Phenomenology of prolonged febrile seizures

Results of the FEBSTAT study

S. Shinnar, MD, PhD D.C. Hesdorffer, PhD D.R. Nordli, Jr., MD J.M. Pellock, MD C. ODell, RN, MSN D.V. Lewis, MD L.M. Frank, MD S.L. Moshe, MD L.G. Epstein, MD A. Marmarou, PhD E. Bagiella, PhD The FEBSTAT Study Team*

ABSTRACT

Background: Febrile status epilepticus (FSE) has been associated with hippocampal injury and
subsequent mesial temporal sclerosis and temporal lobe epilepsy. However, little is known about the semiology of FSE.

Methods: A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the statistic. Results: Among 119 children, the median age was 1.3 years, the mean peak temperature was
103.2F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%.

Address correspondence and reprint requests to Dr. Shlomo Shinnar, Comprehensive Epilepsy Management Center, Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467 sshinnar@aol.com

Conclusions: Febrile status epilepticus is usually focal and often not well recognized. It occurs in
very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop. Neurology 2008;71:170176
GLOSSARY
ED emergency department; FS febrile seizures; FSE febrile status epilepticus; HHV human herpesvirus; ILAE International League Against Epilepsy; IQR interquartile range; MTLE mesial temporal lobe epilepsy; MTS mesial temporal sclerosis.

Supplemental data at www.neurology.org Editorial, page 162

The relationship between prolonged febrile seizures (FS) and subsequent mesial temporal sclerosis (MTS) and mesial temporal lobe epilepsy (MTLE) remains unclear.1-8 A strong association is reported in retrospective studies of adults with refractory MTLE2-4 but prospective studies of FS have failed to confirm this association.5-8 Recent reports have shown that hippocampal injury can occur following FSE, especially if very prolonged ( 90 minutes),9 and that in some cases the children subsequently demonstrate a radiologic picture consistent with MTS.9,10 In retrospective studies of MTLE and MTS, the mean latency to develop MTLE following FS was 8 to 11 years.4,11 Given the low frequency of FSE and the lack of longitudinal imaging studies, even large prospective studies of FS lacked the power to resolve the potential causal relationship between FSE and subsequent MTS and MTLE. Further complicating the analysis of causation is the fact that approximately 20% of patients with childhood onset
e-Pub ahead of print on June 4, 2008, at www.neurology.org. *Members of the FEBSTAT Study Team are listed in the appendix. From Montefiore Medical Center (S.S., C.O., S.L.M.), Albert Einstein College of Medicine, Bronx, NY; Columbia University (D.C.H., E.B.), New York, NY; Childrens Memorial Research Center (D.R.N., L.G.E.), Feinberg School of Medicine, Northwestern University, Chicago, IL; Virginia Commonwealth University (J.M.P., A.M.), Richmond; Duke University Medical Center (D.V.L.), Durham, NC; and Eastern Virginia Medical School (L.M.F.), Norfolk. Supported by grant NS 43209 from NINDS (PI: S. Shinnar). Disclosure: The authors report no disclosures. Presented in part at the annual meeting of the American Epilepsy Society, December 15, 2006, San Diego, CA.

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Copyright 2008 by AAN Enterprises, Inc.

epilepsies of all types have a prior history of FS which in the majority of cases is clearly not causally related.6-8 The Consequences of Prolonged Febrile Seizures in Childhood or FEBSTAT study is a prospective multicenter study designed to address the relationship between FSE, subsequent MTS, and MTLE. It will ultimately recruit 200 children presenting with FSE and follow them over time. In this article, we present the methodology of assembling the cohort and the results of the clinical semiology and phenomenology of the first 119 subjects.
METHODS Population. Eligible were children, ages 1 month through 5 years, who presented with FSE, defined as a seizure or a series of seizures without full recovery in between lasting 30 minutes12,13 that also met the definition of FS.12,14 FS was defined as a provoked seizure where the sole acute provocation was fever (temperature 38.4C, 101.0F) without prior history of afebrile seizures and with no evidence of an acute CNS infection or insult.14,16 Children with known severe neurologic disability prior to entry were excluded. The five recruiting sites were Montefiore and Jacobi Medical Centers in the Bronx, Childrens Memorial Hospital in Chicago, Duke University Medical Center, Virginia Commonwealth University Hospital, and Eastern Virginia Medical School. In addition, the International Epilepsy Consortium at Virginia Commonwealth University was the Data Coordinating Center and the Epidemiology/Biostatistics Core was based at Columbia University.

Figure

Duration of febrile status epilepticus in FEBSTAT Cohort

Recruitment. Emergency department (ED) and hospitalization records were reviewed daily to identify potential subjects., The trigger to screen was any child with FS reportedly lasting 15 minutes. However, to be eligible, the study team had to determine that seizure duration was 30 minutes. Families of eligible subjects were approached for consent to enroll their child in the study. The procedures were approved by the Institutional Review Boards at all participating institutions. Procedures. Subjects were recruited within 72 hours of the episode of FSE. As part of the diagnostic evaluation during the initial hospitalization, the following procedures were performed:
1. Detailed history of the circumstances of the seizure with a focus on duration and focality 2. A structured interview including developmental milestones, past medical history, family history of FS, and epilepsy in first-degree relatives and characteristics of the seizure 3. Neurologic and physical examination 4. Laboratory data summarized including CSF results with 20 WBCs in the CSF considered an exclusionary criterion. However, lumbar punctures were done for clinical indication and absence of a lumbar puncture was not an exclusionary criterion 5. MRI examination 6. EEG 7. Specimens for acute human herpesvirus (HHV)-6 and HHV-7 assays In addition, serum samples from probands and both parents are sent to the National Institute of Neurological Disorders and

(A) Distribution of the duration of febrile status epilepticus (n 119). Circles represent the actual data points which is equivalent to a Kaplan-Meier curve. The smooth line represents the best fit by a Weibull distribution with shape parameter 1.68. (B) Probability that a seizure that has continued to x minutes will not stop between x minutes and x x minutes. Probability, or hazard function, is calculated from the Weibull best fit curve with a shape parameter of 1.68 shown in (A). It is the derivative of the Weibull best fit curve.

Stroke repository at Coriell Institute for Medical Research15 for future genetic analysis.

Consensus process for seizure semiology and duration.

In addition to local coding, FSE was classified by three independent central raters (J.M.P., D.N., S.S.). Materials available for the review included the medical record, including the ED records and the ambulance call sheets, if available, the structured interview, and the comments from the local study team. FSE was coded as continuous or behaviorally intermittent. Seizures were then classified in accordance with the International League Against Epilepsy (ILAE) seizure classification as generalized tonic clonic, simple partial, complex partial, or partial with secondary generalization.16 Seizure classification was based exclusively on clinical features of the seizures and did not rely on imaging or EEG. Finally, the raters classified, based on the medical record, whether the treating clinicians in the ED recognized that the child had SE or not. Disagreements across classifications were discussed and consensus achieved in all cases. A detailed description of the overall methodology and the classification and consensus process can be found in the supplemental detailed methodology file on the Neurology Web site at www.neurology.org.

Statistics. Descriptive analysis was conducted through the determination of a percentage, mean, or median. Standard deviations are presented for means and the interquartile range (IQR) for the median. For the comparison of intermittent vs continuous seizures, comparison of means was performed using the t
Neurology 71 July 15, 2008 171

Table 1

Clinical characteristics of the FEBSTAT cohort (n 119)

No. (%) or median (IQR) 1.3 (0.992.2) 32 (26.9) 55 (46.2) 16 (13.45) 16 (13.45) 64 (53.8)

Table 2

Characteristics of illness in children with febrile status epilepticus (n 119)

No. (%)

Feature Age <1 year 12 years 23 years >3 years Male Development Normal Suspect Abnormal Prior febrile seizures Family history of febrile seizures* First-degree relative Second-degree relative Family history of epilepsy* First-degree relative Second-degree relative

Factor Prior medical care for this illness* None Went to doctor Called doctor Duration of illness before febrile status Unknown <1 hour

87 (76.3) 15 (13.2) 12 (10.5)

34 (28.6) 30 (25.2) 46 (38.7) 9 (7.6)

102 (85.7) 8 (6.7) 9 (7.6) 28 (23.5)

124 hours 24 hours or more Peak temperature during illness Mean peak temperature, F (SD) 101.0101.9F

103.2 (1.4) 18 (15.1) 39 (32.8) 27 (22.7) 35 (29.4) 102.1 (1.9)

29 (25.2) 24 (20.9)

102.0102.9F 103.0103.9F 104.0F or higher

10 (8.7) 32 (27.68)

Mean ED temperature, F (SD)

*Four cases missing information. IQR interquartile range.

*Five are missing this information. ED emergency department.

test, comparison of medians using the Wilcoxon Rank Sum test, and comparison of frequencies using the 2 test.17 For the comparison of each rater to the consensus determination, inter-rater reliability was calculated using the statistic for categorical variables and a 95% CI was constructed.18 A 0.75 was considered to be excellent agreement beyond chance, a of 0.41 to 0.74 was considered to be good agreement, and values of 0.40 were considered to be poor agreement. For continuous variables, inter-rater reliability was determined using the intraclass correlation coefficient comparing each of the three raters. Seizure duration was modeled as a Weibull distribution with two parameters, or the scale parameter, and or the shape parameter.19 A best fit was obtained for the function S(t) e
t/ )

Illness characteristics. Most of the children had not

sought prior medical care for the illness associated with the FSE episode (76%, table 2). Clear viral illnesses predominated (54%) followed by otitis media (18%), pneumonia (5%), and unknown source (14%).
Fever. The characteristics of the fever are summarized

Fit of the Weibull model was assessed with the Log Likelihood statistic.19 The predicted survival curve based upon the computed shape and scale parameters was compared to the Kaplan Meier survival curve.19 RESULTS Population characteristics. As of April 15, 2007, we have recruited 146 subjects. Among the 119 children whose seizure semiology has been evaluated in consensus, the median age was 1.3 years (table 1). Development was normal in 86% and clearly abnormal in only 8%. Approximately 24% had a prior history of FS. A first degree family history of FS was present in 25% and of epilepsy in 9%. The racial and ethnic distribution reflected the populations served by these medical centers, 34% Caucasian, 38% African American, 23% Hispanic, and 6% other.
172 Neurology 71 July 15, 2008

in table 2. The mean peak temperature was 103.2F (median 103.0F). Temperatures were normally distributed. In 30 (25%) children, the seizure was the first manifestation of the febrile illness as duration of recognized fever was less than 1 hour. Twenty-five children (21%) were not febrile in the ED but developed their fever within 24 hours of the episode of FSE.
Characteristics of the episode of FSE. The characteristics of the FSE are summarized in table 3. The median duration was quite long at 68.0 minutes, even though the entry criteria specified 30 minutes and the criteria to screen for eligibility was 15 minutes. A substantial proportion had seizures lasting more than 2 hours (24%). In 87% seizures did not stop spontaneously, ceasing only after the administration of a benzodiazepine class drug. Despite the relatively long seizure durations and the active intervention required to stop them, the ED clinicians, while providing appropriate therapy in most cases, consistently underestimated the duration and failed to recognize

Table 3

Characteristics of febrile status epilepticus (n 119)

No. (%) or median (IQR) 68.0 (47.0105.0) 53 (44.5) 26 (21.8) 12 (10.1) 25 (21.0) 3 (2.5)

Characteristic Duration 3059 minutes 6089 minutes 90119 minutes 120239 minutes 240 minutes or longer Continuous versus intermittent Continuous Intermittent Intermittent with drug therapy Focality Definite Definite cerebral lateralization Probable Possible Definitely generalized Seizure type classification Generalized tonic clonic Atypical absence Simple partial Complex partial Partial with secondary generalization

62 (52.1) 42 (35.3) 15 (12.6)

57 (47.9) 35 (61.4) 23 (19.3) 13 (10.9) 26 (21.8)

39 (32.8) 1 (0.8) 0 (0) 0 (0) 79 (66.4)

Status recognized by nonstudy clinicians Definitely Probably Possibly No 62 (52.1) 14 (11.8) 18 (15.1) 25 (21.0)

IQR

interquartile range.

Continuous and behaviorally intermittent seizures were equally common. Intermittent seizures consisted, in almost all cases of repeated convulsions, without recovery in between. They were somewhat longer (median 82 minutes, IQR 55120) than continuous seizures (median 55 minutes, IQR 45 85, p 0.002) but median duration of total convulsive time was less (38 minutes, IQR 26 60 for intermittent seizures and 55 minutes, IQR 45 85 for continuous seizures, p 0.0001). The median duration of the longest identifiable convulsion in the intermittent group was 25 minutes (IQR 1538) and the median duration of the total estimated convulsive time was 38 minutes (IQR 26 60). There were no differences between continuous and intermittent FSE with respect to characteristics of the children (age, family history), characteristics of the illness or fever, or seizure type (focal vs generalized). Prior work has shown that FSE is more likely to be focal5,20 and indeed the majority of seizures were focal (table 3). Focality was not related to duration of FSE (67% of 60 children with FSE lasting 68 minutes and 68% of 59 children with FSE lasting 68 minutes). Almost all FSE (99%) is convulsive, whether generalized tonic clonic or partial with secondary generalization. In the 77 children with partial seizures, focal onset consisted of focal jerking of an extremity or face in 33 (43%). Other features at onset included staring (n 51, 66%), eye deviation to one side (n 36, 47%), head turning to one side (n 33, 43%), and a period of blankness or impaired consciousness prior to the convulsion (n 29, 38%). Focal features not present at onset included asymmetry of the convulsive seizures (n 30, 39%) and a Todds paresis (n 10, 13%).
Mortality and morbidity. Two children have died to date; both were developmentally delayed. One child died a few weeks after FSE from complications of pulmonary disease and the other child returned to baseline after FSE and died a few months later. In neither case was the death believed to be related to the episode of FSE. Inter-rater reliability. We compared the preconfer-

SE in over a third of the cases, including children with continuous seizures. A logistic regression was performed to assess the association between clinical characteristics and seizure duration using 68 minutes vs 68 minutes for the analysis. There was no significant association between seizure duration and peak temp (OR 0.97), temperature in the ED (OR 0.97), FSE focality (OR 0.95), and family history of FS (OR 1.6) or of epilepsy (OR 0.98). A plot of the distribution of seizure durations is shown in the figure, A. The data are best fit by a Weibull distribution with parameters:

S(t)

t/95.0 1.68

These parameters, and in particular the shape parameter of 1.68, suggest that in this population the longer a seizure lasts, the less likely it is to spontaneously stop (figure, B).

ence readings for each of the three raters with consensus, which was achieved in all cases after conferencing. There was unanimity on whether this was a FS and on whether it was FSE. Inter-rater reliability was excellent for continuous vs behaviorally 0.90, 0.90, 0.90). There was intermittent FSE ( also excellent agreement on seizure duration with an intraclass correlation coefficient of 0.75 among the three observers. Inter-rater reliability concerning recognition of SE in the emergency department was good, ranging from 0.60 to 0.81.
Neurology 71 July 15, 2008 173

As expected, there was less agreement on seizure focality with values of 0.54, 0.74, and 0.89 for each rater compared to consensus. Disagreements were occasionally due to the rater missing a statement in the multiple source documents that was clearly indicative of focality. More often, disagreements centered on the validity of various observations, particularly when information was discrepant or incomplete. Disagreements were not random as one observer was less likely to call a seizure focal. Agreement on definite lateralization in focal seizures was somewhat better with values of 0.62, 0.82, and 0.84 compared with consensus. In FEBSTAT, the median age of 15.6 months is somewhat lower than reported in studies of children with all FS.21,22 At presentation, 86% of our cohort had a normal development, a higher proportion than that reported in other studies of FSE.23 However, children with severe neurologic disability, who were included in those studies, were excluded from our study, because FEBSTAT focuses upon the relationship between prolonged FS, subsequent MTS, and TLE, occurring in otherwise normal adults. Consistent with other cohorts with FS,22,24 there is a preponderance of males for FSE. A family history of epilepsy was present in 9% of firstdegree relatives in our study, which is higher than found in studies of FS.21,22 In a prior study, we found a higher proportion of a positive family history of epilepsy in children with FSE than in controls with brief FS.23 A variety of viral illnesses predominated in our cohort, consistent with the type of illnesses reported in children with FS in general.25 For FEBSTAT, we adopted the older definition of SE as a seizure lasting 30 minutes rather than the newer proposals that redefine it as 5 minutes.26 This was done for several reasons. In terms of when to treat, 5 minutes is a good choice,13,26,27 but for studying consequences, which is the goal of this study, even 30 minutes may be too brief.1,6 This is especially true for FS, where a simple FS is defined as up to 10 or 15 minutes12,14 and animal data suggest that long-term effects only occur if seizures last 20 minutes.28-30 The distribution of seizure durations is best fit by a Weibull distribution.19 Weibull distributions with a shape parameter of one are equivalent to an exponential distribution whereas a shape parameter greater than one (best fit for our data are 1.68) implies that the longer a seizure lasts, the less likely it is to spontaneously stop. This finding may explain the high proportion of children with very prolonged seizures as well as the observation that 87% of FSE stopped only after the administration of a benzodiazDISCUSSION
174 Neurology 71 July 15, 2008

epine. These data are consistent with the observation in adult patients that the longer a seizure lasts, the less likely it is to respond to medication.31 Animal studies in both adult and immature animals suggest that the longer a seizure lasts, the less likely it is to stop.32,33 In a prior study of first unprovoked seizures in children,27 we reported that seizure duration was best fit by postulating two populations, one with brief seizures and one with prolonged ones. Though the majority of FS are brief,5,14,20,24 FEBSTAT only included children with FSE and therefore, could not examine whether there are two distributions of seizure durations in children with FS. Furthermore, as FEBSTAT focused on prolonged seizures, the effect of prolonged seizure duration on the likelihood of a seizure stopping was better ascertained in the FEBSTAT study. The observed tendency of prolonged seizures to continue, sometimes even if treated, may explain the high median seizure duration. This is unlikely to be due to a failure to recognize milder cases of FSE, because all children with FS lasting 15 minutes were screened. The long seizure durations in FEBSTAT suggest that there will likely be adequate power to assess the impact of seizure duration on hippocampal injury and subsequent MTS and MTLE. This was of concern initially as the available human data suggest very prolonged seizures are required to cause hippocampal injury.1,9,10,34,35 While the majority of FS are brief, benign, and need no treatment,36 the FEBSTAT data highlight that the subgroup that are prolonged can be very prolonged and require intervention. Although FSE represents only 5% of all FS,20 it accounts for a quarter of all pediatric SE and more than two thirds of SE in the second year of life.37 It has long been recognized in adults that intermittent forms of SE are very common.13 However, in children, the intermittent form was believed to be uncommon.13 FEBSTAT demonstrates that the intermittent form of SE is common in children. The higher percentage of children with intermittent SE in FEBSTAT may be due to the availability of ED flow sheets, ambulance call sheets, and the structured interview, which together provided better appreciation of the intermittent semiology than was possible in prior studies. It should be noted that the determination of intermittent was done purely on clinical grounds. While children had subsequent EEGs, none were during the episode of FSE as these were all successfully treated in the ED. We found no features aside from somewhat longer duration that distinguished children with continuous FSE from intermittent FSE. The almost equal numbers of both types of SE in FEBSTAT will allow us to determine if the outcome is different.

Prolonged seizures, whether febrile 20 or afebrile,27 are more likely to be focal.6,22 Interestingly, in FEBSTAT there was no relationship between seizure duration and focality, most likely because this is the extreme end of the spectrum of seizure durations. Prior smaller studies have suggested that hippocampal injury occurs only in children with focal and prolonged FSE.9 The results from our large prospective cohort study should provide a more definitive answer to this question. There was surprisingly excellent inter-rater reliability on all measures except focality. The three raters were trained in different programs and approached the cases differently, but all reached similar conclusions regarding almost all aspects of the phenomenology of FSE including duration, which is believed to be a key feature in predicting injury. While we do not have EEG validation of duration, the ambulance call sheets and emergency department records provided excellent and reliable data for assessing seizure duration which was much longer than estimates based on chart reviews alone.23 Consistent with prior studies,38 focality was more controversial. Differences in determining whether focality was present revolved around interpretation of subtle features at onset. Video EEG monitoring of children in this age group with refractory seizures also suggests that a very high proportion are of focal origin.39 The prolonged duration of seizures in this cohort implies that the long-term outcome of the FEBSTAT cohort will address the relationship between FSE and subsequent MTS and MTLE with adequate power. However, given the known long latency periods between FSE and the development of clinical TLE, it will take time before final answers are known.
APPENDIX
FEBSTAT Study Team: Montefiore Medical Center and Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NYShlomo Shinnar, MD, PhD (PI), Jacqueline Bello, MD, Mootoo Chunasamy, RT, MS, Patricia Clements, Ronda L. Facchini, PhD, James Hannigan, RT, George Lantos, MD, Ann Mancini, MA, David Masur, PhD, Solomon L. Moshe, MD, Christine ODell, RN, MSN, Maryana Sigalova, MA, Rachel Steinman, BA. Childrens Memorial Hospital, Chicago, IL Douglas Nordli, MD (PI), John Curran, MD, Leon G. Epstein, MD, Aaliyah Hamidullah, BS, Julie Renaldi, PhD, Mamello Tekateka, BS. Columbia University School of Medicine, New York, NYDale C. Hesdorffer, PhD (PI), Emilia Bagiella, PhD, Emma K.T. Benn, MPH, Stephen Chan, MD, Veronica J. Hinton, PhD. Duke University Medical Center, Durham, NCDarrell Lewis, MD (PI), Melanie Bonner, PhD, James MacFall, PhD, James Provenzale, MD, Elizabeth Rende, RN, MSN, CPNP, Jean Smith, MS, Allen Song, PhD, Yuan Xu, BS. Eastern Virginia Medical School, Norfolk, VAL. Matthew Frank, MD (PI), Joanne Andy, RT, Chris Buescher, Susan Grasso, MD, Diane James, R-EEG T, David Kushner, MD, Susan Landers, RT, Terrie Swack, RN, V.A. Van de Water, PhD. Virginia Commonwealth University, Richmond, VAJohn M. Pellock, MD (PI), Tanya Bazemore, REEG-T, James Culbert, PhD, Kathryn OHara, RN, Jean Snow, RT-R. International Epilepsy Consortium At Virginia Commonwealth University,

Richmond, VAAnthony Mamarou, PhD (PI), Joyce Galloway, Juan Lu, MD, MS, John M. Pellock, MD. Medical safety monitorTracy Glauser, MD, Cincinnati Childrens Hospital.

Received June 4, 2007. Accepted in final form December 14, 2007.

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