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- MATERIALS AND METHODS
Summary: Febrile status epilepticus (SE) represents the extreme end of the complex febrile seizure spectrum. If there are significant sequelae to febrile seizures, they should be more common in this group. We have prospectively identified 180 children aged 1 month to 10 years who presented with febrile SE over a 10-year period in Bronx, New York, and Richmond, Virginia. They were compared with 244 children who presented with their first febrile seizure (not SE) in a prospective study done in the Bronx.
The mean age of the children with febrile SE was 1.92 years, and of the comparison group, 1.85 years. Duration of SE was 30–59 min in 103 (58%), 60–119 min in 43 (24%), and ≥120 min in 34 (18%). Focal features were present in 64 (35%) of cases. There were no deaths and no cases of new cognitive or motor handicap. Children with febrile SE were more likely to be neurologically abnormal (20% vs. 5%; p < 0.001), to have a history of neonatal seizures (3% vs. 0; p = 0.006) and a family history of epilepsy (11% vs. 5%; p = 0.05) and less likely to have a family history of febrile seizures (15% vs. 27%; p = 0.01) than were children in the comparison group. The short-term morbidity and mortality of febrile SE are low. There are differences in the types of children who have febrile SE compared with those who experience briefer febrile seizures. Long-term follow-up of this cohort may provide insight into the relationship of prolonged febrile seizures and subsequent mesial temporal sclerosis.
Febrile seizures are the most common seizures that occur in children. Between 2% and 5% of young children in the United States and Western Europe experience at least one febrile seizure (1–8). Although it is generally accepted that most febrile seizures are benign (1,3–5,9–19), there is still some concern that prolonged febrile seizures may cause brain damage or neurological sequelae (20–31). The issue of whether prolonged febrile seizures are associated with the development of mesial temporal sclerosis (MTS) and intractable mesial temporal lobe epilepsy in later life is one of the most controversial areas in epileptology today.
A major obstacle to further research has been the lack of adequate numbers of cases. Recent reports of acute changes suggesting hippocampal injury have been limited to children with very prolonged febrile seizures (13,15,21–24). In studies of febrile seizures, ∼4–5% last ≥30 min (3–5,9–11,32). Thus, few studies of febrile seizures have included a large number of children with very prolonged febrile seizures.
Between 1984 and 1996, the authors prospectively identified 180 children with febrile status epilepticus (SE) both as part of prospective studies of febrile seizures (9,10,32) and of SE (17,33–36) and as part of ongoing surveillance for cases of febrile SE at our institutions. This article presents the short-term outcomes of these children and a comparison of their clinical characteristics with a cohort of children with a first febrile seizure recruited during the same period (9,10).
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- MATERIALS AND METHODS
There were 180 children with febrile SE and 244 children in the comparison group including 168 children with a simple febrile seizure and 76 with a complex febrile seizure that lasted <30 min. (If one defines prolonged febrile seizure as >15 min, then there were 72 children with a complex febrile seizure that lasted <30 min). The mean age of the children with febrile SE was 1.92 years (range, 0.1–9.1 years). In the 133 children in whom the episode of SE was the first febrile seizure, the mean age was 1.76 years (range, 0.1–9.1 years), whereas in the 47 children with a history of febrile seizures, the mean age was 2.39 years (range, 0.6–9.1 years; p = 0.02).
The age distributions for the children with febrile SE and the febrile seizure comparison group are shown in Fig. 1. Of the 180 subjects with febrile SE, 123 (68%) had their episode of febrile SE when younger than 2 years, and 171 (95%) younger than 5 years. Of the 133 children with SE as their first febrile seizure, 98 (74%) had their episode at younger than 2 years, and 128 (96%) were younger than 5 years. There were no significant differences in the age distributions between the children with febrile SE and the comparison group (mean age, 1.85 years; range, 0.25–9.6 years). There were no significant differences in the age distribution between the children in the comparison group with simple febrile seizures and those with complex febrile seizures (Table 1).
Table 1. Characteristics of children with febrile status epilepticus (SE) and of comparison group with a first febrile seizure (FS)
| ||FSE||Comparison group: first FS|
|All controls||Simple FS||Complex FS|
|All n (%)||First FSa n (%)||n (%)||p Valuea||n (%)||p Valuea||n (%)||p Valuea|
|Number of children||180||133||244|| ||168|| ||76|| |
|Mean age (y)||1.92||1.76||1.88||0.45||1.85||0.57||1.93||0.44|
|Prior febrile seizures||47 (26%)||—||—|| ||—|| ||—|| |
|Prior episode of SE||0 (0%)||0 (0%)||0 (0%)||—||0 (0%)||—||0 (0%)||—|
|Prior neonatal seizures||6 (3%)||4 (3%)||0 (0%)||0.006||0 (0%)||0.01||0 (0%)||0.06|
|Previously neurologically abnormal||38 (21%)||26 (20%)||12 (5%)||<0.001||8 (5%)||<0.001||4 (5%)||0.002|
|Family history of febrile seizuresb||28 (15%)||20 (15%)||63 (27%)||0.01||41 (25%)||0.04||22 (31%)||0.01|
|Family history of epilepsyb||21 (12%)||14 (11%)||12 (5%)||0.05||11 (7%)||0.23||1 (1%)||0.007|
|Focal seizure||64 (35%)||50 (38%)||36 (15%)||<0.001||—|| ||36 (47%)||0.17|
Characteristics of the cohort with febrile SE and the febrile seizure comparison group are shown in Table 1. The episode of febrile SE was the first episode of SE in all cases. Children with febrile SE were more likely than the comparison group to have a history of neonatal seizures (3% vs. 0; p = 0.006), to be neurologically abnormal before the episode (20% vs. 5%; p < 0.001), and to have a family history of epilepsy in a first-degree relative (11% vs. 5%; p = 0.05). They were also less likely than the comparison group to have a family history of febrile seizures (15% vs. 27%; p = 0.01).
The six children with a history of neonatal seizures were all known to be neurologically abnormal before the episode of febrile SE, which was the first febrile seizure in four cases. None of the children in the comparison group had a history of neonatal seizures. Even within the group of 180 children with febrile SE, the rate of neurologic abnormalities in this small group of children was significantly higher than that in the 174 children with febrile SE and no history of neonatal seizures (six of six, 100% vs. 32 of 174, 18%; p < 0.001).
The results are unchanged if the comparison group is limited to the 72 children with a febrile seizure that was focal multiple or lasted ≥15 but <30 min. There were only four children in the comparison group with seizure duration between 10 and 15 min, so the definition used, although of theoretic interest, does not change the results. The results are also unchanged if one limits the analysis to the 168 (93%) children between the ages of 6 months and 6 years, which are regarded as the most common ages for the occurrence of febrile seizures. This only excludes nine children younger than 6 months and three children older than 6 years.
Characteristics of febrile status epilepticus
The characteristics of the episode of febrile SE are shown in Table 2. Approximately one third of the seizures were focal. The episode of febrile SE lasted ≥1 h in 77 (43%) cases and ≥2 h in 34 (19%) cases. The proportion of focal seizures in children with febrile SE was higher than in the overall febrile seizure comparison group, although similar to that seen in the comparison group with complex febrile seizures (Table 1). Within the febrile SE group, there was no clear association between increasing duration of the episode of febrile SE and focality using the chi square for trend (Table 2).
Table 2. Characteristics of episode of febrile status epilepticus (SE)
|Duration of seizurea||All cases||SE as first febrile seizure|
|Number (%)||Focal (%)||Number (%)||Focal (%)|
|30–59 min||103 (58%)||34 (33%)||71 (54%)||24 (33%)|
|60–119 min||43 (24%)||17 (40%)||33 (25%)||13 (39%)|
|120–239 min||28 (15%)||10 (36%)||24 (18%)||10 (42%)|
|≥240 min||6 (3%)||3 (50%)||5 (4%)||3 (60%)|
|All cases||180||64 (35%)||133||50 (37%)|
Morbidity and mortality
There were no deaths within 30 days of the episode of febrile SE in the 180 children included in the cohort. One death was associated with what initially was classified as an episode of febrile SE but which was subsequently diagnosed as probable shigella encephalopathy and excluded from the cohort. The details of the case are presented in the Methods section. No cases of new motor or cognitive deficits were reported. In the 244 children in the comparison group with either simple or complex febrile seizures, there were no deaths and no reports of new motor or cognitive deficits.
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- MATERIALS AND METHODS
The short-term morbidity and mortality of febrile SE in this series is extremely low. This is consistent with the findings of other series of the past 20 years, including both series of febrile seizures (1–11,16) and of SE (11–15,17,18,33–37). Our one fatality, even though he initially appeared to be a case of febrile SE, had presumptive shigella encephalopathy and was therefore not a true case of febrile SE. Earlier series, mostly before the modern era of treatment and that used a definition of SE of 60 min rather than 30, reported a substantial morbidity and mortality associated with febrile SE (20,41). However, this has not been the experience of any subsequent prospective series. Two large prospective studies that used either sibling controls (11) or a national birth cohort (14) found no differences in IQ or academic performance between children who had experienced an episode of febrile SE and controls.
Although the age distribution is similar, the children with febrile SE appear to be different from children with briefer febrile seizures in several important respects. The higher proportion of focal seizures among those with prolonged febrile seizures has been observed by other authors (3,32,43), although without a direct control group for comparison. Whereas the rate of focal seizures is higher than in the comparison group as a whole, it is comparable to the rate among children with complex febrile seizures and does not seem to increase with further increases in duration. This is not surprising when one notes that focality is one of the criteria to be classified as complex. The striking finding in this cohort is the high rate of preexisting neurologic abnormalities in children with febrile SE compared with that in children with briefer febrile seizures, including those with both simple and complex febrile seizures (not SE). Also of note is the higher proportion of children with febrile SE who have a family history of epilepsy and the lower proportion with a family history of febrile seizures. This suggests that there is a subgroup of children with febrile SE that are different from the other children with febrile seizures. Perhaps it is these children who go on to develop medically refractory mesial temporal lobe epilepsy.
The new ILAE guidelines for epidemiologic research stratify febrile seizures by whether there is a history of neonatal seizures (38). This was done because of concern over whether the group with prior neonatal seizures might have a very different prognosis. These concerns appear justified, as all cases with prior neonatal seizures were in the febrile SE group and were neurologically abnormal before the episode of febrile SE.
The comparison group used was a group of children recruited by the authors during the same period and from the same hospital emergency departments as that half of the febrile SE cases from the Bronx. Ideally, a strict control group might have been assembled somewhat differently. As it is, the comparison group was recruited using similar methods and case-finding techniques and similar data-collection methods. All results were essentially unchanged when the comparison group was compared only with the febrile SE cases from the Bronx. Although not perfect, we believe that the comparison group is entirely adequate for examining the differences between children whose first febrile seizure was <30 min and those whose first febrile seizure lasted ≥30 min. It is hard to identify any serious bias that would affect the results obtained in these two hospital-based cohorts.
One of the most controversial issues in epilepsy is whether prolonged febrile seizures cause mesial temporal sclerosis (MTS) (21). Retrospective studies from tertiary epilepsy centers report that many adults with intractable mesial temporal lobe epilepsy had a history of prolonged or atypical febrile seizures in childhood (25–31). However, population-based studies have failed to find this association (3–5,15,44), as have other prospective studies of febrile seizures (9,10,45). Two recent studies of new-onset childhood epilepsy failed to find an association between either temporal lobe epilepsy (44,46) or MTS (46) and a history of prior febrile seizures. In the past 2 years, several reports have documented the occurrence in rare cases of acute and chronic hippocampal changes in children with very prolonged febrile seizures (22–24). The cases reported have all been very prolonged, averaging well over an hour, and have also been focal. In addition, some cases had preexisting focal lesions that may have predisposed them to both prolonged focal seizures and injury (15,21). Pathological data from human temporal lobes resected at surgery for medically refractory mesial temporal lobe epilepsy (47,48) and data from animals with experimentally induced cortical dysplasia also suggest that brains with preexisting temporal lobe pathology may be more vulnerable to damage from prolonged febrile seizures (49). In contrast, findings from an immature rat model of prolonged febrile seizures (50) document that these seizures do not result in loss of hippocampal and amygdala neurons, but cause significant yet transient structural alterations in the normal immature rat (50,51). Given the significant differences between the children with febrile SE and those with briefer febrile seizures, it is possible that there is a vulnerable subgroup of children in whom febrile SE is either a marker for preexisting damage and/or a cause of additional damage to an already vulnerable brain.
The present cohort was assembled with a view to answering some of these questions. The cohort was prospectively identified without bias regarding outcome. Prospective identification also allowed contemporaneous collection of details regarding focality and duration. Further study of this cohort is planned. This will include determination of the occurrence of subsequent epilepsy with emphasis on the time course and the type of epilepsy. Detailed neuroimaging of the entire cohort is also planned to determine the incidence of hippocampal sclerosis after very prolonged febrile seizures and the risk factors associated with it. As no immediate imaging was done in this cohort, these studies will not be able to address the question of when the hippocampal changes occur, but they will place an upper bound on how often they happen.
Acknowledgment: This study would not have been possible without the cooperation of many people. In the Bronx, we thank Ms. Marta Alemany for her help in maintaining the cohort and all of the fellows and faculty in the Division of Pediatric Neurology at the Albert Einstein College of Medicine. Thanks also to the Directors of the Pediatric Emergency Rooms and Intensive Care Units at Montefiore Medical Center, Bronx Municipal Hospital Center, and North Central Bronx Hospital for their help in identifying and recruiting the subjects and for providing their acute medical care. We also acknowledge the cooperation of the New York City Health and Hospital Corporation and Bronx Municipal Hospital Center and North Central Bronx Hospital. In Richmond, special appreciation and thanks are extended to the Department of Neurology and staff at MCV/VCU, the MCV hospital, and all the community hospitals and community physicians in Richmond who participated in the study and referred patients for inclusion in it. The invaluable time and assistance of the Medical College of Virginia Hospital Neurology house staff, SE nurses, and the SE team in caring for the patients and assisting with the protocols are also appreciated.
This work was supported, in part, by grants 1 R01 NS26151 (S. Shinnar), 1 R29 NS27728 and 1 R01 NS31146 (A.T. Berg) and P02-NS25630 (R.J. DeLorenzo) from the National Institute of Neurological Disorders and Stroke, and a Merrit-Putnam fellowship from the Epilepsy Foundation of America (J. Maytal).