Epilepsies of neonatal

onset: seizure type and

evolution
Kazuyoshi Watanabe* MD PhD, Professor of Pediatrics,
Nagoya University School of Medicine, Nagoya;
Kiyokuni Miura MD PhD, Division of Pediatric Neurology,
Aichi Prefectural Colony, Kasugai;
Jun Natsume MD PhD, Department of Pediatrics, Nagoya
University School of Medicine, Nagoya;
Fumio Hayakawa MD PhD, Department of Pediatrics, AnjoKosei Hospital, Anjo;
Sunao Furune MD PhD, Division of Pediatric Neurology, First
Red Cross Hospital;
Akihisa Okumura MD, Department of Pediatrics, Nagoya
University School of Medicine; Nagoya; Japan.
*Correspondence to first author at Department of
Pediatrics, Nagoya University School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
E-mail: kwatana@med.nagoya-u.ac.jp

Neonatal seizures are a manifestation of a variety of organic,

metabolic, or functional disorders of the neonatal brain. Most
are caused by perinatal hypoxicischemic encephalopathy
(HIE), intracranial hemorrhage, or infections. Seizures occurring in neonates with HIE or meningitis are not classified as
epilepsy; they should be classified as situation-related or
occasional seizures. These occasional seizures differ from
epilepsy, a chronic seizure disorder, even if they are followed
by symptomatic epilepsy due to an underlying disorder
(Watanabe et al. 1982b, Clancy and Legido 1991). Previous
studies on neonatal seizures have described seizures of all etiologies, including many occasional seizures (Lombroso
1996). The International Classification (Commission on
Classification and Terminology of the International League
Against Epilepsy 1989) classifies neonatal seizures as undetermined epilepsies with both generalized and focal
seizures. Moreover, it is uncommon for neonates to have
simultaneous generalized and focal seizures.
Epileptic syndromes may change with age. The term agedependent epileptic encephalopathy has been used to
describe a disorder which changes from early infantile
epileptic encephalopathy to West syndrome and then to
LennoxGastaut syndrome (Ohtsuka et al. 1986). However,
other changes with age are also present in epilepsies of
neonatal onset.
The aim of this study is to investigate seizure types of true
neonatal epilepsies and their evolution.
Method
PATIENTS

Most neonatal seizures are occasional seizures and not true

epilepsy. This study investigates seizure types of true neonatal
epilepsies and their evolution with development. Seventy-five
children with epilepsies of onset within 1 month of life, who
were examined between 1970 and 1995, and whose seizure
types could be confirmed with ictal EEG recordings, were
studied. The patients were followed up for a minimum of 3
years and the evolution of epileptic syndromes was
investigated. Sixty-three (84%) of 75 patients had partial
seizures, while nine had generalized seizures, and only three
had both generalized and partial seizures. Twenty-three of 24
neonates with benign familial or non-familial neonatal
convulsions presented with partial seizures; these syndromes
should not necessarily be categorized into generalized epilepsy
as they are in the present International Classification. Agedependent changes were a common feature of symptomatic
neonatal epilepsies. Eighteen (41%) of 44 patients with
symptomatic epilepsies of neonatal onset developed West
syndrome in infancy. Fifteen (83%) of these 18 patients
presented with symptomatic localization-related epilepsy in
the neonatal period. In seven of these 15 patients, West
syndrome was followed by localization-related epilepsy.
Symptomatic localization-related epilepsy with transient
West syndrome in infancy is another type of age-dependent
epileptic syndrome.

318

Developmental Medicine & Child Neurology 1999, 41: 318322

Seventy-five infants participated in the study. Their gestational ages ranged from 37 to 41 weeks, except one who
was born at 36 weeks; birthweights ranged from 1670 to
4300 g. The exclusion of preterm infants was not intentional but may be due to preterm babies being prone to acute
symptomatic seizures. Also, the absolute number of
preterm babies is fewer than term babies. Seven patients
died before 1 year of age. The other patients were followed
up for a minimum of 3 years and their ages at the last followup ranged from 3 to 19 years.
PROCEDURE

Pediatric neurologists with an expertise in epilepsy and

neonatal electroencephalograms (EEG) collected data from
the neonatal-care units of four hospitals on patients who
had onset of epilepsies within 1 month of life. Information
was obtained retrospectively and was available on patients
examined between 1970 and 1995 in one hospital and
between 1984 and 1995 in the others. The inclusion criterion was the occurrence of repetitive seizures due to causes
other than acute brain insults such as hypoxicischemic
events, intracranial hemorrhage, meningitis, encephalitis,
hypocalcemia and other electrolyte abnormalities, or hypoglycemia. All neonates alleged to have had more than one
seizure and who were admitted to the neonatal-care unit
were monitored with EEG for a maximum of 3 hours. Only
patients with seizures confirmed to be epileptic in nature
with ictal EEGs were included. Thus, neonates having infrequent, self-limited, or equivocal epileptic seizures were
excluded. After the neonatal period, the type of seizure was
usually diagnosed clinically, although frequent daily
seizures were recorded with video and EEG monitoring.

Patients reported in previous studies (Watanabe et al.1976,

Watanabe 1981, Aso et al. 1992, Miura et al. 1993) were eligible for inclusion. The following information was collected
using a standardized protocol: gestational age, birthweight,
family history, pre-, peri- and postnatal histories, the presence or absence of underlying disorders, details of neonatal
seizures, ictal and interictal EEG findings in the neonatal
period, neuroimaging studies including CT and/or MRI,
EEG findings during the clinical course, syndromic classification during the clinical course, details of seizure, and
developmental outcome.
The seizure types and syndromes were determined according to those set out by the Commission on Classification and
Terminology of the International League Against Epilepsy
(1981, 1989) with some modifications. The seizure types in
the neonatal period were confirmed with ictal EEG recordings
and classified into partial and/or generalized seizures. But
semiological classification of seizures was not studied for the
following reasons: simultaneous video/EEG recordings were
not performed in all cases, seizure manifestations were protean in neonatal seizures, and the same patient displayed different types of clinical seizures.
Subjects were categorized etiologically throughout followup, because of difficulty in knowing whether a neonate was
neurologically or developmentally normal. Neuroimaging
examinations performed during follow-up were also taken
into consideration. Some disorders or syndromes, such as
Ohtahara syndrome, were easily diagnosed during the neonatal period because they have characteristic features, but others need longer follow-up for accurate diagnosis. Idiopathic
epilepsy is defined as an epilepsy having no underlying cause
other than a possible hereditary predisposition. This was
diagnosed if a subject had no underlying disorders, seizures
were easily controlled, and neurodevelopmental status at follow-up was normal. Symptomatic epilepsies are consequences of a known or suspected disorder of the brain, and
are diagnosed if the subject had an underlying disorder, a
moderate or severe learning disability, or neurological abnor-

malities at follow-up, even if no underlying disorder was

detected. Cryptogenic epilepsy is an epileptic disorder whose
cause is hidden or occult. In this study, it was diagnosed when
a patient had mild developmental delay or seizures that were
refractory for the follow-up period but with no detectable
underlying disorders.
Results
SEIZURE TYPES IN THE NEONATAL PERIOD

Table I shows the type of seizures and epileptic syndromes

occurring in the 75 patients during the neonatal period.
Of the 24 children with idiopathic epilepsies, seven of
eight infants with benign familial neonatal convulsions
(BFNC) presented with partial seizures and one with generalized seizures. The latter displayed generalized tonicclonic
convulsions associated with generalized desynchronization
followed by semirhythmic alpha/theta waves in all regions of
the brain. Of the eight infants with BFNC, the age at onset
was 1 to 6 days in seven and 23 days in one. All of the 16
infants with benign neonatal convulsions (BNC) presented
with partial seizures. The age at onset was 1 to 7 days in 13
neonates and 10 to 22 days in three.
Of the 44 infants with symptomatic epilepsy, five of the
eight infants with early infantile epileptic encephalopathy
(EIEE) with suppressionburst presented with generalized
seizures, namely tonic spasms, and three presented with
tonic spasms and partial seizures. Their age at onset was 1 to
21 days. Two infants with early myoclonic encephalopathy
(EME) had non-ketotic hyperglycinemia and exhibited partial seizures and erratic myoclonia but no generalized
seizures, such as massive myoclonic seizures or tonic
spasms, in the neonatal period. Their age at onset was 1 day
and 25 days, respectively. The EEG of these infants showed
suppressionburst pattern, with bursts lasting from 1 to 5
seconds and suppression lasting from 13 to 60 seconds.
Three of the five infants with holoprosencephaly had semilober type holoprosencephaly and displayed generalized
tonic seizures characterized electroencphalographically by

Table I: Epilepsies of neonatal onset occurring during the neonatal period

Epileptic syndrome

Idiopathic
Benign familial neonatal
convulsions
Benign neonatal convulsions
Symptomatic
Early infantile epileptic
encephalopathy
Early myoclonic encephalopathy
Holoprosencephaly
Tuberous sclerosis
Othera
Cryptogenic
Total

Nr of
patients

Seizure types in the neonatal period

Partial
Generalized
PS+GS
seizures (PS)
seizures (GS)

16

16

2
5
4
25
7
75

2
2
4
25
7
63

0
3
0
0
0
9

0
0
0
0
0
3

aAicardi syndrome, 1; localized cortical dysplasia, 4; microcephaly, 3; 18-trisomy, 2; porencephaly,

1; lissencephaly, 1; congenital cytomegalovirus infection, 1; peroxysomal disease, 1; moderate or
severe learning disability with or without neuroimaging abnormalities, 11.

Epilepsy of Neonatal Onset Kazuyoshi Watanabe et al. 319

desynchronization and recruiting rhythms. Their interictal

EEGs disclosed continuous high-amplitude rhythmic
alpha/theta activity with anteriorposterior amplitude gradient in wakefulness, which became discontinuous and asynchronous during sleep. The other two had alobar
holoprosencephaly and demonstrated rhythmic alpha/theta
activity only in anterior regions. The ictal EEG showed lowvoltage beta waves, followed by rhythmic activity of decreasing frequency and increasing amplitude, and ending with
delta waves in both frontotemporal regions corresponding to
the presence of the forebrain. The clinical seizure consisted
of opening of the eyes, tonic extension of both legs followed
by mouth opening and closing. This might be considered a
variant of a generalized tonic seizure due to the absence of the
posterior brain, although it was provisionally classified as partial seizure by definition. Their age at onset ranged from 0 to
15 days. All four neonates with tuberous sclerosis presented
with partial seizures at 0 to 20 days of age. The other 25
infants with symptomatic epilepsy presented with partial
seizures at 0 to 30 days of age. All seven neonates considered
to have cryptogenic epilepsy presented with partial seizures
at 2 to 14 days of age.
In all, 63 neonates presented with partial seizures, nine
with generalized seizures, and three with both types of
seizures. The neonates with both types of seizures had EIEE.
Partial seizures were observed in both idiopathic and symp-

Table II: Evolution of epileptic syndromes (N=51)

Epileptic syndromes
EIEE and EME
EIEE
WS

EIEE
WS

EIEE
SGE

EIEE
SLRE

EIEE
Seizure free

EIEE
Early death

EME
WS

Holoprosencephaly
SGE
WS

SGE
LRE

SGE
Seizure free

SLRE
SLRE

Tuberous sclerosis
SLRE
SLRE

SLRE
WS

SLRE
WS

Other symptomatic epilepsies

SLRE
WS

SLRE
WS

SLRE
WS

SLRE
WS

SLRE
SLRE

SLRE
Seizure free

Cryptogenic epilepsies
CLRE
CLRE

Nr of patients

SLRE
LGS

1
1
3
1
1
1
2

SLRE
LGS

1
1
1
2
1
1
2

SLRE
SGE/LGS
SGE
SLRE
Death
Seizure free

4
4
1
1
10
5
7

EIEE, early infantile epileptic encephalopathy; EME, early

myoclonic encephalopathy; WS, West syndrome;
LGS: LennoxGastaut syndrome; SLRE, symptomatic localizationrelated epilepsy; SGE, symptomatic generalized epilepsy;
CLRE, cryptogenic localization-related epilepsy.

320

Developmental Medicine & Child Neurology 1999, 41: 318322

tomatic cases, whereas generalized seizures usually took a

form of epileptic spasms or tonic seizures, and were present
mainly in EIEE and semilobar holoprosencephaly.
EVOLUTION OF EPILEPTIC SYNDROMES

Two of the eight infants with BFNC had seizures in infancy

and early childhood, which were easily controlled. It is not
known whether later seizures differed from neonatal
seizures. Three of our 16 patients with BNC had a recurrence
of seizures at 1, 3, and 12 months of age, respectively, all of
which could be easily controlled.
Table II illustrates the evolution of epileptic syndromes,
excluding infants with idiopathic epilepsy. Two of the eight
infants with EIEE developed West syndrome, one developed
symptomatic localization-related epilepsy, one developed
LennoxGastaut syndrome, three developed symptomatic
generalized epilepsy, and one developed localization-related
epilepsy. Two infants with EME developed West syndrome
transiently but had a final diagnosis of localization-related
epilepsy with partial seizures and erratic myoclonia. One of
the three infants with holoprosencephaly, presenting with
symptomatic generalized epilepsy in the neonatal period,
developed West syndrome and then LennoxGastaut syndrome; one developed symptomatic localization-related
epilepsy; and one eventually became seizure-free. Two with
localization-related epilepsy continued to have partial
seizures. All four patients with tuberous sclerosis presented
with symptomatic localization-related epilepsy in the neonatal period. One continued to have partial seizures without
evolutionary changes of epileptic syndrome, and three
developed West syndrome, followed by localization-related
epilepsy in one and symptomatic generalized epilepsy or
LennoxGastaut syndrome in two. Ten of the 25 infants who
presented with other symptomatic localization-related
epilepsies in the neonatal period developed West syndrome,
followed by symptomatic generalized epilepsy in four and
localization-related epilepsy in four; 10 continued to have
partial seizures; and five became seizure-free. All patients
with cryptogenic localization-related epilepsy did not
demonstrate any evolution of epileptic syndrome and continued to have partial seizures.
As a whole, 18 (41%) of 44 patients with symptomatic
epilepsies of neonatal onset developed West syndrome in
infancy. Thirteen of these 18 patients presented with symptomatic localization-related epilepsy in the neonatal period.
Two of them had EIEE, two had EME, and one had semilobar
holoprosencephaly. The two patients with EME were diagnosed as having localization-related epilepsy in the neonatal
period. Thus, 15 (83%) of the above 18 patients presented
with symptomatic localization-related epilepsy in the neonatal period, and in seven of these 15 patients, West syndrome
was followed by localization-related epilepsy.
Discussion
Most of the neonates under study displayed partial seizures,
and generalized seizures were infrequent. Epilepsies with both
generalized and focal seizures were rare and the four neonates
with both types of seizures had EIEE. Partial seizures were
observed in subjects with idiopathic and symptomatic epilepsies, whereas generalized seizures were present mainly in
those with EIEE and semilobar holoprosencephaly. Brief tonic
spasms were seen in the former and tonic seizures associated

with recruiting rhythms were observed in the latter. In contrast,

almost all occasional seizures were partial seizures and tonic
spasms were not present (Watanabe 1993).
BFNC is classified as generalized epilepsy in the current
International Classification, but ictal EEGs of their seizures
have been well documented in a few cases (Giroud et al.
1989, Wakai et al.1990, Andrew and Stafstrom 1993, Hirsh et
al. 1993, Mori et al. 1993, Ronen et al. 1993, Bye 1994).
Twelve of 16 neonates, including our subjects (eight infants),
in whom ictal EEGs were recorded, had partial seizures and
four had generalized seizures. Seven of our eight subjects
demonstrated partial seizures and one was considered to
have generalized seizures, even though their ictal EEGs were
not typical of generalized seizures of older children and
adults, because of no paroxysmal discharges of clearly focal
onset. Wakai et al. (1990) described more typical generalized
tonicclonic convulsions in a 4-month-old infant with BFNC
who had recurrences of seizures at 3 and 4 months of age. In
most families with BFNC, linkage to chromosome 20q has
been reported (Malafosse et al. 1992), but there seems to be
genetic heterogeneity (Ryan et al. 1991, Schiffmann et al.
1991) and the existence of a second locus on chromosome
8q (Steinlein et al. 1995) and an as yet unidentified third
locus has been suggested (Lewis et al. 1996). It remains to be
elucidated whether this genetic difference is reflected by the
difference in seizure types.
Benign neonatal convulsions (BNC) are also classified as
generalized epilepsy in the International Classification. But
most of the reported cases in which seizures were recorded
demonstrated localized paroxysmal discharges. All of our 16
subjects with BNC demonstrated partial seizures. Two infants
with BNC recently reported by Alfonso et al. (1997) showed
generalized attenuation of the background activity, followed
by focal onset paroxysmal discharges in association with bilateral tonicclonic seizures. Initial generalized voltage attenuation is also observed in partial epilepsy of older children and
adults. Thus, they may be considered partial seizures,
because the following discharges are clearly focal. This syndrome should be classified as localization-related epilepsy.
Infants with BFNC may have a recurrence of seizures
beyond the neonatal period. Approximately 10% of patients
had subsequent epileptic seizures in infancy, childhood, or
adolescence (Plouin 1992). Two of our eight infants with
BFNC had seizures in infancy and early childhood, which
were easily controlled. In BNC, a recurrence of seizures has
been reported to be low (Miles and Holmes 1990), but three
of our 16 patients with BNC had a recurrence of seizures,
although the type of subsequent epileptic seizures is
unknown. Gonzalez Ipina et al. (1996) observed central temporal rolandic EEG foci in a few patients with BFNC or BNC
and suggested a possibility of common genetic factors with
benign rolandic epilepsy. BNC may be a heterogenous condition and a long-term follow-up study is necessary to confirm
its benignity and its nature.
EIEE is classified into symptomatic generalized epilepsy in
the International Classification (Commission 1989). The
presence of tonic spasms is indispensable for the diagnosis,
although partial motor seizures may occur (Ohtahara et al.
1992). Five of eight patients under study had tonic spasms,
and three had partial seizures in addition to tonic spasms in
the neonatal period. This syndrome often evolves into West
syndrome and then to LennoxGastaut syndrome. This has

led to the concept of age-dependent epileptic encephalopathy, but other evolutionary changes can occur. Two of our
eight infants with EIEE eventually developed localizationrelated epilepsy with or without passing through the period
of West syndrome. Ohtahara et al. (1992) reported that eight
of 15 patients eventually had focal spikes with or without
passing through the period of hypsarrhythmia. We examined
a child with this syndrome in which suppressionburst patterns were replaced by continuous background EEG with
spindles displaying only focal spikes, which then evolved
into multifocal spikes and then to hypsarrhythmia (Watanabe
et al. 1987). This may contradict the notion that EIEE may be
West syndrome with an early onset (Lombroso 1990).
EME is also categorized as symptomatic generalized
epilepsy in the International Classification. It is characterized
by partial or fragmentary erratic myoclonus, massive myoclonia, partial motor seizures, and suppressionburst pattern on
EEG (Aicardi 1992). The infants under study did not demonstrate generalized seizures and showed only partial seizures
in addition to erratic myoclonia during the neonatal period,
and continued to show partial seizures thereafter. This syndrome may not necessarily be placed under the category of
generalized epilepsy, although some patients with this syndrome may develop West syndrome transiently.
Neonatal epilepsy with rhythmic alpha/theta activity is characterized by a peculiar EEG consisting of high-amplitude rhythmic alpha/theta activity, which is continuous during
wakefulness and becomes discontinuous during sleep, tonic
seizures associated with desynchronization, and recruiting
rhythm followed by oral automatism associated with slow
waves (Watanabe et al. 1976). This is typically seen in neonates
with semilober holoprosencephaly. In alobar holoprosencephaly, rhythmic alpha/theta activity is present only in anterior
regions. In such cases, seizure types are difficult to determine
due to the absence of the brain in posterior regions, although
they were provisionally classified into partial seizures by definition. Continuous high-voltage rhythmic alpha/theta/delta activities are also observed in other cortical dysplasia such as type I
lissencephaly, but are not usually observed in the neonatal
period (Dalla Bernardina et al. 1996). Moreover, they do not
show asynchronous discontinuity in sleep and have no anteriorposterior voltage gradient.
The International Classification classifies neonatal
seizures into undetermined epilepsies with both generalized
and focal seizures. But in this study, only three patients with
EIEE had both generalized and partial seizures in the neonatal period. Therefore, epilepsy with both generalized and
focal seizures is rather exceptional in neonatal epilepsies.
In our present study, seven infants were diagnosed as having cryptogenic epilepsy. They had no evidence of underlying disorders and exhibited normal or mildly delayed
psychomotor development, despite the presence of
intractable partial seizures. They seemed to have idiopathic
epilepsy because of the absence of any apparent cerebral
lesions or definite developmental retardation, but the refractoriness of their seizures suggests the presence of latent
minor cerebral lesions that could not be detected by existing
neuroimaging studies. The presence of such cryptogenic
localization-related epilepsy of neonatal onset has been
described by Natsume et al. (1996). Our subjects and those
studied by Natsume continued having partial seizures without evolutionary changes of epileptic syndromes.

Epilepsy of Neonatal Onset Kazuyoshi Watanabe et al. 321

The concept of age-dependent epileptic encephalopathy

has been applied to EIEE, West, and LennoxGastaut syndromes (Yamatogi and Ohtahara 1981). However, such evolutionary changes of epileptic syndromes are not restricted
to these syndromes but are also observed in other syndromes. As shown in this study, newborn infants with symptomatic epilepsy other than EIEE, EME, and semilobar
holoprosencephaly are particularly prone to localizationrelated epilepsy, and are likely to develop West syndrome
transiently in infancy. Thereafter, they may have localizationrelated epilepsy again or develop LennoxGastaut syndrome
depending upon the extent of brain damage. Symptomatic
localization-related epilepsy with transient West syndrome is
another type of age-dependent epileptic syndrome.
Accepted for publication 19th January 1999.
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