REVIEW URRENT C OPINION
Consequences of febrile seizures in childhood Rod C. Scott a,b
Purpose of review There is a long-standing hypothesis that febrile status epilepticus (FSE) can cause brain injury, particularly to the hippocampus. This review will evaluate recent evidence on the relationships between FSE and later epilepsy and cognitive impairments. Potential strategies for minimizing adverse outcomes will be discussed. Recent findings There are two major longitudinal studies evaluating the outcomes for FSE. These studies provide evidence of acute hippocampal edema that evolves to mesial temporal sclerosis in a small number of children (7%). However, none of these children have developed temporal lobe epilepsy. There is also evidence of more global white matter injury. Development is affected, with a loss of about 10 developmental quotient points and there is evidence for accelerated forgetting. These findings do not correlate with MRI parameters. Therefore, FSE can cause a wide spectrum of injury, but the relationship between this and clinically relevant adverse outcomes remains uncertain. Summary Although there is accumulating evidence that FSE can cause brain injury, the strategies to minimize the impact remain uncertain. Imaging requires sedation, with inherent risks, and may not be appropriate for all children with FSE, given the small number with significant hippocampal edema that could be a biomarker. The alternative of treating all children requires a very safe drug which currently does not exist. Keywords cognition, epilepsy, febrile status epilepticus, hippocampus, MRI
INTRODUCTION Febrile seizures are the most common types of seizures in children under the age of 5 years [1]. Short febrile seizures are usually considered to be benign [1] and not associated with adverse outcomes. However, there is more debate on whether febrile status epilepticus (FSE) is harmful. The goal of this article is to review the evidence for brain injury, epilepsy and cognitive impairments following FSE, and whether current observations support the need for MRI, timing of MRI and what strategies may ultimately reduce adverse outcomes associated with FSE. FSE is defined as a febrile seizure in a previously neurologically normal child between the age of 6 months and 6 years, which lasts for at least 30 min, and is not associated with a central nervous system infection [2]. In the United States, children with pre-existing neurological conditions are also considered to have FSE [3,4 ], and this difference in definition needs to be taken into consideration when comparing studies based in Europe and those based in the United States. The incidence of FSE in Europe is approximately 4/100 000 children/year [2], but there is geographical variability. In Japan, the &&
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incidence is approximately 17/100 000 children/ year [5] and in rural Kenya, the incidence is 168/100 000 children/year [6]. The reasons for this variability are likely to be a complex interaction between genetics, socio-economic status and cause of the fever [7]. The mortality associated with FSE is effectively zero [8]. However, there is concern that there is an increased incidence of morbidity (e.g. subsequent epilepsy, cognitive impairments) in children with FSE, and it is important to identify the frequency of these outcomes as well as the mechanisms underlying them so that novel therapies that could minimize impact can be devised and tested.
a Department of Neurological Science, University of Vermont College of Medicine, Burlington, Vermont, USA and bNeurosciences Unit, UCL Institute of Child Health, London, UK
Correspondence to Rod C. Scott, Department of Neurological Sciences, University of Vermont College of Medicine, Stafford Hall, Room 118C, 95 Carrigan Drive, Burlington, VT 05405, USA. e-mail: Rodney.Scott@med. uvm.edu Curr Opin Pediatr 2014, 26:662–667 DOI:10.1097/MOP.0000000000000153 Volume 26 Number 6 December 2014
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Effects of febrile status epilepticus Scott
KEY POINTS FSE can cause hippocampal injury in a small number of children. Visual evidence for hippocampal edema on MRI could be a biomarker of significant hippocampal injury. Children with FSE have reductions in cognitive and memory scores which may be related to brain injury. Appropriate clinical strategies for minimizing the impact of FSE remain elusive and deserve further study.
HIPPOCAMPAL INJURY There is a long-standing hypothesis that FSE can cause hippocampal injury that matures into mesial temporal sclerosis that is associated with difficultto-treat temporal lobe epilepsy [9,10]. Confirming that FSE can cause mesial temporal sclerosis is important as this will provide justification for the development of strategies that minimize hippocampal injury as a way to reduce the incidence of temporal lobe epilepsy [11]. The above hypothesis was generated on the basis of data collected from epilepsy surgery programs in which it was observed that approximately 30–50% of patients with mesial temporal sclerosis had a history of febrile seizures in childhood. Although this suggests that there is a relationship between FSE and mesial temporal sclerosis, these studies were unable to determine whether the FSE caused mesial temporal sclerosis or whether the mesial temporal sclerosis predisposed children to having FSE. In order to address this issue, there are two major longitudinal studies investigating children with MRI at the time of FSE and at follow-up. The studies have been carried out in London, UK (London study) [12 ,13 ,14–16,17 ] and in the United States [FSE in children (FEBSTAT) study] [4 ,18–22]. The London study identified evidence for hippocampal edema within 5 days of FSE in 24 children recruited to the study [14]. The edema manifested as increases in hippocampal volume and increases in T2 relaxation time. No patient in this original cohort had visually identified evidence of edema or of mesial temporal sclerosis at the time of FSE. FEBSTAT has recruited 199 children with FSE and therefore has greater power to detect abnormalities than the London study. Approximately 10% of the children have visually identified unilateral hippocampal edema predominantly affecting the CA1 regions of the hippocampus [22]. FEBSTAT also carried out electroencephalogram (EEG) in these patients and showed evidence for slowing in the &&
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EEG, particularly over the temporal regions [21]. These findings are consistent with hippocampal edema. In addition, they identified two children with pre-existing mesial temporal sclerosis. Therefore, on the basis of acute imaging data, there is evidence for both acute hippocampal injury and for pre-existing mesial temporal sclerosis. There is also likely to be a spectrum in the severity of the edema, ranging from mild edema, only identified on quantitative imaging, through to obvious edema that can be seen on visual assessment. It is therefore important to establish whether children with hippocampal edema develop MRI evidence for mesial temporal sclerosis at follow-up and whether this could be related to the severity of the acute imaging abnormality. If so, acute imaging could become a biomarker for later adverse outcomes and may be a guide to which children could benefit from therapy [4 ,23]. The children in the London study had follow-up imaging approximately 6 months after the acute event [15]. None of the children developed mesial temporal sclerosis, although there was an increase in hippocampal asymmetry, suggesting that there may be a spectrum of hippocampal injury and it is possible that a small proportion of children would develop mesial temporal sclerosis. A second cohort of 33 children ascertained in London did not have acute MRI, but had imaging at 3 months, 6 months and 1 year following the acute event in order to define the course of hippocampal injury after the initial hippocampal edema had resolved [16]. This study provided evidence for hippocampal volume loss in approximately 20% of the children, but again none had such severity of volume loss to meet criteria for mesial temporal sclerosis [17 ]. In the FEBSTAT cohort, 130 children had follow-up MRI and 9 (7%) children met imaging criteria for mesial temporal sclerosis, all of whom had evidence for acute hippocampal edema [4 ]. Acute EEG findings were not predictive of later mesial temporal sclerosis [4 ]. Approximately half of the children with mesial temporal sclerosis in the FEBSTAT study had additional MRI abnormalities, pre-existing developmental delay, or both. It is interesting to note that there is no relationship between characteristics of the FSE (duration, severity, treatment, etc.) and the presence of edema or later hippocampal abnormalities in either the London study or the FEBSTAT study. This suggests that there is at least one additional factor predicting which children are at risk of brain injury. Overall, these data support the view that FSE can occasionally cause mesial temporal sclerosis and this risk is possibly increased in children with pre-existing neurological abnormalities.
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NONHIPPOCAMPAL IMAGING ABNORMALITIES Both the London group and the FEBSTAT study have reported the data on visual analysis of the scans of children with a history of FSE. The London study identified one child (3%) with a minor abnormality [hippocampal malrotation (HIMAL)] and no children with a major abnormality [16]. In contrast, there were definite abnormalities identified in approximately 28% of the children in the FEBSTAT study [22]. The most likely reason for this is definition. If children with pre-existing neurological impairments who present with status epilepticus associated with fever are included in the London cohort, then the prevalence of imaging abnormalities is 24% [16]. The nature of the abnormalities include malformations of cortical development, evidence for previous hypoxic injury, hydrocephalus, as well as more minor abnormalities such as small white matter hyperintensities and blurring of gray white matter junctions, particularly in the anterior temporal lobe. It is also possible that there are brain abnormalities outside of the hippocampus that are not readily identified on visual inspection of the scans. To evaluate this further, the London group used tract-based spatial statistics on MR diffusion data to study whether there is evidence for white matter abnormalities following FSE. The children show reductions in fractional anisotropy 3 months following FSE, and this recovers over the course of the subsequent year [12 ]. This suggests that there is some widespread subtle brain injury associated with FSE and that injury is not localized to the hippocampus. Thus, there is evidence that FSE can cause brain injury as evidenced on MRI, but this is only relevant if associated with clinical abnormalities such as the development of epilepsy and cognitive impairments. It is of importance that the two studies discussed above are largely consistent with each other, and this further strengthens the case for FSE being able to cause hippocampal sclerosis. &&
RELATIONSHIP BETWEEN FEBRILE STATUS EPILEPTICUS AND EPILEPSY The prevalence of afebrile seizures following FSE is in the order of 5–10% [24]. The estimates depend on the definition of FSE and the quality of the study from which the estimate is taken [24]. Children with pre-existing neurological conditions have a higher incidence of epilepsy than those children who were previously neurologically normal. Children with FSE without neurological or cognitive impairments have the lowest risk for subsequent epilepsy and the risk may not be much greater than the risk in the 664
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general population [25,26]. It might be expected that if there was a relationship between hippocampal injury and epilepsy, then these children would often have temporal lobe epilepsy. It is clear that some of the children have focal seizures, but the structural substrates for the seizures have not been clearly defined. Children with mutations in sodium channel genes SCN1A [Dravet syndrome and general epilepsy with febrile seizuresþ (GEFSþ)] [27–29] and SCN1B [30], as well as those with mutations in the gamma-aminobutyric acid type A genes [31], may present with FSE. These children ultimately develop generalized seizures including absence, tonic-clonic and myoclonic seizures. It is important to note that none of the five children with epilepsy in the FEBSTAT cohort have temporal lobe seizures. However, it may take many years to develop epilepsy and therefore this observation may change over time. Therefore, the relationship between FSE and epilepsy is complex and development of temporal lobe epilepsy associated with mesial temporal sclerosis caused by FSE seems to be an uncommon outcome.
COGNITIVE IMPAIRMENT Given that FSE has been associated with brain injury and the subsequent development of epilepsy, it is reasonable to hypothesize that FSE could also be associated with reductions in cognition. The London group has been studying cognitive outcomes in children with convulsive status epilepticus including those with FSE. Children with FSE have a reduction in developmental quotient of approximately 10 points to a mean of 93 points [13 ]. This reduction in developmental quotient is significantly different to the population expectation of 100 points and also significantly different to a control sample ascertained in London. There is no relationship between hippocampal volume or severity of white matter abnormalities and general cognitive outcomes [13 ]. Thus, it remains uncertain whether the observed cognitive differences are a function of brain injury caused by the FSE, a marker of a preexisting brain abnormality that predisposes to FSE, or a combination of both. The hippocampus is an extremely important structure for memory function and therefore it is important to establish whether memory is impaired in children who have experienced an episode of FSE. It is difficult to apply standardized tests of memory in young children and therefore the London group evaluated memory using a visual paired comparison task [32]. Approximately 1 month after the episode of FSE, the children had evidence for accelerated forgetting when compared to controls. This effect &
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Effects of febrile status epilepticus Scott
was still present 1 year after the acute event, suggesting that memory deficits are permanent [32]. There was also a relationship between the degree of hippocampal asymmetry and the severity of accelerated forgetting, supporting the view that this effect may be a function of hippocampal injury. This leads to the hypothesis that prevention of brain injury could lead to improvements in outcomes of children with FSE.
MECHANISMS OF ADVERSE OUTCOMES In order to define potential treatments that minimize adverse outcomes following FSE, it is essential that the mechanisms of brain injury are defined. The majority of the work addressing this issue has been carried out in models of status epilepticus without fever. The most common models are the lithiumpilocarpine model [33] and the kainate model [34]. This is partly because these models reliably lead to brain injury, whereas the FSE model is closer to replicating the human data in that significant neuronal loss is uncommon, and this model is better suited to understanding epileptogenesis in the absence of significant injury [35,36]. Nevertheless, the nature of the brain injury in the pilocarpine and kainite models is similar to that observed in humans with mesial temporal sclerosis, suggesting that these models are of relevance to understanding brain injury and potential neuroprotection. The mechanism of injury that has received the most attention is excitotoxicity [37,38]. Prevention of brain injury and epileptogenesis is possible with preadministration of the N-methyl-D-aspartate (NMDA) receptor blocker, MK-801, supporting the hypothesis that excitotoxicity is an important mechanism driving adverse outcomes from convulsive status epilepticus (CSE) [39]. However, the use of MK-801 in a more clinically relevant setting with administration after termination of status epilepticus has some effect on the severity of brain injury, but does not prevent the later development of epilepsy. It remains uncertain whether there is a reduction in cognitive impairments. Therefore, this is a disappointing approach and is unlikely to be important for clinical practice. Another potentially important mechanism is inflammation. There is evidence that status epilepticus, including FSE, leads to an up-regulation of cytokines, particularly interleukin (IL)-1b, at the site of seizure origin [40]. The release of this and other cytokines [e.g. tumor necrosis factor (TNF) and IL-6] [41,42] results in up-regulation of selectins, adhesion molecules [including vascular cell adhesion molecule-1 (VCAM-1)] [43,44] and integrins [43]. This signaling cascade promotes diapedesis of leucocytes across the blood–brain barrier which is
hypothesized to be important for modulation of brain injury and subsequent epileptogenesis. This makes targeting the inflammatory process as a neuroprotecitve and antiepileptogenesis strategy very attractive. Pharmacological experiments that have attempted to address the relationships between inflammation and adverse outcomes from CSE have explored the effects of cyclooxygenase-2 (COX-2) inhibitors, erythropoietin, disruption of leukocyte– endothelial interactions, and corticosteroids. There is controversial evidence that reducing inflammation following CSE with COX-2 inhibitors can reduce the severity of subsequent epilepsy. Administering the COX-2 inhibitor celecoxib reduces the severity of hippocampal injury and the frequency of spontaneous recurrent seizures [45]. However, parecoxib reduces the severity of brain injury, but does not alter the frequency or duration of spontaneous recurrent seizures when administered following pilocarpineinduced CSE [46]. Therefore, the approach of modulating a single protein has potential, but more work is required. Targeting inflammation broadly with erythropoietin or corticosteroids is an alternative and potentially rapidly translatable approach. Administration of erythropoietin for 7 days, commencing immediately after the termination of status epilepticus, reduces hippocampal injury, as well as the frequency and severity of subsequent spontaneous recurrent seizures [44,47]. Another broad-spectrum anti-inflammatory is dexamethasone. When this is administered soon after CSE and then daily for 5 days, brain injury is greater than in controls with CSE, and mortality is greater [48 ]. Therefore, it is critical that broad-spectrum agents are more thoroughly evaluated prior to any testing in humans. Disruption of leukocyte–endothelial interactions by blocking P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins a4b1 and aLb2 with antibodies is effective in reducing brain injury and epileptogenesis This finding was confirmed by genetically interfering with PSGL-1 and depleting leukocytes [43]. This suggests an extremely important role for leukocyte vascular interactions in injury and epileptogenesis, but these strategies remain far from clinical practice. Prior to pursuing expensive and difficult studies, it is worth asking whether the magnitude of the clinical problem is large enough to warrant the resources required. &
CONCLUSION Although the evidence supporting the view that brain injury following FSE is possible, the frequency with which severe injury occurs is low. In addition,
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the frequency with which clinically important adverse outcomes directly related to that injury occur (temporal lobe epilepsy, significant amnesia, etc.) remains uncertain. It seems clear that clinically relevant adverse outcomes are possible and the prediction of which children are at particular risk may be possible with MRI imaging acutely. However, this raises several issues that deserve discussion. Children in the age range for FSE all require sedation or anesthesia for MRI, and although this is of low risk, it is not immediately obvious that this low risk is appropriately balanced with potential gain. Even if this risk–benefit ratio is considered to be appropriate for the identification of the less than 10% of children at risk of adverse outcomes, there are currently no clear therapeutic strategies. If a clear strategy is identified, then there is the issue of how such a strategy will be robustly tested in clinical trials [49 ]. It has taken many years to recruit the children into the London and FEBSTAT studies, and these studies would clearly be insufficiently powered to evaluate the impact of a novel intervention in children with visually obvious edema on an acute scan. An alternative is to assert that minor injury is common after FSE and even if the effects on cognition are small, it may be worth minimizing those effects. In this situation, a drug could be given to all children with FSE, independently of MRI, and thus adequate sample sizes would be easier to ascertain. However, the adverse effects of any strategy would need to be extremely low in order to justify administration to many children in whom the potential benefit is small. Although much has been achieved over the past decade or so, several questions remain to be answered. &
Acknowledgements R.C.S. received funding from the Wellcome Trust (Grant number: 060214/HC/RL/MW/kj) and NINDS (R01NS075249). Conflicts of interest R.C.S. is supported by GOSH Children’s Charity and has received travel grants from Glaxo-SmithKline, JanssenCilag, UCB Pharma, and SPL Ltd.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Febrile seizures: Consensus development conference summary. Febrile seizures. Bethesda, MD: National Institutes of Health; 1980. 2. Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006; 368:222–229.
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3. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987; 316:493–498. 4. Lewis DV, Shinnar S, Hesdorffer DC, et al. Hippocampal sclerosis after febrile && status epilepticus: the FEBSTAT study. Ann Neurol 2014; 75:178–185. This is the definitive study on the relationship between FSE and hippocampal sclerosis. Approximately 7% of children with FSE will get hippocampal sclerosis and this is predicted by visual evidence of hippocampal edema on MRI. 5. Nishiyama I, Ohtsuka Y, Tsuda T, et al. An epidemiological study of children with status epilepticus in Okayama, Japan. Epilepsia 2007; 48:1133–1137. 6. Sadarangani M, Seaton C, Scott JA, et al. Incidence and outcome of convulsive status epilepticus in Kenyan children: a cohort study. Lancet Neurol 2008; 7:145–150. 7. Chin RF, Neville BG, Peckham C, et al. Socioeconomic deprivation independent of ethnicity increases status epilepticus risk. Epilepsia 2009; 50:1022– 1029. 8. Pujar SS, Neville BG, Scott RC, Chin RF. Death within 8 years after childhood convulsive status epilepticus: a population-based study. Brain 2011; 134:2819–2827. 9. Honovar M, Meldrum B. Epilepsy. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology. London: Oxford University Press; 1997. pp. 931– 969. 10. Babb TL, Brown WJ. Pathological findings in epilepsy. In: Engel Jr J, editor. Surgical treatment of the epilepsies. New York: Raven Press; 1993. pp. 511–540. 11. Nohria V, Lee N, Tien RD, et al. Magnetic resonance imaging evidence of hippocampal sclerosis in progression: a case report. Epilepsia 1994; 35:1332–1336. 12. Yoong M, Seunarine K, Martinos M, et al. Prolonged febrile seizures cause && reversible reductions in white matter integrity. Neuroimage Clin 2013; 3:515–521. This is the first study evaluating the relationship between FSE and white matter injury outside of the hippocampus. There are reductions in fractional anisotropy in multiple brain regions that recover over the course of a year. The clinical relevance is uncertain. 13. Martinos MM, Yoong M, Patil S, et al. Early developmental outcomes in & children following convulsive status epilepticus: a longitudinal study. Epilepsia 2013; 54:1012–1019. This study revealed that children with FSE have developmental quotients approximately 10 points below expected. Prior to this study, it was assumed that there was no relationship between FSE and cognitive outcomes. It remains unclear whether this difference is a function of brain injury, a brain abnormality predisposing the FSE, or a combination of both. 14. Scott RC, Gadian DG, King MD, et al. Magnetic resonance imaging findings within 5 days of status epilepticus in childhood. Brain 2002; 125:1951– 1959. 15. Scott RC, King MD, Gadian DG, et al. Hippocampal abnormalities after prolonged febrile convulsion: a longitudinal MRI study. Brain 2003; 126:2551– 2557. 16. Yoong M, Madari R, Martinos M, et al. The role of magnetic resonance imaging in the follow-up of children with convulsive status epilepticus. Dev Med Child Neurol 2012; 54:328–333. 17. Yoong M, Martinos MM, Chin RF, et al. Hippocampal volume loss following && childhood convulsive status epilepticus is not limited to prolonged febrile seizures. Epilepsia 2013; 54:2108–2115. This study showed that approximately 20% of children with FSE will have reductions in hippocampal volume over the course of 1 year. Most of the hippocampal volumes remain in the normal range and further follow-up is required to assess whether any children develop mesial temporal sclerosis. 18. Epstein LG, Shinnar S, Hesdorffer DC, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia 2012; 53:1481– 1488. 19. Frank LM, Shinnar S, Hesdorffer DC, et al. Cerebrospinal fluid findings in children with fever-associated status epilepticus: results of the consequences of prolonged febrile seizures (FEBSTAT) study. J Pediatr 2012; 161:1169– 1171. 20. Herrera EA, Alvarez SY, Cobox O, Villeda T. Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2009; 72:1533– 1534. 21. Nordli DR Jr, Moshe SL, Shinnar S, et al. Acute EEG findings in children with febrile status epilepticus: results of the FEBSTAT study. Neurology 2012; 79:2180–2186. 22. Shinnar S, Bello JA, Chan S, et al. MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study. Neurology 2012; 79:871– 877. 23. Provenzale JM, Barboriak DP, VanLandingham K, et al. Hippocampal MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis. AJR Am J Roentgenol 2008; 190:976– 983. 24. Raspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol 2006; 5:769–779. 25. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics 1978; 61:720–727.
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Effects of febrile status epilepticus Scott 26. Verity CM, Ross EM, Golding J. Outcome of childhood status epilepticus and lengthy febrile convulsions: findings of national cohort study. Br Med J 1993; 307:225–228. 27. Marini C, Mei D, Temudo T, et al. Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Epilepsia 2007; 48:1678– 1685. 28. Shi YW, Yu MJ, Long YS, et al. Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures. Genes Brain Behav 2012; 11:170–176. 29. Sijben AE, Sithinamsuwan P, Radhakrishnan A, et al. Does a SCN1A gene mutation confer earlier age of onset of febrile seizures in GEFSþ? Epilepsia 2009; 50:953–956. 30. Wallace RH, Scheffer IE, Parasivam G, et al. Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. Neurology 2002; 58:1426–1429. 31. Wallace RH, Marini C, Petrou S, et al. Mutant GABA(A) receptor gamma2subunit in childhood absence epilepsy and febrile seizures. Nat Genet 2001; 28:49–52. 32. Martinos MM, Yoong M, Patil S, et al. Recognition memory is impaired in children after prolonged febrile seizures. Brain 2012; 135:3153–3164. 33. Cavalheiro EA. The pilocarpine model of epilepsy. Ital J Neurol Sci 1995; 16:33–37. 34. Ben Ari Y. Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985; 14:375–403. 35. Dube C, Chen K, Eghbal-Ahmadi M, et al. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann Neurol 2000; 47:336–344. 36. Dube C, Richichi C, Bender RA, et al. Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis. Brain 2006; 129:911–922. 37. Meldrum B. Excitotoxicity and epileptic brain damage. Epilepsy Res 1991; 10:55–61. 38. Haglid KG, Wang S, Qiner Y, Hamberger A. Excitotoxicity. Experimental correlates to human epilepsy. Mol Neurobiol 1994; 9:259–263.
39. Stafstrom CE, Holmes GL, Thompson JL. MK801 pretreatment reduces kainic acid-induced spontaneous seizures in prepubescent rats. Epilepsy Res 1993; 14:41–48. 40. Dube C, Vezzani A, Behrens M, et al. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol 2005; 57:152– 155. 41. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 2005; 46:1724–1743. 42. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7:31–40. 43. Fabene PF, Navarro MG, Martinello M, et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 2008; 14:1377–1383. 44. Jung KH, Chu K, Lee ST, et al. Molecular alterations underlying epileptogenesis after prolonged febrile seizure and modulation by erythropoietin. Epilepsia 2011; 52:541–550. 45. Jung KH, Chu K, Lee ST, et al. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol Dis 2006; 23:237–246. 46. Serrano GE, Lelutiu N, Rojas A, et al. Ablation of cyclooxygenase-2 in forebrain neurons is neuroprotective and dampens brain inflammation after status epilepticus. J Neurosci 2011; 31:14850–14860. 47. Chu K, Jung KH, Lee ST, et al. Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 2008; 49:1723–1732. 48. Duffy BA, Chun KP, Ma D, et al. Dexamethasone exacerbates cerebral edema & and brain injury following lithium-pilocarpine induced status epilepticus. Neurobiol Dis 2014; 63:229–236. A rapidly translatable approach to limiting inflammation (dexamethasone) following status epilepticus was evaluated in an animal model. This approach led to increased mortality and greater brain injury, highlighting the need for preclinical studies prior to testing in humans. 49. French JA, Kuzniecky R. Can febrile status cause hippocampal sclerosis? Ann & Neurol 2014; 75:173–174. This editorial deals with the potential clinical approaches to acute FSE, given the number of children who have significant hippocampal injury.
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Consequences of febrile seizures in childhood Rod C. Scott a,b
Purpose of review There is a long-standing hypothesis that febrile status epilepticus (FSE) can cause brain injury, particularly to the hippocampus. This review will evaluate recent evidence on the relationships between FSE and later epilepsy and cognitive impairments. Potential strategies for minimizing adverse outcomes will be discussed. Recent findings There are two major longitudinal studies evaluating the outcomes for FSE. These studies provide evidence of acute hippocampal edema that evolves to mesial temporal sclerosis in a small number of children (7%). However, none of these children have developed temporal lobe epilepsy. There is also evidence of more global white matter injury. Development is affected, with a loss of about 10 developmental quotient points and there is evidence for accelerated forgetting. These findings do not correlate with MRI parameters. Therefore, FSE can cause a wide spectrum of injury, but the relationship between this and clinically relevant adverse outcomes remains uncertain. Summary Although there is accumulating evidence that FSE can cause brain injury, the strategies to minimize the impact remain uncertain. Imaging requires sedation, with inherent risks, and may not be appropriate for all children with FSE, given the small number with significant hippocampal edema that could be a biomarker. The alternative of treating all children requires a very safe drug which currently does not exist. Keywords cognition, epilepsy, febrile status epilepticus, hippocampus, MRI
INTRODUCTION Febrile seizures are the most common types of seizures in children under the age of 5 years [1]. Short febrile seizures are usually considered to be benign [1] and not associated with adverse outcomes. However, there is more debate on whether febrile status epilepticus (FSE) is harmful. The goal of this article is to review the evidence for brain injury, epilepsy and cognitive impairments following FSE, and whether current observations support the need for MRI, timing of MRI and what strategies may ultimately reduce adverse outcomes associated with FSE. FSE is defined as a febrile seizure in a previously neurologically normal child between the age of 6 months and 6 years, which lasts for at least 30 min, and is not associated with a central nervous system infection [2]. In the United States, children with pre-existing neurological conditions are also considered to have FSE [3,4 ], and this difference in definition needs to be taken into consideration when comparing studies based in Europe and those based in the United States. The incidence of FSE in Europe is approximately 4/100 000 children/year [2], but there is geographical variability. In Japan, the &&
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incidence is approximately 17/100 000 children/ year [5] and in rural Kenya, the incidence is 168/100 000 children/year [6]. The reasons for this variability are likely to be a complex interaction between genetics, socio-economic status and cause of the fever [7]. The mortality associated with FSE is effectively zero [8]. However, there is concern that there is an increased incidence of morbidity (e.g. subsequent epilepsy, cognitive impairments) in children with FSE, and it is important to identify the frequency of these outcomes as well as the mechanisms underlying them so that novel therapies that could minimize impact can be devised and tested.
a Department of Neurological Science, University of Vermont College of Medicine, Burlington, Vermont, USA and bNeurosciences Unit, UCL Institute of Child Health, London, UK
Correspondence to Rod C. Scott, Department of Neurological Sciences, University of Vermont College of Medicine, Stafford Hall, Room 118C, 95 Carrigan Drive, Burlington, VT 05405, USA. e-mail: Rodney.Scott@med. uvm.edu Curr Opin Pediatr 2014, 26:662–667 DOI:10.1097/MOP.0000000000000153 Volume 26 Number 6 December 2014
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Effects of febrile status epilepticus Scott
KEY POINTS FSE can cause hippocampal injury in a small number of children. Visual evidence for hippocampal edema on MRI could be a biomarker of significant hippocampal injury. Children with FSE have reductions in cognitive and memory scores which may be related to brain injury. Appropriate clinical strategies for minimizing the impact of FSE remain elusive and deserve further study.
HIPPOCAMPAL INJURY There is a long-standing hypothesis that FSE can cause hippocampal injury that matures into mesial temporal sclerosis that is associated with difficultto-treat temporal lobe epilepsy [9,10]. Confirming that FSE can cause mesial temporal sclerosis is important as this will provide justification for the development of strategies that minimize hippocampal injury as a way to reduce the incidence of temporal lobe epilepsy [11]. The above hypothesis was generated on the basis of data collected from epilepsy surgery programs in which it was observed that approximately 30–50% of patients with mesial temporal sclerosis had a history of febrile seizures in childhood. Although this suggests that there is a relationship between FSE and mesial temporal sclerosis, these studies were unable to determine whether the FSE caused mesial temporal sclerosis or whether the mesial temporal sclerosis predisposed children to having FSE. In order to address this issue, there are two major longitudinal studies investigating children with MRI at the time of FSE and at follow-up. The studies have been carried out in London, UK (London study) [12 ,13 ,14–16,17 ] and in the United States [FSE in children (FEBSTAT) study] [4 ,18–22]. The London study identified evidence for hippocampal edema within 5 days of FSE in 24 children recruited to the study [14]. The edema manifested as increases in hippocampal volume and increases in T2 relaxation time. No patient in this original cohort had visually identified evidence of edema or of mesial temporal sclerosis at the time of FSE. FEBSTAT has recruited 199 children with FSE and therefore has greater power to detect abnormalities than the London study. Approximately 10% of the children have visually identified unilateral hippocampal edema predominantly affecting the CA1 regions of the hippocampus [22]. FEBSTAT also carried out electroencephalogram (EEG) in these patients and showed evidence for slowing in the &&
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EEG, particularly over the temporal regions [21]. These findings are consistent with hippocampal edema. In addition, they identified two children with pre-existing mesial temporal sclerosis. Therefore, on the basis of acute imaging data, there is evidence for both acute hippocampal injury and for pre-existing mesial temporal sclerosis. There is also likely to be a spectrum in the severity of the edema, ranging from mild edema, only identified on quantitative imaging, through to obvious edema that can be seen on visual assessment. It is therefore important to establish whether children with hippocampal edema develop MRI evidence for mesial temporal sclerosis at follow-up and whether this could be related to the severity of the acute imaging abnormality. If so, acute imaging could become a biomarker for later adverse outcomes and may be a guide to which children could benefit from therapy [4 ,23]. The children in the London study had follow-up imaging approximately 6 months after the acute event [15]. None of the children developed mesial temporal sclerosis, although there was an increase in hippocampal asymmetry, suggesting that there may be a spectrum of hippocampal injury and it is possible that a small proportion of children would develop mesial temporal sclerosis. A second cohort of 33 children ascertained in London did not have acute MRI, but had imaging at 3 months, 6 months and 1 year following the acute event in order to define the course of hippocampal injury after the initial hippocampal edema had resolved [16]. This study provided evidence for hippocampal volume loss in approximately 20% of the children, but again none had such severity of volume loss to meet criteria for mesial temporal sclerosis [17 ]. In the FEBSTAT cohort, 130 children had follow-up MRI and 9 (7%) children met imaging criteria for mesial temporal sclerosis, all of whom had evidence for acute hippocampal edema [4 ]. Acute EEG findings were not predictive of later mesial temporal sclerosis [4 ]. Approximately half of the children with mesial temporal sclerosis in the FEBSTAT study had additional MRI abnormalities, pre-existing developmental delay, or both. It is interesting to note that there is no relationship between characteristics of the FSE (duration, severity, treatment, etc.) and the presence of edema or later hippocampal abnormalities in either the London study or the FEBSTAT study. This suggests that there is at least one additional factor predicting which children are at risk of brain injury. Overall, these data support the view that FSE can occasionally cause mesial temporal sclerosis and this risk is possibly increased in children with pre-existing neurological abnormalities.
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NONHIPPOCAMPAL IMAGING ABNORMALITIES Both the London group and the FEBSTAT study have reported the data on visual analysis of the scans of children with a history of FSE. The London study identified one child (3%) with a minor abnormality [hippocampal malrotation (HIMAL)] and no children with a major abnormality [16]. In contrast, there were definite abnormalities identified in approximately 28% of the children in the FEBSTAT study [22]. The most likely reason for this is definition. If children with pre-existing neurological impairments who present with status epilepticus associated with fever are included in the London cohort, then the prevalence of imaging abnormalities is 24% [16]. The nature of the abnormalities include malformations of cortical development, evidence for previous hypoxic injury, hydrocephalus, as well as more minor abnormalities such as small white matter hyperintensities and blurring of gray white matter junctions, particularly in the anterior temporal lobe. It is also possible that there are brain abnormalities outside of the hippocampus that are not readily identified on visual inspection of the scans. To evaluate this further, the London group used tract-based spatial statistics on MR diffusion data to study whether there is evidence for white matter abnormalities following FSE. The children show reductions in fractional anisotropy 3 months following FSE, and this recovers over the course of the subsequent year [12 ]. This suggests that there is some widespread subtle brain injury associated with FSE and that injury is not localized to the hippocampus. Thus, there is evidence that FSE can cause brain injury as evidenced on MRI, but this is only relevant if associated with clinical abnormalities such as the development of epilepsy and cognitive impairments. It is of importance that the two studies discussed above are largely consistent with each other, and this further strengthens the case for FSE being able to cause hippocampal sclerosis. &&
RELATIONSHIP BETWEEN FEBRILE STATUS EPILEPTICUS AND EPILEPSY The prevalence of afebrile seizures following FSE is in the order of 5–10% [24]. The estimates depend on the definition of FSE and the quality of the study from which the estimate is taken [24]. Children with pre-existing neurological conditions have a higher incidence of epilepsy than those children who were previously neurologically normal. Children with FSE without neurological or cognitive impairments have the lowest risk for subsequent epilepsy and the risk may not be much greater than the risk in the 664
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general population [25,26]. It might be expected that if there was a relationship between hippocampal injury and epilepsy, then these children would often have temporal lobe epilepsy. It is clear that some of the children have focal seizures, but the structural substrates for the seizures have not been clearly defined. Children with mutations in sodium channel genes SCN1A [Dravet syndrome and general epilepsy with febrile seizuresþ (GEFSþ)] [27–29] and SCN1B [30], as well as those with mutations in the gamma-aminobutyric acid type A genes [31], may present with FSE. These children ultimately develop generalized seizures including absence, tonic-clonic and myoclonic seizures. It is important to note that none of the five children with epilepsy in the FEBSTAT cohort have temporal lobe seizures. However, it may take many years to develop epilepsy and therefore this observation may change over time. Therefore, the relationship between FSE and epilepsy is complex and development of temporal lobe epilepsy associated with mesial temporal sclerosis caused by FSE seems to be an uncommon outcome.
COGNITIVE IMPAIRMENT Given that FSE has been associated with brain injury and the subsequent development of epilepsy, it is reasonable to hypothesize that FSE could also be associated with reductions in cognition. The London group has been studying cognitive outcomes in children with convulsive status epilepticus including those with FSE. Children with FSE have a reduction in developmental quotient of approximately 10 points to a mean of 93 points [13 ]. This reduction in developmental quotient is significantly different to the population expectation of 100 points and also significantly different to a control sample ascertained in London. There is no relationship between hippocampal volume or severity of white matter abnormalities and general cognitive outcomes [13 ]. Thus, it remains uncertain whether the observed cognitive differences are a function of brain injury caused by the FSE, a marker of a preexisting brain abnormality that predisposes to FSE, or a combination of both. The hippocampus is an extremely important structure for memory function and therefore it is important to establish whether memory is impaired in children who have experienced an episode of FSE. It is difficult to apply standardized tests of memory in young children and therefore the London group evaluated memory using a visual paired comparison task [32]. Approximately 1 month after the episode of FSE, the children had evidence for accelerated forgetting when compared to controls. This effect &
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was still present 1 year after the acute event, suggesting that memory deficits are permanent [32]. There was also a relationship between the degree of hippocampal asymmetry and the severity of accelerated forgetting, supporting the view that this effect may be a function of hippocampal injury. This leads to the hypothesis that prevention of brain injury could lead to improvements in outcomes of children with FSE.
MECHANISMS OF ADVERSE OUTCOMES In order to define potential treatments that minimize adverse outcomes following FSE, it is essential that the mechanisms of brain injury are defined. The majority of the work addressing this issue has been carried out in models of status epilepticus without fever. The most common models are the lithiumpilocarpine model [33] and the kainate model [34]. This is partly because these models reliably lead to brain injury, whereas the FSE model is closer to replicating the human data in that significant neuronal loss is uncommon, and this model is better suited to understanding epileptogenesis in the absence of significant injury [35,36]. Nevertheless, the nature of the brain injury in the pilocarpine and kainite models is similar to that observed in humans with mesial temporal sclerosis, suggesting that these models are of relevance to understanding brain injury and potential neuroprotection. The mechanism of injury that has received the most attention is excitotoxicity [37,38]. Prevention of brain injury and epileptogenesis is possible with preadministration of the N-methyl-D-aspartate (NMDA) receptor blocker, MK-801, supporting the hypothesis that excitotoxicity is an important mechanism driving adverse outcomes from convulsive status epilepticus (CSE) [39]. However, the use of MK-801 in a more clinically relevant setting with administration after termination of status epilepticus has some effect on the severity of brain injury, but does not prevent the later development of epilepsy. It remains uncertain whether there is a reduction in cognitive impairments. Therefore, this is a disappointing approach and is unlikely to be important for clinical practice. Another potentially important mechanism is inflammation. There is evidence that status epilepticus, including FSE, leads to an up-regulation of cytokines, particularly interleukin (IL)-1b, at the site of seizure origin [40]. The release of this and other cytokines [e.g. tumor necrosis factor (TNF) and IL-6] [41,42] results in up-regulation of selectins, adhesion molecules [including vascular cell adhesion molecule-1 (VCAM-1)] [43,44] and integrins [43]. This signaling cascade promotes diapedesis of leucocytes across the blood–brain barrier which is
hypothesized to be important for modulation of brain injury and subsequent epileptogenesis. This makes targeting the inflammatory process as a neuroprotecitve and antiepileptogenesis strategy very attractive. Pharmacological experiments that have attempted to address the relationships between inflammation and adverse outcomes from CSE have explored the effects of cyclooxygenase-2 (COX-2) inhibitors, erythropoietin, disruption of leukocyte– endothelial interactions, and corticosteroids. There is controversial evidence that reducing inflammation following CSE with COX-2 inhibitors can reduce the severity of subsequent epilepsy. Administering the COX-2 inhibitor celecoxib reduces the severity of hippocampal injury and the frequency of spontaneous recurrent seizures [45]. However, parecoxib reduces the severity of brain injury, but does not alter the frequency or duration of spontaneous recurrent seizures when administered following pilocarpineinduced CSE [46]. Therefore, the approach of modulating a single protein has potential, but more work is required. Targeting inflammation broadly with erythropoietin or corticosteroids is an alternative and potentially rapidly translatable approach. Administration of erythropoietin for 7 days, commencing immediately after the termination of status epilepticus, reduces hippocampal injury, as well as the frequency and severity of subsequent spontaneous recurrent seizures [44,47]. Another broad-spectrum anti-inflammatory is dexamethasone. When this is administered soon after CSE and then daily for 5 days, brain injury is greater than in controls with CSE, and mortality is greater [48 ]. Therefore, it is critical that broad-spectrum agents are more thoroughly evaluated prior to any testing in humans. Disruption of leukocyte–endothelial interactions by blocking P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins a4b1 and aLb2 with antibodies is effective in reducing brain injury and epileptogenesis This finding was confirmed by genetically interfering with PSGL-1 and depleting leukocytes [43]. This suggests an extremely important role for leukocyte vascular interactions in injury and epileptogenesis, but these strategies remain far from clinical practice. Prior to pursuing expensive and difficult studies, it is worth asking whether the magnitude of the clinical problem is large enough to warrant the resources required. &
CONCLUSION Although the evidence supporting the view that brain injury following FSE is possible, the frequency with which severe injury occurs is low. In addition,
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the frequency with which clinically important adverse outcomes directly related to that injury occur (temporal lobe epilepsy, significant amnesia, etc.) remains uncertain. It seems clear that clinically relevant adverse outcomes are possible and the prediction of which children are at particular risk may be possible with MRI imaging acutely. However, this raises several issues that deserve discussion. Children in the age range for FSE all require sedation or anesthesia for MRI, and although this is of low risk, it is not immediately obvious that this low risk is appropriately balanced with potential gain. Even if this risk–benefit ratio is considered to be appropriate for the identification of the less than 10% of children at risk of adverse outcomes, there are currently no clear therapeutic strategies. If a clear strategy is identified, then there is the issue of how such a strategy will be robustly tested in clinical trials [49 ]. It has taken many years to recruit the children into the London and FEBSTAT studies, and these studies would clearly be insufficiently powered to evaluate the impact of a novel intervention in children with visually obvious edema on an acute scan. An alternative is to assert that minor injury is common after FSE and even if the effects on cognition are small, it may be worth minimizing those effects. In this situation, a drug could be given to all children with FSE, independently of MRI, and thus adequate sample sizes would be easier to ascertain. However, the adverse effects of any strategy would need to be extremely low in order to justify administration to many children in whom the potential benefit is small. Although much has been achieved over the past decade or so, several questions remain to be answered. &
Acknowledgements R.C.S. received funding from the Wellcome Trust (Grant number: 060214/HC/RL/MW/kj) and NINDS (R01NS075249). Conflicts of interest R.C.S. is supported by GOSH Children’s Charity and has received travel grants from Glaxo-SmithKline, JanssenCilag, UCB Pharma, and SPL Ltd.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Febrile seizures: Consensus development conference summary. Febrile seizures. Bethesda, MD: National Institutes of Health; 1980. 2. Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006; 368:222–229.
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3. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987; 316:493–498. 4. Lewis DV, Shinnar S, Hesdorffer DC, et al. Hippocampal sclerosis after febrile && status epilepticus: the FEBSTAT study. Ann Neurol 2014; 75:178–185. This is the definitive study on the relationship between FSE and hippocampal sclerosis. Approximately 7% of children with FSE will get hippocampal sclerosis and this is predicted by visual evidence of hippocampal edema on MRI. 5. Nishiyama I, Ohtsuka Y, Tsuda T, et al. An epidemiological study of children with status epilepticus in Okayama, Japan. Epilepsia 2007; 48:1133–1137. 6. Sadarangani M, Seaton C, Scott JA, et al. Incidence and outcome of convulsive status epilepticus in Kenyan children: a cohort study. Lancet Neurol 2008; 7:145–150. 7. Chin RF, Neville BG, Peckham C, et al. Socioeconomic deprivation independent of ethnicity increases status epilepticus risk. Epilepsia 2009; 50:1022– 1029. 8. Pujar SS, Neville BG, Scott RC, Chin RF. Death within 8 years after childhood convulsive status epilepticus: a population-based study. Brain 2011; 134:2819–2827. 9. Honovar M, Meldrum B. Epilepsy. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology. London: Oxford University Press; 1997. pp. 931– 969. 10. Babb TL, Brown WJ. Pathological findings in epilepsy. In: Engel Jr J, editor. Surgical treatment of the epilepsies. New York: Raven Press; 1993. pp. 511–540. 11. Nohria V, Lee N, Tien RD, et al. Magnetic resonance imaging evidence of hippocampal sclerosis in progression: a case report. Epilepsia 1994; 35:1332–1336. 12. Yoong M, Seunarine K, Martinos M, et al. Prolonged febrile seizures cause && reversible reductions in white matter integrity. Neuroimage Clin 2013; 3:515–521. This is the first study evaluating the relationship between FSE and white matter injury outside of the hippocampus. There are reductions in fractional anisotropy in multiple brain regions that recover over the course of a year. The clinical relevance is uncertain. 13. Martinos MM, Yoong M, Patil S, et al. Early developmental outcomes in & children following convulsive status epilepticus: a longitudinal study. Epilepsia 2013; 54:1012–1019. This study revealed that children with FSE have developmental quotients approximately 10 points below expected. Prior to this study, it was assumed that there was no relationship between FSE and cognitive outcomes. It remains unclear whether this difference is a function of brain injury, a brain abnormality predisposing the FSE, or a combination of both. 14. Scott RC, Gadian DG, King MD, et al. Magnetic resonance imaging findings within 5 days of status epilepticus in childhood. Brain 2002; 125:1951– 1959. 15. Scott RC, King MD, Gadian DG, et al. Hippocampal abnormalities after prolonged febrile convulsion: a longitudinal MRI study. Brain 2003; 126:2551– 2557. 16. Yoong M, Madari R, Martinos M, et al. The role of magnetic resonance imaging in the follow-up of children with convulsive status epilepticus. Dev Med Child Neurol 2012; 54:328–333. 17. Yoong M, Martinos MM, Chin RF, et al. Hippocampal volume loss following && childhood convulsive status epilepticus is not limited to prolonged febrile seizures. Epilepsia 2013; 54:2108–2115. This study showed that approximately 20% of children with FSE will have reductions in hippocampal volume over the course of 1 year. Most of the hippocampal volumes remain in the normal range and further follow-up is required to assess whether any children develop mesial temporal sclerosis. 18. Epstein LG, Shinnar S, Hesdorffer DC, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia 2012; 53:1481– 1488. 19. Frank LM, Shinnar S, Hesdorffer DC, et al. Cerebrospinal fluid findings in children with fever-associated status epilepticus: results of the consequences of prolonged febrile seizures (FEBSTAT) study. J Pediatr 2012; 161:1169– 1171. 20. Herrera EA, Alvarez SY, Cobox O, Villeda T. Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2009; 72:1533– 1534. 21. Nordli DR Jr, Moshe SL, Shinnar S, et al. Acute EEG findings in children with febrile status epilepticus: results of the FEBSTAT study. Neurology 2012; 79:2180–2186. 22. Shinnar S, Bello JA, Chan S, et al. MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study. Neurology 2012; 79:871– 877. 23. Provenzale JM, Barboriak DP, VanLandingham K, et al. Hippocampal MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis. AJR Am J Roentgenol 2008; 190:976– 983. 24. Raspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol 2006; 5:769–779. 25. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics 1978; 61:720–727.
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39. Stafstrom CE, Holmes GL, Thompson JL. MK801 pretreatment reduces kainic acid-induced spontaneous seizures in prepubescent rats. Epilepsy Res 1993; 14:41–48. 40. Dube C, Vezzani A, Behrens M, et al. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol 2005; 57:152– 155. 41. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 2005; 46:1724–1743. 42. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7:31–40. 43. Fabene PF, Navarro MG, Martinello M, et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 2008; 14:1377–1383. 44. Jung KH, Chu K, Lee ST, et al. Molecular alterations underlying epileptogenesis after prolonged febrile seizure and modulation by erythropoietin. Epilepsia 2011; 52:541–550. 45. Jung KH, Chu K, Lee ST, et al. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol Dis 2006; 23:237–246. 46. Serrano GE, Lelutiu N, Rojas A, et al. Ablation of cyclooxygenase-2 in forebrain neurons is neuroprotective and dampens brain inflammation after status epilepticus. J Neurosci 2011; 31:14850–14860. 47. Chu K, Jung KH, Lee ST, et al. Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 2008; 49:1723–1732. 48. Duffy BA, Chun KP, Ma D, et al. Dexamethasone exacerbates cerebral edema & and brain injury following lithium-pilocarpine induced status epilepticus. Neurobiol Dis 2014; 63:229–236. A rapidly translatable approach to limiting inflammation (dexamethasone) following status epilepticus was evaluated in an animal model. This approach led to increased mortality and greater brain injury, highlighting the need for preclinical studies prior to testing in humans. 49. French JA, Kuzniecky R. Can febrile status cause hippocampal sclerosis? Ann & Neurol 2014; 75:173–174. This editorial deals with the potential clinical approaches to acute FSE, given the number of children who have significant hippocampal injury.
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