Seizure (2006) 15, 590—597

www.elsevier.com/locate/yseiz

Increased number of febrile seizures in children

born very preterm: Relation of neonatal, febrile
and epileptic seizures and neurological dysfunction
to seizure outcome at 16 years of age
Eila A. Herrgård a,*, Marjo Karvonen a, Laila Luoma b,
Pia Saavalainen c, Sara Määttä d, Eila Laukkanen e, Juhani Partanen d

a
Department of Pediatrics, Division of Pediatric Neurology, University and University Hospital of Kuopio,
P.O. Box 1777, 70211 Kuopio, Finland
b
Department of Psychiatry, Kellokoski Hospital, Hospital District of Helsinki and Uusimaa, Finland
c
Department of Psychology, University of Joensuu, Finland
d
Department of Clinical Neurophysiology, University and University Hospital of Kuopio,
P.O. Box 1777, 70211 Kuopio, Finland
e
Department of Psychiatry, University and University Hospital of Kuopio, P.O. Box 1777,
70211 Kuopio, Finland

Received 24 March 2006; received in revised form 17 August 2006; accepted 29 August 2006

KEYWORDS Summary
Febrile seizure;
Neonatal seizure; Purpose: In prematurely born population, a cascade of events from initial injury in
Epilepsy; the developing brain to morbidity may be followed. The aim of our study was to assess
Neurological seizures in prematurely born children from birth up to 16 years and to evaluate the
dysfunction; contribution of different seizures, and of neurological dysfunction to the seizure
Prematurity; outcome.
Preterm Methods: Pre- and neonatal data and data from neurodevelopmental examination at
5 years of 60 prospectively followed children born at or before 32 weeks of gestation,
and of 60 matched term controls from the 2 year birth cohort were available from
earlier phases of the study. Later seizure data were obtained from questionnaires at 5,
9, and 16 years, and from hospital records and parent interviews.
Results: In the preterm group, 16 children (27%) exhibited neonatal seizures, 10
children (17%) had seizures during febrile illness and 5 children had epilepsy. Eight
children had only febrile seizures, and 3 of these had both multiple simple and complex
febrile seizures and neurodevelopmental dysfunction. None of the 8 children had
experienced neonatal seizures, 6 had a positive family history of seizures, but none

* Corresponding author. Tel.: +358 17 172412; fax: +358 17 174592.

E-mail address: eila.herrgard@kuh.fi (E.A. Herrgård).

1059-1311/$ — see front matter # 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.seizure.2006.08.004
Increased number of febrile seizures in children born very preterm 591

developed epilepsy. The children with epilepsy had CP and neurocognitive problems,
and all but one had experienced neonatal seizures; two of them had also had fever-
induced epileptic seizures. In controls 3 children (5%) had simple febrile seizures.
Conclusion: Children born very preterm have increased rate of febrile seizures
compared to the controls. However, no cascade from initial injury via febrile seizures
to epilepsy could be shown during the follow-up of 16 years. Symptomatic epilepsy in
prematurely born children is characterised by neonatal seizures, major neurological
disabilities and early onset of epilepsy.
# 2006 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Introduction blems in the birth cohort of children born preterm

Prematurity includes many risk factors for the integ-
rity of the central nervous system (CNS) and for
development prenatally and during first months of
life due to the immaturity of many organ systems.
Seizures may arise from an underlying acute disease
process or the genetic background, or a combination
of genetic predisposition and a pre-existing lesion.
Seizures may initiate a cascade of events leading
over time to functional and structural changes in
neuronal networks. Human and animal studies have
shown that the vulnerability of the brain to different
harmful events is age-specific, i.e. depends on the
maturity of the CNS.1—3
Hypoxic-ischemic cerebral injury perinatally is
associated with both neonatal and later seizures
and neurological disabilities.4 Recent animal studies
have shown that neonatal seizures permanently
disturb neuronal development, induce synaptic
organization and alter plasticity.5—7 These changes
in the neuronal network prime the brain to
increased damage from seizures later in life.5,6
Febrile seizures are the most common type of
seizure in children.8,9 Genetic susceptibility to sei-
zures is critical regarding the type of febrile seizure
and of subsequent epilepsy.10—12 Simple febrile sei-
zures carry only little risk of developing epi-
lepsy.10,13 However, prolonged febrile seizures
may alter hippocampal circuits leading to hyperex-
citable networks.14,15 Several studies have recog-
nised an association between complex febrile
seizures and an increased risk of subsequent tem-
poral lobe epilepsy (TLE).12,16,17
Our prospective study project on prematurely
born children from the beginning was a neurodeve-
lopmental outcome study with extensive back-
ground and morbidity data including seizure data.
In this population we can consider different ele-
ments of epileptogenesis: hypoxic-ischemic and
other adverse events during pre-, peri- and neonatal
period appearing as neurological dysfunction, and
neonatal, febrile and epileptic seizures. The pur-
pose of this study was to examine the occurrence of
different seizures and neurodevelopmental pro-
at 32 weeks of gestation, and to compare the
neurological morbidity at different assessment
points from birth up to the age of 16 years to the
morbidity of the children born at term. Especially,
we wanted to evaluate the contribution of neonatal,
febrile and epileptic seizures, and of neurological
dysfunction to the seizure outcome at 16 years of
age.
Methods
Subjects
The follow-up study of preterm children formed part
of a wider prospective study of risk and control
children born in Kuopio University Hospital during
the study period between 1 April 1984 and 31 March
1986.18,19 The final neonatal study population con-
sisted of 621 children, including all preterm children
and all children small for gestational age (SGA) born
during the study period, and a sample of children
born to hypertensive mothers and their controls
born at term. Ninety-five of these children were
born at 32 weeks of gestation. The gestational age
of the children was assessed according to the date of
the last menstrual period of the mother. The gesta-
tional age of the preterm and of SGA children was
confirmed by the Dubowitz method20 during the first
3 days of life. Eight of the preterm children were
transferred to the group of >32 gestational weeks
on account of their Dubowitz maturity scores. Three
children born at 32 weeks of gestation were not
examined neonatally, and were excluded from the
study. Twenty-two children died during neonatal
period and one at the age of 2 months. One preterm
child did not participate in the clinical examination
at the age of 5 years, since the child had moved
away from the district served by the university
hospital. Thus, 60 out of 95 children born at 32
weeks of gestation were available for the neurode-
velopmental evaluation at 5 years and for seizure
follow-up. A child with Down’s syndrome was
excluded later from further analysis.
592
The control group of 60 term children was
matched with the preterm group for gender, and
educational level as well as socio-economic status of
the parents from a total of 222 term children exam-
ined at the age of 5 years by the same researchers as
the preterm group. The control children belonged to
the birth cohort of the years 1984—1986, and had
also been assessed in the earlier phases of the
follow-up project. In order to maintain the compo-
sition of the original term birth cohort, 84% of the
controls were drawn from the children appropriate
for gestational age (AGA) born to normotensive
mothers, 13% from the AGA children born to hyper-
tensive mothers and 3% from the children born small
for gestational age. The control group served as a
reference group for the preterm children in the
neurological and neuropsychological investigations
at 5 years of age and later in seizure follow-up. The
details of the groups are published earlier.19,21
The study was approved by the Research Ethics
Committee of Kuopio University Hospital. Informed
consent was obtained from the parents of the chil-
dren enrolled in the study.
Pre- and neonatal data
Detailed pre-, peri- and neonatal data were avail-
able from the database of this prospective study
project. The differential diagnosis of neonatal sei-
zures and the classification of the seizures as ‘cere-
bral convulsion’ were performed by an experienced
pediatrician.
Neurological and neuropsychological
examination
A standardized, age-specific neurological examina-
tion22 both for prematurely born and control children
at the age of 5 years was performed by the main
researcher. The Wechsler Preschool and Primary
Scale of Intelligence23 and essential parts of The
Neuropsychological Test Battery for Young Develop-
mentally Disabled Children24 were administered by
the neuropsychologist. For profoundly retarded chil-
dren who could not be evaluated by WPPSI the Bayley
Scale of Infant Development25 was used.
The details of test batteries and scoring criteria
used in neurological and neuropsychological exam-
ination have been described earlier by the
authors.19,21,26 Neurodevelopmental profile com-
prised in addition to general intelligence perfor-
mance in gross motor, fine motor and visual-motor
area of the neurological examination, and atten-
tion, language, visualspatial, sensorimotor and
memory skills of the neuropsychological examina-
tion. Mean scores below the fifth centile for the
E.A. Herrgård et al.
performance of the control group served as a cut-off
point for defining dysfunction in the areas of the
profile. Major neurological dysfunction was defined
as CP, mental retardation, bilateral hearing and
severe visual impairment. If children had no major
dysfunction and had a mean score below the fifth
percentile for the term group at least two of the
entities of neurodevelopmental profile, they were
classified as having minor neurological dysfunction.
Questionnaire and interview of parents
During the neurological assessment at 5 years of age
the parents completed a questionnaire on seizure
disorders in their child concerning epilepsy, febrile
seizures and other seizure disorders, medication
and other health problems. The completed ques-
tionnaire was available for all children. After the
assessment the examiner shortly checked the ques-
tionnaire and discussed about history and neurolo-
gical findings in their child. Hospital records we
examined when needed.
During the follow-up at 9 and 16 years, question-
naires concerning seizure disorders, school perfor-
mance and medication of the children were sent to
the families. At 9 years, completed questionnaires
were available for 53 of the prematurely born chil-
dren (90%) and for 56 of the control group (93%). At
16 years completed questionnaires were available
for 51 children born prematurely (86%) and for 44 of
the control group (73%).
The main researcher interviewed by telephone
all non-responding parents and the parents of the
children with seizures after the questionnaires at
age 9. The seizure history of the child and of other
family members and relatives was obtained as pre-
cisely as possible. The main researcher checked the
hospital records of all children who had a history of
epileptic, febrile or other seizures, and of non-
responders at 9 and 16 years. Febrile seizures were
classified as simple if a seizure duration was less
than 15 min, if a seizure was symmetric and it did
not recur in a period of 24 h, otherwise as complex.
Data analysis
Data were analyzed using SPSS for windows (Version
11.5). Means, S.D.s and ranges are provided for con-
tinuous variables in the tables. The results for cate-
gorized variables are presented as frequencies and
relative frequencies. Fisher’s exact test was used to
compare relative frequencies between groups when
categorical variables were considered. Logistic
regression was used to compare risks for febrile
seizures between the study groups. The risks for
febrile seizures were similarly compared between
Increased number of febrile seizures in children born very preterm 593

neurologically normal children and children having
minor or major neurological dysfunction. The results
of logistic regression analyses were expressed as odds
ratios (OR) and their 95% confidence intervals.
Results
Background factors
The pre-, peri- and neonatal characteristics of the
prematurely born and control children are presented
in Table 1. Rate of risk factors was much higher in the
preterm group compared to the control group.
seizures, one had complex febrile seizures, and
three had both simple and complex febrile seizures.
One prematurely born child had a seizure difficult to
classify during a fever of 398 following sunstroke at
the age of 5.5 years. He had epileptiform EEG and
had febrile seizures in relatives. Two children had
lesional symptomatic epilepsy and their febrile sei-
zures were fever-provoked epileptic seizures. Two
of the prematurely born children with febrile sei-
zures were siblings. Three children from the control
group had febrile seizures (Table 2). None of the
children with febrile seizures, except the two chil-
dren with symptomatic epilepsy from infancy,
developed epilepsy up to 16 years of age.

Neonatal seizures Symptomatic epilepsy

Neonatal seizures were reported in 16 prematurely
born children (27%) (Table 2). On discharge from the
neonatal unit, 5 children were on AED treatment. One
preterm child with neonatal seizures was resusci-
tated at the age of 5 months due to respiratory
difficulties and pneumonia. He developed chronic
epilepsy. None of the controls had neonatal seizures.
Febrile seizures
Up to 9 years of age, 10 of the prematurely born
children (17%) had experienced seizures during feb-
rile illness. Three of the children had simple febrile
In the preterm group, 5 children had symptomatic
epilepsy and only one these did not have neonatal
seizures (Table 3). All these children had epileptic
seizures from infancy. The epilepsy classification
after infancy was partial epilepsy with some secon-
darily generalized seizures. No child was encoun-
tered with a typical seizure pattern for mesial
temporal epilepsy. One prematurely born child with
epilepsy had infantile spasms at the age of 6 months.
In 2 children, AED treatment was discontinued after a
seizure-free period of several years, but the seizures
recurred. A further child has been seizure-free for
over 5 years and withdrawal from AED medication is

Table 1 Pre-, peri- and neonatal characteristics of children in preterm and control groups
Preterm group (n = 60) Control group (n = 60) p
Sex (boys/girls) 29/31 29/31
Gestational weeks
- Mean (S.D.) 29.6 (2.3) 39.7 (1.3)
- Range 23—32 37—42
Birth weight (g)
- Mean (S.D.) 1392 (421) 3487 (444)
- Range 710—2450 2600—4560
Apgar scores <7
- 1 min 36/59 (61%) 3/59 (5%) 0.000
- 5 min 6/58 (10%) 1/60 (2%) 0.059
- 10 min 4/6
Umbilical artery pH < 7.16 a 6/42 (14%) 3/38 (8%) 0.487
Respiratory distress syndrome 30 (50%) 0
Need for respiratory assistance >28 days 9 (15%) 0
Abnormal cranial ultrasound a 13/35 (37%) ND
Exchange transfusion 15 (25%) 0
Hypoglycemia 4 (7%) 0
Pre-eclampsia 11 (18%) 3 (5%) 0.043
Maternal hypertension 14 (23%) 8 (13%) 0.238
Multifetal gestation 16 (27%) 0
ND, not done.
a
Performed only on clinical grounds.
594 E.A. Herrgård et al.

Table 2 Neonatal, febrile and epileptic seizures and cause. She had 3 seizures during septic non-CNS infec-
use of antiepileptic drugs (AED) during follow-up of 16 tion in the course of the induction treatment of acute
year and neurological dysfunction at 5 years lymphoma at the age of 13 years. This child had
Preterm Control previously experienced one febrile seizure and has
(n = 59) a group been seizure-free since these episodes. The other
(n = 60) children had symptomatic epilepsy. In the control
Neonatal seizures 16 (27%) 0 group no child had exhibited non-febrile seizures.
AED during neonatal 15 (25%) 0
period Family history of seizures
AED at discharge from 5 (8%) 0
neonatal unit Six out of 10 children born preterm who experienced
Use of AED after discharge 7 (12%) 0 seizures during febrile illness had a family history of
from neonatal unit up
febrile seizures in the first, second or higher degree
to 5 years
of relatives (Table 3). Two of these had a positive
Febrile seizures family history of epilepsy.
- Simple 3 3
- Simple and complex 3 Neurological dysfunction
- Complex 1
- Difficult to classify 1
The rate of the children with minor neurodevelop-
Seizures during febrile illness mental dysfunction was significantly higher in the
- Fever-induced 2 preterm group than in the controls (Fisher’s exact
epileptic seizures test, p 0.009) (Table 2). Major neurological dysfunc-
Epilepsy diagnosis at 5 5 0 tion was found in 13 children in the preterm group.
years Eleven of the 16 children (69%) with neonatal sei-
Epileptic (non-febrile) 6 0 zures had minor or major neurological dysfunction
seizures after 9 years when assessed at 5 years of age. Three out of 4
Epilepsy diagnosis and 4 0 children with complex febrile seizures had multiple
medication at 16 years
febrile seizures and minor or major neurological
Neurological dysfunction at 5 years dysfunction (Table 4). All children diagnosed as
- Major 13 (22%) having epilepsy had cerebral palsy and neurocogni-
- Minor dysfunction 13/46 (28%) 5 (8%) tive problems.
AED, antiepileptic drug. Rates of febrile seizures for children who are
a
Child with Down syndrome excluded. neurologically normal, have minor or major neuro-
logical dysfunction are presented in Table 5. Neu-
being attempted. One child with epilepsy died at 14 rodevelopmental dysfunction did not increase risk
years due to pneumonia. for febrile seizures (OR 1.071, CI 0.266—4.323).

Other seizure data

Discussion
In the preterm group, 6 children had epileptic seizures
between 9 and 16 years of age. The seizures in one of The rate of febrile seizures in our preterm group was
these children were due to an acute symptomatic 3-fold higher than in the control group. The relative
Table 3 Neonatal, febrile and epileptic (non-febrile) seizures, family history of seizures and neurological dysfunction
in children with seizures after neonatal period
Groups Neonatal Febrile Epileptic Family Neurological
seizures seizures seizures history of dysfunction
seizures at 5 years
Febrile Epilepsy Major Minor
Preterm group
- Epilepsy (n = 5) 4 2a 5 1 0 5 0
- Febrile seizures (n = 8) 0 8 1 5 2 1 2
Control group
- Febrile seizures (n = 3) 0 3 0 1 0 0 0
a
Fever-induced epileptic seizures.
Increased number of febrile seizures in children born very preterm 595

Table 4 Types and number of seizures and neurological dysfunction in preterm children with complex febrile seizures
Cases Types and number Neonatal Epileptic Neurological dysfunction Family history of seizures
of febrile seizures seizures seizures at 5 years
Child 1 5 SFC No No Sensorimotor, visualspatial Febrile seizures
in 18 relatives
1 CFC
Child 2 4 SFC No No Mental retardation Febrile seizures 18
and 28 relatives
1 CFC
Child 3 5 SFC No No Sensorimotor, visualspatial Febrile seizures in
18 relatives
3 CFC
Child 4 1 CFC No No Normal No
SFC, simple febrile seizure; CFC, complex febrile seizure.

frequency of febrile seizures in the control group
was similar to the prevalence of 2—5% for febrile
seizures published in the literature.8,9 In the pre-
term group, 16 children were from a multifetal
gestation, but only two children in the febrile sei-
zure group were siblings. Thus, confounding factors
of this kind cannot explain the high rate of febrile
seizures. However, the majority of children with
febrile seizures had a family history of seizures,
with febrile seizures or epilepsy being reported in
relatives.
Studies on the association between febrile sei-
zures and both family history and environmental
factors have shown heritability to be one of the
most important factors.27—29 Few pre- and perinatal
antecedents of febrile seizures have been
reported.27,30,31 In the study of Nelson and Ellen-
berg,27 neonatal respiratory distress, sepsis and
errors of metabolism were associated with risk of
febrile seizures later in life. In a study by Forsgren
et al.,30 toxemia, prematurity and bilirubinemia
were more common in children with febrile convul-
sions than controls. Vestergaard et al.31 reported a
slightly increased risk of febrile convulsion in chil-
dren exposed to pre-eclampsia. Furthermore,
Bethune et al.28 found an increased risk for febrile
seizures in children discharged from neonatal unit at
or after 28 days. Respiratory distress syndrome,
metabolic problems, pre-eclampsia and long neo-
natal care are factors associated with preterm birth
and by this with neurological morbidity.
According to epidemiological studies, neonatal
seizures are much more common in preterm than
term neonates.32,33 Neonatal seizures are often
associated with hypoxia-ischemia both in preterm
and term neonates and are a warning sign of later
neurological problems.34—36 Reports using clinical
seizure criteria have estimated that 15—20% of
neonates with seizures later develop epilepsy.4,36
In our preterm group, majority of the children with
neonatal seizures showed neurological dysfunction
at the age of 5 years. Five children in the preterm
group had epilepsy, and four of them had neonatal
seizures. All children with epilepsy had major neu-
rological dysfunction such as cerebral palsy or cere-
bral palsy together with mental retardation. Thus,
epilepsy was part of a chronic CNS disorder.
Debate on the relationship between complex
childhood febrile seizures, TLE and hippocampal
sclerosis have existed in the literature for decades.

Table 5 Odds ratios and 95% confidence intervals for febrile seizures in neurologically normal children, in children
with minor or major neurological dysfunction by study groups
Groups Preterm group Control group OR (CI 95%)
(n = 59) (n = 60)
Neurologically normal 33 55
- Febrile seizure + 5 3 3.095 (0.688—13.918)
Major or minor neurodevelopmental dysfunction 26 5
- Febrile seizure + 3a 0
Entire group 59 60
- Febrile seizure + 8a 3 2.980 (0.750—11.843)
a
Children with fever-induced epileptic seizures not included.
596
Antecedent insults such as febrile seizures, perina-
tal injury, CNS infection, or head trauma are recog-
nized as risk factors for mesial temporal epilepsy or
sclerosis.17,37,38 Epileptogenesis comprises an initial
event, later attacks and modulating factors leading
to neuroplastic changes, and further to the func-
tional and structural reorganization that contri-
butes to the expression of spontaneous seizures.
One possibility is that the pre-existing neuronal
injury triggers both the febrile seizures and the
subsequent TLE. van Landingham et al.39 pointed
out that prolonged febrile seizures with focal fea-
tures were associated with mesial temporal sclero-
sis, thus suggesting some underlying pre-existing
lesion. However, in our study no child with febrile
seizures, or febrile seizures and neurological dys-
function developed epilepsy up to the age of 16.
Thus, hippocampal structures are perhaps not so
vulnerable for perinatal risk factors in very preterm
children, and vulnerability increases with increasing
gestational age as the study by Squier et al.3 sug-
gested. However, an important question is, if the
time-window of 16 years for follow-up is yet too
short. A latent period after complex febrile seizures
before spontaneous seizures emerge is on average
from 8 to 11 years.11,17,40 Janszky et al.41 reported
that epilepsy onset in TLE with hippocampal sclero-
sis preceded by febrile seizures is trimodal with a
peak ages of 5.5, 15.3 and 26.7 years.
In our study the prognosis of febrile seizures
seemed good during the follow-up even in children
with neurodevelopmental problems and multiple
and complex febrile seizures. Although experimen-
tal models have been developed to examine rela-
tionships between prolonged febrile seizures and
limbic seizures,7,42 in human population there are
yet many factors in the cascade of epileptogenesis
to resolve as genetic studies43 and our study show. In
our study a low number of study subjects sets its own
limitations, although the study population is repre-
sentative of 2 years birth cohort in the region of
Kuopio University Hospital. However, the results
need a verification in a bigger population of very
prematurely born children and during a longer fol-
low-up to adulthood.
Conclusions
The children born very preterm at 32 weeks of
gestation have increased rate of febrile seizures
compared to the controls. However, no cascade
from initial injury via febrile seizures to epilepsy
could be revealed during the follow-up of 16 years
even in children with complex febrile seizures
and neurodevelopmental problems. Symptomatic
E.A. Herrgård et al.
epilepsy in prematurely born children is charac-
terised by neonatal seizures, major neurological
disabilities and early onset of epilepsy.
Acknowledgement
The study was financially supported by grants from
the Kuopio University Hospital Research Funds, and
the Arvo and Lea Ylppö Foundation.
References
1. Jensen FE, Holmes GL, Lombroso CT, Blume HK, Firkusny IR.
Age-dependant changes in long-term seizure susceptibility and
behavior after hypoxia in rats. Epilepsia 1992;33:971—80.
2. Jensen FE, Baram TZ. Developmental seizures induced by
common early-life insults: short- and long-term effects on
seizure susceptibility. Mental Retardat Dev Disabil Res Rev
2000;6:253—7.
3. Squier W, Salisbury H, Sisodiya S. Stroke in the developing
brain and intractable epilepsy: effect of timing on hippo-
campal sclerosis. Dev Med Child Neurol 2003;45:580—5.
4. Volpe JJ. Hypoxic-ischemic encephalopathy: clinical aspects.
In: Volpe JJ, editor. Neurology of the newborn. 4th edition.
Philadelphia: WB Saunders; 2001. p. 331—94.
5. Schmid R, Tandon P, Stafstrom CE, Holmes GL. Effects of
neonatal seizures on subsequent seizure-induced brain
injury. Neurology 1999;53:1754—61.
6. Holmes GL, Khazipov R, Ben-Ari Y. New concepts in neonatal
seizures. Neuroreport 2002;13:A3—8.
7. White HS. Animal models of epiletogenesis. Neurology
2002;59:S7—14.
8. Verity CM, Butler NR, Golding J. Febrile convulsions in a
national cohort followed up from birth. I–—Prevalence and
recurrence in the first five years of life. Br Med J
1985;290:1307—10.
9. Hauser WA. The prevalence and incidence of convulsive
disorders in children. Epilepsia 1994;35(Suppl. 2):S1—6.
10. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prog-
nostic of unprovoked seizures after febrile convulsions. N
Engl J Med 1987;316:493—8.
11. Baram TZ, Shinnar S, editors. Febrile seizures. San Diego, CA:
Academic Press; 2002.
12. Trinka E, Unterrainer J, Haberlandt E, Luef G, Unterberger I,
Niedermuller U, et al. Childhood febrile convulsions–—which
factors determine the subsequent epilepsy syndrome? A
retrospective study. Epilepsy Res 2002;50:283—92.
13. Verity CM, Golding J. Risk of epilepsy after febrile convul-
sions: a national cohort study. BMJ 1991;303:1373—6.
14. Dube C, Chen K, Eghbal-Ahmadi M, Brunson K, Soltesz I,
Baram TZ. Prolonged febrile seizures in the immature rat
model enhance hippocampal excitability long term. Ann
Neurol 2000;47:336—44.
15. Bender RA, Dube C, Gonzalez-Vega R, Mina EW, Baram TZ.
Mossy fiber plasticity and enhanced hippocampal excitability,
without hippocampal cell loss or altered neurogenesis, in an
animal model of prolonged febrile seizures. Hippocampus
2003;13:399—412.
16. Abou-Khalil B, Andermann E, Andermann F, Olivier A, Ques-
ney LF. Temporal lobe epilepsy after prolonged febrile con-
vulsions: excellent outcome after surgical treatment.
Epilepsia 1993;34:878—83.
Increased number of febrile seizures in children born very preterm
17. French JA, Williamson PD, Thadani VM, Darcey TM, Mattson
RH, Spencer SS, et al. Characteristics of medial temporal
lobe epilepsy: I. Results of history and physical examination.
Ann Neurol 1993;34:774—80.
18. Martikainen MA, Airaksinen EM, Heinonen KM, Castren ML.
The neurological condition of the newborn infant with mater-
nal hypertension, examined at term. Early Hum Dev
1988;16:107—18.
19. Herrgård E, Luoma L, Tuppurainen K, Karjalainen S, Marti-
kainen A. Neurodevelopmental profile at five years of chil-
dren born at 32 weeks gestation. Dev Med Child Neurol
1993;35:1083—96.
20. Dubowitz LMS, Dubowitz V, Coldberg C. Clinical assessment of
gestational age in the newborn infant. J Pediatr 1970;77:1—
10.
21. Luoma L, Herrgård E, Martikainen A. Neuropsychological
analysis of the visuomotor problems in children born preterm
at 32 weeks of gestation. A 5-year prospective follow-up.
Dev Med Child Neurol 1998;40:21—30.
22. Touwen BCL. Examination of the Child with minor neurolo-
gical dysfunction, no. 71. 2nd ed. Clinics in Developmental
Medicine; 1979.
23. Wechsler D. Wechsler preschool and primary scale of intelli-
gence. The Finnish ed. Helsinki: Psykologien Kustannus Oy;
1977.
24. Korkman, M. NEPSY–—a proposed neuropsychologicak test
battery for young developmentally disabled children. Theory
and evaluation. Academic dissertation. University of Hel-
sinki; 1988.
25. Bayley N. Infant scales of development: mental, motor and
behaviour profile. Revised ed. New York: Psychological Cor-
poration; 1969.
26. Luoma L, Herrgård E, Martikainen A, Ahonen T. Speech and
language development of children born at  32 weeks of
gestation. A 5-year prospective follow-up study. Dev Med
Child Neurol 1998;40:380—7.
27. Nelson KB, Ellenberg JH. Prenatal and perinatal antecedents
of febrile seizures. Ann Neurol 1990;27:127—31.
28. Bethune P, Gordon K, Dooley J, Camfield C, Camfield P.
Which child will have a febrile seizure. AJDC 1993;147:
35—9.
29. Kjeldsen MJ, Kyvik KO, Friis ML, Christensen K. Genetic
and environmental factors in febrile seizures: a Danish
population-based twin study. Epilepsy Res 2002;51:167—
77.
597
30. Forsgren L, Sidenvall R, Blomquist HK, Heijbel J, Nystrom L.
Pre- and perinatal factors in febrile convulsions. Acta Pae-
diatr Scand 1991;80:212—25.
31. Vestergaard M, Basso O, Henriksen TB, Ostergaard J, Secher
NJ, Olsen J. Pre-eclampsia and febrile convulsions. Arch Dis
Childhood 2003;88:726—7.
32. Lanska MJ, Lanska DJ, Baumann RJ, Kryscio RJ. A population-
based study of neonatal seizures in Fayette county, Kentucky.
Neurology 1995;45:724—32.
33. Ronen GM, Penney S, Andrews W. The epidemiology of clinical
neonatal seizures in Newfoundland. A population based
study. J Pediatr 1999;134:71—5.
34. Watkins A, Szymonowics W, Jin X, Yu VV. Significance of
seizures in very low-birthweight infants. Dev Med Child
Neurol 1988;30:162—9.
35. Volpe JJ. Neonatal seizures. In: Volpe JJ, editor. Neurology of
the newborn. 4th ed. Philadelphia: WB Saunders; 2001. p.
178—214.
36. Brunquell PJ, Glennon CM, DiMario FJ, Lerer T, Eisenfeld L.
Prediction of outcome based on clinical seizure type in new-
born infants. J Pediatr 2002;140:707—12.
37. Harvey AS, Berkovic SF, Wrennall JA, Hopkins IJ. Temporal
lobe epilepsy in childhood: clinical, EEG, and neuroimaging
findings and syndrome classification in a cohort with new-
onset seizures. Neurology 1997;49:960—8.
38. Sztriha L, Gururaj AK, Bener A, Nork M. Temporal lobe
epilepsy in children: etiology in a cohort with new-onset
seizures. Epilepsia 2002;43:75—80.
39. van Landingham KE, Heinz ER, Cavazos JE, Lewis DV. Magnetic
resonance imaging evidence of hippocampal injury after pro-
longed focal febrile convulsions. Ann Neurol 1998;43:413—26.
40. Mathern GW, Pretorius JK, Babb TL. Influence of the type of
initial precipitating injury and at what age it occurs on course
and outcome in patients with temporal lobe seizures. J
Neurosurg 1995;82(2):220—7.
41. Janszky J, Janszky I, Ebner A. Age at onset in mesial temporal
lobe epilepsy with a history of febrile seizures. Neurology
2004;12(63(7)):1296—8.
42. Dube C, Richichi C, Bender RA, Chung G, Litt B, Baram TZ.
Temporal lobe epilepsy after experimental prolonged febrile
seizures: prospective analysis. Brain 2006;129:911—22.
[Epub 2006 January 30].
43. Baulac S, Gourfinkel-An I, Nabbout R, Huberfeld G, Serratosa
J, Leguern E, et al. Fever, genes, and epilepsy. Lancet Neurol
2004;3:421—30.