Febrile
Status
Epilepticus
Joseph
Maytal,
MD, and Shlomo
Shinnar,
MD, PhD
From the Departments of Neurology and Pediatrics and the Montefiore/Einstein Epilepsy
Management Center, Montefiore Medical Center, and Division of Pediatric Neurology,
Schneider Children’s Hospital, Long Island Jewish Medical Center, The Albert Einstein
College of Medicine, Bronx, New York
ABSTRACT. As part of a study of status epilepticus in
children (Maytal J, Shinnar 5, Moshe SL, Alvarez LA.
Pediatrics. 1989;83:323-331); 44 children with febrile
con-vulsions lasting more than 30 minutes were followed for
a mean of 28 months (range 4 to 72). Thirty children
were followed prospectively. Children with prior afebrile
seizures or evidence of acute central nervous system
infection were excluded. Nine (20%) children had prior
neurological deficits. The duration of the febrile seizure
was 0.5 to 1 hour in 41 cases (85%), 1 to 2 hours in 5
(10%), and greater than 2 hours in 2 children (5%). No
child died or developed new neurological deficits
follow-ing the seizures. The risk of recurrent seizures was
in-creased, but only in the group with prior neurological
abnormality. Six (66%) of these children had subsequent
febrile seizures compared with 12 (34%) of the normal
children (P = .08). Three (33%) had recurrent febrile
status epilepticus compared with only 1 (3%) normal
child (P = .023). The 2 children in the prospective arm
of the study with recurrent febrile status epilepticus were
both neurologically abnormal (P = .035). All 3 of the
children who subsequently had afebrile seizures (2 pro-spective) were neurologically abnormal (P = .006 overall,
P = .035 for prospective only). It is concluded that the
occurrence of febrile status epilepticus in a neurologically
impaired child is a risk factor for subsequent febrile as
well as afebrile seizures. The occurrence of febrile status
epilepticus in an otherwise normal child does not
signif-icantly increase the risk for subsequent febrile (brief or
prolonged) or afebrile seizures in the first few years
following the episode. Pediatrics 1990;86:611-616;
sei-zure, febrile seizures, status epilepticus, epilepsy.
ABBREVIATIONS. NCPP, National Collaborative Perinatal
Project; AED, antiepileptic drug.
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.”2 While it is generally accepted that most febrile seizures are benign,3’4 there is still some concern that prolonged febrile seizures may cause brain damage or neuro-logical sequelae.5 Most febrile seizures are brief. The National Collaborative Perinatal Project (NCPP) birth cohort study,’ which studied more than 1500 children with febrile seizures, found that
most febrile seizures were brief. Only 8% lasted
longer than 15 minutes and 4% longer than 30 minutes. In studies of febrile seizures from Den-mark,6 approximately 10% of the children had an initial febrile seizure lasting longer than 15 mm-utes.
Although prolonged febrile seizures are only a small fraction of all febrile seizures, febrile status epilepticus accounts for approximately one quarter of all episodes of status epilepticus in children.7’8 In a large, hospital-based study of status epilepticus, Aicardi and Chevrie8 found that 59 (25%) of 239 children with status epilepticus had febrile status epilepticus. In a more recent study on the short-term morbidity and mortality of status epilepticus
in children,7 we found that 46 (24%) of 193 children
with status epilepticus had fever as the cause of status. The present report describes the long-term outcome of this group of children with particular emphasis on the occurrence of subsequent seizures.
Received for publication Nov 27, 1989; accepted Mar 30, 1990.
Presented, in part, at the Child Neurology Society Meeting, San
Antonio, TX, October 1989.
Reprint requests to (S.S.) Division of Pediatric Neurology,
VCP-207, Montefiore Medical Center, 111 E 210th St, Bronx, NY
10467.
PEDIATRICS (ISSN 0031 4005). Copyright © 1990 by the
American Academy of Pediatrics.
MATERIALS
AND
METHODS
Subjects in this study are children with febrile
status epilepticus who were recruited into a larger
associated with a febrile illness were identified and followed. Informed consent was obtained from the parents. Infants younger than 1 month of age were excluded. Children with prior episodes of febrile seizures were included. No child could enter the study more than once.
The prospective part of the study included all patients with an episode of febrile status epilepticus between January 1985 and June 1987 who were identified at the time of the acute illness and were evaluated by the authors within 24 to 48 hours. Also included in this part of the study was a small group of four children who had an episode of febrile status epilepticus between January 1985 and June
1987, but who received their initial care elsewhere.
They were referred to us for further evaluation and care more than 48 hours after an initial episode of febrile status epilepticus. A detailed medical history was obtained, including type, cause, and duration of seizures and the treatment given. A neurological examination was performed in all cases. In this observational study, no attempt was made to influ-ence anticonvulsant therapy.
Four patients who were recruited during their acute illness were lost to follow-up and were ex-cluded from the current analysis. These patients left the hospital with no new neurological findings and in stable condition. The ages of the remaining 30 patients in the prospective study ranged from 6 months to 41 months (mean 16.7 months) at the time of status epilepticus. There were 15 males and 15 females. They were then followed either at the Montefiore Epilepsy Management Center or the Bronx Municipal Hospital Pediatric Neurology Clinic, with a mean duration of follow-up of 32.8 months (range 6 to 58). As the episodes of status epilepticus all occurred between January 1985 and June 1987, at least 30 months have elapsed between the time of status and analysis of data. The shorter duration of follow-up available in some cases is due to losses to follow-up.
The retrospective part of the study consisted of 14 children who had an episode of febrile status epilepticus between 1980 and 1984. They were iden-tified by reviewing the records of all children who had been admitted with a diagnosis of febrile status epilepticus from January 1980 through December 1984 and by interviewing patients who were fol-lowed in the pediatric neurology clinics for a history of a prior prolonged febrile seizure. Included in this part of the study are 14 patients whose ages ranged from 10 to 47 months (mean 18.5 months). There were 6 males and 8 females. They were followed either at the Montefiore Epilepsy Management Center or the Bronx Municipal Hospital Pediatric Neurology Clinic, with a mean duration of
follow-up of 40.2 months (range 4 to 83) after the episodes of status. The variable duration of follow-up is primarily a result of losses to follow-up. As, in theory, this group may be skewed to bad outcome, the results are presented separately for the pro-spective group and the overall group.
Status epilepticus was defined as any seizure lasting more than 30 minutes or recurrent seizures lasting a total of more than 30 minutes without the child’s fully regaining consciousness.9 Seizures were classified in accordance with the revised interna-tional classification’0 as generalized (tonic-clonic or tonic) or partial (simple partial, complex partial, or partial with secondary generalization). Febrile sei-zures were defined (using a modification of Hauser et al7’11) as provoked seizures where the sole acute provocation was fever (temperature greater than 38.4#{176}C).Children with evidence of an acute central nervous system infection or electrolyte imbalance were excluded. In accordance with the criteria of
Hauser et al,” all children older than 1 month of age were included, as were children with previously abnormal neurological status. In this study, chil-dren with prior afebrile seizures were excluded. In principle, these definitions are similar but not iden-tical to definition of febrile convulsions used by the NCPP.’ In practice, all children entered into the study also met the criteria for prolonged febrile
convulsions of Nelson and Ellenberg.’
Follow-up consisted of periodic clinic visits with neurological evaluation by the investigators. Neu-rological sequelae were determined by formal neu-rological examination. Cognitive function was as-sessed by mental status testing as part of the neu-rodevelopmental examination. No formal IQ testing was carried out in most children. However, in ad-dition to screening by the examiner, parents were asked whether there were any differences in the child’s functioning after the acute illness. Any re-ported deterioration in performance or function was considered a sign of cognitive impairment. Parents were also contacted periodically by telephone for follow-up to determine the incidence of subsequent febrile and afebrile seizures as well as episodes of subsequent status epilepticus. If the child was given emergency care for seizures after entry to the study, the medical records were reviewed. Prior neurolog-ical status was determined by history and from review of medical records when available.
epilepticus was analyzed as a function of the neu-rological status prior to status epilepticus, duration of the status, the seizure type, and the patient’s age at the initial febrile seizure episode.
x2
statistics and t tests were used. Levels of significance for 2 x 2 tables were calculated using Fisher’s exact test. All P values were computed using two-tailed distri-butions.RESULTS
Population
and Seizure
Characteristics
The study population consisted of 44 children, 30 of whom were identified prospectively. There were 23 girls and 21 boys. Twenty-four of the children were Hispanic, 15 were white, and 5 were black, which corresponds to the ethnic distribution served by our medical centers. The mean duration of fol-low-up was 35.2 months (range 4 to 72). The mean duration of follow-up for the 30 children in the prospective study was 32.8 months (range 6 to 58). Twelve children (27%) were followed for more than 4 years, 23 (52%) for more than 3 years, 29 (66%) for more than 2 years, and 38 (86%) for more than 1 year. All but 1 child were followed for more than 6 months.
The mean age at the time of febrile status epilep-ticus was 16.0 months (range 6 to 47) for all children and 16.7 months (range 6 to 42) for the prospective group. Ten children had their episode of status before the age of 1 year and 42 children (95%) had their episode before 3 years of age. All children were younger than 5 years of age. The 2 children older than 3 years of age (one prospective, one retrospec-tive) were both neurologically abnormal prior to the episode of status epilepticus.
Five patients had a family history of afebrile seizures and seven had a family history of febrile seizures. None of the patients with recurrent afe-brile seizures had a family history of seizures. Thirty-seven children (84%) had generalized
sei-zures and seven (16%) had partial seizures with secondary generalization. By definition, all subjects had febrile seizures lasting at least 30 minutes. Eight subjects (18%) had seizures lasting longer than 1 hour.
Neurological
Sequelae
There were no deaths in the group. There were also no detectable neurological sequelae in any of the children with febrile status epilepticus. A de-tailed analysis of the short-term morbidity
and
mortality among children with status epilepticus has been reported previously.7
Nine children (20%) were neurologically abnor-mal prior to the occurrence of the episode of status. Six were recruited prospectively (20% of the pro-spective population) and three retrospectively (21% of the retrospective population). All the patients described as neurologically abnormal had cerebral palsy of different forms and grades of severity. Six of these patients were also mentally retarded or significantly developmentally delayed. None had any worsening of their neurological deficits follow-ing the episode of febrile status epilepticus.
Risk of Seizures
Following
Febrile
Status
Epilepticus
By definition, none of the patients recruited to the study had prior afebrile seizures. Of 14 patients with prior febrile seizure(s), 1 had a prior episode of febrile status epilepticus. The risk of further seizures following an episode of febrile status epi-lepticus is summarized in Table 1. The data for the prospective group are presented separately but are substantially the same.
There were 18 patients (41%) who experienced further febrile seizures. The risk of recurrent febrile seizures was somewhat higher in the neurologically abnormal group (P = .08) and in children with a
family history of seizures (P = .08) (Table 2).
TABLE 1. Risk of Further Seiz ures Follo wing an Episode of Febrile Status Epilepticus*
Recurrent Seizures Total Neurologically
Normal Neurologically Abnormal P Value Overall group Febrile seizures Afebrile seizures Febrile status epilepticus Any seizure
Prospective only Febrile seizures Afebrile seizures Febrile status epilepticus Any seizure
n = 44
18 (41)
3 (7)
4 (9)
19 (43) n = 30 14 (46)
2 (7) 2 (7) 14 (46)
n = 35
12 (34)
0
1 (3)
12 (34) n = 24 10 (42)
0 0 10 (42)
n = 9
6 (67)
3 (33)
3 (33)
7 (78) n = 6 4 (66) 2 (33) 4 (33) 4 (66) .08 .006 .023 .018 .38 .035 .035 .38
* Values are given as number (%) of patients who experienced further seizures. Levels of
TABLE 2. Risk Factors for Further Febrile Seizures (FS) Risk Factor
n
Present
FS % n
Absent
FS %
P Value
Neurologically abnormal 9 6 67 35 12 34 .08
Age <1 y 10 5 50 34 11 38 .31
Prior febrile seizures 14 7 50 30 1 1 36 .40
Family history febrile seizures 7 1 14 37 17 45 .11
Family history afebrile seizures 5 1 20 39 18 43 .27
Family history any seizures 11 2 18 33 16 48 .08
Duration of status >1 h 8 3 38 36 15 41 .83
Focal status epilepticus 7 2 29 37 16 43 .47
Younger children had only a slightly higher risk of recurrence (Table 2). Among neurologically normal children, 4 of 9 (44%) younger than age 1 had recurrent febrile seizures compared with 8 (30%) of
26 with febrile status after the first year of life. Subsequent febrile seizures were only slightly more frequent in the group with prior febrile seizures (Table 2).
There were four children with two episodes of febrile status epilepticus. Three had another epi-sode after entry into the study and one child had a prior episode of status epilepticus. Three of the four children were neurologically abnormal. The rate of recurrent febrile status in this population was 38% in the neurologically abnormal group but only 3% in the neurologically normal group (P = .023). Both children in the prospective study with recurrent febrile status were neurologically abnormal.
All three children (two prospective) with subse-quent afebrile seizures were neurologically abnor-mal prior to the episode of febrile status epilepticus (Table 1). Two of these three children also had recurrent febrile seizures and one had recurrent febrile status epilepticus. None had a family history of seizures. Despite the small numbers, the higher risk of afebrile seizures in the neurologically abnor-ma! group was statistically significant (P = .006). It remained significant even when only the pro-spective group was analyzed (P = .035).
Treatment
Twenty-one (48%) of the 44 children with febrile
status epilepticus were treated with phenobarbital
therapy for periods of 4 to 72 months (mean 20.1 months). All 9 neurologically abnormal children were treated compared with only 12 (34%) of 35 neurologically normal children (P = .0001). The seizure recurrences in the neurologically abnormal group all occurred while they were still receiving phenobarbital. It should be noted that drug levels were not being monitored as part of this observa-tional study and the levels may well have been subtherapeutic. Three (25%) of the 12
neurologi-cally normal children who were treated had recur-rent febrile seizures while still receiving medica-tions compared with 8 (35%) of the 23 neurologi-cally normal children who were not prescribed medications after discharge (P = .55). One neuro-logically normal child was treated for 12 months without further seizures and experienced a brief febrile seizure after phenobarbital was discontin-ued.
DISCUSSION
The children in our series experienced a very low morbidity and no mortality. Residual brain damage following prolonged febrile seizures has been re-ported by several workers in pathological’3’14 and older clinical studies.’5”6 However, prospective pop-ulation-based studies of children with febrile sei-zures have shown low incidence of acquired mental retardation or neurological abnormalities.”7 In the NCPP, there were 431 children with febrile seizures who had a sibling without febrile seizures and in
whom IQ at age 7was measured in a sibling control study. There were no differences in the IQ scores between the children with febrile seizures and con-trol subjects. This held true even for the 27 children with seizures lasting longer than 30 minutes and the 14 children with febrile seizures lasting more than an hour.’7 We have previously reported a low incidence of neurological sequelae among children with prolonged seizures, including febrile, without an acute neurological or systemic insult.
The risk of further febrile seizures in our popu-lation was 41%, which is comparable with the risk of recurrent febrile seizures reported in other stud-ies.”2”8”9 This is not surprising as prolonged febrile seizures, while clearly associated with an increased risk of subsequent epilepsy, are not clearly associ-ated with an increased risk of further febrile sei-zures.’92’ Of interest is that the group with febrile
status epilepticus and an abnormal neurological
question will, we hope, be addressed by a large prospective study of all febrile seizures which is in
progress.
Of more interest is the risk of recurrent prolonged febrile convulsions. Though some controversy
per-sists as to whether prolonged febrile convulsions
cause brain damage, it is generally believed that brief febrile convulsions are benign and not asso-ciated with neurological sequelae.’4”8 The litera-ture presents conflicting data and does not directly address the issue of whether a prolonged febrile seizure is associated with an increased risk of a subsequent prolonged febrile seizure.’9 In the pres-ent study, the risk of recurrent febrile status epilep-ticus was low in the neurologically normal child but was significantly elevated in the neurologically ab-normal child. While some children have been lost to follow-up, almost all of them are now outside the age group where one would expect to see further episodes of febrile seizures and certainly of febrile
status epilepticus.
In this study, 20% of the children with febrile
status epilepticus were neurologically abnormal
prior to the episode of status. A high proportion of children with prior neurological abnormalities was also found in other series. In the Rochester, Mm-nesota, study, children with prior neurological ab-normalities accounted for 3.8% of all children with febrile seizures but 12% of children with atypical features.22 A proportion of children with prior neu-rological abnormalities is also found in studies of
status epilepticus from any etiology.7’8
The occurrence of a prolonged febrile seizure and an abnormal neurological status are both known
risk factors for subsequent afebrile seizures.”2’23 It
is therefore not surprising that 3 of 9 children with
both risk factors experienced afebrile seizures within a few years. However, none of the 35 neu-rologically normal children with febrile status epi-lepticus has had afebrile seizures. While the long-term risk (over decades) of developing epilepsy is presumably elevated in this group,”2’23 the short-term risks appear low. One recent study of febrile
status epilepticus reports a much higher rate of
subsequent afebrile seizures.24 Unfortunately, the
study has serious flaws. It is a retrospective chart
review of patients who are now active patients in an epilepsy clinic. In addition, they include children with prior afebrile seizure as well as children who were febrile in the context of meningitis or enceph-alitis. This makes their results difficult to interpret. This study also reports a high rate of prior neuro-logical abnormalities.
The most striking finding of this study was the
strength of the association between the presence of
neurological abnormalities and the risk of
subse-quent seizures in children with febrile status epilep-ticus. Seven of nine children with an abnormal neurological examination had subsequent seizures, including three with afebrile seizures and three with recurrent febrile status epilepticus. These recur-rences occurred despite the fact that all these chil-dren were treated with antiepileptic drug (AED) therapy, although their levels may have been sub-therapeutic. On the other hand, the incidence of subsequent seizures in the neurologically normal group, two thirds of whom were not receiving med-ications after discharge, was not substantially dif-ferent than one would expect in children with brief febrile seizures.”2”9’25 These findings would argue against prescribing maintenance AED therapy for neurologically normal children with an episode of febrile status epilepticus. Therapy with AEDs should be considered in neurologically abnormal children with febrile status epilepticus. This group constitutes a tiny fraction of the children with febrile seizures.5’23 Treatment decisions must, how-ever, take into account the morbidity of therapy. The two AEDs thought to be effective in preventing recurrent febrile seizures are phenobarbital and valproate.4’26 There is an increased incidence of adverse behavioral side effects from phenobarbital in this population.26 Recent data have also sug-gested a decrease in cognitive function in children prescribed phenobarbital and raised doubts about its efficacy in preventing febrile seizures.27 This is also the group (young and neurologically abnormal) with an increased risk of the idiosyncratic fatal hepatotoxicity from valproate.28
Rectal diazepam given at the onset of a febrile illness has been shown to reduce the risk of recur-rent febrile seizures.29 Rectal diazepam can also be used at home to terminate a seizure that has begun and does not stop quickly.3#{176}This should lower the risk of status epilepticus and has been used this way in Canada.3#{176}However, rectal diazepam is not approved by the Food and Drug Administration in the United States and is therefore not readily avail-able at the present time.
In summary, the morbidity and mortality of feb-rile status epilepticus are low. The risk of subse-quent episodes of status epilepticus or other sei-zures is significantly increased only in those chil-then who are neurologically abnormal prior to their episode of status. Decisions regarding treatment with AEDs need to consider the relative risk of further seizures and their morbidity against the potential side effects of AEDs in children.
ACKNOWLEDGMENTS
This work was supported, in part, by a Teacher
National Institute of Neurological Disorders and Stroke
(S. Shinnar) and a Merrit-Putnam Epilepsy Fellowship
from the Epilepsy Foundation of America (J. Maytal). We thank all of the fellows and faculty in the Division
of Pediatric Neurology. 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
provid-ing their acute medical care. We also acknowledge the
cooperation of the New York City Health and Hospitals
Corporation and Bronx Municipal Hospital Center and
North Central Bronx Hospital. The authors thank Dr Solomon Moshe for this advice and support throughout
this research and Dr Ann Berg for statistical
consulta-tion. Lisa Pistorino provided secretarial and computer
support.
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