Review Article

Febrile Seizures
Ajay Gupta, MD
ABSTRACT
Purpose of Review: This article provides an update on the current understanding
and management of febrile seizures. Febrile seizures are one of the most common
age-related epileptic convulsions that lead to outpatient consultations, emergency
department visits, and hospital or intensive care admissions.
Recent Findings: The Consequences of Prolonged Febrile Seizures in Childhood
(FEBSTAT) study, an ongoing multicenter prospective longitudinal study, is providing
valuable insights into the subset of patients who develop febrile status epilepticus, the
most life-threatening type of febrile seizures with potential long-term consequences.
Mutations in voltage-gated ion channels and neurotransmitter receptor genes have
been shown to result in familial occurrence of febrile seizures and epilepsy. Acute
abortive treatment of febrile seizures using a commercially available rectal delivery kit
has gained widespread use by nonmedical caregivers as a first-line treatment at home.
Summary: Most febrile seizures are self-limiting episodes with low risk of injury,
death, and long-term neurologic consequences. Most fevers and infections that cause
febrile seizures are relatively benign and do not require extensive testing or procedures.
Long-term management requires thorough assessment and risk stratification to devise
a customized plan for each child, paying attention to the caregiver situation at home
and day care. Most important treatment efforts are directed at caregiver education
and, when appropriate, on effective use of abortive seizure treatment at home.

Address correspondence to
Dr Ajay Gupta, Cleveland
Clinic Lerner College of
Medicine, Cleveland Clinic
Foundation, 9500 Euclid
Avenue, Cleveland OH 44195,
Guptaa1@ccf.org.
Relationship Disclosure:
Dr Gupta has served on the
advisory board of Lundbeck
and has received research
support from the Tuberous
Sclerosis Alliance for the Natural
History Database Study.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Gupta discusses the
unlabeled/investigational use
of benzodiazepines for the
treatment of febrile seizures.
* 2016 American Academy
of Neurology.

Continuum (Minneap Minn) 2016;22(1):5159.

INTRODUCTION
Febrile seizures are one of the most
commonly encountered acute neurologic conditions in children. A consensus
development conference of the National
Institutes of Health (NIH) first formalized
the definition of a febrile seizure as an
event in infancy or childhood, usually
occurring between three months and
five years of age, associated with fever
but without evidence of intracranial
infection or defined cause.1 In 1993,
the International League Against Epilepsy (ILAE) proposed another definition
of a febrile seizure as a seizure occurring in childhood after age 1 month,
associated with a febrile illness not
caused by an infection of the central
nervous system (CNS), without previous neonatal seizures or a previous
unprovoked seizure, and not meeting
Continuum (Minneap Minn) 2016;22(1):5159

criteria for other acute symptomatic

seizures.2 While the two operational
definitions differ in the age range and
specifications of the exclusion criteria,
on a practical level both emphasize a thorough history, physical examination, and
judiciously selected laboratory tests to
rule out intracranial infection, trauma, and
metabolic causes (such as hypoglycemia,
hyponatremia, or dehydration) before
making a diagnosis of a febrile seizure.3
EPIDEMIOLOGY AND
TRIGGERING FACTORS
The incidence of febrile seizures in the
white population is reported to be 2%
to 5%.4 A few studies quote a higher
incidence of 8% to 10% in the Asian
population.5,6 The age range for febrile
seizures in the literature is perplexingly
variable and ranges from 1 month up
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51

Febrile Seizures
KEY POINTS

h The peak age for the

occurrence of febrile
seizures is 18 to
24 months, and the
majority of children with
febrile seizures continue
to have normal growth
and development.

h Mutations in
voltage-gated sodium
channel subunits and
GABA receptor gene
subunits explain family
history of febrile
seizures and epilepsy
in some patients.

52

to 8 years. A national cohort study

reported that 90% of children had their
first febrile seizure before the age of
3 years, with the peak age being 18 to
24 months.4,7 Only 6% of febrile seizures occur before 6 months of age
and 4% after 3 years of age, indicating
that the age of onset is a critical consideration in further evaluation of children
with febrile seizures. The majority of
children with febrile seizures have normal growth and development. Febrile
seizures show no clear sex predilection.
Most febrile seizures occur at or around
the onset of fever. The fever of febrile
seizures is commonly due to self-limiting
viral infections affecting ear, nose, and
throat or respiratory or gastrointestinal
systems, and the risk of CNS infection is
low.3,8 However, recent studies further
specify viral strains in children who
have prolonged febrile seizures or febrile status epilepticus. In the Consequences of Prolonged Febrile Seizures
in Childhood (FEBSTAT) study, febrile
status epilepticus was associated with
the presence of human herpesvirus
(HHV) 6B DNA and RNA in serum (but
not HHV-6A or HHV-7), suggesting acute
HHV-6B viremia. Overall, HHV infections were found in 30% of all patients
with febrile status epilepticus in the
FEBSTAT study, suggesting an HHV-6B
infection as a specific trigger of febrile
status epilepticus.9 Despite this new finding, routine use of viral studies cannot
be recommended in febrile seizures at
this time as they do not have direct
clinical or prognostic implications.
Genetics seem to play a major role in
febrile seizures. As many as 25% to 40%
of children with febrile seizures have a
family history of febrile seizures.10 Recently, a robust relationship has been
demonstrated between familial febrile
seizures and genetically determined
epilepsies. The most established is the
clinically defined syndrome of genetic
epilepsy with febrile seizures plus

(GEFS+). GEFS+ is reported to be caused

by mutations in the subunit genes
(SCN1A, SCN2A, and SCN1B) that compose the neuronal voltage-gated sodium
channel. The GEFS+ phenotype has
also been reported due to mutations
in the GABA-A receptor subunit gene
(GABRG2).11 These conditions may result in a clinical presentation of febrile
seizures, febrile seizures that persist
beyond early childhood, and even febrile seizures with coexisting epilepsy
(afebrile spontaneous seizures) of variable severity and seizure types. Dravet
syndrome is the most severe form of
voltage-gated sodium channelYrelated
epileptic encephalopathy, with febrile
seizures, febrile status epilepticus, the
development of intractable generalized
epilepsy, and severe cognitive impairment. Vast intrafamilial and interfamilial
variation exists in the clinical course of
genetic epilepsies, and genotypephenotype characterization is complex
and poorly understood. It is important
to keep in mind that the majority of
children with febrile seizures do not
have a family history of them, and genetic testing is not routinely warranted.
Other pathophysiologic triggering
factors, such as rate of rise of fever, peak
body temperature during the illness, vaccinations (mainly diphtheria-pertussistetanus and measles-mumps-rubella),
low birth weight and in utero growth
retardation, respiratory alkalosis, and
systemic release of proinflammatory cytokines have been reported. These triggers remain a matter of much debate
and are not helpful in directing clinical
management.12Y17
Febrile infectionYrelated epilepsy syndrome (FIRES) is controversial but touted
as a distinct entity and reported in the
literature. FIRES is a catastrophic epileptic encephalopathy that is clinically
characterized by recurrent febrile seizures and febrile status epilepticus in
the acute phase during infancy, followed

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February 2016

by intractable epilepsy and intellectual impairment. The etiopathogenesis

is unknown, and whether FIRES represents a unique disease is still a matter
of controversy.18
TYPES OF FEBRILE SEIZURES
Because most febrile seizures occur at
home and provoke acute caregiver anxiety, scant data exist on accurate symptomatology, duration, and the clinical
circumstances surrounding them. While,
on interview, the majority of caregivers
report a convulsive seizure, a history of
tonic body stiffening, apnealike episodes,
limpness with pallor or cyanotic hue, and
trembling (like shivering) with altered
awareness are not uncommon descriptions of febrile seizures, and sometimes
it remains undetermined whether the
event was indeed a seizure.
In an attempt to stratify the risk of
developing epilepsy in the future, febrile seizures are classified into two types:
simple febrile seizures and complex febrile seizures.19 Simple febrile seizures
are defined as solitary events during an
illness, usually in the form of nonfocal
convulsions of fewer than 15 minutes in
duration. Complex febrile seizures are
defined as events that do not meet the
criteria of simple febrile seizures, ie, more

than one event within 24 hours or the

same illness, a duration longer than
15 minutes, or focal symptomatology.
It is estimated that about 20% to 30%
of all febrile seizures may be complex
febrile seizures.12,20,21 Febrile status
epilepticus is a subset of complex febrile
seizures that is most severe and potentially life threatening.

KEY POINT

h Between 20% and 30%

of all febrile seizures
may be complex febrile
seizures, defined as
more than one seizure
within 24 hours or
the same illness, a
duration longer than
15 minutes, or
focal symptomatology.

DIAGNOSTIC WORKUP AND

ACUTE TREATMENT OF
FEBRILE SEIZURES
Prompt bedside history and examination are key to establishing the diagnosis, distinguishing complex from simple
febrile seizures, considering differential
diagnoses, and initiating acute treatment (Case 3-1).
Although rare, a child may still be
seizing or in febrile status epilepticus
when first seen. Prompt attention
should be given to airway, breathing,
and circulation, and IV anticonvulsant
agents should be administered. Acute
abortive treatment of prolonged febrile
seizures or frank febrile status epilepticus is no different from any other
status epilepticus. Caution is warranted
in children with a known diagnosis of sodium channelopathies (voltage-gated sodium channelYrelated epilepsies) where

Case 3-1
A 22-month-old boy was referred for an office consultation after a
recent emergency department visit. His mother witnessed whole-body
convulsions that lasted for 2 minutes during a fever of 38.9-C (102-F).
The child had a runny nose for 2 days before he had the fever, which
was later determined to be due to an ear infection. By the time the
child was transported to the emergency department, he had fully
recovered. With temperature control, he became cheerful again and
had good oral intake in the emergency department. His examination
raised no concerns. The childs history had no red flags, and he had
normal growth and development. He was fully immunized.
Comment. This child had a simple febrile seizure. His history is typical
for a febrile seizure that is most likely predicted to have a benign course.
No further tests are warranted. The mother should be educated and
counseled about this condition.

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53

Febrile Seizures
KEY POINT

h Brain imaging, EEG,

and blood testing are
indicated only
infrequently in selected
children with febrile
seizures, and their
widespread use should
be discouraged.

sodium channel blockers such as

fosphenytoin may be relatively contraindicated because of the potential for
worsening of seizures.
Gradually reducing high fever with
antipyretics and gentle measures is generally recommended. It is not known if
such measures impact the duration of
febrile seizures or the chance of recurrence of another febrile seizure.
Finding and treating the cause of
the fever presenting with febrile seizures is key. CNS infection and acute
metabolic/toxic derangement are the
two most important causes that must
be ruled out. A good history and physical
examination as well as rapid and full
postictal recovery in febrile seizures may
establish the often self-limiting nature
of febrile illness without the need for
further tests. Monitoring of vital signs
and close observation of neurologic status
following the febrile seizure are essential
in all children, and other laboratory tests,
including lumbar puncture (for CSF analysis), should be selectively considered
depending on each clinical scenario.
Until proven otherwise, any finding of
CSF pleocytosis, even without remarkable changes in glucose and protein,
should be considered as an evidence of

infection rather than a consequence of

febrile seizures or febrile status epilepticus. A 2012 study showed that even in
febrile status epilepticus, CSF pleocytosis is rarely a result of febrile status
epilepticus.22 The American Academy
of Pediatrics established guidelines for
lumbar CSF testing in children presenting
with febrile seizures (Table 3-1).3
Neuroimaging, brain CT or MRI, is
generally not indicated unless clinical
suspicion of an acute neurologic condition or a history of focal hemiconvulsions
suggesting a structural substrate exists.3,23
EEG is of limited use during febrile
seizures or in the postacute state. Up
to one-third of patients with febrile
seizures, whether simple or complex,
may show transient EEG abnormalities
during the postacute state; however,
EEG alone seldom dictates management of febrile seizures.24,25 EEG may
be justifiable in a subset of patients, as
shown by the FEBSTAT study, an ongoing multicenter prospective longitudinal
study on consequences of prolonged
febrile seizures.26 In this study, EEGs
were performed within 72 hours of febrile status epilepticus. Focal slowing or
attenuation on the EEG was highly associated with acute hippocampal injury

TABLE 3-1 Key Action Statements on the Indications of Lumbar Puncture a(Cerebrospinal Fluid
Examination) in a Child Who Presents With Seizure and Fever
In Any Child Who Presents With a Seizure and Fever,
a Lumbar Puncture:
1a: Should be performed if the child has meningeal signs and symptoms
or history or examination raises a possibility of meningitis or
intracranial infection

B (Overwhelming evidence
from observational studies)

1b: Is an option in an infant 6Y12 months of age when the child is considered
deficient in Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae
immunizations or when immunization status cannot be determined

D (Expert opinion, case reports)

1c: Is an option when the child has been pretreated with antibiotics,
because antibiotic treatment can mask the signs and symptoms
of meningitis

D (Reasoning from clinical

experience, case series)

54

Level of Evidence

Data from Subcommittee on Febrile Seizures; American Academy of Pediatrics, Pediatrics.3

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February 2016

on the brain MRI. The study concluded

that EEG may be a sensitive, reliable,
and noninvasive marker of acute injury
associated with febrile status epilepticus and, hence, a potential marker for
long-term consequences after febrile
status epilepticus.26
POSTACUTE MANAGEMENT,
RISK ASSESSMENT, AND
COUNSELING
Caregivers of children with febrile seizures often express a sense of anxiety
after witnessing a seizure at home. Statements such as I felt as if my child were
dying and I felt powerless to help my
child are commonly used to express
parental concern. Experience tells us that
the caregivers often confuse terms such
as febrile seizures and epilepsy. It is important that physicians clearly differentiate febrile seizures from epilepsy while
discussing treatment goals during counseling. Parents of children with febrile seizures usually ask four questions, which
are answered consecutively in the sections that follow:
& Can this occur again?
& Is this epilepsy or will it become
epilepsy?
& Does this cause brain damage?
& What can I do to stop it next time?
RISK OF RECURRENCE OF
FEBRILE SEIZURES
A second febrile seizure is likely to
occur in about one-third of patients. A
third febrile seizure is reported in about
half of the patients who had a second
febrile seizure, ie, only 15% of the entire febrile seizure cohort will have three
febrile seizures. More than three febrile
seizures are rare and seen in less than 5%
of the febrile seizure cohort.21,27Y29
Age at the time of the first febrile
seizure is cited as the most important
risk factor for recurrence. The younger
the age at the time of the first febrile
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seizure, the higher the risk of febrile

seizure recurrence. One study showed
febrile seizure recurrence in 50% of
patients who were younger than 1 year
of age at the time of the first febrile
seizure. In comparison, only 20% had
febrile seizure recurrence when the
age at the time of the first febrile seizure
was older than 3 years.30 Other risk factors identified in various studies include
history of febrile seizure in first-degree
relatives, relatively low-grade fever during the febrile seizure, and occurrence
of the febrile seizure at the inception
(sometimes before recognition) of
fever/illness.21,28Y30 Ironically, whether
the first febrile seizure was simple or
complex did not seem to affect the
febrile seizure recurrence risk, nor did
the duration of the first febrile seizure.31
However, subsequent febrile seizures
can be prolonged if the initial seizure
was prolonged.32
RISK OF EPILEPSY
The risk of developing unprovoked seizures after a febrile seizure is estimated
to be 2% to 5%.33 This risk is approximately 2 to 3 times the risk of epilepsy
in the general population; however, it
is still low enough to warrant judicious
evaluation in only a few selected children who are at high risk. The most
important predictive risk factors for the
development of epilepsy are developmental delay or an abnormal neurologic examination before the onset of
the febrile seizure, a history of complex
febrile seizures (including febrile status
epilepticus), and a first-degree relative
with epilepsy (Case 3-2). Prolonged febrile
seizures and febrile status epilepticus
are increasingly being recognized as
potential risk factors for epilepsy.19,34Y36
Mechanisms for the development of
epilepsy after a febrile seizure are unclear;
however, these risk factors could possibly
suggest a preexisting congenital, perinatal, or metabolic-genetic vulnerability to

KEY POINTS

h Caregivers often
confuse febrile seizures
with epilepsy. It is
important that
physicians clearly
differentiate between the
two while counseling.

h Age at the time of the

first febrile seizure is
cited as the most
important risk factor for
recurrence of a febrile
seizure. The younger
the age at the time of
the first febrile
seizure, the higher the
risk of recurrence.

h Less than 5% of
children with
febrile seizures will
develop epilepsy.

h Risk factors for

epilepsy in a child with
a febrile seizure are
developmental delay or
abnormal neurologic
examination, complex
febrile seizures, and a
first-degree relative
with epilepsy.

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55

Febrile Seizures

Case 3-2
A 7-month-old infant was referred for consultation 2 weeks after she was
discharged from a hospital. She was admitted for a prolonged convulsive
seizure. Her parents were unaware of the fever or illness until after the
convulsion. The seizure apparently lasted 35 minutes and only stopped
after administration of IV lorazepam in the emergency department. Later,
a fever of 37.8-C (100-F) was noted, and a viral upper respiratory infection
was diagnosed. Blood biochemistry was normal. On further questioning,
the parents reported she had a history of previous febrile seizures at the
age of 3 months and 5 months that were 15 to 20 minutes in duration but
stopped before arriving at the emergency department. The infant was fully
immunized. Concerns regarding hypotonia and delayed motor milestones
were previously noted and confirmed at this office visit. On examination,
truncal ataxia and a few body jerks suggestive of myoclonia were noted.
Comment. This child had complex febrile seizures. In fact, the last episode
was febrile status epilepticus, the most severe form of febrile seizure. She
had many red flags, including early age of onset, the duration of seizures,
low fever or lack of documented fever at the onset of seizures, delayed
development, and abnormal neurologic examination. Her clinical scenario is
consistent with a possibility of an epileptic encephalopathy, such as Dravet
syndrome or other genetic epilepsy. Counseling may be difficult in such
situations when the family is expecting a benign diagnosis of febrile seizures.
Further diagnostic workup, such as EEG and genetic testing, is warranted
to confirm the diagnosis. This child is likely a candidate for initiation of
appropriate long-term anticonvulsant treatment. Also, she is at risk for future
prolonged convulsions, and it is prudent to devise a rescue plan, including
a prompt call to emergency medical services. Longitudinal follow-up is
critical in this child.

seizures that manifests with the second

hit of fever/illness followed by enduring
epilepsy. In a prospective FEBSTAT MRI
study of children presenting with acute
febrile status epilepticus, acute hippocampal injury due to febrile status
epilepticus was commonly seen. It was
found that children with febrile status
epilepticus (defined as a seizure duration longer than 30 minutes) and acute
hippocampal injury commonly had congenital hippocampal malformations/
malrotations that could contribute to
the development of febrile status
epilepticus.34 Long-term follow-up of
the febrile status epilepticus cohort is
ongoing to understand the possible
development of hippocampal sclerosis and mesial temporal lobe epilepsy

56

in these patients. There has been a longstanding observation of the association

of febrile status epilepticus, hippocampal sclerosis, and mesial temporal lobe
epilepsy37; however, the cause-andeffect relationship is yet to be confirmed
and may perhaps be more complex than
previously hypothesized.
While confirming the risk factors discussed above, a 2013 study also identified two other risk factors in multivariate
analyses: the occurrence of four or more
febrile seizures in a child and late age
of febrile seizure onset (older than
3 years).38 This finding may need be
replicated in other larger studies. However, as discussed earlier, it makes sense
as less than 5% of children with febrile
seizures will have more than four seizures

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February 2016

or have their first febrile seizure after

the age of 3 years.
RISK OF FEBRILE STATUS
EPILEPTICUS
Only a small number of patients with
febrile seizures present with febrile
status epilepticus either as the first or
subsequent seizure episode. In a casecontrol study that compared children
with a first febrile seizure, febrile status
epilepticus was associated with younger
age, lower body temperature, longer duration of unrecognized fever before febrile
seizure, female sex, documented structural temporal lobe abnormalities on a
previous brain MRI, and a first-degree
relative with febrile seizures. When such
risk factors exist alone or in combination, it may be prudent to develop an
acute seizure intervention at home, followed by initiating an emergency medical services call for early and effective
treatment of potential febrile status epilepticus. Delayed treatment and the development of febrile status epilepticus
in a child is a risk factor for acute brain
injury, the development of epilepsy, and
long-term neurocognitive disability.31
RISK OF INTELLECTUAL DISABILITY
Longitudinal studies suggest that the
risk of developmental, behavioral, and
academic disability in children with febrile seizures is no greater than in the
general population.21,39Y41 This information should be emphasized when
developing an individualized plan for
each child. However, one should keep
in mind that a subset of children with
prolonged febrile seizures or febrile
status epilepticus could develop longterm neurologic consequences.31
TREATMENT OF FEBRILE SEIZURES
Antipyretic medications and measures
remain controversial in preventing
febrile seizures, but they are generally
recommended to caregivers at home
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as soon as fever is recognized to help

comfort the child. Prompt attention to
diagnose the cause of the fever is essential. A few studies have reported benefit from intermittent benzodiazepines
during fever for preventing febrile seizures and reducing emergency department visits and hospital admissions. A
2- to 3-day course of oral diazepam or
clobazam was used successfully to prevent recurrences.42,43 Such use of benzodiazepines in children is not approved
by the US Food and Drug Administration
(FDA). In addition, benzodiazepines can
cause sedation, can interfere with hydration and feeding, and may delay the
recognition of a serious illness.
Rectal diazepam is available in the
United States as an acute abortive treatment of an ongoing seizure and has been
successfully used in febrile seizures. Caregivers should be educated in the timing
and technique of administering the medication as well as close monitoring after
its use. Using rectal diazepam at home is
an attractive option in the hands of savvy
caregivers but may provide a false sense
of security. Caregivers should be cautioned that if the convulsion continues
after rectal diazepam (total duration
longer than 5 minutes) or sensorium
does not recover, emergency medical
services should be immediately contacted for treatment of potential febrile status epilepticus. A 2014 study
concluded that once established, febrile
status epilepticus rarely stops spontaneously, and it is fairly resistant to antiepileptic medications. Earlier onset of
effective treatment results in shorter
total seizure duration. In this study, even
the subjects who received medication
prior to emergency department arrival
seized for a median of 81 minutes. Unfortunately, 19% of them had suboptimal
dosing of benzodiazepines before arrival
to the emergency department. Therefore,
it may be prudent to suggest administration of rectal diazepam at the onset of

KEY POINTS

h The risk of developmental,

behavioral, and
academic disability in
children with febrile
seizures is no greater
than in the
general population.

h Febrile status
epilepticus is the most
severe and potentially
life-threatening form of
febrile seizures, with
long-term consequences;
it must be emergently
treated just as any other
status epilepticus.

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57

Febrile Seizures
KEY POINT

h Long-term daily
anticonvulsants are not
usually indicated
in children with
febrile seizures.

febrile seizures in children who are at

risk of febrile status epilepticus.44
No justification exists for the use of
daily anticonvulsant medications. Phenobarbital and valproate are touted
to successfully reduce the recurrence
of febrile seizures; however, they may
not reduce the ultimate risk of developing epilepsy. Long-term treatment with
daily anticonvulsants may be justifiable
only in a small subset of children with
complex febrile seizures and febrile status
epilepticus with multiple risk factors
that portend a high risk of epilepsy.
No guidelines exist for initiation of daily
anticonvulsants in febrile seizures, and
it remains a matter of clinical judgment.7
A customized febrile seizure action plan,
surveillance on febrile seizure recurrences,
and monitoring physical and developmental behavioral milestones are critical in
the management of febrile seizures.
CONCLUSION
Febrile seizures are a common neurologic emergency in children. It is important to recognize this condition and
offer a customized evidence-based plan
of care to each family. The majority of
children can be managed by application
of the essential clinical principles outlined
in this article.
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