Seizures are among the most frequent neurological disorders of
the neonatal period, with an incidence between 1.8-5/1,000 live
Newborns exposed to malnutrition in utero seem to be more commonly
In our study, approximately 14% of the newborns treated at the Neonatal
Intensive Care Unit of the Hospital São Lucas (PUCRS) had
at least one clinical episode compatible with seizure( ).
Seizures in the neonatal period may be associated with several etiological
factors, causing permanent or transient injuries to the central
nervous system (CNS). Such condition may occur in utero, at the
time of birth or in the immediate postnatal period. The prognosis
for seizure-stricken newborns is extremely variable. In general,
50% of the patients die or have severe sequelae, and the other 50%
are healthy or have minimal sequelae. This dichotomic prognosis
has direct influence over the treatment of neonatal seizures, which
is totally different from that in other age groups.
A clinical classification of neonatal seizures was proposed in the
1970s, and is still widely used today( , ).
This classification divides seizures into four groups: subtle, clonic,
tonic, and myoclonic. A new classification was proposed later, based
on the clinical findings associated with video-polysomnography,
introducing two new concepts: clinical seizures without electroencephalographic
manifestation and encephalographic seizures without clinical manifestation( ).
These two new concepts caused a lot of controversy, and resulted
in a thorough reevaluation of the criteria for the treatment of
neonatal seizures Currently, there is a third classification based
on a review of the previous one. This new classification, shown
in Table 1, is still controversial since it groups seizures into
neonatal epileptic seizures, and non-epileptic seizures that are
characterized by primitive motor patterns of the cerebral and medullar
trunk( , ).
This new classification does not include the so-called apnea of
infancy. Ictal apnea, initially classified as a subtle seizure,
is quite rare, requiring polysomnography for its adequate diagnosis( , , ).
Table 1 -
Clinical classification of neonatal seizures
Most neonatal seizures are epiphenomena of insults to the CNS during
the perinatal period or reflect transient disorders such as metabolic
changes. Newborns are more susceptible to the development of seizures
than older children or adults. This predisposition may be explained
through several factors that are characteristic of the neonatal
1. The neonatal period is characterized by the fast growth
and development of the central nervous system (CNS). The ontogenetic
process of maturation of the CNS probably makes newborns more vulnerable
to exogenous insults( );
2. There is a predominance of excitatory systems over the
inhibitory ones, thus facilitating convulsive manifestation, in
addition to the extracellular accumulation of potassium, which results
in hyperexcitability( , );
3. Neurotransmitters with inhibitory activity on the CNS
have excitatory activity on the immature CNS( );
4. The dissemination of the epileptogenic activity is more
easily present in the immature brain due to the absence of restrictive
inhibitory factors( );
5. Subcortical structures such as the substantia nigra increase
the epileptogenic activity of the immature CNS( ).
A question is still intriguing neurologists today: do seizures
per se cause brain injury? The most widely discussed hypothesis
today, which would explain brain injury after a prolonged seizure,
is excitotoxicity. In this case, the excessive release of excitatory
amino acids (glutamate, aspartate, quisqualate, and kainic acid),
which stimulate their postsynaptic receptors, determine ionic alterations
that result in the accumulation of intracellular calcium(
Studies using nuclear magnetic resonance spectroscopy suggest that
neonatal seizures do not determine metabolic changes and/or cerebral
hypoperfusion unless significant hypoxemia or severe lactic acidosis
is present( ).
Experimental studies reinforce these clinical findings, showing
there is no evidence that short seizures cause brain injury in immature
animals( , ),
except if their CNS has been previously exposed to other types of
insult ( ).
Differently from other age groups, most neonatal seizures are symptomatic,
one fourth of them is cryptogenic, and just few are idiopathic.
The etiology or associated disorders involve a wide series of neonatal
diseases and metabolic disorders. Neonatal seizures are usually
multifactorial, and their prognosis is strongly related to their
Perinatal care has helped to modify the etiological factors involved
in neonatal seizures with the advent of nuclear magnetic resonance,
which allows diagnosing neuronal migration disorders, through the
advanced assessment of inborn errors of metabolism, and the reduction
of seizures caused by metabolic disorders. However, even with these
diagnostic breakthroughs, it is not possible to determine the apparent
cause of seizures in a significant parcel of the newborn population(
In our environment, perinatal asphyxia is still the most frequently
reported etiology of neonatal seizures(
, , ).
Neonatal Epileptic Syndromes
Early myoclonic encephalopathy or neonatal myoclonic encephalopathy
Aicardi and Goutières(
followed by other authors( ),
were the first to report this syndrome, showing predominant myoclonic
disorders, and electroencephalogram (EEG) with burst-suppression
pattern. Several reports describing early myoclonic encephalopathy
include cases with confirmed or suspected inborn errors of metabolism,
while others show similarity of this syndrome to nonketotic hyperglycemia( , ).
According to Aicardi, early myoclonic encephalopathy seems to
involve several etiologies(
Ictal events comprise partial or fragmentary erratic myoclonias,
massive myoclonia, and tonic infantile spasms. The EEG shows a burst-suppression
pattern characterized by spikes, sharp waves, and slow waves, with
1 to 5 seconds, alternated with periods of flat tracing during 3
to 10 seconds (Figure 1).
Figure 1 - EEG tracing in newborn with refractory seizures, presenting
a burst-suppression pattern
Early infantile epileptic encephalopathy
Early infantile epileptic encephalopathy, described by Ohtahara(
includes tonic spasms (unilateral or bilateral, involving flexor
or extensor muscles) that are hardly controlled with medication
and are associated with the encephalographic burst-suppression pattern
and marked neuropsychomotor development delay. The nosological position
of early infantile epileptic encephalopathy and early myoclonic
encephalopathy in this group of newborns is widely discussed( ).
The main elements that allow distinguishing between them are( , , ):
(1) the presence of tonic spasms in early infantile epileptic encephalopathy
and absence of partial or massive myoclonias as observed in early
myoclonic encephalopathy; (2) a high incidence of family cases and
inborn errors of metabolism in early myoclonic encephalopathy, while
in early infantile epileptic encephalopathy the major etiology is
cerebral malformation; (3) on EEG, paroxysmal bursts seem to be
longer in early infantile epileptic encephalopathy than in early
myoclonic encephalopathy, and the suppression bursts are shorter( );
(4) early infantile epileptic encephalopathy tends to develop into
the West syndrome and, later, into the Lennox-Gastaut syndrome( ).
Benign idiopathic neonatal convulsions
Benign idiopathic neonatal convulsions were initially described
in the literature as "fifth day fits"(
The seizures are clonic, mostly partial, and/or apneic seizures,
but never tonic, occurring around the fifth day of life, with unknown
etiology and favorable evolution. Approximately 60% of the cases
present interictal EEG with Théta pointu alternant pattern( ).
This pattern consists of a dominant, discontinued, alternant, non-reactive
theta activity with sharp waves( ).
Benign familial neonatal convulsions
Benign familial neonatal convulsions (BFNC) are an idiopathic epileptic
syndrome with autosomal dominant transmission, high penetrance,
and favorable evolution(
In BFNC, the seizures often occur on the 2nd and 3rd days of life.
Two genetic loci, EBN1 and EBN2, were mapped in families with BFNC:
the first, in 1989, on chromosome 20q( )
and, the other in 1993, on chromosome 8q( ).
BFNC is associated with mutations in the voltage-gated potassium
channel genes KCNQ2 and KCNQ3( ).
There is no specific EEG pattern.
The treatment of neonatal seizures should always follow the procedures
established by the neonatology service. Figure 2 shows the proposed
procedures, which were divided into three steps for teaching purposes.
Figure 2 - Guidelines for the treatment of neonatal seizures
When faced with a seizure of unknown cause in a newborn, the major
priority is checking for necessary airway aspiration, oxygenation
or ventilation. At the same time, a venous access should be available,
and a glucose solution at 10% should be instilled. A quick test
(Haemoglukotest, Dextrostix, etc.) should be performed immediately
in order to assess the sugar level. The blood sample for lab exams
should initially include electrolytes, serum glucose, and hemogram.
If these tests do not clarify the cause of the seizure, additional
complementary exams should be carried out: creatinine level, ammonia
level, blood culture, inborn error of metabolism screening, lumbar
puncture with cerebrospinal fluid analysis, cranial ultrasound,
and EEG, depending on the clinical status of the patient. Whenever
possible, EEG should be carried out before implementing antiepileptic
Specific treatment of metabolism-related seizures
If the test result shows hypoglycemia (less than 40 mg%), 2 ml/kg
of glucose at 10% (200 mg/kg) should be quickly infused (small volume
bolus during one minute), followed by a slow infusion of glucose
at 10% using 5 microdrops/kg/minute (8 mg/kg/minute). The sugar
level normalizes within a few minutes in most cases(
If seizures are controlled, the sugar level should be regularly
monitored until serum glucose levels stabilize. Newborns with persistent
hypoglycemia may require increased infusion of glucose and, in some
cases, use of corticosteroids (hydrocortisone - 2.5mg/kg every 12
If the newborn presents with hypocalcemia, he/she should receive
calcium gluconate intravenously at 5% at 4ml/kg (200mg/kg), slowly
infused (longer than 10 minutes), with constant monitoring of his/her
heart rate. Gradual or abrupt deceleration of the heart rate during
infusion indicates that it should be discontinued or that infusion
speed should be reduced. After seizures are controlled, the administration
of calcium should continue at 75mg/kg/day until serum levels are
The administration of calcium should be carefully performed due
to the risk of extravasation and consequent necrosis of the tissue.
The rapid infusion of calcium gluconate may also cause hypercalcemia,
reduction of serum phosphorus, and acidosis( ).
Hypomagnesemia (serum magnesium <1.5mg%) is treated with intramuscular
magnesium sulphate at 50% (0.2ml/kg) or with an intravenous dose
of magnesium sulphate at 3%, 2ml/kg, slowly infused (15 to 20 minutes).
The rapid intravenous administration of magnesium may produce low
blood pressure and block the sinoauricular or atrioventricular conduction
system. Serum magnesium levels should be monitored and, if necessary,
the dose should be repeated after 8 to 12 hours. Approximately 50%
of newborns with seizures associated with late-onset hypocalcemia
also present hypomagnesemia and, in these cases, if magnesium is
not administered, the normalization of serum calcium levels may
be hindered, and seizures will persist(
Reduced serum levels of sodium may cause seizures in the newborn.
Hyponatremia is usually treated with concentrated solutions of sodium
(3%). Fluid restriction may be necessary so that dilutional hyponatremia
can be resolved.
In newborns with persistent seizures of unknown cause, a therapeutic
test with pyridoxine is recommended. In this case, pyridoxine should
be intravenously infused at 50 to 100mg and, if possible, there
should be simultaneous monitoring through EEG(
If the seizures are pyridoxine-dependent, they will be controlled
a few minutes after infusion, and EEG should return to normal within
some minutes or hours (Figure 3). If results are not clear after
the first dose, the test should be repeated. Newborns with pyridoxine-dependent
seizures may have apneas and hypotonia after drug infusion( , ).
Figure 3 - EEG in pyridoxine-dependent seizures. a) EEG before pyridoxine
administration; b) EEG after the use of pyridoxine, without burst-suppression
The use of antiepileptic drugs is recommended if seizures persist
after the resolution of metabolic disorders or when the etiological
profile suggests that the seizures will not be controlled (e.g.:
presence of infections, infarct, dysplasia or other malformations
of the CNS)(
- The use of antiepileptic drugs should be avoided if the diagnostic
profile and the physiopathology of the seizures are not well-defined.
- For the abstinence syndrome related to maternal drug use, chlorpromazine
(3mg/kg/day) and phenobarbital (5mg/kg/day) are indicated(
- If seizures persist for longer than 24 hours or if the diagnostic
profile suggests refractoriness, long-acting antiepileptic drugs
should be administered. Phenobarbital is still the drug of choice,
since an intravenous loading dose of 15-20mg/kg may be used, followed
by an oral maintenance dose of 3.5-4.5mg/kg/day. If the intravenous
form is not available, an oral loading dose should be used; the
intramuscular route should be avoided due to its erratic absorption.
The plasma level should be maintained at 20mg/ml. If the seizures
are not controlled, intravenous phenytoin should be combined with
a loading dose of 15-25mg/kg, followed by a maintenance dose of
4-8mg/kg/day, administered twice. The plasma level should be maintained
between 10-20mg/ml. Oral phenytoin should not be used in the first
week of life due to problems with gastrointestinal absorption(
Other antiepileptic drugs that may also be used intravenously include
clonazepam, midazolam, lidocaine and thiopental (Table 2)( , , , ).
Valproate may used in persistent myoclonic seizures at 25-30mg/kg/day
together with liver function tests, and ammonia dosage. Other drugs
that are widely used on adults such as carbamazepine and primidone,
and new drugs such as vigabatrin, lamotrigine and topiramate are
used non-systematically and sporadically during the neonatal period.
However, their safety and pharmacokinetics are not well-known within
this population( , ).
Table 2 -
Other AEDs for IV administration (4,8,46,47)
- Although there is no general agreement in the literature, the
use of short-acting antiepileptic drugs such as diazepam or lorazepam
(whose intravenous formula is not yet available in Brazil)(
is recommended when the etiological profile suggests transient seizures
(related to the abstinence syndrome, sepsis, grade I and II intraventricular
hemorrhage, hypoxia with no evidence of leukomalacia). Diazepam
may be used intravenously at 0.25 to 0.5mg/kg or rectally at 0.5mg/kg;
if necessary, the dose may be repeated every 4-6 hours( , ).
If available, lorazepam may be used intravenously at 0.05-0.10mg/kg,
in an infusion of 2 to 5 minutes( , ).
- The use of antiepileptic drugs should be suspended as soon as
possible. The decision on when the drugs should be discontinued
depends on the clinical status of each patient. The etiology of
the seizures, the absence of clinical or encephalographic seizures,
interictal EEG, and neuroimaging results should be considered(
, , ).
The prognosis for seizure-stricken newborns consists of traditional
methods such as the assessment of neuropsychomotor development,
neurological examination, electroencephalogram, postepileptic development,
and psychological or behavioral disorders(
Neonatal follow-up studies show that the prognosis seems to be
associated with clinical aspects (type of seizure, interictal EEG),
etiological factors, and electroencephalographic findings(
, , , , ).
In our study population, the multifocal encephalographic pattern
and suppression bursts are related to poor prognosis. Continuous
EEG monitoring may also be useful; in this case, abnormal EEG recordings
tend to be associated with poor prognosis(
In a cohort of newborns with seizures followed up at the Hospital
São Lucas (PUCRS), we observed that 22% and 28.3% of the
cases after respectively 12 months and 36 months of follow-up developed
epilepsy. The need for anticonvulsants in the neonatal period, and
congenital infections were significantly associated with the development
of epilepsy. The normal results obtained through the interictal
EEG were related to favorable neurological evolution(
Similar studies conducted elsewhere showed an incidence of postnatal
epilepsy of approximately 20-28%(
We observed a predominance of epilepsy in full-term newborns (30%)
in comparison with preterm newborns (17%)( ).
1. The clinical pattern of neonatal seizures is different from
that observed in other age groups since it shows anatomical, chemical
and physiological immaturity of the developing brain. This means
that an adequate classification for this age group is extremely
2. When we classify neonatal seizures according to their etiology,
we observe that most of them are symptomatic, one fourth of them
is cryptogenic, and just few are idiopathic. This finding is characteristic
of the neonatal period since the etiological factors are more easily
identifiable in this age group.
3. Neonatal seizures usually occur in a multifactorial scenario,
in which the association between one or more factors potentially
harmful to the CNS is present. Such factors include, for instance,
asphyxia, hemorrhage, and hypoglycemia. It is crucial that these
factors be promptly recognized and specifically treated.
4. The prognosis of neonatal seizures seems to be related to the
etiological factor rather than to the severity, duration, or frequency
of the seizures.
5. The electroencephalographic seizures without clinical manifestations
should be treated with antiepileptic drugs. However, in some cases,
polytherapy becomes necessary due to the refractory nature of these