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Keywords:

  • Seizure;
  • Status epilepticus;
  • Epilepsy;
  • Children;
  • Etiology

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Population

Included in this study are 180 children, aged 1 month to 10 years, who presented with febrile SE.

Bronx cohort

The 91 children in the Bronx cohort of febrile SE were prospectively recruited from 1984 to 1996. Some (n = 32) were recruited as part of the prospective portion of a study of SE (17,33) from January 1985 to June 1987, and some as part of a study of first febrile seizures (n = 10) from June 1989 to May 1991 (9,10,32). Children were seen at the affiliated hospitals of the Albert Einstein College of Medicine, Bronx, New York, including Montefiore Medical Center, Bronx Municipal Hospital Center, and North Central Bronx Hospital. Details of those studies, which included other children as well, have been previously published (9,10,17,32,33). The remainder (n = 49) were recruited by one of the authors (S.S.) as part of ongoing prospective surveillance of febrile SE at Montefiore Medical Center and have not been previously reported.

One child who was initially recruited to the study was subsequently excluded. The child had a 5-min generalized tonic–clonic seizure and fever. There was a history of diarrhea and vomiting the previous day, evaluated in the emergency department and sent home. The child remained lethargic with persistent vomiting. Nineteen hours after initial seizure, another 5- to 10-min seizure occurred, which resolved without treatment. When seen again in the emergency department, the child was crying. However, ∼20 min later, the child had a 45-min seizure, which was treated with intravenous lorazepam (LZP) followed by phenytoin (PHT). The child never woke up and was clinically brain dead a short time thereafter. Computed tomography (CT) scan showed diffuse cerebral edema. Laboratory values of significance included a WBC of 3,200 with 10% bands, 49% polys, 35% lymphocytes, and 3% monocytes. Autopsy findings included diffuse cerebral edema and colitis. The child's sibling was later diagnosed with shigellosis. Therefore, in retrospect, the most likely diagnosis was shigella encephalopathy.

Richmond cohort

The 89 children with febrile SE in this cohort were prospectively recruited from 1984 to 1994. They include 62 children recruited between July 1989 and 1994 as part of a large ongoing population-based study of SE cases in the Richmond area that started in July 1989 (34–36). Also included are 27 children prospectively identified by another of the authors (J.M.P.) from 1984 to 1989 as part of ongoing surveillance of childhood SE at the Medical College of Virginia and who were not included in prior reports. Details of the recruitment criteria and overall data for the population-based study in the Richmond area were previously published (34–36).

Comparison group

The comparison group was selected from a group of children with a first febrile seizure prospectively recruited from June 1989 through May 1991 at Jacobi Medical Center, North Central Bronx Hospital and Montefiore Medical Center in the Bronx and from June 1989 through January 1992 at Yale New Haven Hospital, New Haven, Connecticut. Details of the inclusion and exclusion criteria and outcomes for this cohort have been previously published (9,10). To provide a comparison group from the same geographic source of care, the comparison group used for this analysis was limited to those children recruited in the Bronx. We further excluded the 10 children in this cohort with febrile SE, as they are included in the Bronx cohort of children with febrile SE. The comparison group therefore includes 244 children including 168 with a first simple febrile seizure and 76 with a first complex febrile seizure (excluding febrile SE) (10). This is a hospital-based cohort, as is the febrile status epilepticus cohort.

Definitions

Status epilepticus was defined as any seizure lasting ≥30 min or recurrent seizures lasting a total of 30 min without fully regaining consciousness (33,34,37–39). In accordance with the International League Against Epilepsy (ILAE) guidelines for epidemiologic research (38), a febrile seizure was defined as a provoked seizure in which the sole acute provocation was fever (temperature 38.4oC) in a child older than 1 month without history of afebrile seizures. Children with previously abnormal neurologic function were included. Children with prior episodes of febrile seizures or febrile SE were included. However, if a child had two or more episodes of febrile status during the study period, only the first episode was counted. In accordance with the ILAE guidelines for epidemiologic research (38), children with prior neonatal seizures were included. Children with evidence of an acute central nervous system infection or electrolyte imbalance were excluded, as were infants younger than 1 month (16,38). This group with febrile SE is included in the category of a prolonged febrile seizure as defined by NIH Consensus Conference (4,11,16) and by the ILAE guidelines for epidemiologic research in epilepsy (38), as well as all previous epidemiologic studies of febrile seizures (3–12). It represents the extreme end of febrile seizures and has also been included in studies of childhood SE (33–41).

For the comparison group, a simple febrile seizure was defined as an isolated, generalized tonic–clonic febrile seizure lasting <10 minutes (9,16,32,38). This definition is in accordance with the ILAE guidelines for epidemiologic research (38) and has been used in several other epidemiologic studies (1,3,9,32). Febrile seizures lasting 10–29 min, focal febrile seizures, or the occurrence of more than one febrile seizure within the febrile illness were all considered as having complex features. The data are also presented using the 15-min lower limit for duration that was used by Nelson and Ellenberg (4,11).

Procedures

All children were prospectively identified and examined during the acute illness. A detailed medical history was obtained, including type of seizure, and duration of seizures, and the treatment given. Seizure duration was determined using the ambulance call sheets, emergency department records, and interview with the family. When there was doubt, a conservative estimate of the seizure duration was used. The techniques used to estimate duration in these cohorts have been previously published (9,17,32,33–36). A neurologic examination was performed in all cases. Possible causes of the fever and workup done to exclude other causes of the episode of febrile SE were also reviewed. Seizures were classified in accordance with the revised international classification of seizures (39).

A child was considered to be previously abnormal neurologically, if there was a clear documentation in the chart or in the history obtained from the parents that the child was developmentally delayed or that the child had other definite neurologic abnormalities. A history of suggestive or questionable development or other deficits was not sufficient. Whereas some of these children had been previously evaluated by a neurologist, in many cases, the episode of febrile SE was the impetus for the initial neurologic evaluation.

Neurologic sequelae were determined by formal neurologic examination. Cognitive function was assessed by mental status testing as part of the neurodevelopmental examination. No formal IQ testing was carried out in most children. However, in addition to screening by the examiner, parents were asked whether there were any differences in the child's functioning after the acute illness. Any reported deterioration in performance or function was considered a sign of cognitive impairment. In this evaluation of short-term outcomes, outcomes were evaluated at discharge and at last follow-up with a range of follow-up of 1 week to several years. Almost all patients had at least 1 month of follow-up, and the results are based on the assessment at 1 month.

A family history of febrile seizures or of epilepsy was considered positive if present in a first-degree relative (sibling or parent). This is consistent with the definitions used in other epidemiologic studies of seizures (2–5,8–10).

The studies in the Bronx and Richmond have used similar methods. To ensure comparability and consistency, all cases were reviewed by two of the investigators (S.S. and C.O.) and classified in accordance with these definitions (40).

Data analysis

Data were analyzed using standard statistical methods (42). The descriptive statistics included the age distribution, the occurrence of prior febrile seizures, family history of febrile seizures, neurologic function of the patient before the episode of febrile SE, and the occurrence of prior neonatal seizures. Data were analyzed for all cases and also only for those cases with SE as the first febrile seizure. For purposes of comparison with the febrile seizure comparison group, only cases in which SE was the first febrile seizure were used. Means were compared using the Student's t test. Other comparisons were made using chi-square statistics. All p values were computed using two-tailed distributions. A p value <0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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).

image

Figure 1. Age distribution of children with febrile seizures and febrile status epilepticus (SE).

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Table 1. Characteristics of children with febrile status epilepticus (SE) and of comparison group with a first febrile seizure (FS)
 FSEComparison group: first FS
All controlsSimple FSComplex FS
All n (%)First FSa n (%)n (%)p Valuean (%)p Valuean (%)p Valuea
  • a

     p Value is for differences between comparison groups and children with febrile status epilepticus as their first febrile seizure.

  • b

     Family history is missing for seven cases from comparison group, three with simple febrile seizures and four with complex febrile seizures.

Number of children180133244 168 76 
Mean age (y)1.921.761.880.451.850.571.930.44
Prior febrile seizures47 (26%)   
Prior episode of SE0 (0%)0 (0%)0 (0%)0 (0%)0 (0%)
Prior neonatal seizures6 (3%)4 (3%)0 (0%)0.0060 (0%)0.010 (0%)0.06
Previously neurologically abnormal38 (21%)26 (20%)12 (5%)<0.0018 (5%)<0.0014 (5%)0.002
Family history of febrile seizuresb28 (15%)20 (15%)63 (27%)0.0141 (25%)0.0422 (31%)0.01
Family history of epilepsyb21 (12%)14 (11%)12 (5%)0.0511 (7%)0.231 (1%)0.007
Focal seizure64 (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 seizureaAll casesSE as first febrile seizure
Number (%)Focal (%)Number (%)Focal (%)
  • a

     For association between duration and focality, p value for trend is 0.40 for all cases and 0.22 for children whose FSE was the first febrile seizure.

30–59 min103 (58%)34 (33%)71 (54%)24 (33%)
60–119 min43 (24%)17 (40%)33 (25%)13 (39%)
120–239 min28 (15%)10 (36%)24 (18%)10 (42%)
≥240 min6 (3%)3 (50%)5 (4%)3 (60%)
All cases18064 (35%)13350 (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.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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Footnotes
  1. This work was presented, in part, at the Child Neurology Society Meeting, Baltimore, Maryland, October 1995.