The Incidence of Acute and Remote Seizures

in Children with Intraventricular Hemorrhage

Jonathan B. Strober, MD
Robert S. Bienkowski, PhD
Joseph Maytal, MD

Summary: Seizures are a well-known complication of intraventricular hemorrhage (IVH) in

premature infants; however, the rate at which they occur is not known. The authors decided,
therefore, to investigate both the incidence of acute and remote seizures in infants with IVH and
the association with the grade of hemorrhage. One hundred and three infants with IVH were
identified and their records were reviewed for acute seizures, remote seizures, and associated
morbidity and mortality. The average gestational age of these infants was 29 weeks (range, 23-40
weeks). Of the 103 infants, 32 (31%) developed grade 4 IVH; 19 (18%), grade 3 IVH; and 52 (50%),
grades 1 and 2 1VH. Seventeen (17%) patients had acute seizures during their first month of life.
Six of the 61 patients (10%) who survived the neonatal period and for whom follow-up data were
available had, remote seizures. Infants with grade 4 IVH had significantly more acute seizures than
infants with grades 1 and 2. In this cohort, only infants with grades 3 and 4 IVH developed remote
seizures. Furthermore, among infants with grade 4 IVH acute seizures were a significant risk factor
for development of remote seizures. The use of long-term antiepileptic drug therapy in neonates
with a history of acute seizures is not established. These results suggest that antiepileptic drug
therapy beyond the neonatal period should be reserved for infants with grade 4 IVH with history
of acute seizures. Clin Pediatr. 1997;36:643-648

Introduction among premature infants.'-3 De- sual impairments.' Neonatal

pending on the extent of the he- seizures present a high risk for
I ntraventricular hemorrhage morrhage, infants can develop neonatal death and adverse neu-
(IVH) is an important cause seizures, cerebral palsy, mental re- rodevelopmental sequelae for
of morbidity and mortality tardation, hearing deficits, and vi- both preterm and full-term in-
fants.4,5 The information about
the incidence of acute seizures in
Division of Pediatric Neurology and Pediatric Research Center, Schneider Children's Hospital, neonates with IVH is scant,246
Long Island Jewiish Medical Center, The Long Island Campus for the Albert Einstein College and only little information is avail-
of Medicine, New Hyde Park, NY. able about the incidence of re-
Presented in part at the Child Neurology Society Meeting, San Francisco, California,
mote seizures in this population.
October 1994. In one study, 13% of infants with
IVH developed remote seizures;2
Reprint requests and correspondence to: Joseph Maytal, MD, Division of Pediatric Neurology, in another study, 63% of full-term
Schneider Children's Hospital, Long Island Jewish Medical Center, New Hyde Park, New York infants with IVH had remote
11040. seizures, mostly occurring after 1
© 1997 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A. year of age.6

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NOVEMBER 1997 CLINICAL PEDIATRICS 643
 Strober, Bienkowski, Maytal
Prophylactic administration of
antiepileptic drugs to infants with
histories of neonatal seizures is
controversial, and no guidelines
have been established regarding
the role of long-term antiepileptic
drug therapy for these infants.7-9
Many authors suggest continuing
antiepileptic drug therapy be-
yond the neonatal period for in-
fants with histories of perinatal in-
sult and abnormal findings from
neurologic examinations.10-12
However, there are concerns
about potential long-term delete-
rious effects of phenobarbital and
other antiepileptic drugs.12
In this study we investigated
both the incidence of acute and
remote seizures in premature in-
fants who suffered from IVH
while in the neonatal intensive
care unit and the association be-
tween the grade of hemorrhage
and the seizure outcome in these
children.
Materials and Methods
Patients were identified by
searching the neonatal database
for infants with grades 1-4 IVH
who were discharged from the
Schneider Children's Hospital be-
tweenJanuary 1, 1992, and Octo-
ber 15, 1993. Data regarding mor-
bidity and mortality, radiologic
studies, and the occurrence of
acute and remote seizures and
their treatment were obtained
from medical records. All patients
with 1VH had ultrasonograms to
establish the diagnosis. Severity of
IVH was classified as follows:'3
grade 1, hemorrhage limited and
around the choroid plexus; grade
2, hemorrhage into the ventricle
without hydrocephalus; grade 3,
hemorrhage into the ventricle
with development of hydro-
cephalus; grade 4, hemorrhage
into the brain parenchyma and
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the ventricular system in associa- the incidence of acute and re-
tion with ventriculomegaly. mote seizures and to calculate the
Seizures were diagnosed by risk of remote seizures in grade 4
the health caregiver (i.e., doctor IVH children with history of acute
or nurse) witnessing the event neonatal seizures.
and the consulting pediatric neu-
rologist concurring with the diag-
nosis. Seizures were defined clini-
cally as paroxysmal alteration in
Results
neurologic function and were
classified as clonic, tonic, my- Characteristics ofStudy Cohort
oclonic,and subtle.12 Acute One hundred and three in-
seizures were defined as seizures fants (45 females, 58 males) with
occurring during the first month all grades of IVH were identified;
of life. Remote seizures were de- 18 (17%) of these infants experi-
fined as seizures occurring after enced acute and remote seizures.
the first month of life. Other eti- Of the total 103 infants who de-
ologies for acute seizures, e.g., hy- veloped IVH, 32 (31%) had grade
poglycemia, were excluded be- 4. 19 (18%) had grade 3, 21
fore the seizures were ascribed to (20%) had grade 2, and 31 (30%)
IVH. had grade 1 IVH (Table 1). The
Follow-up information for gestational ages of these infants
those infants who survived the ranged from 23 to 40 weeks, with
neonatal period was obtained by an average of 29 weeks for grade
reviewing their records in the Di- 1, 28 weeks for grade 2, and 27
visions of Neurology and of Devel- weeks for grades 3 and 4 IVH. Of
opmental Pediatrics and by tele- the 13 infants who expired during
phoning the pediatricians of the neonatal period, one had
record on the discharge sum- grade 3 IVH, and 12 had grade 4.
maries. Information was obtained Follow-up information was avail-
about seizures after the neonatal able for 61 of the 90 infants who
period and the treatment, as well survived the neonatal period.
as the developmental and physi- This group included 18 of 20
cal status of the children. Devel- (90%) surviving infants who had
opmental delay was categorized as grade 4 IVH. The mean follow-up
mild, moderate, or severe accord- time was 2 years and 7 months
ing to the criteria developed by (range 6 months to 4 years, 3
Saigal et al.'4 Mild disability is de- months).
fined as mild diplegic cerebral Developmental delay was re-
palsy and independent ambula- ported in 30 of the 61 surviving
tion; moderate disability is de- infants for whom follow-up data
fined as moderate cerebral palsy, were available. Eight infants had
inability to walk independently, grade 1 (seven mild delay and one
and a need for some additional moderate delay), one infant had
caregiving; severe disability is de- grade 2 (moderate), five infants
fined as severe cerebral palsy, in- had grade 3 (two mild, two mod-
ability to walk or severe develop- erate, and one severe), and 16 in-
mental retardation, or severe fants had grade 4 IVH (nine mild,
special-sense disorder requiring five moderate, and two severe).
significant additional caregiving. All patients who developed re-
Fisher's Exact Test was used to mote seizures were developmen-
determine the association be- tally delayed, four severely, two
tween the grade of the IVH and moderately, and one mildly.
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 Acute and Remote Seizures in Premature Infants with IVH
Acute Seizures
Acute seizures were recorded
in 17 infants (17%; 95% CI for the
incidence: 10 to 25%). Twelve in-
fants had grade 4 IVH, two had
grade 3, and three had grade 2.
No infants with grade 1 IVH had
acute seizures (Table 1). Because
of the relatively small sample size
and the association of grades 1
and 2 IVH with good prognosis,'
infants with these grades were
combined into a single group for
statistical analysis. Infants with
grade 4 IVH had a significantly
higher proportion of acute
seizures than infants with grades 1
and 2 (P=0.0007, Fisher's Exact
Test). The relative risk of having
acute seizures in infants with
grade 4 IVH versus infants with
grades 1 and 2 was 6.5 (95% CI: 20
to 21.3). However, infants with
grade 3 IVH did not have a signif-
icantly increased proportion of
acute seizures (P=0.6).
The majority of seizures were
characterized as generalized
tonic, which occurred in seven in-
fants with grade 4 IVH, one infant
with grade 3, and two infants with
grade 2. Focal clonic seizures oc-
curred in one infant with grade 4
PVH and one infant with grade 3.
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Other seizure types exhibited by Of the 18 patients with grade 4
infants with grade 4 IVH included IVH whom we followed up, four
generalized clonic, myoclonic, suffered both acute and remote
and subtle seizures. One infant seizures, one suffered acute
with grade 2 had a focal tonic seizures but no remote seizures,
seizure. All infants with acute and one suffered remote seizures
seizures were treated with pheno- but no acute seizures. Thus pa-
barbital and one also required tients who had acute seizures dur-
phenytoin. ing the neonatal period had a ten-
fold greater risk for developing
Remote Seizures chronic seizures than patients
Remote seizures occurred in who did not have acute seizures
six (10%) of the 61 infants for (P=0.008).
whom follow-up information was
available. Five of these infants had
grade 4 IVH and one had grade 3 Discussion
(Table 1). One infant with grade 4
IVH without an acute seizure later In this study we found a high
developed remote seizures. All in- incidence (17%) of acute seizures
fants were treated with either phe- in neonates who suffered IVH.
nobarbital alone or in combina- The data in the literature regard-
tion with carbamazepine or ing this issue are scant and the
phenytoin. None of the 32 infants sample sizes of the few studies
with grades 1 and 2 IVH had that investigated it are small. A
seizures after the neonatal period; previous study of the incidence of
however, five of 18 infants with electrographically confirmed
grade 4 P/H did. The difference seizures in preterm infants by
in proportions is significant Scher et a14 found that 4% had
(P-0.0036). The proportion of in- acute seizures. The number of
fants with grade 3 IVH who devel- seizures in neonates with LVH was
oped remote seizures did not dif- not reported, but 28 of 62 (45%)
fer significantly from the preterm infants with seizures had
proportion of infants with grades IVH. Aso et a12 documented
1 and 2 IVH (P=0.6) seizures in 13% (4/32) of neo-
CLINICAL PEDIATRJ.S
CLINICAL PEDIATRICS
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645
 I
nates with IVH who required EEG
recordings. A study by Sugimoto
et a16 on full-term infants with
IVH reported that four of eight
(50%) had acute seizures. Funato
et al15 performed a continuous
monitoring of the germinal layer
by linear scanning ultrasound and
reported that one of four (25%)
immature infants with IVH devel-
oped acute seizures. The data
from these studies are compared
in Figure 1. In the figure note that
the 95% CI ranges of the studies
are very broad because the sam-
ples are small. Also note that the
confidence intervals for the four
studies overlap. Combining the
data for the four separate studies
yields an estimated incidence for
acute seizure in the range of
15-25%.
Infants with IVH may have
acute seizures from a variety of
causes.12 The high incidence of
acute seizures that we found in in-
fants with grade 4 IVH as com-
pared with the rest of the IVH co-
hort, and as compared with some
historical data on premature in-
fants,16 indicates that parenchy-
Funato et a115
Sugimoto et a16
Aso et a12
Strober et al i -
Combined
I
* I
* I
. I.
0 20
Incidence of Acute Seizure in IVH (% I
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Strober, Rienkowski, Maytal
mal hemorrhage may be a poten-
tially important epileptogenic
factor.
The development of remote
seizures was infrequent in our
IVH cohort (six of 61, 10%, 95%
CI: 4 to 20%); however, the rate
among the infants with grade 4
IVH was much higher (28%). All
but one infant with remote
seizures had a history of acute
seizures. Comparison with other
studies cannot be made directly
because of different recruitment
criteria. In reviewing the out-
comes of very-low-birth-weight in-
fants (less than 1,500 grams),
Cooke'6 found only a 1.8% inci-
dence of remote seizures in a
3-year follow-up period, and
Scher et a14 reported six of 49
(12%) preterm infants studied
with acute seizures later devel-
oped remote seizures.
Our data indicate that infants
with grade 4 IVH and acute
seizures are at increased risk of
developing remote seizures as
compared with infants with grade
4 IVH who did not experience
acute seizures during the neona-
p_
is
40 60
tal period. Similar conclusions
were reached for older children
and adults who had acute seizures
secondary to CNS insults such as
trauma, infection, or hemor-
rhage.'7-'9 Furthermore, the risk
of seizure recurrence following a
remote seizure is increased if the
patient has a history of an acute
seizure following CNS insult.20
Although our overall follow-
up rate was limited, it was high
(90%) for infants with grade 4
IVH, who are usually more im-
paired and have high long-term
morbidity.' In infants with grades
1 and 2 IVH, the follow-up rate
was 62% (32/52). The fact that
none of these 32 patients had re-
mote seizures (Table 1) indicates
that the maximal rate of remote
seizures in this group is about
10% (the 95% confidence for the
ratio of 0/32 is 0 to 0.09). Of the
20 patients who were lost to fol-
low-up in this group, one might
expect two, at most, to have re-
mote seizures. Longer follow-up
will be necessary to assess the true
long-term incidence of seizure re-
currence. The incidence of re-
Figure 1. A comparison of
the incidence of acute
seizures in infants with IVH
in four studies and with a
group that combines data
from all these studies. The
horizontal lines indicate the
95% confidence intervals for
the incidence ratios.
80 100
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NOVEMBER 1997
1997
 Acute and Remote Seizures in Premature Infants with IVH
mote seizures may increase over
time.
Our study lacks electroen-
cephalographic verification of
acute seizures, and as a result we
may have overestimated or under-
estimated the incidence of acute
seizures in the neonatal period.
Nevertheless, in virtually all
neonatal intensive care units,
seizures are diagnosed on clinical
grounds and not by an EEG. An
EEG is usually obtained interic-
tally and therefore has lesser clin-
ical significance.21 Our clinical
data showing increased risk of
seizures in infants with grade 4
IVH can be used to guide the clin-
ician in these situations. These
data also support Volpe's recom-
mendation for empirical treat-
ment approach of neonatal
seizures. 12
The question of whether to
initiate long-term antiepileptic
drug therapy in infants who expe-
rienced IVH and acute seizures
during the neonatal period is of
great importance. In making a de-
cision, the physician must take
into account not only the risk of
seizure recurrence in this popula-
tion and its consequences but also
the risks of antiepileptic drug
therapy. There is a broad range of
practices among neonatologists
and pediatric neurologists regard-
ing prophylactic antiepileptic
drug therapy in infants with his-
tory of acute neonatal seizures.
These practices range from a
brief course of medication in the
nursery to extending treatment
up to 2 years of age.7'12,22,23 Since
the overall incidence of remote
seizures in infants with IVH is low,
the use of long-term prophylactic
antiepileptic drug therapy may
not be justified in most of these
patients. Long-term antiepileptic
therapy should be limited to in-
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fants with grade 4 IVH with a his-
tory of acute neonatal seizures,
because these patients are at a
higher risk for developing remote
seizures. For this group of pa-
tients we recommend antiepilep-
tic drug therapy at least for the
first year of life before tapering
medications is considered.
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