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of Child Neurology

Complex Febrile Seizures: A Practical Guide to Evaluation and Treatment

Anup D. Patel and Jorge Vidaurre
J Child Neurol 2013 28: 762 originally published online 10 April 2013
DOI: 10.1177/0883073813483569

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Topical Review Article
Journal of Child Neurology
28(6) 762-767
Complex Febrile Seizures: A Practical The Author(s) 2013
Reprints and permission:
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Guide to Evaluation and Treatment DOI: 10.1177/0883073813483569
jcn.sagepub.com

Anup D. Patel, MD1 and Jorge Vidaurre, MD1

Abstract
Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children. A complex febrile seizure is one
with focal onset, one that occurs more than once during a febrile illness, or one that lasts more than 10 to 15 minutes. Confusion
still exists on the proper evaluation of a child presenting with a complex febrile seizure. There are ongoing research attempts to
determine the link between complex febrile seizures and epilepsy. Further clarification and understanding of this disorder would
be of great benefit to primary care providers and child neurologists.

Keywords
complex, febrile, seizure, epilepsy, mesial temporal sclerosis, antiepileptic

Received September 17, 2012. Received revised February 22, 2013 and February 25, 2013. Accepted for publication February 28, 2013.

A febrile seizure is defined as a seizure in association with a
febrile illness in the absence of a central nervous system
infection or acute electrolyte imbalance in children.1 Simple
febrile seizures are defined as generalized, lasting less than
10 minutes, and no recurrence within 24 hours or within the
same febrile illness1; a complex febrile seizure is one with focal
onset, one that occurs more than once during a febrile illness, or
one that lasts more than 10 minutes (Figure 1).2 Febrile seizures
are the most common type of childhood seizures, affecting 2%
to 5% of children.3 The age of onset occurs between 6 months
and 5 years.4 The peak incidence occurs at approximately 18
months of age.2 Febrile status epilepticus (seizures >30
minutes) represents about 25% of all episodes of childhood sta-
tus epilepticus and more than two thirds of cases at 2 years of
age.2 Subsequent febrile seizures can be prolonged if the initial
febrile seizure was prolonged.5
Complex febrile seizures are clearly a different subgroup.
They represent 20% to 30% of all febrile seizures, and there
is still little knowledge about their etiology or susceptibility
in different populations.5-7 In the National Collaborative Peri-
natal Project, 1706 children with febrile seizures were identi-
fied from a total of 54,000 and followed from birth until 7
years of age. The initial febrile seizure was defined as complex
in approximately 28%. Focal features were present in 4%, with
prolonged duration (>15 minutes) in 7.6% and recurrent
episodes within 24 hours in 16.2%.5,8 Children with multiple
seizures were at increased risk of experiencing complex febrile
seizures in the first 7 years of life, as compared with children
with only a single episode.9 Similar observations have been
reported by Berg and Shinnar.5 Of 136 children who had recur-
rences, 41.2% had 1 or more complex features. There was a
strong association between the occurrence of focal seizure
onset and prolonged seizure duration.5 The fact that a child
experienced a complex feature during the first febrile seizure
was an important predictor of subsequent epilepsy. The predic-
tors identified for the development of epilepsy in this study
were an abnormal neurological and developmental status of the
child before the seizure, a history of afebrile seizures in a parent
or older sibling, or complex features. Children with complex
febrile seizures already have a 5-fold increased risk of develop-
ing epilepsy.10,11 In contrast, 10% of children with 2 or more of
the previously mentioned risk factors (including complex
features) developed epilepsy, and 13% had seizures without
fever.11 Further, intractable epilepsy and neurological impair-
ment have been found to be more common in children with a
prior prolonged febrile seizure, with no association to any spe-
cific seizure type.10 Prospective studies have found that having
more than 1 complex feature of a febrile seizure (eg, prolonged
and focal) further increased the risk of developing subsequent
unprovoked seizures.12 One limitation of this study, as with
many others, is that no information about the eventual diag-
nosed epilepsy syndrome was provided.
1
Division of Child Neurology, Nationwide Childrens Hospital, Columbus,
OH, USA
Corresponding Author:
Anup D. Patel, MD, Division of Child Neurology, Nationwide Childrens
Hospital, 700 Childrens Drive, E533, Columbus, OH 43205.
Email: anup.patel@nationwidechildrens.org
Patel and Vidaurre
Figure 1. Recommended evaluation.
Pathophysiology
The mechanism by which fever provokes a febrile seizure
remains unclear. However, one theory studied in an animal
model suggests that a febrile seizure can be produced by a
temperature-induced change of susceptible, mutant surface
GABAA receptors.13 Other studies propose a link between
genetic and environmental factors, resulting in an inflamma-
tory process that influences neuronal excitement and predispos-
ing one to a febrile seizure.14 Further evaluation for the
mechanism of a febrile seizure is needed for a full under-
standing.
Genetics
Other genetic epilepsy syndromes have seizures associated
with fever and/or febrile seizures as part of the disease presen-
tation. Dravet syndrome was first described by Charlotte
Dravet in 1978 and commonly presents with seizures induced
by febrile illness. Since then, the disease characterization has
widened.15 A mutation in the a subunit of the sodium channel
(SCN1A) is felt to be associated with Dravet syndrome. Often,
children with Dravet syndrome present with a focal prolonged
febrile seizure that often reoccurs, affecting the same or other
side. Later, they develop myoclonic jerks and experience a
cognitive decline.15 These children develop seizures that are
refractory to treatment. Hattori et al16 determined that certain
predictable risk factors exist for these patients. In their study,
patients with an onset of febrile seizures at or before 7 months
of age, presenting with 5 or more seizures and having seizures
lasting longer than 10 minutes, were more likely to be diag-
nosed with Dravet syndrome and had an increased probability
of testing positive for a mutation within the SCN1A gene. They
also noted that hemiconvulsions, partial seizures, myoclonic
763
seizures, and seizures induced in hot water were highly predic-
tive of being diagnosed with Dravet syndrome.16
However, a mutation within this gene is also associated with
other patients presenting with febrile seizures. An example is
generalized epilepsy with febrile seizures plus. These patients
present with complex febrile seizures, which are often complex
and seen beyond 5 years of age, and develop afebrile seizures
later in childhood.17 These children have been reported to have
a variety of mutations including SCN1A, SCN1B, and
GABGR2, with the latter having an association with absence
seizures.
A newer proposed entity, referred to as febrile infection
related epilepsy syndrome, has been described. Within this
condition, previously normal children present with status epi-
lepticus after fever resolution that can be refractory to emergent
treatment with antiepileptic medications. Many children will
further develop medically refractory epilepsy and issues with
delayed learning.18 A recent article did not find any genetic
link for this epilepsy syndrome.19 Therefore, further delinea-
tion as to a possible cause of a genetic link is necessary for
further clarification of this devastating disorder.
Mesial Temporal Sclerosis
The association between febrile seizures and mesial temporal
sclerosis is still a matter of debate.20 Retrospective studies have
reported an association between prolonged or atypical febrile
seizures and intractable temporal lobe epilepsy; however,
epidemiological studies failed to show a causal relationship
between febrile seizures and temporal lobe epilepsy.20 This
suggests that febrile seizures are a marker of susceptibility to
seizures and future epilepsy (in some cases) rather than a direct
cause. It is clear that a minority of cases of mesial temporal
sclerosis or focal seizures is associated with prior febrile
764
Figure 2. (A) Prolonged T2 signal on the left hippocampus in a 1-year-
old girl with a history of prolonged febrile status. She had a 2-minute
generalized tonic-clonic seizure followed by unresponsiveness and eye
deviation to the right for 60 minutes. (B) Diffusion restriction of the
entire left hippocampus in the same patient.
seizures and that this subgroup of patients can have a better
surgical outcome.10,21
A prospective multicenter study of the consequences of pro-
longed febrile seizures in childhood (FEBSTAT) is providing
insight into children who present with febrile status epilepticus.
Recently, the group reported on magnetic resonance imaging
(MRI) abnormalities after febrile status epilepticus in children.
Journal of Child Neurology 28(6)
Specifically, it reported that an increased risk for MRI abnorm-
alities was seen in children presenting with febrile status epi-
lepticus when compared to children with simple febrile
seizures. Overall, 11.5% of patients with febrile status epilepti-
cus were found to have abnormalities within the hippocampus,
with the majority of abnormalities occurring in the right
hemisphere.22
Evaluation
Imaging
Patients with complex febrile seizures usually seek medical
attention23 and often receive acute neuroimaging mostly in the
form of cranial computed tomography, which is only needed if
one is considering obtaining a lumbar puncture or if a suspicion
for either a space-occupying lesion or herniation exists. How-
ever, the likelihood of discovering a lesion that necessitates
an alternative treatment with neuroimaging is so low that such
studies are unnecessary in most children with complex febrile
seizures.24 High-resolution brain MRI should be considered
on a routine basis for prolonged febrile seizures due to the pos-
sible association between prolonged febrile seizures and mesial
temporal sclerosis.25,26 The goal is to identify these patients
early and consider treatment with antiepileptic drugs if mesial
temporal sclerosis is present on imaging. In addition, earlier
identification of refractory patients who are candidates for
epilepsy surgery would be possible, potentially increasing the
yield for a favorable outcome.27
Neuroimaging has provided evidence that a hippocampal
injury can occasionally occur during prolonged and focal febrile
seizures in infants who otherwise appear normal. Hippocampal
edema and subsequent mesial temporal sclerosis have been
observed after prolonged and focal seizures (Figure 2). It is not
clear if focality and long duration are independent factors.29 An
association between the 2 factors has been found in previous
studies. A pre-existing lesion can increase the propensity for fur-
ther focal prolonged seizures and thus cause further hippocampal
damage. Hesdorffer and colleagues27 found MRI abnormalities
in 14.8% of children with complex febrile seizures, while only
11.4% of 159 children with simple febrile seizures had imaging
abnormalities; however, this was not statistically significant, and
overall, small numbers for each group were present in the study.
The MRI abnormalities were related to a specific subtype of
complex seizures: focal and prolonged. The most common
abnormalities observed were subcortical focal hyperintensity,
abnormal white matter signal, and focal cortical dysplasia. These
findings illustrate the possibility of a pre-existing lesion that pre-
disposes one to prolonged seizures. However, emergent imaging
was not likely to yield an abnormality in patients presenting to
the emergency department with complex febrile seizures or to
alter the emergent treatment course.28
Lumbar Puncture
The evaluation of the child with complex febrile seizures is
another aspect in the assessment of children who present to the
Patel and Vidaurre
emergency department with febrile seizures. The most impor-
tant part of the history and examination is to look for the source
of the fever and rule out the presence of a central nervous
system infection, as complex febrile seizures are much more
frequently associated with meningitis than simple febrile sei-
zures.30 The American Academy of Pediatrics recommended
that a lumbar puncture be strongly considered in infants
younger than 12 months of age after a first complex febrile sei-
zure since signs of meningitis can be absent in young children.
For infants aged 6 to 12 months who present with a seizure and
fever, a lumbar puncture can be considered if the child is defi-
cient in immunization status or when immunization status
cannot be determined because an increased risk of bacterial
meningitis exists. Further, a lumbar puncture is an option for
children who are pretreated with antibiotics (American Acad-
emy of Pediatrics paper). The guidelines jointly developed in
1990 by the Royal College of Physicians and the British Pae-
diatric Association concluded that indications for performing
a lumbar puncture were complex febrile seizures, signs of
meningismus, or a child who is unduly drowsy and irritable
or systematically ill. Few patients with complex febrile sei-
zures have acute bacterial meningitis without other clinical
signs or symptoms of meningitis.28
Electroencephalography (EEG)
Performing EEG within 24 hours of presentation can show gen-
eralized background slowing, which could make identifying
possible epileptiform abnormalities difficult.23 Generalized
slowing on EEG can be present up to 7 days after a child pre-
sents with febrile status epilepticus.31 If interictal epileptiform
abnormalities are present on routine sleep-deprived EEG, the
patient has a higher risk for developing seizures without fever
or epilepsy, with the febrile illness lowering the seizure thresh-
old.20,32 This situation would result in closer outpatient obser-
vation for these patients. As new syndromes that include febrile
seizures in their presentation are described, the role of EEG in
the evaluation of complex febrile seizures can be redefined.31
Treatment
Various antiepileptic agents can effectively prevent recurrent
simple febrile seizures, but the risks of these medications out-
weigh the likely benefits of treatment.2 Nonetheless, complica-
tions with prolonged and/or recurrent seizures can occur.
Treatment options can be stratified into 3 possible categories:
emergency rescue treatment for prolonged or a cluster of
febrile seizures, intermittent treatment at the time of illness,
and chronic daily use of medication.
Emergency Rescue Therapy
Treatment options for complex febrile seizures should include
the use of a rescue seizure medication when the febrile seizure
lasts longer than 5 minutes. The FEBSTAT study team has
shown that prolonged febrile seizures are unlikely to stop
765
spontaneously.22 Intravenous diazepam has been shown to be
effective in aborting seizures in most cases.2,33 Commercially
available rectal preparations of diazepam gel can be effective
in stopping an ongoing seizure when intravenous access is not
available and also can be provided for home use in patients
with a known recurrence of febrile status epilepticus.2 For older
children and adolescents, intranasal midazolam can be an
attractive efficacious option.34 In addition, midazolam can be
a less expensive option compared to commercially available
rectal diazepam. Families can be easily trained about its use
and administration.
Intermittent Therapy
In addition, the use of intermittent benzodiazepine at the onset
of febrile illness can also be considered a treatment option.
Using oral diazepam at the time of febrile illness has been
demonstrated to reduce the recurrence of febrile seizures.3,33,34
However, use of the treatment in this fashion can mask the
presenting symptoms of an underlying central nervous system
illness by complicating the evaluation of mental status. There-
fore, caution for similar use of this treatment option should be
taken prior to its recommendation.
Chronic Medication Use
When considering the use of a chronic antiepileptic medica-
tion, studies have demonstrated the effectiveness of phenobar-
bital, primidone, and valproic acid in preventing the recurrence
of simple febrile seizures; however, the side effects of each
medication outweighed the benefit.3,34 Therefore, prophylactic
antiepileptic drugs are not recommended for the treatment of
simple and most cases of complex febrile seizures. To our
knowledge, no studies of these medications have been per-
formed in preventing the recurrence of only complex febrile
seizures.
Carbamazepine and phenytoin are not effective in prevent-
ing recurrent febrile seizures.3,10 Therefore, these medications
should be avoided if considering treatment for complex febrile
seizures. These medications can also worsen seizures in certain
genetic syndromes with a febrile seizure association such as
seen in patients with Dravet syndrome.13 Although newer
antiepileptic agents can prove to be safer and more effective
in the treatment of recurrent or prolonged febrile seizures, these
medications have not yet been adequately studied in children
with recurrent or complex febrile seizures. In our experience,
levetiracetam7,9,20,35 can be an effective medication in prevent-
ing the reoccurrence of complex febrile seizures.
Further, studies have demonstrated that the use of antipyre-
tic medications such as ibuprofen or acetaminophen has not
been effective in preventing a febrile seizure from occurring
or reoccurring.3 Parental education of efficacy and side effect
profiles should be discussed in detail when considering any
treatment options for complex febrile seizures.36 It is important
to remember that the long-term prognosis in terms of develop-
ing epilepsy, neurological, and cognitive problems is not
766
influenced by the use of antiepileptic medications. Therefore,
the use of daily antiepileptic drugs for patients with simple or
complex febrile seizures is rarely recommended.37 Each case
is unique, and a thoughtful and thorough approach is needed
when discussing options with families of patients with complex
febrile seizures.
Conclusion
Patients with complex febrile seizures should be identified
separately from patients with simple febrile seizures. In regards
to the evaluation for these patients, one should consider per-
forming EEG if more than 1 complex feature is present.21,33
An EEG scan should be obtained in a patient presenting with
a complex febrile seizure with an abnormal neurological and
developmental status because the greatest risk of epilepsy
exists in this population.37 Emergent imaging is not necessary
for patients with complex febrile seizures.9,30 If a patient pre-
sents with focal complex febrile seizures and/or febrile status
epilepticus, one should consider performing brain MRI to eval-
uate for a structural abnormality as an explanation for the sei-
zure.22 Performing a lumbar puncture is often unnecessary for
patients with complex febrile seizures unless the patient is
older than 12 months of age or other signs of a central nervous
system infection exist or in patients who have not returned to a
baseline mental status (Figure 1).15,21 One can consider recom-
mending a lumbar puncture when giving telephone advice to an
inexperienced clinician who is evaluating the patient.
In regards to treatment, acute emergency rescue therapy
should be administered for children with prolonged febrile
seizures.21 Parents can be trained during the first visit to the
medical provider or emergency department. In addition,
patients with identified epileptic syndromes that include sei-
zures with febrile illness as in Dravet syndrome would require
the use of a daily chronic antiepileptic treatment.15
Acknowledgments
The authors thank Dr E. Steve Roach for his assistance and feedback
with this article.
Author Contributions
ADP contributed 65% of the writing, editing, and review of this
submission. JV contributed 35% of the writing, editing, and review
of this submission.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article:
Anup D. Patel, MD, discloses research grants from UCB Pharma and
Eisai and an educational grant and consulting fees from Cyberonics.
Jorge Vidaurre, MD, has nothing to disclose.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
Journal of Child Neurology 28(6)
Ethical Approval
As this is a review, permission from an institutional review board was
not necessary.
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