Seizure (2006) 15, 590—597

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Increased number of febrile in children born very preterm: Relation of neonatal, febrile and epileptic seizures and neurological dysfunction to outcome at 16 years of age

Eila A. Herrga˚rd a,*, Marjo Karvonen a, Laila Luoma b, Pia Saavalainen c, Sara Ma¨a¨tta¨ 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 ; Neonatal seizure; Purpose: In prematurely born population, a cascade of events from initial injury in ; 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. Herrga˚rd).

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 at 32 weeks of gestation, and to compare the Prematurity includes many risk factors for the integ- neurological morbidity at different assessment rity of the central nervous system (CNS) and for points from birth up to the age of 16 years to the development prenatally and during first months of morbidity of the children born at term. Especially, life due to the immaturity of many organ systems. we wanted to evaluate the contribution of neonatal, Seizures may arise from an underlying acute disease febrile and epileptic seizures, and of neurological process or the genetic background, or a combination dysfunction to the seizure outcome at 16 years of of genetic predisposition and a pre-existing lesion. age. Seizures may initiate a cascade of events leading over time to functional and structural changes in neuronal networks. Human and animal studies have Methods shown that the vulnerability of the brain to different harmful events is age-specific, i.e. depends on the Subjects maturity of the CNS.1—3 Hypoxic-ischemic cerebral injury perinatally is The follow-up study of preterm children formed part associated with both neonatal and later seizures of a wider prospective study of risk and control and neurological disabilities.4 Recent animal studies children born in Kuopio University Hospital during have shown that neonatal seizures permanently the study period between 1 April 1984 and 31 March disturb neuronal development, induce synaptic 1986.18,19 The final neonatal study population con- organization and alter plasticity.5—7 These changes sisted of 621 children, including all preterm children in the neuronal network prime the brain to and all children small for gestational age (SGA) born increased damage from seizures later in life.5,6 during the study period, and a sample of children Febrile seizures are the most common type of born to hypertensive mothers and their controls seizure in children.8,9 Genetic susceptibility to sei- born at term. Ninety-five of these children were zures is critical regarding the type of febrile seizure born at 32 weeks of gestation. The gestational age and of subsequent epilepsy.10—12 Simple febrile sei- of the children was assessed according to the date of zures carry only little risk of developing epi- the last menstrual period of the mother. The gesta- lepsy.10,13 However, prolonged febrile seizures tional age of the preterm and of SGA children was may alter hippocampal circuits leading to hyperex- confirmed by the Dubowitz method20 during the first citable networks.14,15 Several studies have recog- 3 days of life. Eight of the preterm children were nised an association between complex febrile transferred to the group of >32 gestational weeks seizures and an increased risk of subsequent tem- on account of their Dubowitz maturity scores. Three poral lobe epilepsy (TLE).12,16,17 children born at 32 weeks of gestation were not Our prospective study project on prematurely examined neonatally, and were excluded from the born children from the beginning was a neurodeve- study. Twenty-two children died during neonatal lopmental outcome study with extensive back- period and one at the age of 2 months. One preterm ground and morbidity data including seizure data. child did not participate in the clinical examination In this population we can consider different ele- at the age of 5 years, since the child had moved ments of : hypoxic-ischemic and away from the district served by the university other adverse events during pre-, peri- and neonatal hospital. Thus, 60 out of 95 children born at 32 period appearing as neurological dysfunction, and weeks of gestation were available for the neurode- neonatal, febrile and epileptic seizures. The pur- velopmental evaluation at 5 years and for seizure pose of this study was to examine the occurrence of follow-up. A child with Down’s syndrome was different seizures and neurodevelopmental pro- excluded later from further analysis. 592 E.A. Herrga˚rd et al.

The control group of 60 term children was performance of the control group served as a cut-off matched with the preterm group for gender, and point for defining dysfunction in the areas of the educational level as well as socio-economic status of profile. Major neurological dysfunction was defined the parents from a total of 222 term children exam- as CP, mental retardation, bilateral hearing and ined at the age of 5 years by the same researchers as severe visual impairment. If children had no major the preterm group. The control children belonged to dysfunction and had a mean score below the fifth the birth cohort of the years 1984—1986, and had percentile for the term group at least two of the also been assessed in the earlier phases of the entities of neurodevelopmental profile, they were follow-up project. In order to maintain the compo- classified as having minor neurological dysfunction. sition of the original term birth cohort, 84% of the controls were drawn from the children appropriate Questionnaire and interview of parents for gestational age (AGA) born to normotensive mothers, 13% from the AGA children born to hyper- During the neurological assessment at 5 years of age tensive mothers and 3% from the children born small the parents completed a questionnaire on seizure for gestational age. The control group served as a disorders in their child concerning epilepsy, febrile reference group for the preterm children in the seizures and other seizure disorders, medication neurological and neuropsychological investigations and other health problems. The completed ques- at 5 years of age and later in seizure follow-up. The tionnaire was available for all children. After the details of the groups are published earlier.19,21 assessment the examiner shortly checked the ques- The study was approved by the Research Ethics tionnaire and discussed about history and neurolo- Committee of Kuopio University Hospital. Informed gical findings in their child. Hospital records we consent was obtained from the parents of the chil- examined when needed. dren enrolled in the study. During the follow-up at 9 and 16 years, question- naires concerning seizure disorders, school perfor- Pre- and neonatal data mance and medication of the children were sent to the families. At 9 years, completed questionnaires Detailed pre-, peri- and neonatal data were avail- were available for 53 of the prematurely born chil- able from the database of this prospective study dren (90%) and for 56 of the control group (93%). At project. The differential diagnosis of neonatal sei- 16 years completed questionnaires were available zures and the classification of the seizures as ‘cere- for 51 children born prematurely (86%) and for 44 of bral ’ were performed by an experienced the control group (73%). pediatrician. The main researcher interviewed by telephone all non-responding parents and the parents of the Neurological and neuropsychological children with seizures after the questionnaires at examination age 9. The seizure history of the child and of other family members and relatives was obtained as pre- A standardized, age-specific neurological examina- cisely as possible. The main researcher checked the tion22 both for prematurely born and control children hospital records of all children who had a history of at the age of 5 years was performed by the main epileptic, febrile or other seizures, and of non- researcher. The Wechsler Preschool and Primary responders at 9 and 16 years. Febrile seizures were Scale of Intelligence23 and essential parts of The classified as simple if a seizure duration was less Neuropsychological Test Battery for Young Develop- than 15 min, if a seizure was symmetric and it did mentally Disabled Children24 were administered by not recur in a period of 24 h, otherwise as complex. the neuropsychologist. For profoundly retarded chil- dren who could not be evaluated by WPPSI the Bayley Data analysis Scale of Development25 was used. The details of test batteries and scoring criteria Data were analyzed using SPSS for windows (Version used in neurological and neuropsychological exam- 11.5). Means, S.D.s and ranges are provided for con- ination have been described earlier by the tinuous variables in the tables. The results for cate- authors.19,21,26 Neurodevelopmental profile com- gorized variables are presented as frequencies and prised in addition to general intelligence perfor- relative frequencies. Fisher’s exact test was used to mance in gross motor, fine motor and visual-motor compare relative frequencies between groups when area of the neurological examination, and atten- categorical variables were considered. Logistic tion, language, visualspatial, sensorimotor and regression was used to compare risks for febrile memory skills of the neuropsychological examina- seizures between the study groups. The risks for tion. Mean scores below the fifth centile for the febrile seizures were similarly compared between Increased number of febrile seizures in children born very preterm 593 neurologically normal children and children having seizures, one had complex febrile seizures, and minor or major neurological dysfunction. The results three had both simple and complex febrile seizures. of logistic regression analyses were expressed as odds One prematurely born child had a seizure difficult to ratios (OR) and their 95% confidence intervals. 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 Results lesional symptomatic epilepsy and their febrile sei- zures were fever-provoked epileptic seizures. Two Background factors of the prematurely born children with febrile sei- zures were siblings. Three children from the control The pre-, peri- and neonatal characteristics of the group had febrile seizures (Table 2). None of the prematurely born and control children are presented children with febrile seizures, except the two chil- in Table 1. Rate of risk factors was much higher in the dren with symptomatic epilepsy from infancy, preterm group compared to the control group. developed epilepsy up to 16 years of age.

Neonatal seizures Symptomatic epilepsy

Neonatal seizures were reported in 16 prematurely In the preterm group, 5 children had symptomatic born children (27%) (Table 2). On discharge from the epilepsy and only one these did not have neonatal neonatal unit, 5 children were on AED treatment. One seizures (Table 3). All these children had epileptic preterm child with neonatal seizures was resusci- seizures from infancy. The epilepsy classification tated at the age of 5 months due to respiratory after infancy was partial epilepsy with some secon- difficulties and pneumonia. He developed chronic darily generalized seizures. No child was encoun- epilepsy. None of the controls had neonatal seizures. tered with a typical seizure pattern for mesial temporal epilepsy. One prematurely born child with Febrile seizures epilepsy had infantile spasms at the age of 6 months. In 2 children, AED treatment was discontinued after a Up to 9 years of age, 10 of the prematurely born seizure-free period of several years, but the seizures children (17%) had experienced seizures during feb- recurred. A further child has been seizure-free for rile illness. Three of the children had simple febrile 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. Herrga˚rd 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 50tion was found in 13 children in the preterm group. years Eleven of the 16 children (69%) with neonatal sei- Epileptic (non-febrile) 60zures had minor or major neurological dysfunction seizures after 9 years when assessed at 5 years of age. Three out of 4 Epilepsy diagnosis and 40children 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 Inthe 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 51050 - 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 Bethune et al.28 found an increased risk for febrile was similar to the prevalence of 2—5% for febrile seizures in children discharged from neonatal unit at seizures published in the literature.8,9 In the pre- or after 28 days. Respiratory distress syndrome, term group, 16 children were from a multifetal metabolic problems, pre-eclampsia and long neo- gestation, but only two children in the febrile sei- natal care are factors associated with preterm birth zure group were siblings. Thus, confounding factors and by this with neurological morbidity. of this kind cannot explain the high rate of febrile According to epidemiological studies, neonatal seizures. However, the majority of children with seizures are much more common in preterm than febrile seizures had a family history of seizures, term neonates.32,33 Neonatal seizures are often with febrile seizures or epilepsy being reported in associated with hypoxia-ischemia both in preterm relatives. and term neonates and are a warning sign of later Studies on the association between febrile sei- neurological problems.34—36 Reports using clinical zures and both family history and environmental seizure criteria have estimated that 15—20% of factors have shown heritability to be one of the neonates with seizures later develop epilepsy.4,36 most important factors.27—29 Few pre- and perinatal In our preterm group, majority of the children with antecedents of febrile seizures have been neonatal seizures showed neurological dysfunction reported.27,30,31 In the study of Nelson and Ellen- at the age of 5 years. Five children in the preterm berg,27 neonatal respiratory distress, sepsis and group had epilepsy, and four of them had neonatal errors of metabolism were associated with risk of seizures. All children with epilepsy had major neu- febrile seizures later in life. In a study by Forsgren rological dysfunction such as cerebral palsy or cere- et al.,30 toxemia, prematurity and bilirubinemia bral palsy together with mental retardation. Thus, were more common in children with febrile convul- epilepsy was part of a chronic CNS disorder. sions than controls. Vestergaard et al.31 reported a Debate on the relationship between complex slightly increased risk of febrile convulsion in chil- childhood febrile seizures, TLE and hippocampal dren exposed to pre-eclampsia. Furthermore, 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 + 3 a 0 Entire group 59 60 - Febrile seizure + 8 a 3 2.980 (0.750—11.843) a Children with fever-induced epileptic seizures not included. 596 E.A. Herrga˚rd et al.

Antecedent insults such as febrile seizures, perina- epilepsy in prematurely born children is charac- tal injury, CNS infection, or head trauma are recog- terised by neonatal seizures, major neurological nized as risk factors for mesial temporal epilepsy or disabilities and early onset of epilepsy. sclerosis.17,37,38 Epileptogenesis comprises an initial event, later attacks and modulating factors leading to neuroplastic changes, and further to the func- Acknowledgement tional and structural reorganization that contri- butes to the expression of spontaneous seizures. The study was financially supported by grants from One possibility is that the pre-existing neuronal the Kuopio University Hospital Research Funds, and injury triggers both the febrile seizures and the the Arvo and Lea Ylppo¨ Foundation. subsequent TLE. van Landingham et al.39 pointed out that prolonged febrile seizures with focal fea- tures were associated with mesial temporal sclero- References sis, thus suggesting some underlying pre-existing lesion. However, in our study no child with febrile 1. Jensen FE, Holmes GL, Lombroso CT, Blume HK, Firkusny IR. seizures, or febrile seizures and neurological dys- Age-dependant changes in long-term seizure susceptibility and function developed epilepsy up to the age of 16. behavior after hypoxia in rats. Epilepsia 1992;33:971—80. Thus, hippocampal structures are perhaps not so 2. Jensen FE, Baram TZ. 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