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ebrile Status Epilepticus: Currenttate of Clinical and Basic Research

aba Ahmad, MD,* and Eric D. Marsh, MD, PhD*,†

Febrile status epilepticus occurs in up to 5% of all cases of febrile seizures and has beenlinked to the development of focal epilepsy. This article reviews the clinical characteristicsand treatment issues of febrile status. Controversy exists regarding the relationship offebrile status epilepticus to the subsequent development of epilepsy. This subject isdiscussed by first reviewing the clinical research literature and then highlighting the basicscience research regarding this controversial question. The current literature appears tosupport a role for febrile status in the development of focal epilepsy but is clearly neithernecessary nor sufficient in the focal epileptogenisis process. Multiple insults are likelynecessary for a child with febrile status epilepticus to develop epilepsy later in life.Semin Pediatr Neurol 17:150-154 © 2010 Elsevier Inc. All rights reserved.

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ebrile seizures (FSs) affect 2% to 5% of children betweenthe ages of 6 months and 5 years.1,2 They are the most

ommon cause of a seizure for a person to experience. FSs arelassified as “simple FS” if they are brief in duration (�15inutes) and have no lateralizing features. An FS that isrolonged (�15 minutes), has focal features, or recurs within4 hours is termed a “complex FS.”2,3 A FS longer than 30inutes is classified as febrile status epilepticus (FSE). FSE issubtype of complex FS and often has multiple complex

eatures, such as seizure focality or prior neurologic history.SE is an important pediatric neurologic condition becausef its high incidence and because of the potential relationshipo subsequent focal epilepsy. Hence, we briefly review thelinical and research literature and attempt to synthesize theurrent understanding of FSE and its relationship to futurepilepsy.

linical FSEnumber of studies since the 1970s have elucidated the

linical characteristics of FSE.2-9 Febrile status occurs in ap-roximately 5% of febrile convulsions3-5 and accounts forbout 25% of all childhood cases of status epilepticus. A

Department of Neurology, University of Pennsylvania School of Medicine,Philadelphia, PA.

Division of Neurology, Department of Pediatrics, Children’s Hospital of Phil-adelphia, Philadelphia, PA.

ddress reprint requests to Eric D. Marsh, MD, PhD, Division of Neurology,Children’s Hospital of Philadelphia, 502E Abramson Research Building,3415 Civic Center Boulevard, Philadelphia, PA 19104. E-mail: marshe@

semail.chop.edu

50 1071-9091/10/$-see front matter © 2010 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2010.06.004

umber of studies have quantified the age (mean, 14-23onths), duration (30-greater than 240 minutes), and semi-

logy of the seizures associated with FSE.2-9 FSE is almostlways convulsive, either partial onset with secondary gener-lization or generalized. There is an increased incidence ofocal seizures in patients with FSE compared with those withimple FS.3,5,7 The seizures are often either unilateral limb orace jerking, eye deviation, head version, convulsion asym-etry, or associated with postictal Todd paresis.7 Half of the

ases of FSE do not consist of continuous convulsive activityut rather are intermittent in nature, without clinical recov-ry between events.7

Other clinical information from these early studies andore recently from the FEBSTAT study has found that chil-ren with FSE are more likely to have a family history ofpilepsy and occur in children who had a prior neurologicbnormality.3,5,7 FSE is also more likely to occur if the firstebrile seizure was FSE. Febrile SE, compared with afebrileE, does not lead to death or new disability.3,5,7,10 One pos-ible reason for FSEs more positive outcome is the generallyapid response to treatment.

The treatment of FSE is similar to the treatment of otherorms of SE. Although by definition, FSE is a febrile seizureasting 30 minutes, treatment should be initiated with ben-odiazepines 5 minutes into the seizure. A number of studiesave shown that in FSE, as with nonfebrile seizures, a seizurehat has not resolved by 5 minutes is less likely to stop spon-aneously. Rectal diazepam is the standard of care for theut-of-hospital setting, whereas parenteral benzodiazepine isoutinely used in the emergency room. If the seizure does not

top, a repeat dose of benzodiazepine is given followed by

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Febrile status epilepticus 151

ntravenous fosphenytoin and then phenobarbital. If theseeasures fail, which is rare for FSE, then starting a refractory

tatus epilepticus protocol is indicated. (See Abend andarsh for a discussion of refractory SE protocols.11) Other

reatment issues in FSE include using antipyretics to treat theever, finding the fever source (usually viral illness), and theonsideration of prophylactic treatment. A number of studiesave shown that although antipyretics make the child moreomfortable, they do not prevent recurrent FS.12 Prophylaxiss generally not indicated even if the patient has had FSE.13-15

owever, if frequent FSE or extreme parental anxiety overecurrent FSs exist, then phenobarbital16 and valproic acid15

ave been studied as a daily medication and diazepam asntermittent therapy.17 Other antiepileptic medications maye effective but have not been systematically studied. Overall,he treatment of FSE is similar to SE. There is, however, aajor issue regarding FSE that is unique to this clinical situ-

tion. This issue is the possible relationship to future epi-epsy.

SE Causes Mesialemporal Lobe Epilepsy?

ust as FS is the most common type of childhood seizure,esial temporal lobe epilepsy (MTLE) is the most common

ocal epilepsy syndrome in adults. A long debate has sim-ered about the relationship of FSE to MTLE.In retrospective studies, complex FS and FSE have been

ssociated with the development of epilepsy, particularlyTLE. The most common pathology encountered in MTLE

s mesial temporal sclerosis (MTS).18 Falconer et al18 were therst to report that 30% of patients with MTS had a history ofrolonged FSs in childhood compared with only 6% of thoseithout MTS. A number of subsequent retrospective surgi-

al-based studies have found a similar association.19,20 How-ver, a few prospective and population-based retrospectivetudies have failed to show a causative link between FS andTLE21-23 although these studies have not evaluated patientsith FSE alone. Although the retrospective and prospectiveata are incongruent, most neurologists believe a link ex-

sts.24-26 Two prevailing hypotheses exist to explain the pos-ible relationship between FSE and MTLE. The first hypoth-sis states that FSE causes acute hippocampal injury that laterevelops into MTS and MTLE. The alternative hypothesis ishat FS, FSE, and MTLE are all different symptoms of anlready injured hippocampus or genetic predisposition toemporal lobe seizures.

Differentiating these 2 possibilities is difficult for a numberf reasons. First, the development of MTLE usually lags manyears behind the initial episode of FSE, making prospectivetudies difficult to accomplish. Second, before the initial FSE,etermining if previous occult brain injury or developmentalbnormalities exist is not possible. Third, the genetics of FSr FSE and MTLE are unknown. One might expect an overlapf potential susceptibility loci or causal genes if there is aommon genetic predisposition. Because little is known

bout these potential mechanisms of FSE inducing MTLE, a c

umber of studies in both people and animals have beenerformed or are being performed to address the problem.

agnetic Resonancemaging Abnormalities After FSElarge number of studies trying to link FSE to MTLE have

sed magnetic resonance imaging (MRI) data after FSE. Thispproach began with a number of case series showing T2ignal changes in the hippocampi of children who recentlyad prolonged FSE.27,28 After these original case studies, aumber of prospective case series addressed the issue in aore systematic fashion.One of the initial larger case series of 27 infants with com-

lex FS observed MRI abnormalities in 6 of the 15 withateralized or prolonged events.29 In 2 of these infants, thereas preexisting hippocampal atrophy consistent with priorerinatal insult. In the remaining 4 subjects, the degree ofippocampal signal abnormality correlated with the durationf the FSE. VanLandingham et al29 suggested the rapid reso-ution of edema on MRI might indicate a preexisting pathol-gy, and what is observed to be rapid development of MTS innumber of reported cases after FSE may in fact be an un-erlying developmental disorder or the result of a prior in-ult.

To further investigate these imaging abnormalities, a lon-itudinal study performed by Scott et al30,31 observed thatithin 2 days after FSE there was prolonged T2 relaxation

nd increased hippocampal volume suggesting edema. Thisas not seen in patients with FSE. Four to 8 months later, 14f the 21 children with an initial T2 signal abnormality hado difference in hippocampal volumes or T2 relaxation timeompared with controls on the repeat MRI, indicating a res-lution of the acutely observed hippocampal edema. How-ver, in 5 of the 14 patients, there was a hippocampal volumesymmetry outside the 95th percentile for control, and 3 ofhe 5 had an absolute hippocampal volume that was less thanhe 95th percentile. Surprisingly, none of the patients metriteria for MTS because of the absence of T2 signal abnor-ality.30,31 These results are possibly consistent with FSE-

nduced neuronal cell loss that may develop into MTS in aubset of patients with hippocampal volume asymmetry. Al-ernatively, the hippocampal asymmetry could represent areexisting abnormality, which is only appreciated after theesolution of the acute hippocampal edema. Some evidenceo support the latter hypothesis stems from familial studies ofsolated hippocampal dysgenesis.32,33 In these families, therere members who have FSE and MTS but also individualsith MTS in the absence of a history of FSs.Although the prior studies did not clearly show the devel-

pment of MTS after FSE, Provenzale et al34 followed 11hildren for up to 2 years and correlated the degree of hip-ocampal T2 signal hyperintensity with the subsequent de-elopment of MTS and MTLE. The children with FSE firstnderwent initial imaging at 72 hours, which was repeated 3o 23 months later. Seven of the 11 children had T2 signal

hanges that moderately correlated with the duration of FSE.

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152 S. Ahmad and E.D. Marsh

ive of the 7 children with hippocampal T2 hyperintensityfter FSE had volume loss and signal abnormality on MRIonsistent with MTS. Four of these 5 went on to developpilepsy (2 with confirmed TLE).34 The available datatrongly suggest that a prolonged FSE can induce acute signalhange in the hippocampus. However, a number of issuesemain, such as the pathophysiologic significance of the T2-eighted changes observed after FSE. This and many other

ssues can potentially be answered by basic science research.

xperimental FSEhe main experimental model of FSE is hyperthermia in-uced prolonged FSs in rat pups.35 The first work on thisodel reported on the development of age-specific seizuresithout the development of spontaneous seizures later on in

ife.36 Subsequent studies have shown that 35% of rats withnduced FSs on P10 (approximately equivalent to a 3- to2-month-old child) develop electroclinical seizures indulthood.37 These original studies have reported on changesn excitability,38,39 gene expression,40 and network effects41

ut without cell loss, clear mossy fiber sprouting, or neuro-enesis.40-42 This experimental model will allow researcherso begin to answer a number of the questions raised by thelinical studies.

One major question regarding the clinical MRI studies ishe significance of T2 signal abnormalities. Does the hip-ocampal T2 signal change signify acute swelling or is thereermanent hippocampal injury? Although the original stud-

es on the experimental FSE model did not report cell death,t was unclear if the rats would develop similar MRI findingso the children with FSE. Dube et al43 serially examined ratsith MRI after experimental FSE and found acute T2 signal

bnormality on MRI without any associated neuronal loss.urther work, applying multimodal imaging, including mag-etic resonance spectroscopy and volumetry, found histo-

ogic changes in the hippocampus on long-term imaging fol-ow-up, which did not correlate with volume loss.44 Onistologic analysis, there was no increase in astrocytes touggest gliosis, but there was a slight decrease in neuronal cellolume.45 Interestingly, there was increased fiber density andnisotropy in the dentate gyrus after FSE, possibly indicatinghat there is mossy fiber reorganization.41 This subtle mossyber sprouting is associated with a lowered seizure threshold

n 100% of rats that experienced experimental FSE in earlyevelopment compared with only 25% of controls,36 sup-orting the hypothesis that FSE can result in long-term ax-nal reorganization.Another question potentially answered by the experimen-

al FSE data is the requirement of previous underlying brainamage in order for FSE to lead to MTLE. To address this

ssue, Scantlebury et al46 induced a focal cortical lesion in ratups and subsequently produced prolonged FSE. These au-hors found spontaneous seizures occurring in 86% of rats,ith the seizures arising ipsilateral to the lesion.46 In compar-

son, only 35% of normal rats exposed to FSE develop spon-

aneous seizures.37 This supports the notion of “multiple hits” H

n which an “injured” or predisposed brain is more likely toevelop epilepsy after FSE.Because no major structural changes have been proven to

e associated with FSE, various investigators have beentudying the genetic and molecular changes in the hippocam-us after the seizure. On a cellular level, evidence of alteredippocampal gene expression after FSE has been reported forproteins involved in controlling neuronal excitability. First,SE has been shown to alter the kinetics of the hyperpolar-

zation-activated depolarizing current because of changes inhe hyperpolarization-activated cyclic nucleotide gated chan-els (HCNs).38 In experimental FSE, there is evidence ofltered gene expression of the subtypes of HCNs in CA1 andA3, altering the neuronal HCN phenotype, modulating ex-itability, and possibly lowering seizure threshold. Thesehanges correlated with the duration of seizure activity.47 Inddition to the changes in the HCNs, the increased expres-ion of neuropeptide Y (NPY), a neuromodulator found in aubset of interneurons, has been reported after FSE.48 In-reased neuropeptides Y is believed to act to enhance inhibi-ion and prevent the development of subsequent seizures.

Animal models of FSE are not only being used to under-tand the potential mechanisms of future spontaneous sei-ures but are also used to begin to elucidate why fever leads toeizures. One view states that fever alters ion channel kineticsnd axonal conduction shifting the normal network activity.49

nother view asserts that the mediators of fever directly altereuronal function. A number of studies have looked at theole cytokines, specifically interleukin (IL)-1�. IL-1� is re-eased in the brain in the setting of both fever and hyperther-

ia.50 This particular cytokine seems necessary to generateS in rats based on evidence that rats lacking the IL-1R1 geneave a much higher temperature threshold to develop FS.51

n the hippocampus, IL-1� receptors are expressed in highensity,52 and their stimulation triggers a cascade of down-tream effects through mitogen activated protein (MAP) ki-ase and nuclear factor kappa-light-chain-enhancer of acti-ated B cells (NF-�B) signaling. This could alter genexpression and transform normal neuronal circuitry into ep-leptic circuitry.

iral Mediationore recently, there are implications that viruses are in-

olved in the pathophysiology of MTS after FSE. Humanerpes virus (HHV) 6 B is a ubiquitous herpes virus that

nfects many cell types including glial cells. It has been foundore commonly in subsets of patients who undergo surgery

or MTLE compared with subjects undergoing surgery foreocortical epilepsy.53 Other viruses have also been impli-ated in MTLE. A recent study by Karatas et al54 found viralNA for HHV-6 and 8 and human simplex virus (HSV-1) inof 33 subjects in the pathology specimens after surgery for

efractory MTLE.54 In the 3 patients with HHV-6 viral DNAound in the temporal lobe, all reported a history of both FSsnd a family history of epilepsy. Several studies indicate that

HV-6 is a common primary infection associated with FSs55

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Febrile status epilepticus 153

nd a common cause of febrile illness during the peak inci-ence of FSs.

esearch Data Synthesishe fundamental question remains: does FSE result in dam-ge to the hippocampus and MTLE later in life? Recent evi-ence suggests that prolonged FSs do cause hippocampal

njury in humans on MRI. The animal data also suggest thatnduced FSE alters neuronal structure, function, and genexpression. This implies that FSE alone may be enough toromote epileptogenesis. However, animal models for hu-an disease are by their very nature incomplete and must be

orroborated by human studies. More likely than FSE aloneeading to focal epilepsy, multiple mechanisms are poten-ially at work in epileptogenesis after FSE. Understandinghy FSE does not lead to MTLE in some people may be as

mportant as elucidating why it does in others.

n Answer on the Horizonhe FEBSTAT study, an ongoing prospective multicentertudy trying to elucidate the long-term consequences of FSE,ill give further insight into the risk of developing MTLE andTS after FSE.7 This study evaluates the circumstances sur-

ounding the FSE, characteristics of the seizures, family andevelopmental history, MRI and electroencephalographicata, and assays for HHV-6 and HHV-7 at the time of pre-entation. This study will follow children for several years tossess the risk of MTLE after FSE and may give insight intohose factors, particularly those evident on presentation,hich put people at the greatest risk.

onclusionst this time, although there certainly is an association of aistory of FSE in patients with MTS and MTLE, there haseen no causal data showing that FSE indeed causes MTLEnd MTS in humans. It seems likely that “multiple hits” areecessary for FSE to develop years later into MTLE and MTS.hese multiple factors include traumatic insults, a geneticredisposition, immunologic- and viral-mediated processes,nd other as-yet-unknown factors. As more is discoveredegarding FSE and MTLE, there may be novel targets identi-ed that play a role in the development of MTLE after FSEnd perhaps new strategies of prevention, such as immuneediators, vaccines, or neuroprotective agents. Also, with

he results of the FEBSTAT study, neurologists may be able todentify a target population for which these prevention andreatment strategies may prove to be most effective.

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