Original Article
Symptomatic Neonatal Seizures Followed by Febrile Status Epilepticus: The two-Hit Hypothesis for the Subsequent Development of Epilepsy
Journal of Child Neurology 2015, Vol. 30(5) 615-618 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814533004 jcn.sagepub.com
Carlotta Spagnoli, MD1, Maria Roberta Cilio, MD, PhD2, Elena Pavlidis, MD1, and Francesco Pisani, MD1
Abstract Neonatal seizures have been associated with the later development of postneonatal epilepsy, mainly beginning within the first year of life. Mechanisms of epileptogenesis in the immature brain still need to be fully elucidated but a two-hit hypothesis, showing that an early insult heightens later susceptibility to seizure-induced brain damage, has been demonstrated in animal models. We describe 2 cases of preterm babies sustaining recurrent neonatal seizures in the context of a severe perinatal brain damage who presented with symptomatic epilepsy only after the occurrence of an episode of febrile status epilepticus. In the context of preexisting perinatal brain damage, febrile status epilepticus acted as a second hit for developing epilepsy, confirming animal evidence. Keywords neonatal seizures, two-hit hypothesis, postneonatal epilepsy, febrile status epilepticus, preterm birth Received February 16, 2014. Accepted for publication March 28, 2014.
Neonatal seizures are associated with an increased risk of subsequent neurologic sequelae.1 Because of the ability of neonatal seizures to cause enduring dysfunctional changes in activitydependent processes,2 some of those children experiencing seizures in the neonatal period develop postneonatal epilepsy at early ages.3 Postneonatal epilepsy incidence is reported to vary between 20% and 28%,4 and its onset is usually at early ages without any further intervening event. Febrile seizures, a common event in early childhood, have been associated to the development of epilepsy in up to 40% of patients,5 and a potential explanation for this association could be that prolonged febrile seizures might cause epilepsy by damaging the developing brain.6 Results from a recent case-control study suggest that the occurrence of a febrile status epilepticus as the first febrile seizure can be interpreted as a marker of a lower seizure threshold associated with an inability to stop seizure activity once established.7 Alternatively, febrile status epilepticus could act as a second hit in patients with severe perinatal brain injury manifesting with neonatal seizures, as suggested by experimental models.8 In this study, we discuss how febrile status epilepticus could act as a second hit determining symptomatic epilepsy in 2 patients with a similar perinatal history characterized by premature birth, severe brain damage, and neonatal seizures. We believe that they represent a well-characterized human example of what the current basic researches are proposing as a two-hit model to explain epileptogenesis in the developing brain.
Case Summary The first patient is a boy, now 11 years old, who was born at 24 weeks of gestational age by spontaneous vaginal delivery with stained amniotic fluid, a birth weight of 780 g and Apgar scores of 1 at 1 minute and 6 at 5 minutes, developing bronchopulmonary dysplasia, optic retinopathy of prematurity grade 3, and a right hypertensive pneumothorax. Additionally, the finding of increased neutrophile and reduced platelet count was suggestive of systemic infection even if cultures remained negative. He required repeated blood and irradiated platelet transfusions. Moreover, during the neonatal period, he suffered from recurrent multifocal clonic, myoclonic, tonic, and subclinical seizures from the fifth day of life, which were refractory to phenobarbital but partially responded to valproic acid. When first evaluated, at seizure onset, he was profoundly hypotonic and hyporeactive. Polygraphic EEGs showed a disorganized 1
Child Neuropsychiatry Unit, Neuroscience Department, University of Parma, Parma, Italy 2 Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, University of California, San Francisco, CA, USA Corresponding Author: Carlotta Spagnoli, MD, Department of Neuroscience, University of Parma, Via Gramsci 14, 43126 Parma, Italy. Email: [email protected]
616
Figure 1. Patient 1’s wake electroencephalogram (EEG) at 8 years: diffuse medium-high amplitude delta-theta background activity, moderately asymmetrical due to a left-posterior prevalence of the higher and slower components, with superimposed low-voltage fast rhythms. Multifocal paroxysmal discharges (spikes and spike-and-slow waves), predominantly located in the left midposterior quadrant (doublebanana montage, 10 seconds/page speed, 1600-Hz high-pass filter, 10-Hz low-pass filter, 70 mV amplitude).
discontinuous trace with prolonged interburst intervals, and the presence of high-amplitude, sharp theta activity over both temporal regions, bilateral positive rolandic sharps, and mechanical brushes in the midposterior regions (left more than right). Ictal activity was characterized by multifocal discharges in the alpha-beta range with a left centrotemporal or posterior emphasis, less frequently with a right temporal onset. Cranial ultrasonography demonstrated a grade 3 bilateral intraventricular hemorrhage evolving into a tetraventricular hydrocephalus, confirmed by a brain MRI, which required ventriculoperitoneal shunting, and the postsurgical period was complicated by drainage blockade and infection. During the follow-up, he presented spastic cerebral palsy, nystagmus, and paradoxical dysphagia. Repeated electroencephalograms (EEGs) showed multifocal epileptiform abnormalities with a left centroparietal and/or posterior emphasis (Figure 1). At 6 years of age, he was admitted to the pediatric intensive care unit for a focal febrile status epilepticus characterized by nystagmus and clonic jerks of the right arm, interrupted by intravenous diazepam administration. Since then, he developed epilepsy with the same seizure semiology as reported above, usually of brief duration, which well responded to valproic acid but recurred at every attempt of antiepileptic drugs discontinuation, autonomously tried by parents. The second patient is a girl, now aged 10 years, born at 28 weeks of gestational age with a birth weight of 850 g by urgent cesarean section due to fetal distress and maternal hypertension. Given Apgar scores of 2 at 1 minute and 7 at 5 minutes, she required intubation and ventilation. Upon examination, she showed a markedly reduced tone. Her neonatal seizures started at 4 weeks of life. She experienced focal clonic recurrent
Journal of Child Neurology 30(5) seizures (affecting either side, with right hemisphere predominance) and myoclonic seizures only partially responsive to phenobarbital, which was withheld after 12 days. Her neonatal EEGs showed a depressed (especially in the left hemisphere), asymmetrical, and mainly asynchronous background activity, with biphasic spikes, at times in runs, over both centrotemporal regions, with right predominance, and mechanical brushes (predominantly with a right posterior topography). Clonic events correlated with the appearance of a low-voltage alphabeta activity over the anterior regions, mainly expressed over the right hemisphere. Two months later, she presented with brief spontaneously remitting short-lived electroclinical seizures of clonic type. Her brain magnetic resonance imaging (MRI) showed a posthemorrhagic hydrocephalus with widespread damage to the subcortical white matter, more severe in the left hemisphere (Figure 2). She developed cerebral palsy, central visual impairment, severe psychomotor delay, and aggressive behavior, but no further seizures were observed. Febrile status epilepticus occurred at the age of 3 years characterized by autonomic features (mydriasis, tachycardia, and drooling), cyanosis, loss of consciousness, and clonic jerks of all limbs, lasting longer than 30 minutes. Afterwards, she developed epilepsy with seizures characterized by mydriasis, tachycardia, head deviation to the left, generalized hypertonus, and loss of consciousness, usually of short duration. Currently she is experiencing an average of 2 seizures per month. Her current medications comprise carbamazepine, topiramate, and diazepam. An example of her wake EEG activity is reported in Figure 2.
Discussion We present 2 cases of preterm newborns with neonatal seizures in the context of extensive perinatal brain damage in whom the occurrence of epilepsy was triggered by an episode of febrile status epilepticus. Because of the ability of neonatal seizures to cause enduring dysfunctional changes in activity-dependent processes,2 these children develop post-neonatal epilepsy at early ages,3 even in the absence of any further intervening event, with figures of 73.3% within the first year of life.1 This clinical phenomenon could be best interpreted as an expression of epileptogenesis. As demonstrated in animal models, following an initial insult, induction of immediate early genes and regulation of ion channels and receptors take place. The intervening subacute phase is characterized by neuronal death, neurotrophic factors expression (modulating synaptic plasticity and maturational onset of potassium chloride cotransporter 2-KCC2 expression), microglial activation and transcriptional expression changes, whereas the final, chronic stage, is characterized by sprouting, neurogenesis, and gliosis, although differences are observed depending on the experimental model and subjects’ age.9 Interestingly, in some circumstances the initial brain damage requires a second hit in order to develop spontaneous recurrent seizures as in the case of our patients who became epileptic after the episode of febrile status epilepticus. This so-called two-hit hypothesis suggests that seizures in the immature brain
Spagnoli et al
617
Figure 2. On the left (A), patient 2’s brain magnetic resonance imaging (MRI) at 7 years of age. Axial T1-weighted image showing ventricular dilation with widespread damage to the subcortical white matter more severe on the left. Encephalomalacic areas are visible at the nucleocapsular, thalamic, and corona radiata levels. On the right (B), patient 2’s wake electroencephalogram (EEG) at 10 years: diffuse medium-high amplitude theta background activity. Paroxysmal discharges (spikes, spike-and-slow waves and poly-spike-and-slow waves) arising from the left frontocentral region, with a tendency toward homolateral and contralateral diffusion (double-banana montage, 10 seconds/page speed, 1600-Hz high-pass filter, 30-Hz low-pass filter, 150 mV amplitude).
result in changes causing the mature brain to be more prone to seizure-induced injury in adulthood.10 In fact, in murine two-hit models of kainate-induced11 and flurothyl-induced8 neonatal seizures, the presence of a neonatal insult has been associated with an increased susceptibility to seizure-induced injury in adolescence8 and adulthood8,11 even in the absence of any detectable cell loss. Furthermore, the occurrence of status epilepticus in postnatal day 15 rats has been reported to increase sensitivity to later-life insults.11,12 To our knowledge, there is only 1 study directly assessing the association between the occurrence of neonatal seizures, febrile seizures, and the development of subsequent epilepsy in preterm babies.13 These authors found that of the 5 children developing epilepsy, 2 had also fever-induced epileptic seizures.13 However, the authors did not provide information on age at onset of either febrile seizures or epilepsy so that the temporal relationship among those events remains unknown. In order to overcome limitations in extrapolating data from animal models to human newborns, in whom neonatal seizures often display a neocortical rather than a hippocampal origin,4 an experimental model of flurothyl-induced recurrent neocortical neonatal seizures was developed, allowing demonstration of an enhanced long-term excitability in pyramidal cells of the somatosensory cortex, with an N-methyl-D-aspartate (NMDA) receptor-dependent effect on synaptic transmission.14 Very interestingly, whereas recurrent seizures in the neonatal period reduced the threshold to proconvulsant agents later in life, these animals did not develop spontaneous seizures. This is especially relevant in the context of our patients, because it favors the hypothesis that spontaneous seizures might not have developed in the absence of a second hit.
Moreover, epilepsy risk after febrile seizures has already been reported to be increased in some subgroups of patients: children with cerebral palsy, Apgar score of less than 7 at 5 minutes, a birth weight of less than 2500 g, or a gestational age at birth of less than 37 weeks,6 well corresponding to the clinical characteristics of our patients. Additionally, it has been suggested that preexisting brain damage, a family history of seizures, and early environmental factors might increase susceptibility to seizure-induced brain damage.15,16 Febrile status epilepticus is more frequently reported in patients with a history of neonatal seizures and who are neurologically abnormal before the episode.16 Among patients with a history of neonatal seizures, febrile status epilepticus was the first febrile seizure in 4 cases out of 6, and the rate of neurologic abnormalities was significantly higher (100%) than in those children with no history of neonatal seizures (18%).16 To assess the functional and clinical consequences of febrile seizures in the context of brain damage, febrile seizure models have now been developed in which hyperthermia-induced seizures are provoked in animals undergoing focal cortical damage.17 In this context, febrile status epilepticus is associated with the occurrence of spontaneous seizures in 86% of rats, whereas in the absence of any preexisting brain damage, a 25% prevalence of spontaneous recurrent seizures was observed.18 Interestingly, a localized cortical dysplasia induced in newborn rats resulted in atypical or prolonged hyperthermic seizures occurring at a lower threshold, with a shorter latency and increased severity compared with seizures experienced by rats in the control group,19 leading to the hypothesis that atypical hyperthermic seizures could favor the development of chronic epilepsy in lesioned rats.
618 The clinical course of our patients evolving from braindamage-induced neonatal seizures to symptomatic epilepsy through a silent period interrupted, or shortened, by the occurrence of febrile status epilepticus very closely recapitulates what the experimental animal models have already outlined and seems to corroborate their findings. In particular, we think this study represents a well-characterized human example of what the current basic science research is proposing as a two-hit model to explain epileptogenesis in the developing brain. Author Contributions CS and FP conceptualized and designed the study. CS and EP collected clinical data. CS drafted the initial manuscript. MRC, EP, and FP critically reviewed and revised the manuscript. FP designed the data collection instruments and coordinated and supervised data collection. All authors approved the final manuscript as submitted. There were no ‘‘ghost writers.’’
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval In accordance with current practice at our Institution, an informed consent form was signed by patients’ parents to approve the use of patient information or material for scientific purposes, and the informed consent was placed in the patient’s hospital chart.
References 1. Pisani F, Piccolo B, Cantalupo G, et al. Neonatal seizures and postneonatal epilepsy: a 7-y follow-up study. Pediatr Res. 2012; 72:186-193. 2. Baram TZ. The brain, seizures and epilepsy throughout life: understanding a moving target. Epilepsy Curr. 2012;12:7-12. 3. Ellenberg JH, Hirtz DG, Nelson KB. Age at onset of seizures in young children. Ann Neurol. 1984;15:127-134. 4. Mizrahi EM. Acute and chronic effects of seizures in the developing brain: lessons from clinical experience. Epilepsia. 1999; 40:S42-S50. 5. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med. 1987;316:493-498.
Journal of Child Neurology 30(5) 6. Vestergaard M, Pedersen CB, Sidenius P, et al. The long-term risk of epilepsy after febrile seizures in susceptible subgroups. Am J Epidemiol. 2007;165:911-918. 7. Hesdorffer DC, Shinnar S, Lewis DV, et al. Risk factors for febrile status epilepticus: a case-control study. J Pediatr. 2013; 163:1147-1151. 8. Schmid R, Tandon P, Stafstrom CE, Holmes GL. Effects of neonatal seizures on subsequent seizure-induced brain injury. Neurology. 1999;53:1754-1761. 9. Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5:380-391. 10. Hoffmann AF, Zhao Q, Holmes GL. Cognitive impairment following status epilepticus and recurrent seizures during early development: support for the ‘‘two-hit hypothesis.’’ Epilepsy Behav. 2004;5:873-877. 11. Koh S, Storey TW, Santos TC, et al. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood. Neurology. 1999;53:915-921. 12. Giorgi FS, Malhotra S, Hasson H, et al. Effects of status epilepticus early in life on susceptibility to ischemic injury in adulthood. Epilepsia. 2005;46:490-498. 13. Herrga˚rd EA, Karvonen M, Luoma L, et al. 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. Seizure. 2006; 15:590-597. 14. Isaeva E, Isaev D, Savrasova A, et al. Recurrent neonatal seizures result in long-term increases in neuronal network excitability in the rat neocortex. Eur J Neurosci. 2010;31:1446-1455. 15. Berkovic SF, Scheffer IE. Febrile seizures: genetics and relationship to other epilepsy syndromes. Curr Opin Neurol. 1998;11: 129-134. 16. Shinnar S, Pellock JM, Berg AT, et al. Short-term outcomes of children with febrile status epilepticus. Epilepsia. 2001;42: 47-53. 17. Hardiman O, Burke T, Phillips J, et al. Microdysgenesis in resected temporal neocortex: incidence and clinical significance in focal epilepsy. Neurology. 1988;38:1041-1047. 18. Scantlebury MH, Gibbs SA, Foadjo B, et al. Febrile seizures in the predisposed brain: a new model of temporal lobe epilepsy. Ann Neurol. 2005;58:41-49. 19. Scantlebury MH, Ouellet PL, Psarropoulou C, Carmant L. Freeze lesion-induced focal cortical dysplasia predisposes to atypical hyperthermic seizures in the immature rat. Epilepsia. 2004;45: 592-600.
Symptomatic Neonatal Seizures Followed by Febrile Status Epilepticus: The two-Hit Hypothesis for the Subsequent Development of Epilepsy
Journal of Child Neurology 2015, Vol. 30(5) 615-618 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814533004 jcn.sagepub.com
Carlotta Spagnoli, MD1, Maria Roberta Cilio, MD, PhD2, Elena Pavlidis, MD1, and Francesco Pisani, MD1
Abstract Neonatal seizures have been associated with the later development of postneonatal epilepsy, mainly beginning within the first year of life. Mechanisms of epileptogenesis in the immature brain still need to be fully elucidated but a two-hit hypothesis, showing that an early insult heightens later susceptibility to seizure-induced brain damage, has been demonstrated in animal models. We describe 2 cases of preterm babies sustaining recurrent neonatal seizures in the context of a severe perinatal brain damage who presented with symptomatic epilepsy only after the occurrence of an episode of febrile status epilepticus. In the context of preexisting perinatal brain damage, febrile status epilepticus acted as a second hit for developing epilepsy, confirming animal evidence. Keywords neonatal seizures, two-hit hypothesis, postneonatal epilepsy, febrile status epilepticus, preterm birth Received February 16, 2014. Accepted for publication March 28, 2014.
Neonatal seizures are associated with an increased risk of subsequent neurologic sequelae.1 Because of the ability of neonatal seizures to cause enduring dysfunctional changes in activitydependent processes,2 some of those children experiencing seizures in the neonatal period develop postneonatal epilepsy at early ages.3 Postneonatal epilepsy incidence is reported to vary between 20% and 28%,4 and its onset is usually at early ages without any further intervening event. Febrile seizures, a common event in early childhood, have been associated to the development of epilepsy in up to 40% of patients,5 and a potential explanation for this association could be that prolonged febrile seizures might cause epilepsy by damaging the developing brain.6 Results from a recent case-control study suggest that the occurrence of a febrile status epilepticus as the first febrile seizure can be interpreted as a marker of a lower seizure threshold associated with an inability to stop seizure activity once established.7 Alternatively, febrile status epilepticus could act as a second hit in patients with severe perinatal brain injury manifesting with neonatal seizures, as suggested by experimental models.8 In this study, we discuss how febrile status epilepticus could act as a second hit determining symptomatic epilepsy in 2 patients with a similar perinatal history characterized by premature birth, severe brain damage, and neonatal seizures. We believe that they represent a well-characterized human example of what the current basic researches are proposing as a two-hit model to explain epileptogenesis in the developing brain.
Case Summary The first patient is a boy, now 11 years old, who was born at 24 weeks of gestational age by spontaneous vaginal delivery with stained amniotic fluid, a birth weight of 780 g and Apgar scores of 1 at 1 minute and 6 at 5 minutes, developing bronchopulmonary dysplasia, optic retinopathy of prematurity grade 3, and a right hypertensive pneumothorax. Additionally, the finding of increased neutrophile and reduced platelet count was suggestive of systemic infection even if cultures remained negative. He required repeated blood and irradiated platelet transfusions. Moreover, during the neonatal period, he suffered from recurrent multifocal clonic, myoclonic, tonic, and subclinical seizures from the fifth day of life, which were refractory to phenobarbital but partially responded to valproic acid. When first evaluated, at seizure onset, he was profoundly hypotonic and hyporeactive. Polygraphic EEGs showed a disorganized 1
Child Neuropsychiatry Unit, Neuroscience Department, University of Parma, Parma, Italy 2 Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, University of California, San Francisco, CA, USA Corresponding Author: Carlotta Spagnoli, MD, Department of Neuroscience, University of Parma, Via Gramsci 14, 43126 Parma, Italy. Email: [email protected]
616
Figure 1. Patient 1’s wake electroencephalogram (EEG) at 8 years: diffuse medium-high amplitude delta-theta background activity, moderately asymmetrical due to a left-posterior prevalence of the higher and slower components, with superimposed low-voltage fast rhythms. Multifocal paroxysmal discharges (spikes and spike-and-slow waves), predominantly located in the left midposterior quadrant (doublebanana montage, 10 seconds/page speed, 1600-Hz high-pass filter, 10-Hz low-pass filter, 70 mV amplitude).
discontinuous trace with prolonged interburst intervals, and the presence of high-amplitude, sharp theta activity over both temporal regions, bilateral positive rolandic sharps, and mechanical brushes in the midposterior regions (left more than right). Ictal activity was characterized by multifocal discharges in the alpha-beta range with a left centrotemporal or posterior emphasis, less frequently with a right temporal onset. Cranial ultrasonography demonstrated a grade 3 bilateral intraventricular hemorrhage evolving into a tetraventricular hydrocephalus, confirmed by a brain MRI, which required ventriculoperitoneal shunting, and the postsurgical period was complicated by drainage blockade and infection. During the follow-up, he presented spastic cerebral palsy, nystagmus, and paradoxical dysphagia. Repeated electroencephalograms (EEGs) showed multifocal epileptiform abnormalities with a left centroparietal and/or posterior emphasis (Figure 1). At 6 years of age, he was admitted to the pediatric intensive care unit for a focal febrile status epilepticus characterized by nystagmus and clonic jerks of the right arm, interrupted by intravenous diazepam administration. Since then, he developed epilepsy with the same seizure semiology as reported above, usually of brief duration, which well responded to valproic acid but recurred at every attempt of antiepileptic drugs discontinuation, autonomously tried by parents. The second patient is a girl, now aged 10 years, born at 28 weeks of gestational age with a birth weight of 850 g by urgent cesarean section due to fetal distress and maternal hypertension. Given Apgar scores of 2 at 1 minute and 7 at 5 minutes, she required intubation and ventilation. Upon examination, she showed a markedly reduced tone. Her neonatal seizures started at 4 weeks of life. She experienced focal clonic recurrent
Journal of Child Neurology 30(5) seizures (affecting either side, with right hemisphere predominance) and myoclonic seizures only partially responsive to phenobarbital, which was withheld after 12 days. Her neonatal EEGs showed a depressed (especially in the left hemisphere), asymmetrical, and mainly asynchronous background activity, with biphasic spikes, at times in runs, over both centrotemporal regions, with right predominance, and mechanical brushes (predominantly with a right posterior topography). Clonic events correlated with the appearance of a low-voltage alphabeta activity over the anterior regions, mainly expressed over the right hemisphere. Two months later, she presented with brief spontaneously remitting short-lived electroclinical seizures of clonic type. Her brain magnetic resonance imaging (MRI) showed a posthemorrhagic hydrocephalus with widespread damage to the subcortical white matter, more severe in the left hemisphere (Figure 2). She developed cerebral palsy, central visual impairment, severe psychomotor delay, and aggressive behavior, but no further seizures were observed. Febrile status epilepticus occurred at the age of 3 years characterized by autonomic features (mydriasis, tachycardia, and drooling), cyanosis, loss of consciousness, and clonic jerks of all limbs, lasting longer than 30 minutes. Afterwards, she developed epilepsy with seizures characterized by mydriasis, tachycardia, head deviation to the left, generalized hypertonus, and loss of consciousness, usually of short duration. Currently she is experiencing an average of 2 seizures per month. Her current medications comprise carbamazepine, topiramate, and diazepam. An example of her wake EEG activity is reported in Figure 2.
Discussion We present 2 cases of preterm newborns with neonatal seizures in the context of extensive perinatal brain damage in whom the occurrence of epilepsy was triggered by an episode of febrile status epilepticus. Because of the ability of neonatal seizures to cause enduring dysfunctional changes in activity-dependent processes,2 these children develop post-neonatal epilepsy at early ages,3 even in the absence of any further intervening event, with figures of 73.3% within the first year of life.1 This clinical phenomenon could be best interpreted as an expression of epileptogenesis. As demonstrated in animal models, following an initial insult, induction of immediate early genes and regulation of ion channels and receptors take place. The intervening subacute phase is characterized by neuronal death, neurotrophic factors expression (modulating synaptic plasticity and maturational onset of potassium chloride cotransporter 2-KCC2 expression), microglial activation and transcriptional expression changes, whereas the final, chronic stage, is characterized by sprouting, neurogenesis, and gliosis, although differences are observed depending on the experimental model and subjects’ age.9 Interestingly, in some circumstances the initial brain damage requires a second hit in order to develop spontaneous recurrent seizures as in the case of our patients who became epileptic after the episode of febrile status epilepticus. This so-called two-hit hypothesis suggests that seizures in the immature brain
Spagnoli et al
617
Figure 2. On the left (A), patient 2’s brain magnetic resonance imaging (MRI) at 7 years of age. Axial T1-weighted image showing ventricular dilation with widespread damage to the subcortical white matter more severe on the left. Encephalomalacic areas are visible at the nucleocapsular, thalamic, and corona radiata levels. On the right (B), patient 2’s wake electroencephalogram (EEG) at 10 years: diffuse medium-high amplitude theta background activity. Paroxysmal discharges (spikes, spike-and-slow waves and poly-spike-and-slow waves) arising from the left frontocentral region, with a tendency toward homolateral and contralateral diffusion (double-banana montage, 10 seconds/page speed, 1600-Hz high-pass filter, 30-Hz low-pass filter, 150 mV amplitude).
result in changes causing the mature brain to be more prone to seizure-induced injury in adulthood.10 In fact, in murine two-hit models of kainate-induced11 and flurothyl-induced8 neonatal seizures, the presence of a neonatal insult has been associated with an increased susceptibility to seizure-induced injury in adolescence8 and adulthood8,11 even in the absence of any detectable cell loss. Furthermore, the occurrence of status epilepticus in postnatal day 15 rats has been reported to increase sensitivity to later-life insults.11,12 To our knowledge, there is only 1 study directly assessing the association between the occurrence of neonatal seizures, febrile seizures, and the development of subsequent epilepsy in preterm babies.13 These authors found that of the 5 children developing epilepsy, 2 had also fever-induced epileptic seizures.13 However, the authors did not provide information on age at onset of either febrile seizures or epilepsy so that the temporal relationship among those events remains unknown. In order to overcome limitations in extrapolating data from animal models to human newborns, in whom neonatal seizures often display a neocortical rather than a hippocampal origin,4 an experimental model of flurothyl-induced recurrent neocortical neonatal seizures was developed, allowing demonstration of an enhanced long-term excitability in pyramidal cells of the somatosensory cortex, with an N-methyl-D-aspartate (NMDA) receptor-dependent effect on synaptic transmission.14 Very interestingly, whereas recurrent seizures in the neonatal period reduced the threshold to proconvulsant agents later in life, these animals did not develop spontaneous seizures. This is especially relevant in the context of our patients, because it favors the hypothesis that spontaneous seizures might not have developed in the absence of a second hit.
Moreover, epilepsy risk after febrile seizures has already been reported to be increased in some subgroups of patients: children with cerebral palsy, Apgar score of less than 7 at 5 minutes, a birth weight of less than 2500 g, or a gestational age at birth of less than 37 weeks,6 well corresponding to the clinical characteristics of our patients. Additionally, it has been suggested that preexisting brain damage, a family history of seizures, and early environmental factors might increase susceptibility to seizure-induced brain damage.15,16 Febrile status epilepticus is more frequently reported in patients with a history of neonatal seizures and who are neurologically abnormal before the episode.16 Among patients with a history of neonatal seizures, febrile status epilepticus was the first febrile seizure in 4 cases out of 6, and the rate of neurologic abnormalities was significantly higher (100%) than in those children with no history of neonatal seizures (18%).16 To assess the functional and clinical consequences of febrile seizures in the context of brain damage, febrile seizure models have now been developed in which hyperthermia-induced seizures are provoked in animals undergoing focal cortical damage.17 In this context, febrile status epilepticus is associated with the occurrence of spontaneous seizures in 86% of rats, whereas in the absence of any preexisting brain damage, a 25% prevalence of spontaneous recurrent seizures was observed.18 Interestingly, a localized cortical dysplasia induced in newborn rats resulted in atypical or prolonged hyperthermic seizures occurring at a lower threshold, with a shorter latency and increased severity compared with seizures experienced by rats in the control group,19 leading to the hypothesis that atypical hyperthermic seizures could favor the development of chronic epilepsy in lesioned rats.
618 The clinical course of our patients evolving from braindamage-induced neonatal seizures to symptomatic epilepsy through a silent period interrupted, or shortened, by the occurrence of febrile status epilepticus very closely recapitulates what the experimental animal models have already outlined and seems to corroborate their findings. In particular, we think this study represents a well-characterized human example of what the current basic science research is proposing as a two-hit model to explain epileptogenesis in the developing brain. Author Contributions CS and FP conceptualized and designed the study. CS and EP collected clinical data. CS drafted the initial manuscript. MRC, EP, and FP critically reviewed and revised the manuscript. FP designed the data collection instruments and coordinated and supervised data collection. All authors approved the final manuscript as submitted. There were no ‘‘ghost writers.’’
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval In accordance with current practice at our Institution, an informed consent form was signed by patients’ parents to approve the use of patient information or material for scientific purposes, and the informed consent was placed in the patient’s hospital chart.
References 1. Pisani F, Piccolo B, Cantalupo G, et al. Neonatal seizures and postneonatal epilepsy: a 7-y follow-up study. Pediatr Res. 2012; 72:186-193. 2. Baram TZ. The brain, seizures and epilepsy throughout life: understanding a moving target. Epilepsy Curr. 2012;12:7-12. 3. Ellenberg JH, Hirtz DG, Nelson KB. Age at onset of seizures in young children. Ann Neurol. 1984;15:127-134. 4. Mizrahi EM. Acute and chronic effects of seizures in the developing brain: lessons from clinical experience. Epilepsia. 1999; 40:S42-S50. 5. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med. 1987;316:493-498.
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