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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 strong association between the occurrence of focal seizure
febrile illness in the absence of a central nervous system onset and prolonged seizure duration.5 The fact that a child
infection or acute electrolyte imbalance in children.1 Simple experienced a complex feature during the first febrile seizure
febrile seizures are defined as generalized, lasting less than was an important predictor of subsequent epilepsy. The predic-
10 minutes, and no recurrence within 24 hours or within the tors identified for the development of epilepsy in this study
same febrile illness1; a complex febrile seizure is one with focal were an abnormal neurological and developmental status of the
onset, one that occurs more than once during a febrile illness, or child before the seizure, a history of afebrile seizures in a parent
one that lasts more than 10 minutes (Figure 1).2 Febrile seizures or older sibling, or complex features. Children with complex
are the most common type of childhood seizures, affecting 2% febrile seizures already have a 5-fold increased risk of develop-
to 5% of children.3 The age of onset occurs between 6 months ing epilepsy.10,11 In contrast, 10% of children with 2 or more of
and 5 years.4 The peak incidence occurs at approximately 18 the previously mentioned risk factors (including complex
months of age.2 Febrile status epilepticus (seizures >30 features) developed epilepsy, and 13% had seizures without
minutes) represents about 25% of all episodes of childhood sta- fever.11 Further, intractable epilepsy and neurological impair-
tus epilepticus and more than two thirds of cases at 2 years of ment have been found to be more common in children with a
age.2 Subsequent febrile seizures can be prolonged if the initial prior prolonged febrile seizure, with no association to any spe-
febrile seizure was prolonged.5 cific seizure type.10 Prospective studies have found that having
Complex febrile seizures are clearly a different subgroup. more than 1 complex feature of a febrile seizure (eg, prolonged
They represent 20% to 30% of all febrile seizures, and there and focal) further increased the risk of developing subsequent
is still little knowledge about their etiology or susceptibility unprovoked seizures.12 One limitation of this study, as with
in different populations.5-7 In the National Collaborative Peri- many others, is that no information about the eventual diag-
natal Project, 1706 children with febrile seizures were identi- nosed epilepsy syndrome was provided.
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 1
Division of Child Neurology, Nationwide Children’s Hospital, Columbus,
seizures were at increased risk of experiencing complex febrile OH, USA
seizures in the first 7 years of life, as compared with children
Corresponding Author:
with only a single episode.9 Similar observations have been Anup D. Patel, MD, Division of Child Neurology, Nationwide Children’s
reported by Berg and Shinnar.5 Of 136 children who had recur- Hospital, 700 Children’s Drive, E533, Columbus, OH 43205.
rences, 41.2% had 1 or more complex features. There was a Email: anup.patel@nationwidechildrens.org
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Patel and Vidaurre 763
Pathophysiology seizures, and seizures induced in hot water were highly predic-
tive of being diagnosed with Dravet syndrome.16
The mechanism by which fever provokes a febrile seizure
However, a mutation within this gene is also associated with
remains unclear. However, one theory studied in an animal
other patients presenting with febrile seizures. An example is
model suggests that a febrile seizure can be produced by a
generalized epilepsy with febrile seizures plus. These patients
temperature-induced change of susceptible, mutant surface
present with complex febrile seizures, which are often complex
GABAA receptors.13 Other studies propose a link between
and seen beyond 5 years of age, and develop afebrile seizures
genetic and environmental factors, resulting in an inflamma-
later in childhood.17 These children have been reported to have
tory process that influences neuronal excitement and predispos-
a variety of mutations including SCN1A, SCN1B, and
ing one to a febrile seizure.14 Further evaluation for the
GABGR2, with the latter having an association with absence
mechanism of a febrile seizure is needed for a full under-
seizures.
standing.
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-
Genetics lepticus after fever resolution that can be refractory to emergent
treatment with antiepileptic medications. Many children will
Other genetic epilepsy syndromes have seizures associated
further develop medically refractory epilepsy and issues with
with fever and/or febrile seizures as part of the disease presen-
delayed learning.18 A recent article did not find any genetic
tation. Dravet syndrome was first described by Charlotte
link for this epilepsy syndrome.19 Therefore, further delinea-
Dravet in 1978 and commonly presents with seizures induced
tion as to a possible cause of a genetic link is necessary for
by febrile illness. Since then, the disease characterization has
further clarification of this devastating disorder.
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 Mesial Temporal Sclerosis
side. Later, they develop myoclonic jerks and experience a The association between febrile seizures and mesial temporal
cognitive decline.15 These children develop seizures that are sclerosis is still a matter of debate.20 Retrospective studies have
refractory to treatment. Hattori et al16 determined that certain reported an association between prolonged or atypical febrile
predictable risk factors exist for these patients. In their study, seizures and intractable temporal lobe epilepsy; however,
patients with an onset of febrile seizures at or before 7 months epidemiological studies failed to show a causal relationship
of age, presenting with 5 or more seizures and having seizures between febrile seizures and temporal lobe epilepsy.20 This
lasting longer than 10 minutes, were more likely to be diag- suggests that febrile seizures are a marker of susceptibility to
nosed with Dravet syndrome and had an increased probability seizures and future epilepsy (in some cases) rather than a direct
of testing positive for a mutation within the SCN1A gene. They cause. It is clear that a minority of cases of mesial temporal
also noted that hemiconvulsions, partial seizures, myoclonic sclerosis or focal seizures is associated with prior febrile
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764 Journal of Child Neurology 28(6)
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
Figure 2. (A) Prolonged T2 signal on the left hippocampus in a 1-year- complex seizures: focal and prolonged. The most common
old girl with a history of prolonged febrile status. She had a 2-minute abnormalities observed were subcortical focal hyperintensity,
generalized tonic-clonic seizure followed by unresponsiveness and eye
abnormal white matter signal, and focal cortical dysplasia. These
deviation to the right for 60 minutes. (B) Diffusion restriction of the
entire left hippocampus in the same patient. 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
seizures and that this subgroup of patients can have a better the emergency department with complex febrile seizures or to
surgical outcome.10,21 alter the emergent treatment course.28
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. Lumbar Puncture
Recently, the group reported on magnetic resonance imaging The evaluation of the child with complex febrile seizures is
(MRI) abnormalities after febrile status epilepticus in children. another aspect in the assessment of children who present to the
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Patel and Vidaurre 765
emergency department with febrile seizures. The most impor- spontaneously.22 Intravenous diazepam has been shown to be
tant part of the history and examination is to look for the source effective in aborting seizures in most cases.2,33 Commercially
of the fever and rule out the presence of a central nervous available rectal preparations of diazepam gel can be effective
system infection, as complex febrile seizures are much more in stopping an ongoing seizure when intravenous access is not
frequently associated with meningitis than simple febrile sei- available and also can be provided for home use in patients
zures.30 The American Academy of Pediatrics recommended with a known recurrence of febrile status epilepticus.2 For older
that a lumbar puncture be strongly considered in infants children and adolescents, intranasal midazolam can be an
younger than 12 months of age after a first complex febrile sei- attractive efficacious option.34 In addition, midazolam can be
zure since signs of meningitis can be absent in young children. a less expensive option compared to commercially available
For infants aged 6 to 12 months who present with a seizure and rectal diazepam. Families can be easily trained about its use
fever, a lumbar puncture can be considered if the child is defi- and administration.
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
Intermittent Therapy
children who are pretreated with antibiotics (American Acad- In addition, the use of intermittent benzodiazepine at the onset
emy of Pediatrics paper). The guidelines jointly developed in of febrile illness can also be considered a treatment option.
1990 by the Royal College of Physicians and the British Pae- Using oral diazepam at the time of febrile illness has been
diatric Association concluded that indications for performing demonstrated to reduce the recurrence of febrile seizures.3,33,34
a lumbar puncture were complex febrile seizures, signs of However, use of the treatment in this fashion can mask the
meningismus, or a child who is unduly drowsy and irritable presenting symptoms of an underlying central nervous system
or systematically ill. Few patients with complex febrile sei- illness by complicating the evaluation of mental status. There-
zures have acute bacterial meningitis without other clinical fore, caution for similar use of this treatment option should be
signs or symptoms of meningitis.28 taken prior to its recommendation.
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766 Journal of Child Neurology 28(6)
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Patel and Vidaurre 767
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