Brain & Development xxx (2015) xxx–xxx www.elsevier.com/locate/braindev
Original article
Pediatric epilepsy following neonatal seizures symptomatic of stroke Agnese Suppiej a,⇑, Massimo Mastrangelo b, Laura Mastella c, Patrizia Accorsi d, Luisa Grazian e, Gianluca Casara f, Cinzia Peruzzi g, Maria Luisa Carpanelli h, Augusta Janes i, Annalisa Traverso a, Bernardo Dalla Bernardina j a
Child Neurology and Clinical Neurophysiology, Pediatric University Hospital, Padua, Italy b Pediatric Neurology Unit, V. Buzzi Hospital, A.O. ICP, Milan, Italy c Child Neuropsychiatry, Vicenza, Italy d Child Neuropsychiatric Unit, Civile Hospital, Brescia, Italy e Pediatric Unit, Ca’ Foncello Hospital, Treviso, Italy f Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy g Child Neuropsychiatry, Ospedale Maggiore, Novara, Italy h Department of Neurology, Alessandro Manzoni Hospital, Lecco, Italy i Division of Neonatology, Santa Maria della Misericordia Hospital Udine, Italy j Unit of Child Neuropsychiatry, University of Verona, Verona, Italy Received 2 August 2014; received in revised form 11 April 2015; accepted 12 May 2015
Abstract Background: Neonatal seizures are a risk factor for later epilepsy and their etiology is known to be implicated in the outcome but, little is known about this issue in the subgroup of seizures symptomatic of perinatal arterial ischemic stroke. The aim of this study was to describe the long term risk of epilepsy after electroencephalographic confirmed neonatal seizures symptomatic of perinatal arterial ischemic stroke. Design/subject: Fifty-five patients with electroclinical ictal data, vascular territory confirmed by neuroimaging and a minimum follow up of 3.5 years were identified from a multi-centre prospective neonatal seizures registry. Primary outcome was occurrence of post-neonatal epilepsy. The association of outcome with family history of epilepsy, gender, location of the infarct, neonatal clinical and electroencephalogram data were also studied. Results: During a mean follow up of 8 years and 5 months, 16.4% of the patients developed post neonatal epilepsy. The mean age at first post neonatal seizure was 4 years and 2 months (range 1–10 years and 6 months). Location of the infarct was the only statistically significant risk factor (p = 0.001); epilepsy was more represented in males but the difference was not statistically significant. Conclusions: Neonatal seizures symptomatic of perinatal arterial ischemic stroke had lower risk and later onset of post-neonatal epilepsy, compared to seizures described in the setting of other perinatal brain insults. Our data have implications for counseling to the family at discharge from neonatal intensive care unit. Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Arterial ischemic stroke; Outcome; Thrombosis; EEG monitoring; Seizures etiology
⇑ Corresponding author at: Child Neurology and Clinical Neurophysiology, Pediatric University Hospital, Padua, Via Giustiniani, 3, 35128 Padova, Italy. Tel.: +39 49 8218094; fax: +39 49 8215430. E-mail address: [email protected] (A. Suppiej).
http://dx.doi.org/10.1016/j.braindev.2015.05.010 0387-7604/Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
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A. Suppiej et al. / Brain & Development xxx (2015) xxx–xxx
1. Introduction
2. Patients and methods
Seizures are more common in the neonatal period than in any other period of life, affecting 2.6 per 1000 live births in population based studies [1] and 8.6% of infants admitted to Neonatal Intensive Care Units [2]. Occurrence of seizures in a neonate often reflects a severe underlying neurological dysfunction and is a risk factor for adverse neurological outcome. Post-neonatal epilepsy has been reported in up to 56% of children with history of neonatal seizures, but estimates vary widely [3–6]. The major determinant of post-neonatal epilepsy in neonates with seizures, among multiple predictors reported in the literature, was etiology [7] but, when evaluating the outcome of neonates with seizures, a variety of etiologies of perinatal brain damage are grouped together. The International League Against Epilepsy recently suggested the categorization of epileptic conditions on the basis of etiology, the syndrome definition in the case of acute symptomatic seizures [8] will includes the perinatal brain insult leading to seizures (defined as a constellation) [9,10]. Perinatal arterial ischemic stroke is the second most common etiology of neonatal seizures, following perinatal asphyxia [7], but, in the literature, there has been little emphasis on the occurrence of later epilepsy in the well defined epileptic condition of acute symptomatic seizures due to perinatal arterial stroke. Indeed, acute presentation with neonatal seizures is seen in up to 72% of the patients affected by perinatal arterial ischemic stroke [11]; the remaining patients may present acutely with altered level of consciousness and muscle tone, respiratory and feeding difficulties [11] or with hemiparesis in the first months of life (so called presumed perinatal stroke or delayed presentation of perinatal stroke) [12] which are considered a different population in terms of pathogenesis of brain damage and outcome [13]. Differential diagnosis with other conditions mimicking stroke in a neonate with seizures involves neuroimaging documenting an ischemic lesion in a known vascular territory [8]. The diagnosis of neonatal seizures cannot be based on clinical observation alone but requires video-EEG documentation. In fact the clinical correlate of ictal EEG pattern may be minimal, or, by contrast, abnormal non epileptic movements may mimic seizures [14]. In order to recruit adequate number of patients homogeneous for etiology, multi-center studies are needed. The present study aimed to describe the long term risk of developing epilepsy and to identify possible risk factors in the well characterized and homogeneous population of patients with EEG confirmed neonatal seizures symptomatic of arterial ischemic stroke recruited from a multi-center prospective registry.
From the registry of the Study Group on Neonatal Seizures of the Italian League Against Epilepsy and the Neonatal Neurology Section of the Italian Society of Neonatology we identified patients presenting with neonatal seizures symptomatic of arterial ischemic stroke in the period from 1st January 1990 to 30th June 2010. Inclusion criteria were: seizures confirmed by ictal EEG recording, arterial ischemic stroke confirmed by neuroimaging documenting abnormal signal intensity in a vascular territory and follow up P3.5 years. In order to avoid factors possibly confounding prognosis, we did not select patients having dysmorphic features suggestive of a genetic syndrome, congenital cyanotic heart disease, sepsis, metabolic disorders and those in whom arterial ischemic stroke occurred associated to clinical or neuroimaging evidence of global perinatal asphyxia. The retrospective study was performed with data, previously agreed by the study group. In the registry, data are collected prospectively and included in a report file after clinical and video-EEG discussion which takes place monthly. The format for prospective data collection agreed by the study group include: family history, demographic and perinatal data, neonatal neurological examination [15] and neurological examination at follow up [16], EEG background activity and ictal EEG pattern [17], classification of neonatal seizures [9,18,19], status epilepticus [14]. A neonatal seizure was defined as a sudden rhythmic, repetitive, and stereotyped EEG discharge lasting for at least 10 s on two or more EEG channels [9,18,19]; clinical only seizures were not classified as seizures. Status epilepticus was defined as a continuous seizure lasting at least 30 minutes or repeated seizures whose total duration exceeds 50% of one hour EEG tracing [14]. The EEG of each neonate was discussed by the multidisciplinary team of the Study Group including at least two electroencephalographers experts of neonatal EEG. Consensus regarding the definitions of status epilepticus, electrographic seizure and background activity was reached before inclusion in the Registry. From the report file of each patient, we collected family history of epilepsy, perinatal data, neonatal neurological status, electro-clinical characteristics of neonatal seizures and neuroimaging data. We also inspected follow up data and, in case of diagnosis of post-neonatal epilepsy, we evaluated age at onset of epilepsy, epileptic diagnosis, antiepileptic treatment and response to treatment. Post neonatal epilepsy was defined and classified based on the International Classification of seizures and of Epileptic Syndromes [10,20].
Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
A. Suppiej et al. / Brain & Development xxx (2015) xxx–xxx
The square Pearson test (for qualitative non-ordinal variables) and Fisher Exact test were used to examine the distribution of epilepsy at the time of last follow up with respect to demographic and neonatal data. STATISTICA 6.0 for Windows (StatSoft, Tulsa, UK) was used for statistical analyses. The significance was set at p < 0.05. The institutional review boards of participating centers approved the study. Informed parental consent was obtained from parents at each center. 3. Results Fifty-five patients born at 10 centers of the north Italy were selected for the present study; 56% were males and 38% were born by caesarean section. The mean gestational age was 40 weeks (range 36–43) and the mean birth weight was 3365 g (range 2450–4440). The neonatal neurological examination was abnormal in 49% of the cases. The most frequent vascular territory affected was that of the left middle cerebral artery, involved in 27/55 cases (49%), while 13/55 (24%) had right middle cerebral artery involvement, 8/55 (14%) multiple vessels involvement, and the remaining patients had various other single vessels involvement. Neonatal seizures started between 1 and 7 days of life in all but two infants in whom onset was at 16 and 15 days respectively. Neonatal seizures were characterized by obvious motor manifestations in more than half of the cases (56%), in the remaining the ictal symptoms were more or less evident consisting in loss of contact and staring often associated with autonomic manifestations. Status epilepticus was observed in 25/55 (45%) of cases, the interictal EEG was mildly abnormal in 44/55 (80%) and severely abnormal in 7/55 (12%) of the cases during a mean EEG monitoring duration of 52 hours (range 36–60), the ictal EEG was focal in 78% of the cases, multifocal in the remaining. Neonatal seizures were treated with Phenobarbital in 56% of the patients while 36% needed more than one antiepileptic drug to treat clinical and subclinical recurrences. In all patients Phenobarbital was stopped before discharge. At a mean follow up of 8 years and 5 months (range 3 years and 6 months–20 years) 29/55 cases (53%, CI 40–63%) had intellectual or motor deficit. Nine out of 55 children (16.4% CI 6–26%) developed epilepsy at a mean age of 4 years and 2 months (range 1–10 years and 6 months) with 7/9 having an age at onset >2 years. All patients, but one, had focal epilepsy with good seizure control under antiepileptic treatment. The remaining patient had drug resistant (after 2 drugs at correct doses) epileptic encephalopathy. At last follow up 7/9 patients had hemiplegic cerebral palsy, of the remaining children one had suboptimal impairment, the other minimal neurological dysfunction according to Touwen [16].
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The infants without post neonatal epilepsy did not differ significantly from those with epilepsy in gestational age (p = 0.76 by Fisher exact test), birth weight (p = 0.45 by Fisher exact test), caesarean delivery (p = 0.07 by Fisher exact test), neonatal neurological examination (p = 0.06 by square Pearson test), ictal (p = 0.55 by square Pearson test) and interictal EEG (p = 0.3 by Fisher exact test), occurrence of status epilepticus (p = 0.046 by square Pearson test) and treatment (p = 0.18 by square Pearson test). None of the infants in both groups had family history of epilepsy. The risk of developing epilepsy was higher when right middle cerebral artery and multiple territories were involved (Fisher Exact test: p = 0.0011, OR 20.3 (CI 2.3–179); there was a prevalence of epilepsy in males even if not statistically significant (Fisher Exact test: p = 0.14, OR 3.8 (CI 0.72–20). All epileptic males had right middle cerebral artery or multiple arteries involvement but we did not find an association between territory and gender (v2 p = 0.51). 4. Discussion In the present study post-neonatal epilepsy occurred in about 16% of the patients with previous history of neonatal seizures symptomatic of perinatal arterial ischemic stroke. The mean age at onset was 4 years, and the majority of patients had focal epilepsy with seizure responsive to antiepileptic treatment. These results are in contrast with research on the outcome of patients suffering from neonatal seizures symptomatic of other perinatal brain insults where an earlier onset, often with infantile spasms or refractory multifocal seizures, has been reported [1,3,21]. A later onset and lower frequency of post neonatal epilepsy in our study can be explained by less severe and less diffuse brain damage in our population. Indeed, differently from previous studies, we considered a homogeneous population of patients with acute seizures symptomatic only of arterial ischemic stroke with no other additional risk factors. Indeed, the prognostic evaluation of neonatal seizures is complicated by the coexistence of multiple etiologies and risk factors. The high incidence of chronic epilepsy in the study of Clancy and Legido [3] in which 56% of neonates with EEG confirmed seizures developed epilepsy may reflect, for example, the recruitment of patients with more severe brain damage since their population included comatose neonates with severe abnormalities on interictal background EEG activity. Such patients often develop epileptic encephalopathy within the first year of life. In the study by Pisani et al. [21] the finding of abnormalities in fetal cerebral ultrasounds and family history of epilepsy as independent risk factors for later epilepsy suggest the recruitment of a population including patients with genetic or prenatal etiology of seizures. Considering predictors of post-neonatal epilepsy, in our
Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
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population we found that location of the infarct had a significant role. A more severe prognosis can be expected in patients with multiple vessels involvement, but more data will be needed to explore the hypothesis of possible differences in mechanisms underlying vascular territory involvement [11]. By contrast, results of the present study reflect the outcome of a homogeneous and specific epileptic condition within the field of neonatal seizures. In order to avoid potential independent risk factors for poor neurodevelopment outcome and epilepsy, patients with associated etiologies other than stroke, such as global perinatal asphyxia [22,23] were not included. This approach is in agreement with the revised concepts for organization of seizures and epilepsies of the International League Against Epilepsy which suggest the importance of defining etiology in the study of patients with seizures or epilepsy [8,9]. Beside the difficulty in comparing our result with literature on the outcome of seizures occurring in neonates with mixed perinatal brain insults, our results are not comparable with studies on the outcome of perinatal arterial ischemic stroke. In fact these studies evaluated post neonatal epilepsy in a population of neonates presenting both acutely with seizures and without neonatal seizures [24,25]. The incidence of post neonatal epilepsy was in these studies higher than in the present study [24,25]. The better outcome in our population may be explained by the absence of patients presenting clinically without neonatal seizures; this hypothesis is supported by the worse outcome reported by other authors when perinatal stroke does not occur in the setting of acute neonatal seizures [26–28]. Furthermore an earlier onset of epilepsy was reported [24] in patients with evidence of stroke in the fetal ultrasounds, typically presenting in the first months of life with abnormal hand use but not seizures [12,13]. The systematic use of the EEG for selection and monitoring of patients in our study may have allowed the selection of less severe patients, further explaining the relatively low risk of epilepsy observed. In fact, EEG monitoring helps to exclude seizures activity in patients with abnormal non epileptic movements, which may occur in the setting of severe brain damage; moreover the EEG supports identification and treatment of seizures with minimal or absent clinical signs, avoiding amplification of ischemic injury on neonatal immature brain [29]. Unfortunately, our study was not designed to investigate this issue and seizure burden after PB treatment was not calculated. A further limitation of the present study is not having collected data on the underlying etiologies of stroke. 5. Conclusion In conclusion the present study propose the evaluation of neonatal seizures as a function of the type of
epileptic diagnosis which was made with the methodological approach suggested by the International League Against Epilepsy. The definition of a homogeneous population of patients with acute seizures symptomatic only of arterial ischemic stroke and no other additional risk factors, allowed a patient selection with characteristics different from previous studies, possibly explaining an occurrence of subsequent epilepsy lower than previously reported. Furthermore the onset of post neonatal epilepsy was later than described in the setting of other perinatal brain insult and seizures responded well to antiepileptic treatment. It is important to provide the parents with information on the outcome of the specific condition affecting their child. Our results have implications for counseling to the family at discharge from neonatal intensive care unit and for planning the follow up. Acknowledgements The authors thank Dr. Mario Ermani of the Biostatistical Unit of Department of Neurosciences, University of Padova, for the help in the statistical analysis. References [1] Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 1999;134:71–5. [2] Sheth RD, Hobbs GR, Mullett M. Neonatal seizures: incidence, onset, and etiology by gestational age. J Perinatol 1999;19:40–3. [3] Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia 1991;32:69–76. [4] Khan RL, Nunes ML, da Silva LF Garcias, da Costa JC. Predictive value of sequential electroencephalogram (EEG) in neonates with seizures and its relation to neurological outcome. J Child Neurol 2008;23:144–50. [5] Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology 2007;69:1816–22. [6] Garfinkle J, Shevell MI. Cerebral palsy, developmental delay, and epilepsy after neonatal seizures. Pediatr Neurol 2011;44: 88–96. [7] Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117:1270–80. [8] Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010;51:671–5. [9] Mastrangelo M, Van Lierde A, Bray M, Pastorino G, Marini A, Mosca F. Epileptic seizures, epilepsy and epileptic syndromes in newborns: A nosological approach to 94 new cases by the 2001 proposed diagnostic scheme for people with epileptic seizures and with epilepsy. Seizure 2005;14:304–11. [10] Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005–2009. Epilepsia 2010;51:676–85.
Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
A. Suppiej et al. / Brain & Development xxx (2015) xxx–xxx [11] Kirton A, Armstrong-Wells J, Chang T, Deveber G, Rivkin MJ, Hernandez M, et al. Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics 2011;128:e1402–10. [12] Golomb MR, MacGregor DL, Domi T, Armstrong DC, McCrindle BW, Mayank S, et al. Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. Ann Neurol 2001;50:163–8. [13] Suppiej A, Franzoi M, Gentilomo C, Battistella PA, Drigo P, Gavasso S, et al. High prevalence of inherited thrombophilia in ‘presumed peri-neonatal’ ischemic stroke. Eur J Hematol 2008;80:71–5. [14] Wusthoff CJ. Diagnosing neonatal seizures and status epilepticus. J Clin Neurophysiol 2013;30:115–21. [15] Prechtl HFR. The neurological examination of the full term newborn infant. 2nd ed. Clinics in Developmental Medicine, No. 63. S.I.M.P. with Heinemann Medical, London. Lippincott, Philadelphia; 1977. [16] Touwen BLC. Neurological Development in Infancy. Clinics in Developmental Medicine, No.53. S.I.M.P. with Heinemann Medical, London. Lippincott, Philadelphia; 1976. [17] Lombroso CT. Neonatal polygraphy in full-term and premature infants: a review of normal and abnormal findings. J Clin Neurophysiol 1985;2:105–55. [18] Blume WT, Lu¨ders HO, Mizrahi E, Tassinari C, Van Emde Boas W, Engel Jr J. Glossary of descriptive terminology for ictal semiology: report of the ILAE taskforce on classification and terminology. Epilepsia 2001;42:1212–8. [19] Shellhaas RA, Clancy RR. Characterization of neonatal seizures by conventional EEG and single-channel EEG. Clin Neurophysiol 2007;118:2156–61. [20] Engel Jr J. International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and
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Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
Original article
Pediatric epilepsy following neonatal seizures symptomatic of stroke Agnese Suppiej a,⇑, Massimo Mastrangelo b, Laura Mastella c, Patrizia Accorsi d, Luisa Grazian e, Gianluca Casara f, Cinzia Peruzzi g, Maria Luisa Carpanelli h, Augusta Janes i, Annalisa Traverso a, Bernardo Dalla Bernardina j a
Child Neurology and Clinical Neurophysiology, Pediatric University Hospital, Padua, Italy b Pediatric Neurology Unit, V. Buzzi Hospital, A.O. ICP, Milan, Italy c Child Neuropsychiatry, Vicenza, Italy d Child Neuropsychiatric Unit, Civile Hospital, Brescia, Italy e Pediatric Unit, Ca’ Foncello Hospital, Treviso, Italy f Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy g Child Neuropsychiatry, Ospedale Maggiore, Novara, Italy h Department of Neurology, Alessandro Manzoni Hospital, Lecco, Italy i Division of Neonatology, Santa Maria della Misericordia Hospital Udine, Italy j Unit of Child Neuropsychiatry, University of Verona, Verona, Italy Received 2 August 2014; received in revised form 11 April 2015; accepted 12 May 2015
Abstract Background: Neonatal seizures are a risk factor for later epilepsy and their etiology is known to be implicated in the outcome but, little is known about this issue in the subgroup of seizures symptomatic of perinatal arterial ischemic stroke. The aim of this study was to describe the long term risk of epilepsy after electroencephalographic confirmed neonatal seizures symptomatic of perinatal arterial ischemic stroke. Design/subject: Fifty-five patients with electroclinical ictal data, vascular territory confirmed by neuroimaging and a minimum follow up of 3.5 years were identified from a multi-centre prospective neonatal seizures registry. Primary outcome was occurrence of post-neonatal epilepsy. The association of outcome with family history of epilepsy, gender, location of the infarct, neonatal clinical and electroencephalogram data were also studied. Results: During a mean follow up of 8 years and 5 months, 16.4% of the patients developed post neonatal epilepsy. The mean age at first post neonatal seizure was 4 years and 2 months (range 1–10 years and 6 months). Location of the infarct was the only statistically significant risk factor (p = 0.001); epilepsy was more represented in males but the difference was not statistically significant. Conclusions: Neonatal seizures symptomatic of perinatal arterial ischemic stroke had lower risk and later onset of post-neonatal epilepsy, compared to seizures described in the setting of other perinatal brain insults. Our data have implications for counseling to the family at discharge from neonatal intensive care unit. Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Arterial ischemic stroke; Outcome; Thrombosis; EEG monitoring; Seizures etiology
⇑ Corresponding author at: Child Neurology and Clinical Neurophysiology, Pediatric University Hospital, Padua, Via Giustiniani, 3, 35128 Padova, Italy. Tel.: +39 49 8218094; fax: +39 49 8215430. E-mail address: [email protected] (A. Suppiej).
http://dx.doi.org/10.1016/j.braindev.2015.05.010 0387-7604/Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
2
A. Suppiej et al. / Brain & Development xxx (2015) xxx–xxx
1. Introduction
2. Patients and methods
Seizures are more common in the neonatal period than in any other period of life, affecting 2.6 per 1000 live births in population based studies [1] and 8.6% of infants admitted to Neonatal Intensive Care Units [2]. Occurrence of seizures in a neonate often reflects a severe underlying neurological dysfunction and is a risk factor for adverse neurological outcome. Post-neonatal epilepsy has been reported in up to 56% of children with history of neonatal seizures, but estimates vary widely [3–6]. The major determinant of post-neonatal epilepsy in neonates with seizures, among multiple predictors reported in the literature, was etiology [7] but, when evaluating the outcome of neonates with seizures, a variety of etiologies of perinatal brain damage are grouped together. The International League Against Epilepsy recently suggested the categorization of epileptic conditions on the basis of etiology, the syndrome definition in the case of acute symptomatic seizures [8] will includes the perinatal brain insult leading to seizures (defined as a constellation) [9,10]. Perinatal arterial ischemic stroke is the second most common etiology of neonatal seizures, following perinatal asphyxia [7], but, in the literature, there has been little emphasis on the occurrence of later epilepsy in the well defined epileptic condition of acute symptomatic seizures due to perinatal arterial stroke. Indeed, acute presentation with neonatal seizures is seen in up to 72% of the patients affected by perinatal arterial ischemic stroke [11]; the remaining patients may present acutely with altered level of consciousness and muscle tone, respiratory and feeding difficulties [11] or with hemiparesis in the first months of life (so called presumed perinatal stroke or delayed presentation of perinatal stroke) [12] which are considered a different population in terms of pathogenesis of brain damage and outcome [13]. Differential diagnosis with other conditions mimicking stroke in a neonate with seizures involves neuroimaging documenting an ischemic lesion in a known vascular territory [8]. The diagnosis of neonatal seizures cannot be based on clinical observation alone but requires video-EEG documentation. In fact the clinical correlate of ictal EEG pattern may be minimal, or, by contrast, abnormal non epileptic movements may mimic seizures [14]. In order to recruit adequate number of patients homogeneous for etiology, multi-center studies are needed. The present study aimed to describe the long term risk of developing epilepsy and to identify possible risk factors in the well characterized and homogeneous population of patients with EEG confirmed neonatal seizures symptomatic of arterial ischemic stroke recruited from a multi-center prospective registry.
From the registry of the Study Group on Neonatal Seizures of the Italian League Against Epilepsy and the Neonatal Neurology Section of the Italian Society of Neonatology we identified patients presenting with neonatal seizures symptomatic of arterial ischemic stroke in the period from 1st January 1990 to 30th June 2010. Inclusion criteria were: seizures confirmed by ictal EEG recording, arterial ischemic stroke confirmed by neuroimaging documenting abnormal signal intensity in a vascular territory and follow up P3.5 years. In order to avoid factors possibly confounding prognosis, we did not select patients having dysmorphic features suggestive of a genetic syndrome, congenital cyanotic heart disease, sepsis, metabolic disorders and those in whom arterial ischemic stroke occurred associated to clinical or neuroimaging evidence of global perinatal asphyxia. The retrospective study was performed with data, previously agreed by the study group. In the registry, data are collected prospectively and included in a report file after clinical and video-EEG discussion which takes place monthly. The format for prospective data collection agreed by the study group include: family history, demographic and perinatal data, neonatal neurological examination [15] and neurological examination at follow up [16], EEG background activity and ictal EEG pattern [17], classification of neonatal seizures [9,18,19], status epilepticus [14]. A neonatal seizure was defined as a sudden rhythmic, repetitive, and stereotyped EEG discharge lasting for at least 10 s on two or more EEG channels [9,18,19]; clinical only seizures were not classified as seizures. Status epilepticus was defined as a continuous seizure lasting at least 30 minutes or repeated seizures whose total duration exceeds 50% of one hour EEG tracing [14]. The EEG of each neonate was discussed by the multidisciplinary team of the Study Group including at least two electroencephalographers experts of neonatal EEG. Consensus regarding the definitions of status epilepticus, electrographic seizure and background activity was reached before inclusion in the Registry. From the report file of each patient, we collected family history of epilepsy, perinatal data, neonatal neurological status, electro-clinical characteristics of neonatal seizures and neuroimaging data. We also inspected follow up data and, in case of diagnosis of post-neonatal epilepsy, we evaluated age at onset of epilepsy, epileptic diagnosis, antiepileptic treatment and response to treatment. Post neonatal epilepsy was defined and classified based on the International Classification of seizures and of Epileptic Syndromes [10,20].
Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
A. Suppiej et al. / Brain & Development xxx (2015) xxx–xxx
The square Pearson test (for qualitative non-ordinal variables) and Fisher Exact test were used to examine the distribution of epilepsy at the time of last follow up with respect to demographic and neonatal data. STATISTICA 6.0 for Windows (StatSoft, Tulsa, UK) was used for statistical analyses. The significance was set at p < 0.05. The institutional review boards of participating centers approved the study. Informed parental consent was obtained from parents at each center. 3. Results Fifty-five patients born at 10 centers of the north Italy were selected for the present study; 56% were males and 38% were born by caesarean section. The mean gestational age was 40 weeks (range 36–43) and the mean birth weight was 3365 g (range 2450–4440). The neonatal neurological examination was abnormal in 49% of the cases. The most frequent vascular territory affected was that of the left middle cerebral artery, involved in 27/55 cases (49%), while 13/55 (24%) had right middle cerebral artery involvement, 8/55 (14%) multiple vessels involvement, and the remaining patients had various other single vessels involvement. Neonatal seizures started between 1 and 7 days of life in all but two infants in whom onset was at 16 and 15 days respectively. Neonatal seizures were characterized by obvious motor manifestations in more than half of the cases (56%), in the remaining the ictal symptoms were more or less evident consisting in loss of contact and staring often associated with autonomic manifestations. Status epilepticus was observed in 25/55 (45%) of cases, the interictal EEG was mildly abnormal in 44/55 (80%) and severely abnormal in 7/55 (12%) of the cases during a mean EEG monitoring duration of 52 hours (range 36–60), the ictal EEG was focal in 78% of the cases, multifocal in the remaining. Neonatal seizures were treated with Phenobarbital in 56% of the patients while 36% needed more than one antiepileptic drug to treat clinical and subclinical recurrences. In all patients Phenobarbital was stopped before discharge. At a mean follow up of 8 years and 5 months (range 3 years and 6 months–20 years) 29/55 cases (53%, CI 40–63%) had intellectual or motor deficit. Nine out of 55 children (16.4% CI 6–26%) developed epilepsy at a mean age of 4 years and 2 months (range 1–10 years and 6 months) with 7/9 having an age at onset >2 years. All patients, but one, had focal epilepsy with good seizure control under antiepileptic treatment. The remaining patient had drug resistant (after 2 drugs at correct doses) epileptic encephalopathy. At last follow up 7/9 patients had hemiplegic cerebral palsy, of the remaining children one had suboptimal impairment, the other minimal neurological dysfunction according to Touwen [16].
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The infants without post neonatal epilepsy did not differ significantly from those with epilepsy in gestational age (p = 0.76 by Fisher exact test), birth weight (p = 0.45 by Fisher exact test), caesarean delivery (p = 0.07 by Fisher exact test), neonatal neurological examination (p = 0.06 by square Pearson test), ictal (p = 0.55 by square Pearson test) and interictal EEG (p = 0.3 by Fisher exact test), occurrence of status epilepticus (p = 0.046 by square Pearson test) and treatment (p = 0.18 by square Pearson test). None of the infants in both groups had family history of epilepsy. The risk of developing epilepsy was higher when right middle cerebral artery and multiple territories were involved (Fisher Exact test: p = 0.0011, OR 20.3 (CI 2.3–179); there was a prevalence of epilepsy in males even if not statistically significant (Fisher Exact test: p = 0.14, OR 3.8 (CI 0.72–20). All epileptic males had right middle cerebral artery or multiple arteries involvement but we did not find an association between territory and gender (v2 p = 0.51). 4. Discussion In the present study post-neonatal epilepsy occurred in about 16% of the patients with previous history of neonatal seizures symptomatic of perinatal arterial ischemic stroke. The mean age at onset was 4 years, and the majority of patients had focal epilepsy with seizure responsive to antiepileptic treatment. These results are in contrast with research on the outcome of patients suffering from neonatal seizures symptomatic of other perinatal brain insults where an earlier onset, often with infantile spasms or refractory multifocal seizures, has been reported [1,3,21]. A later onset and lower frequency of post neonatal epilepsy in our study can be explained by less severe and less diffuse brain damage in our population. Indeed, differently from previous studies, we considered a homogeneous population of patients with acute seizures symptomatic only of arterial ischemic stroke with no other additional risk factors. Indeed, the prognostic evaluation of neonatal seizures is complicated by the coexistence of multiple etiologies and risk factors. The high incidence of chronic epilepsy in the study of Clancy and Legido [3] in which 56% of neonates with EEG confirmed seizures developed epilepsy may reflect, for example, the recruitment of patients with more severe brain damage since their population included comatose neonates with severe abnormalities on interictal background EEG activity. Such patients often develop epileptic encephalopathy within the first year of life. In the study by Pisani et al. [21] the finding of abnormalities in fetal cerebral ultrasounds and family history of epilepsy as independent risk factors for later epilepsy suggest the recruitment of a population including patients with genetic or prenatal etiology of seizures. Considering predictors of post-neonatal epilepsy, in our
Please cite this article in press as: Suppiej A et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev (2015), http:// dx.doi.org/10.1016/j.braindev.2015.05.010
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population we found that location of the infarct had a significant role. A more severe prognosis can be expected in patients with multiple vessels involvement, but more data will be needed to explore the hypothesis of possible differences in mechanisms underlying vascular territory involvement [11]. By contrast, results of the present study reflect the outcome of a homogeneous and specific epileptic condition within the field of neonatal seizures. In order to avoid potential independent risk factors for poor neurodevelopment outcome and epilepsy, patients with associated etiologies other than stroke, such as global perinatal asphyxia [22,23] were not included. This approach is in agreement with the revised concepts for organization of seizures and epilepsies of the International League Against Epilepsy which suggest the importance of defining etiology in the study of patients with seizures or epilepsy [8,9]. Beside the difficulty in comparing our result with literature on the outcome of seizures occurring in neonates with mixed perinatal brain insults, our results are not comparable with studies on the outcome of perinatal arterial ischemic stroke. In fact these studies evaluated post neonatal epilepsy in a population of neonates presenting both acutely with seizures and without neonatal seizures [24,25]. The incidence of post neonatal epilepsy was in these studies higher than in the present study [24,25]. The better outcome in our population may be explained by the absence of patients presenting clinically without neonatal seizures; this hypothesis is supported by the worse outcome reported by other authors when perinatal stroke does not occur in the setting of acute neonatal seizures [26–28]. Furthermore an earlier onset of epilepsy was reported [24] in patients with evidence of stroke in the fetal ultrasounds, typically presenting in the first months of life with abnormal hand use but not seizures [12,13]. The systematic use of the EEG for selection and monitoring of patients in our study may have allowed the selection of less severe patients, further explaining the relatively low risk of epilepsy observed. In fact, EEG monitoring helps to exclude seizures activity in patients with abnormal non epileptic movements, which may occur in the setting of severe brain damage; moreover the EEG supports identification and treatment of seizures with minimal or absent clinical signs, avoiding amplification of ischemic injury on neonatal immature brain [29]. Unfortunately, our study was not designed to investigate this issue and seizure burden after PB treatment was not calculated. A further limitation of the present study is not having collected data on the underlying etiologies of stroke. 5. Conclusion In conclusion the present study propose the evaluation of neonatal seizures as a function of the type of
epileptic diagnosis which was made with the methodological approach suggested by the International League Against Epilepsy. The definition of a homogeneous population of patients with acute seizures symptomatic only of arterial ischemic stroke and no other additional risk factors, allowed a patient selection with characteristics different from previous studies, possibly explaining an occurrence of subsequent epilepsy lower than previously reported. Furthermore the onset of post neonatal epilepsy was later than described in the setting of other perinatal brain insult and seizures responded well to antiepileptic treatment. It is important to provide the parents with information on the outcome of the specific condition affecting their child. Our results have implications for counseling to the family at discharge from neonatal intensive care unit and for planning the follow up. Acknowledgements The authors thank Dr. Mario Ermani of the Biostatistical Unit of Department of Neurosciences, University of Padova, for the help in the statistical analysis. References [1] Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 1999;134:71–5. [2] Sheth RD, Hobbs GR, Mullett M. Neonatal seizures: incidence, onset, and etiology by gestational age. J Perinatol 1999;19:40–3. [3] Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia 1991;32:69–76. [4] Khan RL, Nunes ML, da Silva LF Garcias, da Costa JC. Predictive value of sequential electroencephalogram (EEG) in neonates with seizures and its relation to neurological outcome. J Child Neurol 2008;23:144–50. [5] Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology 2007;69:1816–22. [6] Garfinkle J, Shevell MI. Cerebral palsy, developmental delay, and epilepsy after neonatal seizures. Pediatr Neurol 2011;44: 88–96. [7] Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117:1270–80. [8] Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010;51:671–5. [9] Mastrangelo M, Van Lierde A, Bray M, Pastorino G, Marini A, Mosca F. Epileptic seizures, epilepsy and epileptic syndromes in newborns: A nosological approach to 94 new cases by the 2001 proposed diagnostic scheme for people with epileptic seizures and with epilepsy. Seizure 2005;14:304–11. [10] Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005–2009. Epilepsia 2010;51:676–85.
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