Indian J Pediatr (September 2014) 81(9):909916

DOI 10.1007/s12098-014-1532-2

REVIEW ARTICLE

Recent Advances in Febrile Seizures

Rekha Mittal

Received: 6 May 2014 / Accepted: 2 July 2014 / Published online: 8 August 2014
# Dr. K C Chaudhuri Foundation 2014

Abstract Febrile seizures are the most common seizures of

childhood. A family history of febrile seizures is common, and
the disorder is genetically heterogenous. While guidelines are
available for management of simple febrile seizures, the management of complex febrile seizures is individualised. After a
febrile seizure, it is important to rule out CNS infection and
the decision to perform a lumbar puncture should be based on
the clinical condition of the child. Neuroimaging and EEG are
not required immediately in workup for simple or complex
febrile seizures. Recurrence of febrile seizures may be managed at home by the parents with benzodiazepines. If the
recurrences are multiple or prolonged and parents are unable
to give home treatment, intermittent benzodiazepine prophylaxis may be given. Continuous antiepileptic prophylaxis may
be given only to the children where intermittent prophylaxis
has failed. Febrile seizures are also associated with increased
risk of epilepsy, but this cannot be prevented by any form of
treatment. There is also an increased risk of mesial temporal
sclerosis, but whether this is an effect or cause of febrile
seizures is as yet unclear. There is no increase in neurological
handicaps or mortality following febrile seizures.
Keywords Febrile seizures . Neurodiagnostic evaluation .
Recurrence . Epilepsy . Prophylaxis

Introduction
Febrile seizures (FS) are the most common seizure disorder of
childhood. After years of differing opinions regarding the
approach to the neurodiagnostic evaluation or the long- term
R. Mittal (*)
Department of Pediatric Neurology, Max Superspeciality Hospital,
Patparganj, Delhi 110 092, India
e-mail: drrekhamittal@rediffmail.com

management of these children, there appears to be emerging

consensus on some aspects of the problem.

Definition
The National Institute of Health (NIH) consensus statement
defines a FS 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 for the seizure [1]. This definition excludes
seizures with fever in children who have previously had
afebrile seizures. However the The International League
Against Epilepsy (ILAE) defines an FS as A seizure occurring in childhood after one month of age, associated with a
febrile illness not caused by an infection of the central nervous
system, without previous neonatal seizures or a previous
unprovoked seizure, and not meeting criteria for other acute
symptomatic seizures [2]. The two definitions differ only in
the age limits (three vs. one month respectively).
The drawbacks of the definitions are : (a) In the NIH
definition, the term event is very vague. A number of events
can occur during fever- rigors, delirium, syncopal seizures,
benign paroxysmal vertigo, breath holding spell. (b) The
degree of fever is not specified, but 3838.5 C is acceptable
to most. The degree of fever at the time of convulsion is often
unknown. In many children fever is often discovered after the
FS. There is no data to suggest that the rate of rise of temperature is more important than the degree of fever in precipitating a seizure. (c) The absence of intracranial infection or the
illness is unproven in some of the cases. Some acute febrile
encephalopathies with normal CSF may be indistinguishable
from severe FS with neurological sequelae. (d) The definition
does not exclude children with pre-existing neurological deficits or developmental delays. These children behave

910

differently from children who are neurologically normal and

have been excluded from many studies on febrile seizures.

Incidence
Two to four percent of all children below the age of five years
suffer from FS, but variations in incidence is reported in
various places [3]. Incidence of 10.3 % has been reported in
a study from South India [4]. The prevalence of FS in India
was found to be 2.27 per 1,000 population in a North Indian
study [5], while it was 3.285.71/1,000 in South India [6].

Age of First Attack

In 50% of children the first attack of FS occurs in the second
year of life, and in 90% before 3 y age [7].

Indian J Pediatr (September 2014) 81(9):909916

Genetics
Huge advances have been made in the study of genetics of FS.
Evidence suggests that the disorder is genetically complex,
and FS are an extremely heterogeneous group for which there
is no single mode of inheritance. Six susceptibility FS loci
named from FEB1 to FEB 6 have been identified on various
chromosomes. In some families with the syndrome of generalized epilepsy and febrile seizures plus (GEFS+), mutations
in the voltage-gated sodium channel -1, -2 and -1 subunit
genes (SCN1A, SCN2A and SCN1B) and the GABAA receptor
-2 subunit gene (GABRG2) have been identified [15], and it
is possible that FS may be a channelopathy [16]. The role of
cytokines, especially interleurkin 6 has also been reported
with the occurrence of the interleukin 6 gene -174 GG being
found to be significantly higher in children with a family
history of FS [17].
However, the causative gene has not been identified in
most patients with FS.

Sex
Some studies report higher rates in boys [8], but others find the
incidence equal in both sexes.

Family History
Approximately 2540% of children with FS have a family
history of FS [9]. The more the relatives are affected, the
greater the risk. If one parent has FS, the risk of FS in offspring
is 1025 %, one sibling leads to 10% risk and one parent plus
one sib gives rise to 50 % risk of FS [10].

Types of Infection in Which Febrile Seizures Can Occur

(Table 1)
Almost any infection which causes fever can cause FS. However since viral upper respiratory infections are the
commonest cause of fever in children in the susceptible age
group, FS occur most commonly in these infections [10].
DPT and MMR vaccines are associated with a higher risk
of FS, but there is no long- term morbidity following these
seizures as compared to children who have FS without vaccinations [18].

Pathophysiology

Types of Seizures in Febrile Seizures

FS occur at an age where seizure threshold is low, but the

exact pathophysiology is still largely unknown. FS requires a
genetic susceptibility to FS in addition to acute seizure triggering factors, but how exactly these seizures are provoked by
fever is not understood.
Respiratory alkalosis resulting from hyperventilation due
to fever may increase neuronal excitability, producing seizures
in susceptible children [11].
Another hypothesis is that cytokines may have a role in the
genesis of FS. Recent reports have suggested that plasma
Interleukin 1-B, Interleukin 1-RA and Interleukin 6 may be
involved in FS, but the results are conflicting. Some studies
have shown significantly higher levels of IL- 1B and IL -6 in
children who have FS as compared to those without FS [12,
13], but these results are not consistent [14].

FS are generalised tonic, clonic or tonic clonic seizures. They

are occasionally hypotonic, but never myoclonic. Myoclonic
jerks during fever, known as febrile myoclonus, are reported
and have mistakenly been diagnosed as febrile seizures, with
children being subjected to unnecessary neurodiagnostic evaluation. They have no associated neurological sequelae [19, 20].

Table 1 Types of infection in which febrile seizures can occur

Upper/lower respiratory infections
Otitis media
Urinary tract infections
Acute gastroenteritis: Shigellosis
Post vaccine: DPT, polio, measles, MMR

Indian J Pediatr (September 2014) 81(9):909916

If partial seizures occur they may be unilateral, and may be

followed by Todds paralysis, suggesting a focal origin of the
seizures [10].

Types of Febrile Seizures

Febrile seizures are of two types [21]:
Simple: < 15 min duration, no focal features suggestive of
focal origin of seizure, and only one attack in one febrile
episode of fever.
Complex: Focal features present, > 15 min duration,
more than one attack in one febrile episode.
Only around 20 % of first FS are complex; the rest are
simple [7, 21].

Management of Febrile Seizures

Despite their benign nature and prognosis, FS are extremely stressful for the families as well as the medical staff.
After many years of confusion regarding their immediate
and long term management, there appears to be a consensus on some aspects of management of simple FS
[2224]; however there are no well defined guidelines on
the management of complex FS, and management is
individualised [25].
Management of First Attack of Febrile Seizures
The management of the first attack of FS involves a 6 pronged
approach:
(a) Control seizure (b) Control fever (c) Rule out CNS
infection (d) Find and treat cause of fever (e) Subsequent
investigations (if required) (f) Counsel parents.
a) Control Seizure
In case a child is brought to hospital with continuing
seizures or status epilepticus, the first step is to control the
seizure. The management is as for any other acute seizure
as per hospital protocol, as well as measures like airway
management, respiratory and circulatory support, as required. Prolonged febrile seizures must be treated as status
epilepticus. However if the seizure has stopped spontaneously before arrival at the hospital, and only history of
febrile seizures is given, the child only needs to be observed, and no anticonvulsant medication is required.
Drugs used to control seizure are shown in Table 2.
b) Control Fever
Fever should be treated to comfort the child. If the
child has recovered from the post ictal phase, and is

911

conscious, but fever persists, antipyretics paracetamol/

ibuprofen may be given. Tepid sponging is often given,
but no data is available on its efficacy in preventing a
seizure from occurring again. The RCP/BPA Joint Working Group did not recommend physical methods such as
fanning, cold bathing and tepid sponging [24].
c) Rule out CNS Infection
Any CNS infection can present with fever and seizures. Since the signs and symptoms of meningitis may
not always be apparent in infants with meningitis, relying
on only the clinical features may result in missing out on
some of the cases of meningitis; hence it was felt for many
years that the younger children (less than 12 mo) with FS
should be subjected to a lumbar puncture (LP). The RCP/
BPA Joint Working Group [24] recommends a LP if there
are features of meningism, the seizure is a complex FS,
the child is drowsy, irritable or systemically ill, and if the
child is less than 18 mo age (probably) and definitely, if
the child is less than 12 mo of age. The Group considered
that ideally decision should be made by an experienced
doctor; if lumbar puncture is not performed, the child
should remain under observation and be reviewed after a
few hours. However, the indications of LP to rule out
CNS infection in children presenting with fever and seizures, have been the subject of debate over the last many
years. Recent reviews [26], suggest that the overall prevalence of meningitis in children presenting with fever with
seizures is low (ranging from 04%), and if the history
and physical examination are normal, it is extremely
unlikely that the child has meningitis, even in children
with complex FS [27]. A childs age, sex, degree of fever,
and results of routinely performed blood tests do not have
any diagnostic value in predicting meningitis. Thus, a
lumbar puncture following a FS is unnecessary and unjustified in an infant without other signs of meningitis. In
an apparently well child who subsequently deteriorates, a
previously normal lumbar puncture does not rule out
bacterial meningitis. Observation and regular review by
the nursing and medical staff in the first few hours after
the convulsion, especially for evidence of meningitis, is more likely to detect children with bacterial meningitis and obviates the need for a painful and invasive
procedure.
The issue of LP in at least simple FS in neurologically
normal children has been somewhat resolved by the
American Academy of Pediatrics (AAP) guidelines [23]
for management of children with simple FS (children with
complex FS, pre-existing neurological deficits and previous afebrile seizures are excluded). These indications for
LP in any child with fever and seizures are summarized in
Table 3. In all cases where the LP is not done, a period of
observation (812 h) is required to ensure that the child
has become neurologically normal.

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Indian J Pediatr (September 2014) 81(9):909916

Table 2 Drugs used for febrile seizures treatment and prevention of recurrence
Name of drug

Route

Dose

Diazepam

IV
*Rectal

0.20.4 mg/kg
FS termination
May be repeated after 5 min.
0.30.5 mg/kg/dose oral or
FS termination
parenteral preparation of DZP
0.30.5 mg/kg/dose oral or
Intermittent FS prophylaxis Given for 48 h at onset of fever as seizure risk is
parenteral preparation of DZP
high during the first 48 h of fever.

Oral

0.30.5 mg/kg 8 hrly for 48 h

Midazolam

Indication

*Buccal
0.2 mg/kg of the IV solution
*Intranasal 0.2 mg/kg of the IV solution

Remarks

Intermittent FS prophylaxis Given for 48 h at onset of fever as seizure risk is

high during the first 48 h of fever.

Clobazam

IV/IM
Oral

0.1 mg/kg
1 mg/kg, single dose/d

Valproate

Oral

35 mg/kg/d

Dripped into buccal area after turning head to one side.

It is dripped slowly into the nose. It is as effective
as IV DZP. No side effects have been reported.
FS termination
IM route can be used in case there is no IV access.
Intermittent FS prophylaxis Fewer side effects, lesser sedation than diazepam.
Prevents recurrences in 90 % cases.
Long term FS prophylaxis

1020 mg/kg/d

Long term FS prophylaxis

Phenobarbitone Oral

FS termination
FS termination

*Useful for prehospital management, or if no IV access

d) Find and Treat Cause of Fever

While managing the seizure, it is important to evaluate
the child for the cause of fever in every episode of FS, as
is done for any other febrile illness, and treat the underlying illness causing the fever.
e) Subsequent Investigations
EEG: 3545% patients with FS show paroxysmal
EEG abnormalities [28]. Children with complex FS are
more likely to have EEG abnormalities, and many practitioners order EEGs for children with complex FS. However, an EEG is not required for the diagnosis or management of FS, whether simple or complex, even when they
are recurrent [16, 23, 29]. It is also of limited use in
identifying a structural abnormality. Even in complex
FS, it is not clear whether an abnormal EEG can predict

future recurrences or epilepsy [30]. Thus an abnormal

EEG does not change the management of FS, and is
therefore not recommended as part of the assessment of
a child with febrile seizures. The author recommends an
EEG only if the child has an afebrile seizure on follow up.
Neuroimaging: Neuroimaging is not required for evaluating simple FS [23, 24]. Even for complex FS, CT scans
in the emergency department are not indicated, as very
few patients have been found to have intracranial pathology, in absence of other symptoms or signs [31, 32]. Later
neuroimaging with MRI may be done in:
&
&

Pre-existing or post ictal neurological abnormality.

Complex FS, especially if there is doubt about whether
they were actually FS.

Table 3 Indications for lumbar puncture in first febrile seizure

Complex
febrile seizure

Simple febrile seizure (Previously neurologically normal)

Definite LP

Simple febrile seizures (Previously

neurologically abnormal)

LP is an option

Any age: Definite LP* Any age : Features of meningitis Any age: Pretreatment with antibiotics**
Clinical judgement
or intracranial infection
Less than 12 mo :
Unimmunized with H. influenzae and S. pneumoniae,
or immunization status is not clear***
* May be omitted if the child has become neurologically normal at the time of reporting to the hospital
** The type of antibiotic, route, number of days and CSF penetration characteristics of the antibiotic given have not been specified and require further
studies for clarification on these issues
***In India, where children are often malnourished and unimmunized or with unknown immunization status, an LP would be recommended in most
children less than 12 mo of age presenting with FS

Indian J Pediatr (September 2014) 81(9):909916

f) Counseling of Parents
It is essential to explain the benign nature of the FS as
well as risks and prognosis of FS to the parents. Home
management of seizures must also be explained and demonstrated to the parents.

Hospitalization
After the first FS, a policy of hospitalizing a child if there are
any indications of lumbar puncture may be followed, as given
by the RCP/BPA Joint Working Group [24], as also any child
whose home is far away from the medical facility, and parents
seem unable to cope with the seizure at home should it recur.
In subsequent FS, admission is usually not necessary. Most
children require only observation till they are awake and alert.

Risks Following Febrile Seizures, and Approach

to Minimise Them
Risk of Recurrence
35% of all children will have recurrence after the first FS [33].
>50% of recurrences occur within 12 mo and >90% of recurrences occur within 24 mo of the first seizure [16]. Risk
factors for recurrences [16, 33] are given in Table 4. Recurrent
FS tend to be prolonged if the initial FS was prolonged.
Management of Recurrence
Since 65 % children do not have recurrences, it is extremely
important that parents should be explained and reassured
about the mostly benign nature of the illness, and taught home
management of febrile seizures, in case they recur.
Pre hospital management may be done by parents, paramedical staff or primary care physicians even before transportation to the hospital, if the seizure does not terminate within
5 min (Table 2). Rectal diazepam was used traditionally.
However, recent reports indicate the similar efficacy of intranasal or buccal midazolam, which is easier to give, and also
more acceptable to parents [34].

913

Prevention of Recurrence
Although FS are benign, under certain circumstances, FS
need to be prevented if possible, because the seizures cause
so much anxiety and worry in the parents.
a) Intermittent Prophylaxis in All Febrile Episodes
Antipyretics: Administration of antipyretics theoretically reduces the risk of febrile seizures; however this
has been refuted by controlled trials, and its efficacy in
preventing FS recurrence is doubtful. Antipyretics may,
however be given to reduce fever as in any other febrile
illness [22], and most practitioners continue to advise their
use, even without a prescription. Either paracetamol 15
mg/kg/dose 6 hourly or ibuprofen 5 mg/kg/dose 8 hourly
may be used [35].
Intermittent benzodiazepines prophylaxis: A number
of studies have shown the efficacy of benzodiazepines
in preventing FS if given in adequate doses for 23 d at
onset of fever; both diazepam and clobazam are effective,
and prevent recurrences in 8090 % of the cases [36, 37].
However clobazam has been found to have fewer side
effects and maybe preferred over diazepam [38, 39].
However, the doses used are high, may result in drowsiness and ataxia that might interfere with the carers and
doctors ability to detect a serious illness. Lower doses are
not effective [40].
Recent studies show that there is no difference in long
term outcome, whether intermittent prophylaxis is used or
early control of seizures is used; this therapy does not
decrease the incidence of later epilepsy in children with
febrile seizures [22, 26, 41, 42].
The decision to use intermittent benzodiazepine prophylaxis should be based on a number of factors (Fig. 1):
the balance between the potential benefits and risks, the
wishes and abilities of the childs parents, and the childs
frequency and pattern of febrile illnesses and type of FS.
Duration of prophylaxis is 2 y seizure free period or till 5 y
of age, whichever is earlier [35].
b) Continuous Prophylaxis
Phenobarbitone at a dose of 45 mg/kg/d was thought
to reduce the number of febrile recurrences. However,

Table 4 Risk factors for recurrent febrile seizures and epilepsy

Risk factors for recurrence of FS

Risk factors for epilepsy following FS

Age of onset<12 mo (most important factor in prediciting recurrences)

Complex FS *
Family history of FS in first degree relative
FS with a relatively low fever
FS with short duration between onset of fever and FS

Developmental or neurological abnormalities before first seizure

Complex FS
Family history of epilepsy in a first degree relative

*Small increase in risk of recurrence

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Indian J Pediatr (September 2014) 81(9):909916

Fig. 1 Practical management of

FS

First FS

No recurrences

No treatment

Control seizure
Control fever
Rule out CNS infection
Find and treat cause of fever
Subsequent investigations
Counsel parents & teach home management

Few recurrences
of simple/ complex FS

Prolonged multiple recurrences /

Several risk factors for recurrences present/
Age < l y
with
Difficulty in home seizure treatment
Medical centre not close by
Severe parental anxiety

Home mangement of
seizure
Intermittent benzodiazepine
Continued severe
recurrences
especially with :
Low temperature
at onset
Short duration of
fever before
seizure occurs

Continuous antiepileptic prophylaxis

phenobarbitone has a number of behavioral side effects,

intolerable behavior being reported in 9%21% of children taking the drug, besides lowering the IQ which
may persist. Sodium valproate has also been shown to
prevent febrile recurrences, and is probably more effective, but also has a risk of hepatotoxicity, and other side
effects. Phenytoin and carbamazepine are not useful,
and there are no reports yet on the usefulness of the
newer antiepielptic drugs in preventing febrile seizures.
Recent studies have cast doubt on the effectiveness
of anticonvulsants in preventing recurrences of febrile
seizures, and in view of the side effects, long term
continuous prophylaxis is no longer recommended for
preventing recurrences in simple FS [22, 40].
No guidelines are available as to which cases
must be given this form of treatment, if at all. It
can only be considered arbitrarily in the small subgroup of patients where multiple risk factors are
present and children have prolonged or very frequent FS in whom a trial of intermittent benzodiazepine has been ineffective (Fig. 1). Table 4 shows

the various drugs used for treatment and intermittent

and long term prophylaxis of FS.

Risk of Epilepsy
Overall risk of epilepsy following FS is 25 % (double that of
the general population of children) [43]; approximately 1319
% children who develop epilepsy have had previous febrile
seizures [44]. Risk factors for epilepsy are different from those
for recurrent febrile seizures [7] (Table 3). Risk of epilepsy
with no risk factors is only 0.9 %; with 2 or more risk factors it
is 2 % . However, if febrile seizures are prolonged, approximately 9.4 % of the children may develop epilepsy [7, 45].
It has been proven almost beyond doubt that no treatment neither continuous anticonvulsant nor intermittent benzodiazepines, is going to alter the risk of epilepsy, and prevent its
development at a later date. Hence, there is no justification for
use of any of these treatment modalities for reducing risk of
epilepsy, irrespective of the neurological status of the child, or
whether the child had simple or complex febrile seizures [16].

Indian J Pediatr (September 2014) 81(9):909916

915

Risk of Mesial Temporal Sclerosis

Summary

Risk of mesial temporal sclerosis (MTS) associated with FS

remains a controversial issue. Retrospective studies suggest
that there is a strong association between the development of
refractory temporal epilepsy/mesial temporal sclerosis and
complex FS (especially prolonged or focal) [46, 47]. However, prospective and controlled, population based studies do not
confirm this [48]. Even if there is an association between the
two, it remains unclear whether the prolonged FS were the
cause of MTS, or whether a pre-existing MTS predisposes the
child to have prolonged FS. However, current opinion postulates that there is an association between prolonged FS and
pre-existing lesions within the temporal lobe, and these later
facilitate the development of MTS.

Febrile seizures are the commonest seizures in childhood.

Majority of the seizures are simple febrile seizures, which
are benign and associated with only a slightly higher risk of
epilepsy as compared to the normal population. While many
aspects neurodiagnostic evaluation and the long term management are well defined in children with SFS, the management
of children with CFS is controversial and individualised.

Conflict of Interest None.

Source of Funding None.

Mental and Neurological Development

References

Mental and neurological development remains normal if they

were normal before onset of FS. No additional deficits or
neurocognitive decline have been reported after the onset of
FS [49, 50].

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Mortality
There is no increased risk or incidence of mortality in children
with FS, including febrile status epilepticus, and excluding
infections of the central nervous system [51]. This is clearly
very important and should be emphasized in discussions about
FS with families.

Genetic Syndrome of Generalised Epilepsy with Febrile

Seizures Plus (GEFS+)
Febrile seizures plus means febrile seizures continuing beyond the age 6 y, when typically the febrile seizures disappear
in most of the children. The syndrome was initially described
in 1997 [52]; detailed studies were conducted in a large family
with many affected members with febrile seizures, associated
with other seizure types. The syndrome may manifest with
just an isolated febrile seizure, which is the mildest manifestation, simple FS, febrile seizures plus, or seizures with other
associated afebrile seizures which could be myoclonic, atonic
or absence seizures. The most severe manifestations are the
Dravet syndrome and myoclonic astatic epilepsy, which are
associated with poorly controlled epilepsy and poor neurological outcome. Except for these two syndromes, the prognosis
is generally good and the febrile or afebrile seizures remit over
time [53]. The genetics of the syndrome have been briefly
discussed in the Family History and Genetics section.

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