstrated that the developing brain is more
resistant than the adult brain to seizure induced necrosis, more recent work has shown that
early life seizures can affect the developing brain nonetheless by altering neuronal circuitry,
which can result in impaired learning and memory, and enhanced susceptibility to epilepsy
later in life (reviewed in [11]). Animal models of early life seizures display developmental
alterations that can include reduced density of dendritic spines in hippocampal pyramidal
neurons, decreased neurogenesis, delayed neuronal loss, and changes in hippocampal
plasticity such as decreased capacity for long-term potentiation, reduced susceptibility to
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kindling and enhanced paired-pulse inhibition [21–24]. Human studies in children with
hypoxic-ischemic injury show an independent association between seizures and impaired
brain metabolism, as well as poor long-term neurodevelopmental outcome [25, 26].

Management Goals
The overall management goal for neonatal seizures is to quickly and accurately identify, and
abolish electrographic seizures, while determining the most likely underlying etiology.
Neonatal seizures are often the first sign of neurologic dysfunction, and are frequently an
indication of serious underlying brain injury [27, 28]. Therefore, a suspicion of seizures in a
newborn should be treated as a neurological emergency, and prompt rapid and thorough
evaluation to identify the cause, as well as emergent medical management to abolish
seizures while preventing secondary injury by maintaining physiologic temperature, glucose,
oxygenation, ventilation, and blood pressure.

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Seizure Detection and Monitoring

Common methods for identifying neonatal seizures are outlined in Table 1. Clinical
evaluation of seizures is approximately 50% accurate for events detected at the bedside.
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Furthermore, clinical detection requires constant observation by the bedside staff, and even
so will fail to detect seizures with no or very subtle clinical correlate (for example eye
deviation or subtle clonic movements that are covered by the infant’s blanket). Subclinical
seizures account for the majority of all seizures in neonates, especially in the setting of
severe brain injury, and in children who have received seizure medications [7, 29–31].

Recent guidelines from the American Clinical Neurophysiology Society set the standard for
neurophysiology monitoring in neonates [32]. Continuous video-electroencephalograpy
(cEEG), with electrodes placed according to the international 10–20 system, modified for
neonates, is the gold standard for monitoring [33–35]. Barriers to implementing this
technology include the need for specialized training for the application and interpretation of
the recording, as well as variable access to equipment, and high cost. Once initiated, cEEG
should be maintained until electrographic seizures have resolved for at least 24 hours, or 3–4
clinical events have been captured and determined not to be seizures [32].

Amplitude-integrated electroencephalography (aEEG, a simplified bedside neurophysiology

tool that can be applied and interpreted by neonatologists, nurses, or other Intensive Care
Nursery bedside staff) is used to supplement or even replace cEEG in a growing number of
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centers. Since aEEG uses a limited number of channels to record EEG signal that is heavily
processed (filtered, rectified, and displayed on a semi-logarithmic amplitude and time-
compressed scale), there are several limitations to this technology that must be taken into
account when it is used for management of neonatal seizures (Table 1). Machines that allow
for concurrent monitoring and display of aEEG (at the bedside) and cEEG (in the
neurophysiology lab or remotely) using the same hardware have been suggested as a way to
optimize use of both technologies, such that the both the bedside team and neurologist can
be readily involved in the rapid, real-time management of electrographic seizures (Figure 1)
[36].

Automated seizure detection - with an alarm to alert the bedside practitioner in the case of
suspected seizures - is an attractive option that may offer the most practical solution for
wide-scale implementation of seizure detection and management. However, there have been
several challenges that limit the development of automated detection algorithms, including:
highly variable nature of neonatal seizure patterns, high frequency of potential artifacts in
the intensive care nursery, and uncertainty regarding the gold standard against which
algorithms are tested given the limited information regarding inter-rater reliability among
human expert readers (reviewed in [42]). Newer algorithms that use machine learning, as
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well as temporal and spatial weighting hold promise [43–46].

Diagnostic Evaluation
Initial evaluation of a neonate with suspected seizures should also focus on rapid
identification of the etiology. Emergent evaluation of serum glucose and risk factors for
infection is an important first step, since hypoglycemia and bacterial meningitis can lead to
permanent injury if left untreated [8]. Additional bedside evaluations must include
measurement and treatment of electrolyte disturbance. Comprehensive history and physical
examination are important tools to assess for risk factors and signs of both common and rare
causes of neonatal seizures. Further evaluation, including genetic testing, serum amino
acids, ammonia, lactate, and very long chain fatty acids, urine organic acids and sulfites, and
cerebrospinal fluid studies for glucose, glycine, lactate and neurotransmitters, as well as
additional testing for inborn errors of metabolism may be warranted on a case-by-case basis,

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especially in the setting of medically refractory seizures of unknown etiology, or a burst-

suppression pattern on EEG in a neonate without brain injury.
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Detailed neuroimaging using magnetic resonance (MR) is essential to identify underlying

injury or developmental abnormalities, and to help clinicians and the family to better
understand the prognosis [47]. Cranial ultrasound, which is readily available at the bedside
in most units, is important for rapid initial assessment of a sick neonate to identify large
space occupying lesions, such as hemorrhage, arteriovenous malformations or
hydrocephalus, but is insensitive for global and focal hypoxic-ischemic injury, especially in
the days after the ictus. Computed tomography (CT) exposes the infant to ionizing radiation
and provides inferior resolution to MRI in most settings, and so should be avoided.

Pharmacologic Strategies
There are no evidence-based guidelines for the pharmacological management of neonatal
seizures [48, 49]. Expert opinion supports use of pharmacological treatments with a goal of
abolishing electrographic seizures, even those without clinical correlate [42]. However,
evidence is lacking regarding the relative benefit versus potential harm of anticonvulsants
used to treat seizures in neonates, many of which can lead to neuronal apoptosis in animal
models [50].

Since seizures are refractory to initial doses of medication in approximately 50% of cases
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[51], frequent re-evaluation of cEEG and bedside monitoring is essential to accurately

identify and treat ongoing seizures in real time. Though data are lacking regarding optimal
treatment paradigms for neonatal seizures, experts advocate rapid administration of an
adequate loading dose of medication since acute symptomatic seizure burden is highest at
the onset [52], and patients with fewer seizures are easier to treat [51]. Similarly, experts
advocate treatment of both clinical and subclinical seizures given similar pathophysiology,
and that the only difference between the two may be slight anatomical differences in their
cortical distribution [42]. Use of algorithms or guidelines to direct the treatment of neonatal
seizures has gained favor given evidence that treatment guidelines can improve outcomes in
other settings [53]. As discussed below, the optimal medication for seizure therapy in
neonates is not known, and so guidelines should focus on an institution-specific, consensus-
based protocol with input and acceptance by both neonatology and neurology services to
help prevent unnecessary delays in treatment that may result from discussions over
medication choice in the setting of an actively seizing neonate.

The optimal duration of pharmacologic therapy for acute symptomatic seizures is not
known. Treatment practices are variable in spite of good evidence that there is no harmful
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effect of early discontinuation of seizure therapy, and no difference in seizure recurrence

risk among neonates who are maintained on therapy versus those whose medication is
maintained until several months of age [54–56] (Box 2).

Box 2
Principles for acute symptomatic neonatal seizure management
Rapid and accurate electrographic seizure identification
Rapid titration of medication(s) to abolish electrographic seizures
Early discontinuation of medication once seizures have resolved

International survey data support the use of phenobarbital as the first-line medication based
on expert consensus [57–59] (Table 2). A single randomized, controlled trial found that

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phenobarbital and phenytoin were equally efficacious as first-line agents for seizure
cessation among term infants with seizures [51]. However, seizure control (defined by the
study parameters as an 80% reduction in the severity of seizures), was achieved in fewer
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than half of the infants [51]. This result is supported by newer studies, which demonstrate
that up to 50% of neonatal seizures are refractory to first line medications, and an additional
30% fail second line therapy [60].

Levetiracetam is gaining increasing support, in spite of limited efficacy data [61, 62]. This is
likely due to the ready availability of an intravenous formulation in the United States, as
well as a favorable safety and tolerability profile among children and adults [63]. In contrast
to older agents such as phenobarbital and phenytoin, levetiracetam does not appear to
enhance neuronal apoptosis in animal models [64, 65], and may in fact have neuroprotective
and antiepileptogenic effects [66, 67]. The optimal neonatal dosage of levetiracetam is not
yet known: reported doses range from 5 to 60mg/kg day (reviewed in [68]). However, the
high volume of distribution and rapid clearance in neonates may necessitate a higher loading
dose and more frequent dosing to maintain serum concentrations in the range used for adults
and children [69, 70]. Published studies of the clinical efficacy of levetiracetam that report
seizure reduction or resolution in 35–80% are limited by lack of standardized dosing, limited
EEG monitoring, no placebo comparison, and/or variable timing and definition for
determining the outcome [71–73].
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Common agents for refractory seizures include midazolam infusion, which may be effective
for neonatal status epilepticus, and lidocaine, which is widely used for refractory neonatal
seizures in Europe [74–81]. Topiramate is an antiseizure medication that has multiple
mechanisms of anticonvulsant action, and is an interesting option for acute symptomatic
neonatal seizures because it appears to have neuroprotective effects in animal models of
seizures and brain injury [82, 83]. A recently developed intravenous preparation of
topiramate that is well tolerated in adult volunteers and has equivalent bioavailability to the
oral formulation holds promise for use in neonates [84, 85].

Bumetanide is a loop diuretic that has been proposed as an adjunct to GABA-ergic drugs
like phenobarbital to help overcome the depolarizing action of immature neurons to GABA
agonists. The mechanism of action is presumed to be through reduction in intracellular
chloride concentrations, thus rendering the normally excitatory response of immature cells
with high NKCC1 expression to an inhibitory response [86]. Preclinical studies demonstrate
mixed effects, with reduction in seizure frequency and duration, as well as enhanced
neuroprotective efficacy when combined with phenobarbital [87–89]. A single clinical study
showed reduction in seizure frequency and duration following bumetanide treatment [90].
Though promising as an add-on agent for neonatal seizures, the potential for adverse effects
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such as ototoxicity, and partial central nervous system bioavailability may ultimately limit
the utility of bumetanide [91].

Information about agents other than phenobarbital and phenytoin is largely derived from
case series rather than randomized, blinded, clinical trials, and so the true efficacy of these
medications is not known. Seizures due to acute symptomatic causes such as hypoxic-
ischemic brain injury and stroke rarely persist beyond a few days of life, making any add-on
agent appear more effective than the initial therapy [52]. Furthermore, older studies do not
include prolonged, video-EEG monitoring, and so non-convulsive seizures, which are very
common following administration of phenobarbital, may go undetected.

If the underlying etiology of medically refractory seizures is unknown after initial screening
laboratory and imaging studies, a trial of pyridoxine, pyridoxal 5′-phosphate and folinic acid
should be considered, and a screening metabolic evaluation should be performed [9].

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Summary/Discussion
Neonatal seizures are common and frequently reflect serious underlying brain injury.
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Prolonged cEEG is the gold standard for seizure monitoring, however availability remains
limited at many centers. Phenobarbital, the preferred first choice medication internationally,
is effective in only 50% of cases and may be harmful, especially when used in high doses or
for prolonged periods. However, there is abundant evidence from animal models to show
that seizures themselves disrupt the developing brain, and so there is urgent need for
research to develop safe, accurate and widely available methods for identifying and treating
electrographic seizures.

Acknowledgments
Project Support

HCG is supported by the NINDS K23NS066137, the Pediatric Epilepsy Research Foundation, and the Neonatal
Brain Research Institute.

Dr. Glass is supported by the NINDS K23NS066137, the Pediatric Epilepsy Research Foundation, and the Neonatal
Brain Research Institute. Dr. Glass thanks Jessica Kan for assistance with research and Dr. Dawn Gano for careful
review of the manuscript.

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Key Points
1. Seizures occur in 1–5 per 1000 live births, and are among the most common
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neurologic conditions managed by a neonatal neurocritical care service.

2. The high rate of seizures in the neonatal period reflects age-specific
developmental mechanisms that lead to relative excitability.
3. Neonatal seizures are often caused by serious underlying brain injury such as
hypoxia-ischemia, stroke or hemorrhage.
4. Clinical detection is unreliable; continuous, video-electroencephalogram is the
gold standard in monitoring for presence and burden of neonatal seizures.
5. Seizures are refractory to first line medications in ~50%; expert opinion
supports rapid treatment to abolish acute symptomatic seizures, and early
discontinuation of medication(s).
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Figure 1.
Amplitude-integrated EEG (left) and EEG (right) from a term male with multiple
intracranial hemorrhages and seizures that were refractory to phenobarbital 40mg/kg and
fosphenytoin 30mg/kg, and abated after 60mg/kg levetiracetam. aEEG and EEG are
recorded from a single machine at the bedside. Data are displayed differently for different
users: the bedside team sees the aEEG display at left, which shows long term trends and
allows a quick review of suspicious segments of EEG. The neurophysiologist can confirm
the seizures through the review of conventional, neonatal montage EEG.
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Table 1
Diagnosis of neonatal seizures.
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Conventional video-EEG (cEEG) • Gold standard for seizure detection

• Recommended by the American Clinical Neurophysiology Society for monitoring neonates
with paroxysmal events and/or at high risk for seizures [32]

Amplitude-integrated EEG (aEEG) • Lower sensitivity and specificity than cEEG (reviewed in [36])
• 100% sensitivity for status epilepticus [37]
• Lowest sensitivity for seizures that are brief, focal, distal from recording electrodes [38, 39]
• Raw EEG tracing helps to distinguish artifact from seizure [40]
• Experienced readers perform better than non- experts [41]

Clinical evaluation • Accuracy ~50% [6]

• Will not identify the majority of seizures (i.e., subclinical or non-convulsive seizures) [7, 29–
31]
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Table 2
Pharmacologic treatment for acute symptomatic neonatal seizures
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Medication Dosage Side Effects Notes

Levetiracetam Optimal dosing not known Mild sedation/ Limited information regarding
Loading dose: 40–60 mg/kg intravenously Daily drowsiness, and dosing and side effects for
dosing: 30 mg/kg/day (target levels not known) irritability neonatal population.
[92]
Lidocaine Loading dose: 2 mg/kg over a period of 10 min, Arrhythmia Should only be given in the
followed by a continuous infusion of 6 mg/kg intensive care setting with
per hour during the first 12 h; 4 mg/kg per hour continuous cardiac monitoring. In
for the next 12 h, and 2 mg/kg per hour for the case of cardiac arrhythmia, the
last 12 h* infusion should be discontinued
immediately. Lidocaine should
not be given to patients with a
congenital heart disease, or to
neonates who have been treated
with pro-arrhythmic drugs like
phenytoin.
Lorazepam 0.05–0.1 mg/kg intravenously Respiratory May cause myoclonus in very-
depression, depressed low-birth-weight infants.
level of
consciousness, and
hypotension.
Midazolam Loading dose: 0.2 mg/kg intravenously, followed Respiratory
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by continuous infusion (1 mcg/kg/minute) depression, depressed

increasing by 0.5–1 mcg/kg/minute every 2 level of
minutes to 2–5 mcg/kg/minute consciousness, and
hypotension.
Phenobarbital Loading dose: 20 mg/kg intravenously, repeated Respiratory Prolonged half-life in first week
once as needed Daily dosing: 5 mg/kg/day depression, depressed of life (43–217 hours) limits need
(target level 40–60 mcg/mL) level of for weaning phenobarbital in the
consciousness, case of short-term therapy.
hypotension, and
hypotonia.
Idiosyncratic skin
rash, hepatotoxicity,
and blood dyscrasia
Phenytoin and fosphenytoin Loading dose: 20 mg/kg intravenously Daily Infusion site reaction Fosphenytoin has fewer
dosing: 5 mg/kg/day (target level 10–20 mcg/ and arrhythmia with cardiovascular, central nervous
mL) intravenous system, and local cutaneous side
phenytoin. effects than phenytoin. Significant
Idiosyncratic skin variability and changes in
rash, hepatotoxicity, pharmacokinetics over the first
and blood dyscrasia weeks of life may lead to
inconsistent drug levels.

*
NB Lower doses recommended for neonates undergoing therapeutic hypothermia [79].
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