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Febrile Seizures: Evaluation and Treatment

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Febrile Seizures: Evaluation and Treatment
Anup D. Patel, MD, and M. Scott Perry, MD
Abstract
• Objective: To review the current understanding and
management of febrile seizures.
• Methods: Review of the literature.
• Results: Febrile seizures are a common manifestation
in early childhood and very often a benign occur-
rence. For simple febrile seizures, minimal evaluation
is necessary and treatment typically not warranted
beyond reassurance and education of caregivers. For
complex febrile seizures, additional evaluation in rare
cases may suggest an underlying seizure tendency,
though most follow a typical benign course of febrile
seizures. In some cases, as-needed benzodiazepines
used for prolonged or recurrent febrile seizures may
be of value. There are well described epilepsy syn-
dromes for which febrile seizures may be the initial
manifestation and it is paramount that providers rec-
ognize the signs and symptoms of these syndromes
in order to appropriately counsel families and initiate
treatment or referral when warranted.
• Conclusion: Providers caring for pediatric patients
should be aware of the clinical considerations in man-
aging patients with febrile seizures.
Key words: febrile seizure; Dravat syndrome; GEFS+; PCDH19;
FIRES; complex febrile seizure.
A
febrile seizure is defined as a seizure in associa-
tion with a febrile illness in the absence of a cen-
tral nervous system infection or acute electrolyte
imbalance in children older than 1 month of age without
prior afebrile seizures [1]. The mechanism by which
fever provokes a febrile seizure is unclear [2]. Febrile sei-
zures are the most common type of childhood seizures,
affecting 2% to 5% of children [1]. The age of onset is
between 6 months and 5 years [3]; peak incidence occurs
at about 18 months of age. Simple febrile seizures are
the most common type of febrile seizure. By definition,
they are generalized, last less than 10 minutes and only
occur once in a 24-hour time-period. A complex febrile
seizure is one with focal onset or one that occurs more
www.jcomjournal.com Vol. 24, No. 7 July 2017 JCOM 325
Case-based review
than once during a febrile illness, or lasts more than 10
minutes. Febrile status epilepticus, a subtype of complex
febrile seizures, represents about 25% of all episodes of
childhood status epilepticus. They account for more than
two-thirds of cases during the first 2 years of life.
The risk of reoccurrence after presenting with one
febrile seizure is approximately 30%, with the risk being
60% after 2 febrile seizures and 90% after 3 [4–6]. Some
families have an autosomal dominant inheritance pattern
with polygenic inheritance suspected for the majority of
patients presenting with febrile seizures.
Multiple chromosomes have been postulated to be
associated with genetic susceptibility for febrile seizures,
with siblings having a 25% increased risk and high con-
cordance noted in monozygotic twins [7]. The patho-
physiology for febrile seizures has been associated with a
genetic risk associated with the rate of temperature rise
with animal studies suggesting temperature regulation
of c-aminobutyric acid (GABA) a receptors [2]. Other
studies propose a link between genetic and environmental
factors resulting in an inflammatory process which influ-
ences neuronal excitement predisposing one to a febrile
seizure [8].
Debate exists between the relation of febrile seizures
and childhood vaccinations. Seizures are rare follow-
ing administration of childhood vaccines. Most seizures
following administration of vaccines are simple febrile
seizures [9]. Febrile seizures associated with vaccines are
more associated with underlying epilepsy. In a study of
patients with vaccine-related encephalopathy and febrile
status epilepticus, the majority of patients were found to
have Dravet syndrome; it was determined that the vaccine
may have triggered an earlier onset of the presentation for
Dravet in those predestined to develop this disease but did
not adversely impact ultimate outcome [10].
From the Nationwide Children’s Hospital, Columbus, OH
(Dr. Patel) and Cook Children’s Medical Center, Fort Worth,
TX (Dr. Perry).
 Febrile Seizures
In this article, we review simple and complex febrile
seizures with a focus on clinical management. Epilepsy syn-
dromes associated with febrile seizures are also discussed.
Cases are provided to highlight important clinical con-
siderations.
Case 1: Simple Febrile Seizure
A 9-month-old infant and his mother present
to the pediatrician. The mother notes that the
infant had an event of concern. She notes the infant had
stiffness in all 4 extremities followed by jerking that last-
ed 30 to 60 seconds. The infant was not responsive dur-
ing the event. He was sleepy afterward, but returned to
normal soon after the event ended. After, she noted that
the infant felt warm and she checked his temperature. He
had a fever of 101°F. The infant has normal development
and no other medical problems.
• What are management considerations for of febrile seizures. The seizure usually is the first noticed
simple febrile seizure?
A simple febrile seizure is the most common type of
febrile seizure. They are generalized, lasting less than 10
minutes and only occur once in a 24-hour period. There
is no increased risk of developing epilepsy or developmen-
tal delay for patients after the first simple febrile seizures
when compared to other children [5,6]. The diagnosis
is based on history provided and a physical examination
including evaluation of body temperature [11,12].
No routine laboratory tests are needed as a result of a
simple febrile seizure unless obtained to assist in identify-
ing the fever source [3,11]. Routine EEG testing is not
recommended for these patients [3,11]. Routine imaging
of the brain is also not needed [3,11]. Only if a patient
has signs of meningitis should a lumbar puncture be
performed [11]. The American Academy of Pediatrics
states that a lumbar puncture is strongly considered for
those younger than 12 months if they present with their
first complex febrile seizure as signs of meningitis may be
absent in young children. For infants 6 to 12 months of
age, a lumbar puncture can be considered when immuni-
zation status is deficient or unknown [13,14]. Also, a lum-
bar puncture is an option for children who are pretreated
with antibiotics [11]. For patients younger than 6 months,
data is lacking on the percentage of patients with bacterial
meningitis following a simple febrile seizure.
326 JCOM July 2017 Vol. 24, No. 7 www.jcomjournal.com
Daily preventative therapy with an anti-epilepsy medi-
cation is not necessary [3,11]. A review of several treat-
ment studies shows that some anti-epileptic medica-
tions are effective in preventing recurrent simple febrile
seizures. Studies have demonstrated the effectiveness of
phenobarbital, primidone, and valproic acid in prevent-
ing the recurrence of simple febrile seizures; however,
the side effects of each medication outweighed the ben-
efit [3]. Carbamazepine and phenytoin have not been
shown to be effective in preventing recurrent febrile
seizures [3].
For anxious caregivers with children having recurrent
febrile seizures, a daily medication or treating with an
abortive seizure medication at the time of a febrile illness
can be considered [3,5,6,15]. Treating with an abortive
medication may mask signs and symptoms of meningitis
making evaluation more challenging [16]. Evidence does
not support that using antipyretic medications such as
acetaminophen or ibuprofen will reduce the recurrence
symptom due to the rise of temperature being the cause
of the febrile seizure in an otherwise well child prior to
the seizure [11,17]. Damage to the brain and associated
structures is not found with patients presenting with
simple febrile seizures [5,6]. Education on all of these
principles is strongly recommended for caregiver reas-
surance.
Case 2: Complex Febrile Seizures
A 1-year-old child presents to the emergency
department. Mother was with the child and she
noticed stiffness followed by jerking of the left arm and
leg, which quickly became noted in both arms and legs.
The episode appeared to last for 15 minutes before EMS
arrived to the house. A medication was given to the child
by EMS that stopped the event. EMS noted the child had
a temperature of 101.5°F. The child was previously healthy
and has had normal development thus far.
• What is the epidemiology of complex febrile
seizure?
A complex febrile seizure is one with focal onset, or one
that occurs more than once during a febrile illness or lasts
more than 10 minutes. They are less common, represent-
ing only 20% to 30% of all febrile seizures [18–20]. In

The National Collaborative Perinatal Project (NCPP),
1706 children with febrile seizures were identified from
54,000 and were followed from birth until 7 years of age.
The initial febrile seizure was defined as complex in about
28%. For all febrile seizures, focal features were present
in 4%, prolonged duration (> 10 minutes) in 7.6%, and
recurrent episodes within 24 hours in 16.2% [21]. Similar
observations have been reported by Berg and Shinnar
[5,6]. Of 136 children who had recurrences, 41.2% had
one or more complex features and the strongest cor-
relate of having recurrent complex febrile seizure was
the number of recurrent seizures. They also found that
children with complex recurrences had other recurrences
that were not complex; however, complex features had a
tendency to recur. Further, a strong association between
focal onset and prolonged duration was found [5,6].
Previous studies established a correlation between com-
plex attacks, particularly prolonged ones and young age
(age < 1 year) [5,6]. Additionally, children with seizures
with a relatively low fever (< 102°F) were slightly more
likely to have a complex febrile seizure as the initial epi-
sode [5,6].
Children with febrile seizures are already at 4- to
5-fold increased risk for subsequent unprovoked seizures.
A history of febrile seizures has been found in 13% to
18% of children with new-onset epilepsy. In the NCPP
study, the predictors identified for the development of
epilepsy following febrile seizures were an abnormal
neurological and developmental status of the child
before the seizure, a history of afebrile seizures in a par-
ent or prior-born sibling, or complex features [21]. Ten
percent of children with 2 or more of the previously
mentioned risk factors (including complex features) de-
veloped epilepsy and 13% of them had seizures without
fever [20,22]. Further, intractable epilepsy and neu-
rological impair-ment have been found to be more
common in children with prior prolonged febrile sei-
zure, with no association to any specific seizure type
[18,23–25]. The association between febrile seizures
and mesial temporal sclerosis (MTS) is a commonly
debated topic. Retrospective studies have reported an
association between prolonged or atypical febrile sei-
zures and intractable temporal lobe epilepsy. Epide-
miological studies fail to show a causal relationship
between febrile seizures and temporal lobe epilepsy
[26]. 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
www.jcomjournal.com Vol. 24, No. 7 July 2017 JCOM 327
Case-based review
of cases of MTS or complex partial seizures are associated
with prior febrile seizures [20,22].
• What is the risk of intracranial pathology in
complex febrile seizure?
Patients with complex febrile seizures usually seek medi-
cal attention [27]. However, the risk of acute pathology
necessitating treatment changes based on neuroimaging
was found to be very low and likely not necessary in the
evaluation of complex febrile seizures during the acute
presentation [27]. Imaging with a high-resolution brain
MRI could be considered later on a routine basis for
prolonged febrile seizures due to the possible association
between prolonged febrile seizures and mesial temporal
sclerosis [19,28,29].
Neuroimaging has provided evidence that hippo-
campal injury can occasionally occur during prolonged
and focal febrile seizures in infants who otherwise
appear normal. It has been speculated that a pre-existing
abnormality increases the propensity to focal prolonged
seizures and further hippocampal damage. Hesdorffer
and colleagues [30] found definite abnormalities on
MRI in 14.8% of children with complex febrile seizures
and 11.4 % of simple febrile seizures among 159 children
with a first febrile seizure. However, MRI abnormalities
were related to a specific subtype of complex seizures:
focal and prolonged. The most common abnormalities
observed were subcortical focal hyperintensity, an abnor-
mal white matter signal, and focal cortical dysplasia.
• What are important aspects of the clinical
evaluation?
The evaluation and management of the child with
complex febrile seizures is debated as well. The most
important part in the history and examination is to look
for the source of the fever and rule out the presence of a
CNS infection, since complex febrile seizures are much
more frequently associated with meningitis than simple
febrile seizures [16]. The American Academy of Pediatrics
recommended that a lumbar puncture be strongly consid-
ered in infants younger than 12 months after a first febrile
 Febrile Seizures
seizure and should be considered in children between
12 and 18 months of age, since signs of meningitis may
be absent in young children [13]. If the threshold for a
lumbar puncture is low in infants with febrile seizures in
general, it should be even lower for children with com-
plex febrile episodes for all the factors mentioned above.
The guidelines developed in 1990 by the Royal College
of Physicians and the British Paediatric Association con-
cluded that indications for performing an lumbar puncture
were complex febrile seizure, signs of meningismus, or a
child who is unduly drowsy and irritable or systematically
ill [21].
Obtaining an EEG within 24 hours of presentation
may show generalized background slowing, which could
make identifying possible epileptiform abnormalities dif-
ficult [22]. Therefore, a routine sleep deprived EEG when
the child is back to baseline can be more useful in identi-
fying if epileptiform abnormalities are present. If epilepti-
form abnormalities are present on a routine sleep deprived
EEG, this may suggest the patient is at higher risk for
developing future epilepsy and the febrile illness lowered
the seizure threshold; however, it is unclear whether clini-
cal management would change as a result [31].
• What treatment options are available?
Complications with prolonged and/or recurrent seizures
can occur. Treatments options can be stratified into 3
possible categories: emergency rescue treatment for pro-
longed or a cluster of febrile seizures, intermittent treat-
ment at the time of illness, and chronic use of medica-
tion. Treatment options for complex febrile seizures may
include the use of a rescue seizure medication when the
febrile seizure is prolonged. Rectal preparations of diaz-
epam gel can be effective in stopping an ongoing seizure
and can be provided for home use in patients with known
recurrence of febrile status epilepticus [3]. For children
and adolescents where a rectal administration is not ideal,
intranasal versed can be utilized instead of rectal diaz-
epam. In addition, the use of an intermittent benzodiaz-
epine at the onset of febrile illness can also be considered
a treatment option. Using oral diazepam at the time of
a febrile illness has been demonstrated in reducing the
recurrence of febrile seizures [3]. Other studies have
shown similar results when using buccal midazolam [32].
No adequate studies have been performed using second-
328 JCOM July 2017 Vol. 24, No. 7 www.jcomjournal.com
or third-generation anti-epilepsy medications in the treat-
ment of recurrent of complex febrile seizures [3].
It is unclear whether benefit is present to using inter-
mittent benzodiazepine doses prior or during a febrile
illness for those prone for recurrent febrile seizures [33].
Physicians may consider this option in patients with fre-
quent recurrent seizures, when caregivers can identify the
fever before the seizure occurs.
Overall, parental education of efficacy and side effect
profiles should be discussed in detail when considering
any treatment options for complex febrile seizures [34].
It is important to remember that the long-term prognosis
in terms of developing epilepsy or neurological and cog-
nitive problems is not influenced by the use of antiepilep-
tic medications for recurrent febrile seizures [17]. Even in
the case of prolonged febrile seizures in otherwise neuro-
developmentally normal children, antiepileptics have not
been shown to cause damage to the brain [19].
Febrile Status Epilepticus
Febrile status epilepticus is a subtype of complex febrile
seizures and is defined as a febrile seizure lasting greater
than 30 minutes. Overall, febrile status epilepticus
accounts for approximately 5% of all presentations of
febrile seizures [35]. It represents about 25% of all epi-
sodes of childhood status epilepticus and more than two-
thirds of cases during the first 2 years of life. Literature
suggests that an increased risk for focal epilepsy exists
[36]. Children presenting with febrile status epilepticus
are more likely to have a family history of epilepsy and
a history of a previous neurological abnormality [22].
It is likely to reoccur if the first presentation was febrile
status epilepticus. However, increased risk for death or
developmental disability as a result of the seizure is not
seen [37].
The prospective multicenter study of the consequences
of prolonged febrile seizures in childhood (FEBSTAT)
has been conducted. The study reported that febrile status
epilepticus is usually focal (67% of episodes), occurs in very
young children (median age 1.3 years), and is frequently
the first febrile seizure [22]. In this study, the median
duration of the seizure was about 68 minutes and 24%
of children had an episode lasting more than 2 hours. In
87% of the events, seizures did not stop spontaneously and
benzodiazepines were needed. Focal features observed
were eye and head deviation, staring, and impaired con-
sciousness prior to the seizure and an asymmetric convul-
sion or Todd’s paresis.
 Case-based review

Table. Epilepsy Syndromes Frequently Associated with Seizures in the Setting of Fever

Dravet PCDH19-Associated
GEFS+ Syndrome Epilepsy HHE FIRES
Age at onset <1y <1y <1y <4y From childhood to
adulthood
Common Tonic-clonic, Hemiclonic, tonic- Focal seizures present- Hemiclonic pre- Focal seizures pre-
seizure types myoclonic, clonic, absence, ing in clusters, tonic, senting as status senting as status
absence, myoclonic, tonic, tonic-clonic epilepticus epilepticus
atonic, focal clonic
Status epilepticus Rare Common Rare Common Common
Family history Strong Rare Rare Rare Rare
Common None specific. Clobazam, valproate, No specific antiepileptic Benzodiazepines All antiepileptic
treatments Depends on fre- stiripentol. Avoid drugs known to be more 1st line. Multiple drugs can be tried;
quency of seizures. sodium-channel effective other antiepileptic often continuous
PRN benzodiaz- antiepileptic drugs. drugs can be infusions are needed.
epines common. used. Ketogenic diet
Prognosis Varies—most Moderate-severe Mild-moderate develop- Permanent hemi- Poor seizure control,
normal to mild developmental delays, mental delays. Remis- plegia in 80% developmental delays.
delays. Remission autism, ADHD. sion in 1/3 of patients. Mortality in 30%.
in many patients. Unlikely to remit.

Case 3: Epilepsy Syndromes Associated
with Febrile Seizures
A 1-year-old female presents for evaluation of
seizures that began at age 8 months. Seizures
are described as occurring in the setting of fever with
bilateral symmetric tonic clonic activity lasting durations
of less than 10 minutes on average, but at least 2 instances
of seizure lasting 20 minutes or more. The family notes
that seizures have occurred almost every time the child
has had a febrile illness and often cluster over several
days. They report at least 1 seizure that occurred in the
absence of fever. Development has been normal to date
and an EEG done by their primary provider was also
normal.
• What epilepsy syndromes are associated with
febrile seizures?
While febrile seizures represent a benign and infrequent
type of seizure in the majority of patients, rare circum-
stances exists for which febrile seizures represent the first
symptom of an epilepsy syndrome. The severity of these
syndromes can vary from milder phenotypes of Genetic
Epilepsy with Febrile Seizures Plus syndrome (GEFS+)
to the more devastating epileptic encephalopathy of
Dravet syndrome. Recognizing the early signs and symp-
toms of these disorders, particularly the more severe phe-
notypes, is essential to avoid misdiagnosis and misleading
reassurance. Likewise, early recognition of many of these
syndromes may alter the treatment paradigm which in
turn may impact outcome. The sections below provide
an overview of the most common epilepsy syndromes
for which febrile seizures are a central and often initial
symptom of the disorder (Table).
Genetic Epilepsy with Febrile Seizures Plus
GEFS+ was first described in 1997 following recognition
of a pattern of febrile seizures followed later by the devel-
opment of various epilepsy syndromes within the same
family [38]. As such, the syndrome is defined based on
the familial occurrence of febrile and afebrile seizures in
at least 2 family members and can have a wide range of
phenotypes. The most common presentation is of typical
febrile seizures which can persist beyond the typical upper
age limit of 6 years. Unprovoked generalized seizures of
multiple types (ie, myoclonic, absence, atonic) occur at a
later age, though focal seizures may also be present. The
presence of focal onset seizures led to the naming change
from “generalized” epilepsy with febrile seizures plus as
it was previously referred. Seizure frequency and sever-
ity may vary between family members, as can response
to treatment, making prognosis difficult to predict.

www.jcomjournal.com Vol. 24, No. 7 July 2017 JCOM 329

 Febrile Seizures
As even in typical febrile seizures a family history of febrile
seizure may be common, it may be difficult to diagnose
the syndrome after the initial febrile seizure. However,
if the family history is strong for a family member with
a GEFS+ phenotype, one can appropriately counsel the
family on the possibility that a similar course may evolve.
While the majority of GEFS+ patients have milder phe-
notypes, some more severe phenotypes can have cogni-
tive delays. Dravet syndrome falls within the spectrum
of GEFS+ and is a prime example of the phenotypic
continuum to more severe presentations in some patients.
The syndrome is believed to be inherited in an auto-
somal dominant fashion with incomplete penetrance.
Multiple genes have been implicated as a cause, though
only 11.5% of families with clinical GEFS+ may have
mutations [39]. SCN1A, encoding the α-subunit of
the voltage-gated sodium channel is most frequently
reported in GEFS+ families, yet is only found in 10%
[38]. When associated with GEFS+, SCN1A mutations
are more often missense type, whereas truncating and
nonsense mutations are more commonly encountered
in Dravet syndrome. Mutations in SCN1B encoding
the β1 subunit of the voltage-gated sodium channel has
also been reported [40]. Finally, the GABA(A) receptor
gamma 2 subunit GABRG2 has been found in <1% of
GEFS+ families [39]. The variability in causative genes
underscores the reasons for phenotype variability and it
is likely that other modifier genes are responsible for the
heterogeneity within GEFS+ families [41].
Dravet Syndrome
Dravet syndrome, often referred to as severe myoclonic
epilepsy of infancy, was first described in 1978 and
has since become one of the most recognized genetic
epilepsy syndromes [42]. The clinical presentation often
begins with seizures in the first year of life, frequently
in the setting of febrile illness. The initial seizures are
generalized or hemiclonic in the majority and are often
prolonged evolving to status epilepticus. Unlike typical
febrile seizures, one should suspect Dravet syndrome in
children that present with repetitive bouts of complex
febrile seizures or febrile status epilepticus, especially if
the associated seizure semiology is of hemiclonic type. In
addition, seizures in the setting of modest hyperthermia
(ie, hot baths) should raise suspicion for this condition.
Commonly EEG and MRI are normal in the first year of
life and psychomotor development remains normal until
typically the second year of life [43].
330 JCOM July 2017 Vol. 24, No. 7 www.jcomjournal.com
By the second year, other seizure types including
myoclonic, atypical absence, clonic, and tonic seizures
arise. The EEG frequently begins to show generalized
spike wave and polyspike wave discharges. Seizures con-
tinue occurring frequently during early childhood, often
resulting in status epilepticus. Cognitive development
begins to stagnate between the ages of 1 and 4 years
with emergence of autistic traits and hyperactivity [44].
Development may stabilize between the ages of 5 and
16 years, but fails to demonstrate much improvement
[44]. Higher frequency of seizures may correlate with
increase in cognitive impairment and behavior problems,
supporting the need for rapid diagnosis and appropriate
therapy [44].
Over the years, several cases of atypical or borderline
Dravet syndrome have been described, most highlight-
ing the absence of myoclonic seizures [45]. Others may
present with primarily clonic or tonic-clonic type seizures
only [46]. Despite these differences, all cases share a
similar drug resistance and cognitive delay and are cat-
egorized as Dravet syndrome.
In 2001, Claus et al discovered the genetic alteration
in SCN1A responsible for 70% of Dravet syndrome cases
[47]. The disorder is inherited in an autosomal dominant
fashion, though 40% to 80% of mutations resulting in
Dravet syndrome are de novo [48]. Mutations can be
present in other family members, as this syndrome is part
of the spectrum of GEFS+, though parental phenotypes
are often much less severe. Approximately 50% of muta-
tions resulting in Dravet syndrome are truncating, while
the other 50% are missense mutations involving splice
site or pore forming regions leading to loss of function
[49]. Finally, small and large chromosome rearrange-
ments make up 2% to 3% of cases [50]. Other genes re-
ported to result in Dravet syndrome include SCN1B and
GABRG2 mutations. In addition, PCDH19 can produce
a phenotype similar to Dravet syndrome in females and is
discussed in more detail below.
With the emergence of more rapid and cheaper forms
of genetic testing, molecular diagnosis can now be made
earlier in life before all the typical clinical features of Dra-
vet syndrome arise. As a result, one might hope to alter
treatment strategy and gear therapy towards the most
effective medications. While drug resistance is the norm
for the condition, certain drugs such as benzodiazepines,
valproate, and stiripentol may be most effective [43].
Topiramate and levetiracetam have been reported as effi-
cacious in small series, as has the ketogenic diet [51–55].

Varieties of medications which target sodium channels
are known to exacerbate seizures in Dravet syndrome and
should be avoided, including lamotrigine, carbamazepine,
oxcarbazepine, and phenytoin [56]. In addition to main-
tenance therapy, it is important to provide patients with a
rescue plan for acute seizures in an effort to avoid status
epilepticus. In addition, measures to avoid overheating
may provide additional benefit.
Case 3 Continued
After a careful history, the physician discovers
that the child also has frequent myoclonic sei-
zures described as brief jerks of the extremities or sud-
den forward falls. The family notes they have seen these
seizures more frequently since antiepileptic therapy was
started. The physician recognize that this child may have
Dravet syndrome and suspect her medication may be
resulting in aggravation of seizures.
The physician decides to discontinue the medication
suspected to aggravate the seizures and chooses to start
the child on clobazam. The physician also begins evalu-
ation for Dravet syndrome by sending directed SCN1A
genetic testing. The testing comes back negative for mu-
tations in the SCN1A gene.
• What other investigations would be warranted
now?
PCDH19
PCDH19 was first recognized as a cause of epilepsy and
mental retardation limited to females (EFMR), a syn-
drome characterized by onset of seizures in infancy or
early childhood with predominantly generalized type sei-
zures including tonic-clonic, absence, myoclonic, tonic,
and atonic [57]. Since that initial description, the pheno-
type associated with PCDH19 mutations has expanded
to include female patients with primarily focal epilepsy,
variable cognitive impairment, and commonly onset with
seizures in the setting of fever [58,59]. Typically seizures
begin around age 10 months presenting as a cluster of
focal seizures in the setting of fever, often followed by
a second cluster 6 months later [59]. Generalized sei-
zures occur in a small proportion of patients (9%) and
this feature, along with relatively fewer bouts of status
epilepticus and less frequent seizures (most monthly to
yearly frequency) can differentiate PCDH19 associated
www.jcomjournal.com Vol. 24, No. 7 July 2017 JCOM 331
Case-based review
epilepsy from Dravet syndrome [59]. Seizures tend to
improve with age and no particular antiepileptic drug
has been found especially efficacious in the syndrome.
Unlike Dravet syndrome, up to a third of patients with
this syndrome may ultimately become seizure-free [59].
Cognitive development is normal prior to seizure
onset in the majority of patients and most but not all
patients will develop some cognitive impairment ranging
from mild to severe [59]. It is the more severe patients
that most often have overlapping characteristics of Dravet
syndrome, thus PCDH19 mutations should be investi-
gated in female patients with Dravet phenotype yet nega-
tive SCN1A testing.
PCDH19 is a calcium-dependent adhesion protein
involved in neuronal circuit formation during develop-
ment and in the maintenance of normal synaptic circuits
in adulthood [60,61]. Disease causing mutations in
PCDH19 are primarily missense (48.5%) or frameshift,
nonsense, and splice-site mutations resulting in premature
termination codon [59]. Ninety percent of mutations are
de novo. When inherited, the disorder is X-linked and may
come from an unaffected father or a mother that is simi-
larly affected or not, suggesting variable clinical severity in
females and gender-related protections in males [59].
Case 3 Continued
Given the negative SCN1A testing, the physi-
cian chooses to pursue other genetic testing that
may explain the patient’s phenotype. A more extensive
“epilepsy gene panel” that includes 70 different genes
associated with epilepsy syndromes is ordered.
Hemiconvulsion-Hemiplegia Epilepsy
Syndrome
Hemiconvulsion-hemiplegia epilepsy syndrome (HHE)
is characterized by the occurrence of unilateral convul-
sive status epilepticus followed by transient or permanent
ipsilateral hemiplegia. The syndrome occurs in otherwise
healthy children often in the setting of nonspecific febrile
illness before the age of 4 years, with peak occurrence in
the first 2 years of life [62]. Seizures are characterized
by unilateral clonic activity with EEG demonstrating
rhythmic 2–3 Hz slow wave activity and spikes in the
hemisphere contralateral to the body involvement. MRI
frequently demonstrates diffusion changes congruent
with EEG findings, often in the perisylvian region. The
hemiplegia that remains following status epilepticus is
permanent in up to 80% of cases [63]. As hemiplegia
 Febrile Seizures
can occur following complex febrile seizures, it is recom-
mended a minimum duration of hemiplegia of 1 week
be used to differentiate HHE [64]. Status epilepticus is
persistent in this syndrome and can last for hours if un-
treated. Focal onset seizures will often continue to occur
in the patient even after the status has been aborted.
The etiology of HHE is variable with many cases idio-
pathic. Some cases are reported as symptomatic, as the
syndrome can present in the setting of other underlying
brain disorders such as Sturge-Weber and tuberous scle-
rosis complex. While some viruses have been proposed
as a cause, they are not found in the cerebral spinal fluid
of patients [65]. Treatment consists of rapid treatment
of status epilepticus with benzodiazepines as first-line
therapy, often followed by other intravenous antiepileptic
drugs as necessary.
Febrile Infection–Related Epilepsy Syndrome
Febrile infection–related epilepsy syndrome (FIRES) is
presented under several names in the literature including
idiopathic catastrophic epileptic encephalopathy [66],
devastating encephalopathy in school-age children [67],
new-onset refractory status epilepticus [68], as well as
fever-induced refractory epileptic encephalopathy syn-
drome [69] and fever-induced refractory epileptic en-
cephalopathy in school-age children [70]. All describe
rare catastrophic epilepsy presenting in otherwise healthy
children during or days following a febrile illness. While
febrile illness precedes the epilepsy in 96% of cases, up
to 50% of patients may not have fever at the time they
present [41,65]. While age of onset is typically in early
childhood, presentation in adulthood also occurs. Initial
seizures are often focal, presenting as forced lateral head
or eye deviation, oral or manual automatisms, and clonic
movements of the face and extremities. Seizures will
inevitably progress to status epilepticus with ictal onset
often multifocal predominating in the perisylvian regions
[41]. MRI is often normal at onset or shows only subtle
swelling of the mesial temporal structures. Over months,
MRI often shows T2-hyperintensity and atrophy of the
mesial temporal structures, though as many as 50% of
MRIs may remain normal [71].
The evaluation for cause in FIRES is often unreward-
ing. Inflammatory markers are typically absent from both
serum and CSF. CSF may show minimal pleocytosis with
negative oligoclonal bands and absence of common recep-
tor antibodies. Treatment is equally unrewarding with
patients typically failing conventional antiepileptic drugs
332 JCOM July 2017 Vol. 24, No. 7 www.jcomjournal.com
and continuous infusions titrated to burst suppression.
Immunomodulatory therapies are mostly ineffective as
well. The most useful therapy reported has been the
keto-genic diet with efficacy in up to 50% of patients
[72]. Recently, therapeutic hypothermia has also been
reported to be effective in 2 cases [73]. For the majority of
patients, therapy will remain ineffective and seizures will
continue for weeks to months with gradual resolution,
though seizures often continue intermittently following
the end of status epilepticus. Prognosis is poor for seizure
control and neurocognitive recovery with mortality of
30% reported [41].
Case 3 Conclusion
The epilepsy gene panel ordered returns with
the result of a disease-causing mutation in the
PCDH19 gene. The child is diagnosed with PCDH19-
associated epilepsy and is treated with phenobarbital. For
the first years of life, she presents on average once per
year with a cluster of seizures in the setting of febrile
illness which is often managed with short durations of
scheduled benzodiazepines. Seizures slow by age 6. She
has mild delays in speech and receives some accommoda-
tions through her school system. By age 10, she has been
seizure-free for several years. She is able to be weaned off
medications without recurrence of seizures.
Summary
Febrile seizures are a common manifestation in early
childhood and very often a benign occurrence. For
simple febrile seizures, minimal evaluation is necessary
and treatment typically not warranted beyond reassur-
ance and education of caregivers. For complex febrile
seizures, additional evaluation in rare cases may suggest
an underlying seizure tendency, though most follow a
typical benign course of febrile seizures. In some cases, as
needed benzodiazepines used for prolonged or recurrent
febrile seizures may be of value. There are well described
epilepsy syndromes for which febrile seizures may be the
initial manifestation and it is paramount that providers
recognize the signs and symptoms of these syndromes
in order to appropriately counsel families and initiate
treatment or referral when warranted. Providers should
have a high index of suspicion for these syndromes when
they encounter children that repeatedly present with
prolonged febrile seizures, clusters of febrile seizures,
or febrile seizures in addition to afebrile seizure events.
Early referral, diagnosis, and treatment has the potential

to alter outcome in some of these syndromes, thus the
importance of becoming familiar with these diagnoses.
Corresponding author: Anup D. Patel, MD, Nationwide
Children's Hospital, Columbus, OH 43205, anup.patel@
nationwidechildrens.org.
Financial disclosures: Dr. Patel disclosed that he has consulted
for GW Pharmaceuticals and Supernus and is on the Scientific
Advisory Board for UCB Pharma.
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