Seizures in Children
Content
Principles of
management
of
Neonatal Seizures
Moderator : Dr. Dilip Singh
Presented by : Dr. Abdul Quddoos
Neonatal seizures
• Definition : A seizure is defined clinically as a
paroxysmal alteration in neurologic function, i.e.
motor, behavior and/or autonomic function. This
definition includes:
•1. Epileptic seizures: phenomena associated with
corresponding EEG seizure activity e.g. clonic & focal tonic
seizures,
•2. Non-epileptic seizures: clinical seizures without
corresponding EEG correlate e.g. subtle and generalized
tonic seizures
•3. EEG seizures: abnormal EEG activity with no clinical
correlation.
Diagnostic dilemmas:
Clinical Vs EEG criteria
Neonatal seizures are generally brief and subtle
in clinical appearance, unusual behaviors may
be difficult to recognize and classify .
Confirmation of suspicious clinical events as
seizures using coincident EEG recordings is now
strongly recommended.
Using either routine EEG studies (Glauser
and Clancy, 1992) or continuous synchronized
video-EEG-polygraphic recordings (Mizrahi
and Kellaway,1998) , more reliable start and
end points of electrographically confirmed
seizures can be established before
decisions are made regarding treatment
intervention.
Rigorous physiologic monitoring of non–
central nervous system (CNS) measures
also assists in the recognition and
management of seizures.
Clinical Seizure Criteria
Historically subdivided into five categories:
Focal clonic
Multifocal or migratory clonic,
Tonic,
Myoclonic,
Subtle seizures
(Volpe, 2001) .
A more recent classification expands these clinical
subtypes, adopting a strict temporal occurrence of
specific
clinical
events
with
coincident
electrographic seizures, to distinguish neonatal
clinical “nonepileptic” seizures from “epileptic”
seizures.
(Mizrahi and
Kellaway, 1998)
.
Before a seizure evaluation is initiated, the
normal occurrence of alterations in cardiorespiratory regularity, body movements,
and other behaviors during active sleep
(rapid eye movement [REM] sleep), quiet
sleep (non-REM [NREM] sleep), or waking
states should be appreciated.
(Da Silva et al, 1998;
Scher,1996).
Classification and Clinical
Characteristics
of Neonatal Seizures
Subtle seizure activity—now termed motor
automatisms and buccolingual movements
—is the most frequently observed category
of neonatal seizures.
Motor Automatisms : cont.
Clonic Seizures
Tonic Seizures
Electrographic Seizures
Electrographic
seizures are typically defined as
repetitive, rhythmic, stereotypic activity lasting at
least 10 seconds that evolve in amplitude frequency
and morphology (Patrizi et al. 2003,Clancy and Ledigo
1987; Scher et al. 1993b; Bye and Flanagan 1995) .
Both term and preterm infants have the ability to
generate a multitude of ictal events but generally
seizures originate in the central and temporal
regions (Shellhaas et al. 2007; Bourez-Swart et al.
2009) .
Electrographic Seizures : cont.
Electrographic seizures characteristically consist
of monophasic repetitive discharges or spikeand-wave activity (Patrizi et al. 2003) .
The onset, morphology and propagation patterns
of neonatal seizures are richly varied, which do
not always correlate with the underlying
pathology.
An electrographic seizure should have a clear
onset and conclusion, but these can be difficult
to identify.
Electrographic Seizures : cont.
Clancy and Ledigo (1987) found that the mean
duration of electrographic seizures in the
neonate was 2–3 minutes, with 97% of all
seizures lasting 9 minutes or less and only
0.4% lasting 30 minutes or longer .
Neonatal status epilepticus was reported in
one third of full-term infant EEG recordings and
in 20% of the total cohort of preterm and fullterm infant EEG recordings (Scher et al, 1993) .
Electrographic Seizures : cont.
Status epilepticus is defined as continuous
seizure activity for 30 minutes or 50% of
the recording time.
If clinicians relied only on clinical criteria,
status
epilepticus
underdiagnosed.
Without
would
be
EEG
confirmation,
the
underdiagnosis of status epilepticus would
contribute to brain injury.
Electrographic Seizures : cont.
One
study estimated that 25% of neonates
expressed persistent electrographic seizures
despite resolution of their clinical seizure
behaviors after receiving one or more antiepileptic
medications;
this
phenomenon
is
termed
electroclinical uncoupling. (Scher, 1994)
Uncoupling of the clinical and electrographic
expressions
of
neonatal
seizures
after
antiepileptic medication administration also
contributes to the underestimation of the true
seizure duration and frequency of status
epilepticus .
Electroclinical dissociation
There is asynchrony between the clinical and
electrical representation of neonatal seizures:
in only one-third of cases studied with video
surveillance were the clinical and electrical
manifestations simultaneous (Weiner et al.
1991; Mizrahi and Kellaway 1998) .
Subtle stereotyped behaviour may or may
not be associated with characteristic EEG
changes, and continuous electrical monitoring
detects many clinically silent seizures.
A study by Malone et al. (2009) has shown
that there is both over- and underdiagnosis
of neonatal seizures if EEG monitoring is
not used, and we would advocate using
EEG if at all possible to confirm the
presence of true neonatal seizures.
aEEG
is now widely used in NICUs,
especially since the introduction of
therapeutic hypothermia for hypoxic–
ischaemic encephalopathy.
aEEG does have limitations, however,
and short seizures, especially those less
than 1 minute in duration, are missed,
as are low-voltage seizures and seizures
which remain localised (Rennie et al.
2004; Shellhaas and Clancy 2007).
aEEG will usually detect seizures which
are of high amplitude, generalised over a
wide area and which are of long duration.
Etiology of Neonatal Seizures
AGES 1-4 DAYS; cont.
AGES 4-14 DAYS; cont.
Approach to an infant with neonatal
seizures
History
Complete description of seizure
Associated eye movements
Restraint of episode by passive flexion of the
affected limb
Change in color of skin (mottling or
cyanosis).
Autonomic phenomena.
Infant was conscious or sleeping at the
time of seizure should be elicited.
The day of life on which the seizures
occurred.
Antenatal history
Intrauterine infection
Maternal diabetes
Narcotic addiction
A history of sudden increase in fetal
movements may be suggestive of
intrauterine convulsions.
Perinatal history
• Perinatal asphyxia is the commonest cause
•
•
•
•
•
•
•
of neonatal seizures
Fetal distress
Decreased fetal movements
Instrumental delivery
Need for resuscitation in the labor room
Apgar scores
Abnormal cord pH (<7) and base deficit
(>10 mEq/L)
Use of a Pudendal block for mid-cavity
forceps may be associated with accidental
injection of the local anesthetic into the
Feeding history
Appearance of clinical features including
lethargy, poor activity, drowsiness, and
vomiting after initiation of breast-feeding
may be suggestive of inborn errors of
metabolism.
Late onset hypocalcemia should be
considered in the presence of top feeding
with cow’s milk.
Family history
Consanguinity in parents
Seizures or mental retardation
Early fetal/neonatal deaths -inborn errors
of metabolism.
History of seizures in either parent or
sib(s) in the neonatal period may suggest
benign familial neonatal convulsions
(BFNC).
General examination
Vital signs: Heart rate, respiration, blood
pressure, capillary refill time and
temperature.
Gestation, birth weight, and weight for
age should be recorded.
The neonate should also be examined
for the presence of any obvious
malformations or dysmorphic features.
Systemic examination
Presence of hepatosplenomegaly or an
abnormal urine odor may be suggestive of
IEM.
The skin should be examined for the
presence of any neuro-cutaneous markers.
Investigations
Essential laboratory investigations include:
Blood glucose
Serum calcium, ionized calcium if possible
Serum magnesium
Lactate
Serum sodium
Serum urea and creatinine
Lumbar puncture
Blood culture
Cranial ultrasound scan.
EEG
Additional investigations
Neuroimaging (CT, MRI)
Screen for congenital infections (TORCH)
Inborn errors of metabolism (IEM).(S.
Ammonia, Pyruvate & lactate, urine and
serum organic and amino acid analysis).
Arterial blood gas
Second-line investigations for seizures
(not all are indicated in every case)
Second-line investigations : cont.
Second-line investigations : cont.
Rennie and Roberton’s textbook of
neonatology
Imaging
Neurosonography
• All infants with seizures.
• Detection
of
intraventricular
parenchymal hemorrhage
• Unable
to detect
hemorrhage.
SAH
and
and
subdural
CT scan
Subarachnoid hemorrhage and
Developmental malformations.
Magnetic resonance imaging (MRI)
Cerebral dysgenesis
Lissencephaly
Neuronal migration disorders.
Management
• Initial medical management:
The first step in successful management of seizures is
to nurse the baby in thermoneutral environment and
to ensure airway, breathing, and circulation (TABC).
Oxygen should be started if needed, IV access should
be secured, and blood should be collected for glucose
and other investigations.
A brief relevant history should be obtained and quick
clinical examination should be performed. All this
should not require more than 2-5 minutes.
Corrective Therapies
Rapid infusion of glucose or other supplemental
electrolytes should be initiated before antiepileptic
medications are considered.
Hypoglycemia can be readily corrected by
intravenous administration of 5 to 10 mg/kg of a
10% to 15% dextrose solution, followed by an
infusion of 8 to 10 mg/kg/minute.
Persistent
hypoglycemia
may
require
more
hypertonic glucose solutions.
Rarely, prednisone, 2 mg/kg/day, may be needed to
establish a glucose level within the normal range
(Scher, 2001b).
Hypocalcemia-induced
seizures should be
treated with an intravenous infusion of 200
mg/kg of calcium gluconate.
This dosage should be repeated every 5 to 6
hours over the first 24 hours.
Serum magnesium concentrations also should
be measured, because hypomagnesemia may
accompany hypocalcemia; 0.2 mg/kg of
magnesium sulfate should be given by
intramuscular injection (Scher, 2001b).
Disorders of serum sodium are rare causes of
neonatal seizures. Either fluid restriction or
replacement with hypertonic solutions is generally
the mode of therapy for correcting sodium
dysmetabolism.
Pyridoxine dependency requires the injection of 50
to 500 mg of pyridoxine during a seizure with
coincident EEG monitoring.
A beneficial pyridoxine effect occurs either
immediately or over the first several hours.
A daily dose of 50 to 100 mg of pyridoxine should
then be administered.(Scher, 2001).
Antiepileptic medications
Who should be treated
When to begin treatment
Which drug to use
How long.
Antiepileptic medications: who to
treat
Neonates with clinical seizures should receive
medications ; brief electrographic seizures need
not be treated.
Others suggest more aggressive treatment of
electrographic seizures, because uncontrolled
seizures potentially have an adverse effect on
immature brain development (Dwyer and Wasterlain,
1982; Wasterlain, 1997) .
Others warn that early administration of an AED,
such as phenobarbital , even before signs of HIE
appear, may have adverse effects on outcome in
term infants (Ajayi et al, 1998).
In the current state of knowledge most
neonatologists would treat a baby who
had more than three clinical seizures in
an hour, or a single clinical seizure
lasting more than 3 minutes, although
every attempt should be made to obtain
an EEG.
Anti-epileptic
drugs (AED) should be
considered in the presence of even a single
clinical seizure since clinical observations
tend to grossly underestimate electrical
seizures and facilities for continuous EEG
monitoring are not universally available.
If
aEEG is being used, eliminating all
electrical seizure activity should be the goal
of AED therapy.
Drug Therapy
Phenobarbital remains the current first-line
treatment of neonatal seizures worldwide, in
spite of evidence that it is effective in only about
a third of cases and there is concern about the
effects of this drug on brain development,
including apoptosis (Painter et al.1999; Bittigau et al.
2002; Boylan et al. 2004; Kaindl et al. 2006; Ikonomidou
and Turski 2010).
Recently
published surveys from Israel,
Australia and the USA indicate that there are
large variations in practice, both between
neonatologists and neurologists and between
countries (Bassan et al. 2008; Guillet et al. 2008).
In
a
recent
European survey, Vento and
colleagues (2010) showed almost unanimous use
of phenobarbital as a first-line drug, followed
by midazolam, phenytoin and lidocaine as
second- and third-line drugs
Phenytoin is our current second-line
choice, although this drug needs to be
used with caution (and given slowly
intravenously) in babies with hypoxic
ischaemia
who
often
have
cardiac
depression.
The preferred loading dose of phenytoin is
15 to 20 mg/kg. (Painter et al, 1978, 1981).
About a third of babies fail to respond to a
combination of phenobarbital and phenytointhey are usually suffering from severe hypoxic–
ischaemic encephalopathy and their prognosis
is poor.
The choice of third-line anticonvulsant varies,
but one of the benzodiazepines is often chosen.
Lorazepam is given IV at a dose of 0.05
to 0.1 mglkg.
Diazepam dose is 0.3 mg/kg IV @ infusion
rate of 0.3 mg/kg/hour IV
Midazolam
is
a
short-acting
benzodiazepine that has been used as a
continuous IV infusion (0.1-0.4 mg/kg/hour)
after an initial loading dose (0.15 mglkg).
Midazolam is effective for the control of status
epilepticus in adults and children, but has
shown varying results in babies (Boylan et al.
2004; Castro-Conde 2005; Sirsi et al.2008) .
Recent evidence from a number of small studies
does seem to indicate that midazolam may be a
useful treatment for seizures in babies, but the
exact dose and dosing regimen have not been
established (Castro-Conde 2005; Sirsi et al. 2008)
In addition, there are concerns about safety:
midazolam can cause myoclonus in
preterms (Montenegro et al. 2001).
Lidocaine has a very narrow therapeutic range
and accumulates in the blood, may induce
seizures at higher levels.
There are reports of success with this agent,
mainly from Scandinavia. (Hellstrom-Westas et al.
1988; Kobayashi et al. 1999)
Lidocaine has been used as an IV infusion of 4
mglkg/hour with decreasing doses over 4 to 5
days.
Novel Antiepileptic Drug
Approaches
An
age-dependent high expression of a
chloride cotransporter is thought to be
responsible for the high incidence of seizure in
the newborn period and the lack of response to
conventional drugs used in older children and
adults (Dzhala et al 2005a).
Bumetanide is now considered a promising
antiepileptic drug with a developmental target,
namely the immature chloride cotransporter
NKCC1.
Bumetanide (NKCC1 blocker) has been used as a
diuretic in term and preterm babies for around 30
years and several studies have validated its efficacy
and safety, including pharmacokinetics and dosefinding studies (Sullivan et al. 1996; Lopez-Samblas 1997).
It is considered a safe drug in the neonatal period,
even in critically ill infants (Ward & Lam 1977; Aranda et
al. 1980; Turmen et al. 1982; Robertson et al. 1986; Walker
et al. 1988; Walker et al. 1989; Wells et al. 1992; Shankaran
et al. 1995; Sullivan et al. 1996 a and b; Lopez-Samblas et
al. 1997; Clark et al. 2006).
Newer AEDs such as topiramate (NMDA
antagonist) and levetiracetam have been
anecdotally reported to improve acute
neonatal seizures (Abend et al. 2011; Glass et
al. 2011; Khan et al. 2011).
NNF Recommendations 2010
*consider using pyridoxine at these steps
Maintenance anticonvulsants
Phenobarbital in a dose of 5 mg/kg/day is the usual
maintenance anticonvulsant chosen for the
newborn.
Phenytoin is not a good choice for long-term therapy.
There is very little experience with alternative
maintenance therapy at the present time and
combinations are best avoided.
Resistant cases should be treated with a
combination of phenobarbital and carbamazepine,
although sodium valproate can be successful in
some cases.
Discontinuation of Drug Use
Discontinuation of drugs before discharge
from the NICU is recommended, because
then clinical assessments of arousal, tone,
and behavior will not be hampered by
medication effect.
Newborns with congenital or destructive
brain lesions on neuroimaging or those
with persistently abnormal findings on
neurologic examination at the time of
discharge may require a slower taper off
medication over several weeks or months.
In most children with neonatal seizures,
the seizures rarely reoccur during the first
2 years of life, and prophylactic AED
administration need not be maintained
past 3 months of age, even in the child at
risk.
*low risk of seizure recurrence after early
withdrawal of AED therapy in the neonatal period
(Hellstrom-Westas et al,1995).
Older infants who present with specific
epileptic syndromes, such as infantile
spasms,
will
not
respond
to
the
conventional AEDs that were initially begun
during the neonatal period.
This honeymoon period without seizures
commonly persists for many years in most
children, before isolated or recurrent
seizures appear.
Prognosis
The prognosis depends largely on the cause
of the seizures
Worse for those with hypoxic–ischaemic
encephalopathy, meningitis and cerebral
malformations
Better for hypocalcaemia, benign familial
neonatal seizures, subarachnoid haemorrhage
or stroke (Tekgul et al. 2006)
Mortality and morbidity are greater in preterm
babies (Scher et al. 1993a; van Zeben et al.1990)
The number of electrographic seizures is
not in general an indicator of prognosis,
nor is the clinical seizure type.
There is increasing consensus that
seizures (including electrographic seizures
which are clinically silent) which persist
despite third-line AEDs carry a poor
prognosis (McBride et al.2000).
The background EEG can be helpful, and a
normal background EEG with well organised sleep
stages has consistently been shown to be
associated with an 80% chance of normal
development (Rose and Lombroso 1970; Holmes and
Lombroso 1993; Tekgul et al. 2006).
The risk of subsequent epilepsy after neonatal
seizures also depends on the aetiology, and is
more likely if spike and sharp-wave activity
persists on the EEG at 3 months (Clancy and Legido
1991).
The later seizure type includes infantile
spasms, minor motor seizures ,complex
partial and tonic-clonic seizures, which
often only emerge after a year or so.
In a Dutch study, the incidence of post-
neonatal epilepsy after treatment of
clinical and subclinical neonatal seizures
detected with continuous aEEG was 9.4%
(Toet et al 2005).
THANK YOU
management
of
Neonatal Seizures
Moderator : Dr. Dilip Singh
Presented by : Dr. Abdul Quddoos
Neonatal seizures
• Definition : A seizure is defined clinically as a
paroxysmal alteration in neurologic function, i.e.
motor, behavior and/or autonomic function. This
definition includes:
•1. Epileptic seizures: phenomena associated with
corresponding EEG seizure activity e.g. clonic & focal tonic
seizures,
•2. Non-epileptic seizures: clinical seizures without
corresponding EEG correlate e.g. subtle and generalized
tonic seizures
•3. EEG seizures: abnormal EEG activity with no clinical
correlation.
Diagnostic dilemmas:
Clinical Vs EEG criteria
Neonatal seizures are generally brief and subtle
in clinical appearance, unusual behaviors may
be difficult to recognize and classify .
Confirmation of suspicious clinical events as
seizures using coincident EEG recordings is now
strongly recommended.
Using either routine EEG studies (Glauser
and Clancy, 1992) or continuous synchronized
video-EEG-polygraphic recordings (Mizrahi
and Kellaway,1998) , more reliable start and
end points of electrographically confirmed
seizures can be established before
decisions are made regarding treatment
intervention.
Rigorous physiologic monitoring of non–
central nervous system (CNS) measures
also assists in the recognition and
management of seizures.
Clinical Seizure Criteria
Historically subdivided into five categories:
Focal clonic
Multifocal or migratory clonic,
Tonic,
Myoclonic,
Subtle seizures
(Volpe, 2001) .
A more recent classification expands these clinical
subtypes, adopting a strict temporal occurrence of
specific
clinical
events
with
coincident
electrographic seizures, to distinguish neonatal
clinical “nonepileptic” seizures from “epileptic”
seizures.
(Mizrahi and
Kellaway, 1998)
.
Before a seizure evaluation is initiated, the
normal occurrence of alterations in cardiorespiratory regularity, body movements,
and other behaviors during active sleep
(rapid eye movement [REM] sleep), quiet
sleep (non-REM [NREM] sleep), or waking
states should be appreciated.
(Da Silva et al, 1998;
Scher,1996).
Classification and Clinical
Characteristics
of Neonatal Seizures
Subtle seizure activity—now termed motor
automatisms and buccolingual movements
—is the most frequently observed category
of neonatal seizures.
Motor Automatisms : cont.
Clonic Seizures
Tonic Seizures
Electrographic Seizures
Electrographic
seizures are typically defined as
repetitive, rhythmic, stereotypic activity lasting at
least 10 seconds that evolve in amplitude frequency
and morphology (Patrizi et al. 2003,Clancy and Ledigo
1987; Scher et al. 1993b; Bye and Flanagan 1995) .
Both term and preterm infants have the ability to
generate a multitude of ictal events but generally
seizures originate in the central and temporal
regions (Shellhaas et al. 2007; Bourez-Swart et al.
2009) .
Electrographic Seizures : cont.
Electrographic seizures characteristically consist
of monophasic repetitive discharges or spikeand-wave activity (Patrizi et al. 2003) .
The onset, morphology and propagation patterns
of neonatal seizures are richly varied, which do
not always correlate with the underlying
pathology.
An electrographic seizure should have a clear
onset and conclusion, but these can be difficult
to identify.
Electrographic Seizures : cont.
Clancy and Ledigo (1987) found that the mean
duration of electrographic seizures in the
neonate was 2–3 minutes, with 97% of all
seizures lasting 9 minutes or less and only
0.4% lasting 30 minutes or longer .
Neonatal status epilepticus was reported in
one third of full-term infant EEG recordings and
in 20% of the total cohort of preterm and fullterm infant EEG recordings (Scher et al, 1993) .
Electrographic Seizures : cont.
Status epilepticus is defined as continuous
seizure activity for 30 minutes or 50% of
the recording time.
If clinicians relied only on clinical criteria,
status
epilepticus
underdiagnosed.
Without
would
be
EEG
confirmation,
the
underdiagnosis of status epilepticus would
contribute to brain injury.
Electrographic Seizures : cont.
One
study estimated that 25% of neonates
expressed persistent electrographic seizures
despite resolution of their clinical seizure
behaviors after receiving one or more antiepileptic
medications;
this
phenomenon
is
termed
electroclinical uncoupling. (Scher, 1994)
Uncoupling of the clinical and electrographic
expressions
of
neonatal
seizures
after
antiepileptic medication administration also
contributes to the underestimation of the true
seizure duration and frequency of status
epilepticus .
Electroclinical dissociation
There is asynchrony between the clinical and
electrical representation of neonatal seizures:
in only one-third of cases studied with video
surveillance were the clinical and electrical
manifestations simultaneous (Weiner et al.
1991; Mizrahi and Kellaway 1998) .
Subtle stereotyped behaviour may or may
not be associated with characteristic EEG
changes, and continuous electrical monitoring
detects many clinically silent seizures.
A study by Malone et al. (2009) has shown
that there is both over- and underdiagnosis
of neonatal seizures if EEG monitoring is
not used, and we would advocate using
EEG if at all possible to confirm the
presence of true neonatal seizures.
aEEG
is now widely used in NICUs,
especially since the introduction of
therapeutic hypothermia for hypoxic–
ischaemic encephalopathy.
aEEG does have limitations, however,
and short seizures, especially those less
than 1 minute in duration, are missed,
as are low-voltage seizures and seizures
which remain localised (Rennie et al.
2004; Shellhaas and Clancy 2007).
aEEG will usually detect seizures which
are of high amplitude, generalised over a
wide area and which are of long duration.
Etiology of Neonatal Seizures
AGES 1-4 DAYS; cont.
AGES 4-14 DAYS; cont.
Approach to an infant with neonatal
seizures
History
Complete description of seizure
Associated eye movements
Restraint of episode by passive flexion of the
affected limb
Change in color of skin (mottling or
cyanosis).
Autonomic phenomena.
Infant was conscious or sleeping at the
time of seizure should be elicited.
The day of life on which the seizures
occurred.
Antenatal history
Intrauterine infection
Maternal diabetes
Narcotic addiction
A history of sudden increase in fetal
movements may be suggestive of
intrauterine convulsions.
Perinatal history
• Perinatal asphyxia is the commonest cause
•
•
•
•
•
•
•
of neonatal seizures
Fetal distress
Decreased fetal movements
Instrumental delivery
Need for resuscitation in the labor room
Apgar scores
Abnormal cord pH (<7) and base deficit
(>10 mEq/L)
Use of a Pudendal block for mid-cavity
forceps may be associated with accidental
injection of the local anesthetic into the
Feeding history
Appearance of clinical features including
lethargy, poor activity, drowsiness, and
vomiting after initiation of breast-feeding
may be suggestive of inborn errors of
metabolism.
Late onset hypocalcemia should be
considered in the presence of top feeding
with cow’s milk.
Family history
Consanguinity in parents
Seizures or mental retardation
Early fetal/neonatal deaths -inborn errors
of metabolism.
History of seizures in either parent or
sib(s) in the neonatal period may suggest
benign familial neonatal convulsions
(BFNC).
General examination
Vital signs: Heart rate, respiration, blood
pressure, capillary refill time and
temperature.
Gestation, birth weight, and weight for
age should be recorded.
The neonate should also be examined
for the presence of any obvious
malformations or dysmorphic features.
Systemic examination
Presence of hepatosplenomegaly or an
abnormal urine odor may be suggestive of
IEM.
The skin should be examined for the
presence of any neuro-cutaneous markers.
Investigations
Essential laboratory investigations include:
Blood glucose
Serum calcium, ionized calcium if possible
Serum magnesium
Lactate
Serum sodium
Serum urea and creatinine
Lumbar puncture
Blood culture
Cranial ultrasound scan.
EEG
Additional investigations
Neuroimaging (CT, MRI)
Screen for congenital infections (TORCH)
Inborn errors of metabolism (IEM).(S.
Ammonia, Pyruvate & lactate, urine and
serum organic and amino acid analysis).
Arterial blood gas
Second-line investigations for seizures
(not all are indicated in every case)
Second-line investigations : cont.
Second-line investigations : cont.
Rennie and Roberton’s textbook of
neonatology
Imaging
Neurosonography
• All infants with seizures.
• Detection
of
intraventricular
parenchymal hemorrhage
• Unable
to detect
hemorrhage.
SAH
and
and
subdural
CT scan
Subarachnoid hemorrhage and
Developmental malformations.
Magnetic resonance imaging (MRI)
Cerebral dysgenesis
Lissencephaly
Neuronal migration disorders.
Management
• Initial medical management:
The first step in successful management of seizures is
to nurse the baby in thermoneutral environment and
to ensure airway, breathing, and circulation (TABC).
Oxygen should be started if needed, IV access should
be secured, and blood should be collected for glucose
and other investigations.
A brief relevant history should be obtained and quick
clinical examination should be performed. All this
should not require more than 2-5 minutes.
Corrective Therapies
Rapid infusion of glucose or other supplemental
electrolytes should be initiated before antiepileptic
medications are considered.
Hypoglycemia can be readily corrected by
intravenous administration of 5 to 10 mg/kg of a
10% to 15% dextrose solution, followed by an
infusion of 8 to 10 mg/kg/minute.
Persistent
hypoglycemia
may
require
more
hypertonic glucose solutions.
Rarely, prednisone, 2 mg/kg/day, may be needed to
establish a glucose level within the normal range
(Scher, 2001b).
Hypocalcemia-induced
seizures should be
treated with an intravenous infusion of 200
mg/kg of calcium gluconate.
This dosage should be repeated every 5 to 6
hours over the first 24 hours.
Serum magnesium concentrations also should
be measured, because hypomagnesemia may
accompany hypocalcemia; 0.2 mg/kg of
magnesium sulfate should be given by
intramuscular injection (Scher, 2001b).
Disorders of serum sodium are rare causes of
neonatal seizures. Either fluid restriction or
replacement with hypertonic solutions is generally
the mode of therapy for correcting sodium
dysmetabolism.
Pyridoxine dependency requires the injection of 50
to 500 mg of pyridoxine during a seizure with
coincident EEG monitoring.
A beneficial pyridoxine effect occurs either
immediately or over the first several hours.
A daily dose of 50 to 100 mg of pyridoxine should
then be administered.(Scher, 2001).
Antiepileptic medications
Who should be treated
When to begin treatment
Which drug to use
How long.
Antiepileptic medications: who to
treat
Neonates with clinical seizures should receive
medications ; brief electrographic seizures need
not be treated.
Others suggest more aggressive treatment of
electrographic seizures, because uncontrolled
seizures potentially have an adverse effect on
immature brain development (Dwyer and Wasterlain,
1982; Wasterlain, 1997) .
Others warn that early administration of an AED,
such as phenobarbital , even before signs of HIE
appear, may have adverse effects on outcome in
term infants (Ajayi et al, 1998).
In the current state of knowledge most
neonatologists would treat a baby who
had more than three clinical seizures in
an hour, or a single clinical seizure
lasting more than 3 minutes, although
every attempt should be made to obtain
an EEG.
Anti-epileptic
drugs (AED) should be
considered in the presence of even a single
clinical seizure since clinical observations
tend to grossly underestimate electrical
seizures and facilities for continuous EEG
monitoring are not universally available.
If
aEEG is being used, eliminating all
electrical seizure activity should be the goal
of AED therapy.
Drug Therapy
Phenobarbital remains the current first-line
treatment of neonatal seizures worldwide, in
spite of evidence that it is effective in only about
a third of cases and there is concern about the
effects of this drug on brain development,
including apoptosis (Painter et al.1999; Bittigau et al.
2002; Boylan et al. 2004; Kaindl et al. 2006; Ikonomidou
and Turski 2010).
Recently
published surveys from Israel,
Australia and the USA indicate that there are
large variations in practice, both between
neonatologists and neurologists and between
countries (Bassan et al. 2008; Guillet et al. 2008).
In
a
recent
European survey, Vento and
colleagues (2010) showed almost unanimous use
of phenobarbital as a first-line drug, followed
by midazolam, phenytoin and lidocaine as
second- and third-line drugs
Phenytoin is our current second-line
choice, although this drug needs to be
used with caution (and given slowly
intravenously) in babies with hypoxic
ischaemia
who
often
have
cardiac
depression.
The preferred loading dose of phenytoin is
15 to 20 mg/kg. (Painter et al, 1978, 1981).
About a third of babies fail to respond to a
combination of phenobarbital and phenytointhey are usually suffering from severe hypoxic–
ischaemic encephalopathy and their prognosis
is poor.
The choice of third-line anticonvulsant varies,
but one of the benzodiazepines is often chosen.
Lorazepam is given IV at a dose of 0.05
to 0.1 mglkg.
Diazepam dose is 0.3 mg/kg IV @ infusion
rate of 0.3 mg/kg/hour IV
Midazolam
is
a
short-acting
benzodiazepine that has been used as a
continuous IV infusion (0.1-0.4 mg/kg/hour)
after an initial loading dose (0.15 mglkg).
Midazolam is effective for the control of status
epilepticus in adults and children, but has
shown varying results in babies (Boylan et al.
2004; Castro-Conde 2005; Sirsi et al.2008) .
Recent evidence from a number of small studies
does seem to indicate that midazolam may be a
useful treatment for seizures in babies, but the
exact dose and dosing regimen have not been
established (Castro-Conde 2005; Sirsi et al. 2008)
In addition, there are concerns about safety:
midazolam can cause myoclonus in
preterms (Montenegro et al. 2001).
Lidocaine has a very narrow therapeutic range
and accumulates in the blood, may induce
seizures at higher levels.
There are reports of success with this agent,
mainly from Scandinavia. (Hellstrom-Westas et al.
1988; Kobayashi et al. 1999)
Lidocaine has been used as an IV infusion of 4
mglkg/hour with decreasing doses over 4 to 5
days.
Novel Antiepileptic Drug
Approaches
An
age-dependent high expression of a
chloride cotransporter is thought to be
responsible for the high incidence of seizure in
the newborn period and the lack of response to
conventional drugs used in older children and
adults (Dzhala et al 2005a).
Bumetanide is now considered a promising
antiepileptic drug with a developmental target,
namely the immature chloride cotransporter
NKCC1.
Bumetanide (NKCC1 blocker) has been used as a
diuretic in term and preterm babies for around 30
years and several studies have validated its efficacy
and safety, including pharmacokinetics and dosefinding studies (Sullivan et al. 1996; Lopez-Samblas 1997).
It is considered a safe drug in the neonatal period,
even in critically ill infants (Ward & Lam 1977; Aranda et
al. 1980; Turmen et al. 1982; Robertson et al. 1986; Walker
et al. 1988; Walker et al. 1989; Wells et al. 1992; Shankaran
et al. 1995; Sullivan et al. 1996 a and b; Lopez-Samblas et
al. 1997; Clark et al. 2006).
Newer AEDs such as topiramate (NMDA
antagonist) and levetiracetam have been
anecdotally reported to improve acute
neonatal seizures (Abend et al. 2011; Glass et
al. 2011; Khan et al. 2011).
NNF Recommendations 2010
*consider using pyridoxine at these steps
Maintenance anticonvulsants
Phenobarbital in a dose of 5 mg/kg/day is the usual
maintenance anticonvulsant chosen for the
newborn.
Phenytoin is not a good choice for long-term therapy.
There is very little experience with alternative
maintenance therapy at the present time and
combinations are best avoided.
Resistant cases should be treated with a
combination of phenobarbital and carbamazepine,
although sodium valproate can be successful in
some cases.
Discontinuation of Drug Use
Discontinuation of drugs before discharge
from the NICU is recommended, because
then clinical assessments of arousal, tone,
and behavior will not be hampered by
medication effect.
Newborns with congenital or destructive
brain lesions on neuroimaging or those
with persistently abnormal findings on
neurologic examination at the time of
discharge may require a slower taper off
medication over several weeks or months.
In most children with neonatal seizures,
the seizures rarely reoccur during the first
2 years of life, and prophylactic AED
administration need not be maintained
past 3 months of age, even in the child at
risk.
*low risk of seizure recurrence after early
withdrawal of AED therapy in the neonatal period
(Hellstrom-Westas et al,1995).
Older infants who present with specific
epileptic syndromes, such as infantile
spasms,
will
not
respond
to
the
conventional AEDs that were initially begun
during the neonatal period.
This honeymoon period without seizures
commonly persists for many years in most
children, before isolated or recurrent
seizures appear.
Prognosis
The prognosis depends largely on the cause
of the seizures
Worse for those with hypoxic–ischaemic
encephalopathy, meningitis and cerebral
malformations
Better for hypocalcaemia, benign familial
neonatal seizures, subarachnoid haemorrhage
or stroke (Tekgul et al. 2006)
Mortality and morbidity are greater in preterm
babies (Scher et al. 1993a; van Zeben et al.1990)
The number of electrographic seizures is
not in general an indicator of prognosis,
nor is the clinical seizure type.
There is increasing consensus that
seizures (including electrographic seizures
which are clinically silent) which persist
despite third-line AEDs carry a poor
prognosis (McBride et al.2000).
The background EEG can be helpful, and a
normal background EEG with well organised sleep
stages has consistently been shown to be
associated with an 80% chance of normal
development (Rose and Lombroso 1970; Holmes and
Lombroso 1993; Tekgul et al. 2006).
The risk of subsequent epilepsy after neonatal
seizures also depends on the aetiology, and is
more likely if spike and sharp-wave activity
persists on the EEG at 3 months (Clancy and Legido
1991).
The later seizure type includes infantile
spasms, minor motor seizures ,complex
partial and tonic-clonic seizures, which
often only emerge after a year or so.
In a Dutch study, the incidence of post-
neonatal epilepsy after treatment of
clinical and subclinical neonatal seizures
detected with continuous aEEG was 9.4%
(Toet et al 2005).
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