Infantile Childhood, and Adolescent Epilepsies

Review Article
Infantile, Childhood, and

Address correspondence to
Dr Elaine Wirrell, Mayo Clinic,
200 1st St SW, Rochester,
MN 55905, wirrell.elaine@
mayo.edu.
Relationship Disclosure:
Dr Wirrell receives royalties
Adolescent Epilepsies
from UpToDate, Inc, and Elaine Wirrell, MD
research support from the
American Epilepsy Society
Infrastructure Award and the
Dravet Syndrome Foundation. ABSTRACT
Unlabeled Use of
Product/Investigational
Purpose of Review: Infantile, childhood, and adolescent epilepsies comprise a
Use Disclosure: diverse group of entities. Careful characterization of epilepsy into a specific electro-
Dr Wirrell reports no disclosure. clinical syndrome or etiology assists greatly in understanding both the natural history of
* 2016 American Academy the seizure disorder (pharmacoresistant versus pharmacoresponsive and self-limited
of Neurology.
versus lifelong) and the best therapeutic options for the child.
Recent Findings: Tremendous growth has been seen in the understanding of both
genetic factors predisposing to epilepsy and neuroimaging techniques. Additionally,
a number of studies have focused on the efficacy of certain therapies in specific
syndromes or etiologies.
Summary: This article reviews both common epilepsy syndromes (including benign
focal epilepsy of childhood, absence epilepsy, and juvenile myoclonic epilepsy) and
the rarer syndromes with associated management implications (eg, Dravet syndrome,
progressive myoclonic epilepsy, and mitochondrial disorders) and addresses genetic
and metabolic investigations.
Continuum (Minneap Minn) 2016;22(1):60–93.
INTRODUCTION many children have a specific elec-

Epilepsy is one of the most common troclinical syndrome, defined as “a
neurologic disorders of childhood, with complex of signs and symptoms that
an estimated incidence of 40 to 50 per define a unique epileptic condition.”3
100,000 persons per year.1 The inci- Such syndromes denote specific clinical
dence is highest in the first year of life, seizure types, EEG findings, characteris-
becoming lower in later childhood and tic clinical features (eg, age at onset and
adolescence. Approximately 20% to associated neurologic and psychological
25% of cases are pharmacoresistant, findings), and underlying pathophysio-
resulting not only in disabling seizures logic or genetic mechanisms. Identify-
but also profound consequences on ing the underlying cause of epilepsy or
cognitive development, behavior, emo- specific electroclinical syndrome is crit-
tional well-being, and quality of life. ical to understanding its natural history
Additionally, children with pharma- and best treatment options.
coresistant seizures are at greater risk This article highlights the clinical
of injury and death due to accidents, characteristics, appropriate neuroim-
status epilepticus, and sudden unex- aging, genetic and metabolic evalua-
pected death in epilepsy (SUDEP). tions, and management of the most
The impact of pharmacoresistant epi- common syndromes as well as the less
lepsy on development appears most common syndromes that have associ-
severe in early life.2 ated management implications. Epi-
Epilepsy in children is due to a lepsies are organized based on the
diverse group of etiologies. Additionally, usual ages at presentation.
60 www.ContinuumJournal.com February 2016
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

KEY POINTS
INFANTILE-ONSET EPILEPSIES in all infants who do not have a clear h Pediatric epilepsy is
The following epilepsy syndromes etiology. As cortical dysplasia may be pharmacoresistant 20%
begin in the first 2 years of life. difficult to detect in infancy, an MRI to 25% of the time, and
may be repeated at 6-month intervals the impact of intractable
West Syndrome and certainly after age 24 to 30 months seizures on development
West syndrome is the most common in cases with persisting seizures. In is most profound early
epileptic encephalopathy with an inci- those without a known cause after MRI, in life.
dence of 3 to 4.5 per 10,000 live births. further investigations are warranted.4 h A focal pathology
Clinical features. West syndrome Genetic studies are higher yield than should be suspected in
comprises a triad of (1) epileptic extensive metabolic testing, unless children with asymmetric
spasms, (2) hypsarrhythmia, and (3) imaging suggests an inborn error of spasms or those with
arrest or regression of psychomotor metabolism. A comparative genomic focal seizures coinciding
development. Typical onset is from 3 hybridization array and, if this is with spasms.
to 12 months of age. Epileptic spasms nondiagnostic, an epilepsy gene panel
consist of sudden flexion, extension, or should be considered. Whole exome
mixed flexion-extension movements sequencing should be considered if
that last 1 to 2 seconds in the proximal the etiology remains unknown and
and truncal muscles and occur in clus- seizures persist or developmental de-
ters that last several minutes often lay is evident. Initial metabolic studies
shortly after waking. Typically, clusters should include serum lactate, amino
are seen several times per day. Spasms acids, and urine organic acids to
may be symmetric, asymmetric, or evaluate for mitochondrial disorders,
unilateral and occasionally can be clini- aminoacidopathies, and organic acidurias.
cally subtle. Focal seizures may precede Further metabolic testing can in-
or follow spasms and should suggest an clude !-aminoadipic semialdehyde
underlying focal pathology. (pyridoxine-dependent epilepsy),
Many children with West syndrome CSF for pyridoxal 5¶-phosphate
have a history of perinatal complica- (pyridoxal 5¶-phosphateYdependent
tions and developmental delay. Im- epilepsy), neurotransmitters (neuro-
paired visual attention is often seen transmitter disorders), lactate (mito-
and can worsen after spasm onset. chondrial disorders and glucose
Abnormal findings on motor examina- transporter deficiency), and glucose
tion or microcephaly are common. A (glucose transporter deficiency). This
Wood’s lamp may assist in visualizing testing could be undertaken if the
cutaneous findings of neurocutaneous initial studies are negative.
disorders such as tuberous sclerosis. Hypsarrhythmia, the classic finding
Organomegaly, unusual odor, or dys- on interictal EEG, is characterized by
morphic features would suggest a very high-amplitude asynchronous slow
metabolic or genetic etiology. waves, multifocal spikes, and polyspikes
Investigations. A clear etiology is (Figure 4-1A). It is most prominent
evident in approximately half of infants during quiet sleep, often attenuated
after initial clinical examination and during wakefulness, and may be absent
neuroimaging and in three-fourths fol- in rapid eye movement (REM) sleep.
lowing further genetic and metabolic Absence of hypsarrhythmia in a
investigations. Structural etiologies, in- child with a suspicious history does
cluding cortical malformations, tuber- not exclude West syndrome. Such
ous sclerosis, and perinatal brain cases should be considered for
injury, are most common, and brain prolonged EEG to record spasms.
MRI is a necessary initial investigation During spasms, the EEG shows a
Continuum (Minneap Minn) 2016;22(1):60–93 www.ContinuumJournal.com 61

Pediatric Epilepsy
FIGURE 4-1 EEG of a 7-month-old boy with West syndrome. A, High-amplitude and excessively slow background with
multifocal discharges characteristic of hypsarrhythmia. B, During an actual spasm, there is a high-amplitude,
generalized spike-wave complex followed by generalized attenuation.

KEY POINT
high-voltage, often generalized, sharp or Prognosis. Most children with West h The usual antiepileptic
slow wave followed by an electro- syndrome have intellectual disability at drugs have limited
decrement (Figure 4-1B). follow-up, and underlying etiology is efficacy in West
Treatment. First-line treatments in- the most critical predictor of develop- syndrome. First-line
clude adrenocorticotropic hormone mental outcome. A recent meta-analysis therapies include
(ACTH), prednisolone, or vigabatrin.5 documented good neurodevelopmental adrenocorticotropic
Vigabatrin is the treatment of choice in outcome in 54% of infants with cryp- hormone, prednisolone,
infantile spasms due to tuberous scle- togenic spasms versus only 12.5% or vigabatrin.
rosis, with seizure cessation being seen with symptomatic spasms.7 Relatively
in 95% of cases, and also appears favorable symptomatic etiologies in-
effective in focal cortical dysplasia. Lim- clude Down syndrome, neurofibro-
iting treatment duration to 6 months matosis type 1, preterm infants with
minimizes the risk of retinal toxicity. periventricular leukomalacia, and neo-
ACTH may have greater short-term natal hypoglycemia. Additional factors
efficacy than vigabatrin once infants predictive of outcome include shorter
with tuberous sclerosis are excluded. treatment lag; favorable response to
Although one large study reported initial therapy; absence of other seizure
similar short-term efficacy of ACTH and types prior to spasms; and absence of
high-dose oral prednisolone (40 mg/d to atypical spasms, focal seizures, or asym-
60 mg/d),6 at present insufficient evi- metric EEG abnormalities.
dence exists that other steroids are as Infantile spasms are age dependent
effective as ACTH. and typically resolve by the early
In children with focal cortical struc- preschool years. However, 50% to
tural abnormalities, expedient referral 90% of patients evolve to other syn-
for possible surgical therapy is indicated dromes, most commonly Lennox-
if both hormonal therapy and vigabatrin Gastaut syndrome, focal epilepsy, or
fail to control spasms (Case 4-1). multifocal epilepsy.
Case 4-1
A 25-month-old girl presented with epileptic spasms that had been
occurring since she was 7 months of age. She was the product of a healthy
pregnancy and delivery and appeared developmentally normal prior to
spasm onset. Her EEG at diagnosis confirmed hypsarrhythmia, and she was
treated with high-dose adrenocorticotropic hormone (ACTH). Spasms
resolved for 6 weeks but then recurred and remained refractory to a
second course of ACTH, vigabatrin, topiramate, and pyridoxine and a trial
of the ketogenic diet. Her initial MRI was normal at 8 months of age, and
extensive genetic and metabolic evaluations were unrevealing. Around 18
months of age, her development plateaued. She underwent video-EEG
monitoring, and clusters of asymmetric spasms were recorded, with right
eye deviation and greater involvement of her right upper extremity. A
repeat MRI showed a region of T2 hyperintensity in the left frontal region,
which was consistent with a focal cortical dysplasia (Figure 4-2). She
underwent surgical resection of this region and exhibited postoperative
transient right upper extremity weakness, which markedly improved with
therapy. At 6 years of age, she was seizure free, off antiepileptic drugs, and
doing well at school, although she received resource help with reading.
Continued on page 64

Pediatric Epilepsy
KEY POINT
h Dravet syndrome should
Continued from page 63
be suspected in a child
with recurrent prolonged
focal febrile seizures
beginning before
18 months of age.
FIGURE 4-2 Imaging of the patient in Case 4-1. Coronal

fluid-attenuated inversion recovery (FLAIR)
MRI shows a region of T2 hyperintensity
in the left frontal region (arrow), suggestive of focal
cortical dysplasia.
Comment. The asymmetric manifestations of this child’s clinical seizures

suggested focal pathology, as was ultimately found on imaging. Such cases
may be amenable to surgical therapy if spasms are refractory to medical
treatment, and earlier intervention may maximize cognitive development.
Children with West syndrome have by fever or hyperthermia. Classically,

an elevated risk of death, with a seizures switch sides, starting on the
mortality rate of 10% by age 3 years right with some events and the left with
and 18% by age 10 years in one study.8 others; this alternating pattern is highly
suggestive of Dravet syndrome. Seizures
Dravet Syndrome may be falsely generalized, meaning that
Dravet syndrome (previously called se- there are either bilateral EEG changes
vere myoclonic epilepsy of infancy) is a but focal clinical events or bilateral EEG
relatively rare intractable childhood epi- changes at onset that become asymmet-
lepsy syndrome with an estimated prev- ric as the seizure evolves. The ictal EEG
alence of 1 in 40,900 live births.9 Boys may also show topographic change with
and girls are equally affected. a seizure starting in a specific focus,
Clinical features. Epilepsy onset is spreading to one or both hemispheres,
before age 18 months with prolonged and ending focally.
hemiconvulsive seizures (with or with- In the early preschool years, other
out secondary generalization), triggered seizure types emerge, including

KEY POINT
myoclonic, atypical absence, and focal cating in 50% (mostly nonsense, h SCN1A testing in Dravet
seizures. Tonic seizures are unusual. frameshift, splice site, or missense syndrome should
Obtundation status, in which the child mutations, with the latter predomi- include sequencing,
appears poorly responsive for several nantly affecting the pore-forming re- and, if negative, testing
hours, has erratic myoclonus predom- gion of the SCN1A sodium channel).9 for large-scale
inantly affecting the fingers and Intragenic deletions or whole gene duplications and
orobuccal muscles, and discrete inter- deletions account for 2% to 3% of deletions is required.
spersed massive myoclonic jerks that cases; duplications and amplifications
may interfere with sleep, may also be are rare. Testing should, therefore,
seen. Typically, obtundation status is include SCN1A sequencing, and, if
noted on awakening, and convulsive negative, testing for large-scale duplica-
seizures may initiate, occur during, or tions and deletions is required. Rarely,
terminate this status. Reflex seizures other gene mutations can be seen in
are also frequent with provoking fac- children with a Dravet phenotype.
tors, including hyperthermia (eg, EEG findings in Dravet syndrome
caused by fever, immersion in hot are not specific. The background is
water, intense physical exercise, or normal at epilepsy onset, but by 1 to
high ambient temperature), photosen- 2 years of age, most patients show
sitivity, or pattern sensitivity. Most diffuse background theta slowing.
commonly, reflex myoclonic jerks are Epileptiform discharges (usually gen-
noted; however, convulsive or focal eralized) are seen in approximately
seizures may also be triggered. Some one-fourth of patients at epilepsy
patients may self-trigger seizures by onset. Between the ages of 2 and
rapid eye blinking while staring at a 5 years, an increase in paroxysmal
bright source or pattern. abnormalities (which can be general-
Development is normal at epilepsy ized, focal, or multifocal) is seen. Photic
onset but slows around the time of stimulation and eye closure may elicit
onset of myoclonus and nonconvulsive discharges in up to one-fourth of cases
seizures. The degree of intellectual (Figure 4-3). In older children and
disability varies markedly from border- adults, multifocal and focal interictal
line to severe impairment. More severe discharges are most common, and
impairment has been linked to higher discharges may be absent in approxi-
frequency of both convulsive and non- mately 25% of patients.
convulsive seizures. The neurologic Neuroimaging studies are typically
examination is typically normal at epi- normal, although scans done later in life
lepsy onset; however, ataxia, slight pyra- may show mild atrophy, hippocampal
midal signs, and a crouch gait (increased sclerosis, or loss of gray-white definition.
knee and hip flexion and ankle dorsi- Treatment. Dravet syndrome is
flexion, often with a mild flexible extremely pharmacoresistant. The goals
kyphosis) may develop over time. of treatment are to avoid prolonged
Investigations. SCN1A mutations status epilepticus, reduce frequency of
are found in 80% of patients. De novo briefer seizures, and avoid problematic
mutations account for 95% of cases; adverse effects of multiple antiepileptic
however, 5% of patients show familial drugs (AEDs) used at high doses.10
mutations in which affected relatives Sodium channel blocking agents, in-
have a much milder clinical picture with cluding carbamazepine, oxcarbazepine,
genetic epilepsy with febrile seizures lamotrigine, and phenytoin, should be
plus (GEFS+) phenotypes. SCN1A mu- avoided as they exacerbate seizures.
tations in Dravet syndrome are trun- First-line therapy typically involves

Pediatric Epilepsy
FIGURE 4-3 EEG of a 2-year-old girl with Dravet syndrome showing a generalized spike-wave discharge triggered by
photic stimulation.
KEY POINT valproic acid or clobazam, although add-on fenfluramine in a small study in
h Sodium channel agents topiramate, levetiracetam, and possibly which 7 of 12 patients achieved seizure
should be avoided in zonisamide may also have efficacy. freedom for at least 1 year after 1 to
Dravet syndrome.
Stiripentol is often considered if first- 19 years of treatment.13 Clinical trials
Valproic acid or clobazam
line therapy is ineffective and has been are currently under way to deter-
are first-line agents.
shown in a prospective randomized mine efficacy of cannabinoids. Vagus
placebo-controlled study to result in a nerve stimulation has been tried with
69% reduction of seizures.11 It also limited effectiveness.
reduces status epilepticus, need for Given patients’ predisposition to-
rescue medications, hospitalizations, ward recurrent prolonged seizures,
and emergency department visits.12 caregivers of children with Dravet
However, stiripentol is not currently syndrome should be taught to admin-
US Food and Drug Administration ister a home dose of rescue benzodi-
(FDA)Yapproved and, in the United azepine. Additionally, a treatment plan
States, must be obtained through an for management of prolonged seizures
Investigational New Drug (IND) appli- should be provided to the family and
cation to the FDA. The ketogenic diet their nearest emergency department.
also has documented efficacy with Prognosis. While seizures remain
sustained seizure reduction in one- medically refractory in most pa-
half to two-thirds of children. Remark- tients, prolonged seizures and status
able efficacy was also documented with epilepticus become much less frequent

in mid to late childhood. Absences and With the exception of rare cases on
myoclonic seizures either markedly the severe end of the phenotypic
reduce or resolve by early adulthood, spectrum, children with GEFS+ are
and brief nocturnal generalized tonic- typically neurologically and developmen-
clonic seizures are the main seizure tally normal. Antecedent birth and devel-
type. Temperature sensitivity persists in opmental histories are unremarkable.
up to half of patients, but photic and Investigations. GEFS+ is usually
pattern sensitivity typically resolve by inherited in an autosomal dominant
adulthood. Developmentally, most pa- manner with incomplete penetrance. It
tients with Dravet syndrome have mod- remains a clinical diagnosis, and genetic
erate to severe disability and cannot live testing is not required. While numerous
independently as adults.14 genes have been implicated in GEFS+
Several studies have reported an (eg, SCN1A, SCN1B, SCN2A, GABRG2,
increased mortality rate in children and GABRD), mutations are identified
with Dravet syndrome, with approxi- in only a minority of affected families
mately 15% dying by early adulthood overall. This suggests that GEFS+ most
due to status epilepticus, SUDEP, or likely follows complex inheritance and
accidental death.14Y18 that more than one gene is involved,
including possible modifying genes,
Genetic Epilepsy With Febrile with environmental contribution.
Seizures Plus An EEG is not indicated in simple
GEFS+ is a common familial electro- febrile convulsions. It is typically
clinical syndrome in which two or more obtained in children with afebrile
family members have symptoms consis- seizures, and the findings in GEFS+
tent with this diagnosis.19 Phenotypes are heterogeneous and depend on
range from mild to severe, and phe- seizure type. The background and
notypic heterogeneity is usual. Age at sleep patterns are typically normal,
onset is between 6 months and 6 years, although diffuse slowing may be seen
and boys and girls are equally affected. in individuals on the severe phenotyp-
Clinical features. At the mildest ic end of the spectrum with either
end of the phenotypic spectrum are myoclonic-atonic epilepsy or Dravet
children with febrile seizures alone, syndrome. In individuals with general-
which may be recurrent, prolonged, ized seizures, the interictal recording
focal, or clustered. Other children have typically shows generalized discharges,
febrile seizures plus, in which febrile which can become fragmented and
seizures either continue beyond the age may appear focal or multifocal in sleep.
of 6 years or afebrile seizures coexist In those with temporal lobe epilepsy,
with febrile seizures. Most commonly, focal discharges are seen.
afebrile seizures are brief generalized Neuroimaging is generally not re-
convulsive events; however, other types quired; if done, it is typically normal.
of generalized (typical absence, myo- Rarely, hippocampal sclerosis can be
clonic, myoclonic-atonic, or atonic) or seen in patients with GEFS+ and
focal seizures may also be seen. At the temporal lobe epilepsy.
severe end of the spectrum are individ- Treatment. Prophylactic AEDs are
uals with either myoclonic-atonic epi- not indicated for simple febrile seizures.
lepsy or Dravet syndrome. Some If they are prolonged or clustered, a
individuals may also present with tem- home dose of rescue benzodiazepine
poral lobe epilepsy with or without therapy could be administered. Prophy-
hippocampal sclerosis. lactic antiepileptic therapy for afebrile

Pediatric Epilepsy
KEY POINT
h Panayiotopoulos seizures should be geared toward the and familial hemiplegic migraine.
syndrome should be seizure type. Benzodiazepines (such Seizures are pharmacoresponsive and
suspected in a a s clobazam and clonazepam), self-limited.
previously well late levetiracetam, valproic acid and its de-
preschool or early rivatives, and topiramate are usually CHILDHOOD-ONSET EPILEPSIES
school-aged child who effective in the treatment of GEFS+. The following epilepsies typically have
presents with a Because many mutations in GEFS+ their onset in the childhood years.
nocturnal seizure with may alter sodium channel function,
pronounced autonomic sodium channel blockers such as phe- Panayiotopoulos Syndrome
features such as ictal nytoin, carbamazepine, oxcarbazepine, (Early-Onset Benign Occipital
vomiting or retching. Epilepsy)
and lamotrigine may potentially be
more problematic. Panayiotopoulos syndrome accounts
Prognosis. Generally, most seizures for 1% to 2% of pediatric focal epilepsy
in GEFS+ are pharmacoresponsive cases with a peak age at onset of 5 years.
and self-limited, in most cases resolv- The condition is slightly more common
ing before puberty. Development re- in girls and affects neurologically nor-
mains normal. mal children.
Clinical features. Seizures are char-
Familial and Nonfamilial acterized by prominent autonomic
Benign Focal Epilepsies features (eg, nausea, retching, and
Benign focal epilepsies affect develop- vomiting) and usually occur at night.
mentally normal infants and may be Tonic eye deviation is common, but
familial or nonfamilial.20 visual hallucinations are rare. Seizures
Benign epilepsy in infancy is a often become dyscognitive and may
nonfamilial syndrome that presents at evolve to hemiconvulsions or general-
a peak age of 4 to 6 months, most ized convulsions. Duration can be
typically with a cluster of focal seizures prolonged; up to one-third develop
consisting of behavioral arrest, automa- focal status epilepticus, but seizure
tisms, and mild convulsive movements. frequency is low with 33% of patients
Seizures may progress to secondary having only a single seizure.
generalization. The interictal EEG is It has been speculated that Panayi-
typically normal, as is neuroimaging. otopoulos syndrome is the result of a
Seizures are pharmacoresponsive but combination of multifocal cortical hy-
may occur in another cluster weeks to perexcitability and an unstable auto-
months later. As malformations of cor- nomic nervous system. The syndrome
tical development can be challenging to is an age-specific epilepsy syndrome,
see on MRI in young infants, careful and no causal gene has been identified.
follow-up is needed to confirm the Investigations. The interictal EEG
benign nature of the epilepsy. shows high-amplitude, frequent, focal,
Various familial benign neonatal or multifocal spikes that typically
and infantile epilepsies have also increase in sleep and may show
been described with a number of fixation-off sensitivity, in which activa-
implicated genes, including KCNQ2, tion of discharge is seen when the
KCNQ3, and PRRT2. These are typically patient is not actively looking at some-
inherited as autosomal dominant thing. Location is often, but not always,
conditions with incomplete pene- in the occipital region; the centrotemporal
trance, and families may also have and parietal regions are also common
other neurologic disorders, inclu- foci. Spikes often shift in focus on
ding paroxysmal choreoathetosis subsequent recordings. Ictal recordings

KEY POINT
are rare; however, rhythmic theta or delta vals. Frequent seizures are seen in only h Benign epilepsy with
activity with intermixed spikes that 6%, while 13% to 21% will have only a centrotemporal spikes
usually start posteriorly have been single event. Postictal Todd paresis is should be suspected in
reported. Uncommonly, Panayiotopoulos seen in 7% to 16% and may suggest previously well
syndrome can evolve to continuous focal onset in those presenting with a school-aged children
spike and wave in slow sleep. generalized nocturnal seizure. who present with focal
If the history and EEG are typical, Affected children are usually neuro- seizures affecting the
neuroimaging is not required. However, developmentally normal, although 16% lower face or with early
MRI should be considered with atypi- will have a history of febrile seizures. morning generalized
cal features. A genetic component consistent tonic-clonic seizures.
The EEG shows
Treatment. Prophylactic AED treat- with complex inheritance has been
high-amplitude
ment may not be needed if seizures shown, but a causal gene has not
centrotemporal
are infrequent. If treatment is started, been found. Acquired or environmen- sharp waves.
levetiracetam, oxcarbazepine, and car- tal factors are likely necessary for
bamazepine are frequent choices; no expression of the seizure disorder.
particular AED has been shown to be Investigations. The EEG shows
superior. Intermittent use of benzodi- high-amplitude, diphasic, unilateral or
azepines should be considered for the bilateral, centrotemporal spikes or
child with prolonged events. sharp waves, which have a character-
Prognosis. Remission of active epi- istic horizontal dipole (maximal nega-
lepsy typically occurs within 1 or 2 years tivity in centrotemporal and positivity
from onset, and children can then dis- in frontal regions) and are followed by
continue prophylactic medications. Cog- aftercoming slow waves (Figure 4-4).
nitive and social outcome is excellent. Discharges are markedly activated in
drowsiness and non-REM sleep, and
Benign Epilepsy With the background is normal. Few re-
Centrotemporal Spikes ports of recorded rolandic seizures
(Benign Rolandic Epilepsy) exist, but two unique features are
Benign epilepsy with centrotemporal noted: (1) dipole reversal of ictal
spikes accounts for 6% to 10% of all discharge with electropositivity in the
childhood epilepsies and has a peak age centrotemporal region and negativity
at onset of 7 to 8 years, resolving by age in the frontal area and (2) absence of
16. Boys are more commonly affected. postictal slowing.
Clinical features. Focal seizures with Approximately 0.7% of children
clonic or tonic activity of one side of the with no seizure history show typical
lower face or tongue; paresthesia of the rolandic discharges on their awake
tongue, lips, gum, and cheek; drooling; recording. Thus, this EEG finding
and dysarthria are classic features of the should be considered incidental if
condition. Hemiconvulsions are more clinical symptoms are not suggestive
common in young children, and evolu- of benign epilepsy of childhood with
tion to bilateral convulsive activity is centrotemporal spikes.
frequent in sleep. Seizures typically Imaging is not required in a neuro-
occur shortly after falling asleep or logically normal child with a charac-
before awakening; however, 15% of teristic clinical history and EEG. MRI is
patients have seizures in both sleep usually normal but may show hippo-
and wakefulness and 20% to 30% in the campal asymmetry, white matter ab-
waking state alone. Seizures are typ- normalities, or developmental lesions
ically brief and often occur in clusters in a minority of cases. MRI should be
interspersed by long seizure-free inter- considered with atypical features.

Pediatric Epilepsy
FIGURE 4-4 EEG of a developmentally normal 8-year-old boy who presented with an early morning generalized
tonic-clonic seizure. EEG shows prominent independent left and right centrotemporal discharges in sleep
characteristic of benign epilepsy of childhood with centrotemporal spikes.
KEY POINT Treatment. Prophylactic medication Electrical Status Epilepticus in

h Children with benign may not be required for children with Slow Sleep
epilepsy with infrequent nocturnal focal seizures. If ESES comprises two similar but dis-
centrotemporal spikes
recurrent generalized or diurnal seizures tinct syndromes: continuous spike
achieve remission,
occur, or if they are sufficiently disturb- and wave in slow sleep (CSWS) and
most often by early
adolescence, and
ing to the child or the family, treatment Landau-Kleffner syndrome.
can discontinue is generally started. AEDs prescribed for Clinical features. In both CSWS
antiepileptic drugs. focal seizures have equivalent efficacy, and Landau-Kleffner syndrome, marked
with 50% to 65% of patients having no fur- activation of epileptiform discharges
ther seizures once medication is started. occurs during non-REM sleep to the
Prognosis. Remission occurs in point that they become nearly continu-
essentially all children: 50% by age ous (Figure 4-5).22 In association with
6 years, 92% by age 12 years, and the EEG change, children experience
99.8% by age 18 years.21 Although developmental regression, which is
learning and behavior problems may more global in CSWS and predomi-
be seen in the acute phase, long-term nantly affects receptive language in
psychosocial outcome is excellent Landau-Kleffner syndrome. The cause
with no increase in psychiatric or of CSWS is heterogeneous; how-
personality problems and excellent ever, approximately half of cases have
occupational status. Rarely, this syn- early developmental lesions, including
drome evolves atypically to electrical malformations of cortical develop-
status epilepticus in slow sleep (ESES). ment or vascular insults (particularly
Such deterioration has been infre- involving the thalamus), and a signifi-
quently reported with carbamazepine, cant minority have various genetic ab-
phenobarbital, and lamotrigine. normalities (Case 4-2). In distinction,

FIGURE 4-5 EEG of a 5-year-old boy with a history of seizures, developmental regression, and hyperactivity showing nearly continuous,
bilaterally synchronous discharges in sleep characteristic of a diagnosis of electrical status epilepticus in slow sleep.
Case 4-2
A 5-year-old girl with a history of perinatal stroke and right hemiparesis (Figure 4-6A) presented with two
prolonged right hemiconvulsive seizures occurring during an intercurrent illness. Her awake EEG showed
frequent spikes from the left frontal and temporal regions, and she was started on oxcarbazepine. When
she presented for follow-up 2 months later, although she had no further prolonged seizures, brief
right-sided seizure activity persisted, and she had a marked decline in her behavior and learning. She
often appeared vacant and had poor ability to sustain attention on a task. She had several falls with
injury. A repeat EEG showed nearly continuous left-sided discharge during sleep (Figure 4-6B), consistent
with electrical status epilepticus in slow sleep (ESES). She also had recorded atypical absence seizures that
correlated with her vacant spells. Her oxcarbazepine was stopped, and she was started on levetiracetam
without significant benefit. She was then treated with high-dose diazepam (0.5 mg/kg at bedtime) with
marked improvement in her cognition, resolution of falls, and fewer vacant episodes. A repeat sleep EEG
4 weeks later showed only occasional left-sided discharges.
Comment. Children with perinatal thalamic injury are at high risk of developing ESES. Certain
medications, including oxcarbazepine, may also increase this risk. A history of developmental regression,
particularly of language, as well as worsening nonconvulsive seizures (absences and atonic events) should
suggest the diagnosis, which is confirmed by sleep EEG recording.
Epilepsy associated with continuous spike and wave in slow sleep is polymorphic and severe, with many
patients having multiple daily events, including generalized tonic-clonic, atypical absence, myoclonic,
atonic, and focal seizures. In distinction, seizures in Landau-Kleffner syndrome are much less frequent and
are focal or secondarily generalized.

Pediatric Epilepsy
FIGURE 4-6 Imaging and EEG of the patient in Case 4-2. A, Axial T2-weighted fluid-attenuated inversion recovery (FLAIR)
MRI showing a remote left middle cerebral artery infarction. T2 hyperintensity is also seen in the left
thalamus. B, EEG shows nearly continuous left-sided discharge during sleep.

KEY POINTS
Landau-Kleffner syndrome is seen in affects otherwise neurologically nor- h Electrical status
children with normal imaging and re- mal children. epilepticus in slow
flects one end of the epilepsy-aphasia Clinical features. Typical absence sleep presents with
spectrum. Additionally, GRIN2A muta- seizures are the only seizure type at developmental
tions have been identified to play a presentation and characteristically regression along with
role in a significant minority of epilepsy- occur very frequently (often 10 to nearly continuous
aphasia spectrum disorders.23 50 times per day). Generalized tonic- epileptiform discharges
Treatment. In a child with ESES clonic seizures may develop in 30% to on sleep EEG. Most
and documented regression, treatment 40% of patients but usually do not antiepileptic drugs are
goals include both improved seizure begin before adolescence. Absences poorly efficacious, and
high-dose diazepam
control and reduction of interictal EEG are brief (less than 20 to 30 seconds),
or steroids are
abnormalities to maximize learning abrupt in onset, and triggered by
often needed.
and memory.24 Medications that can hyperventilation. Mild facial myoclo-
exacerbate such activity, including nus is common, but prominent eyelid h Childhood absence
epilepsy presents in
oxcarbazepine and carbamazepine, or perioral myoclonia or massive my-
neurologically normal
should be discontinued. Selected AEDs, oclonus of the limbs or head should
school-aged children
including valproate, ethosuximide, leve- suggest an alternative diagnosis. with absence seizures as
tiracetam, lamotrigine, and sulthiame Investigations. The EEG back- the only seizure type.
(which is not FDA approved in the ground is usually normal but may show Ethosuximide is
United States), have been reported to posterior bilateral rhythmic delta activ- first-line treatment.
be potentially beneficial in small case ity, consisting of 3-Hz high-voltage slow
series but not consistently. High-dose activity in the parietooccipital regions
benzodiazepines or steroids are often that is attenuated by eye opening and
used as first-line agents. Surgery can often enhanced by hyperventilation.
also be considered, particularly in The ictal EEG shows generalized 3-Hz
children with CSWS with neuroimag- spike-wave (Figure 4-7), and during
ing abnormalities. sleep, discharges often become more
Prognosis. Seizures ultimately re- fragmented. Photosensitivity may be
solve or markedly decrease in frequency seen; however, prominent photosensi-
by puberty, even in cases with symp- tivity and polyspike discharges suggest
tomatic etiologies. The electrographic greater likelihood of progression to
pattern of ESES also resolves in pu- juvenile myoclonic epilepsy. Etiology
berty. However, the neuropsycholog- is presumed to be genetic, and imag-
ical prognosis is more worrisome with ing is not required.
less than half of children achieving Treatment. Ethosuximide is consid-
normal intelligence and language ered first-line treatment of childhood
function. Factors predictive of poorer absence epilepsy, with valproic acid and
outcome include earlier onset of ESES lamotrigine considered second-line.25
and longer duration until effective Most cases of childhood absence epi-
therapy is initiated, which under- lepsy are pharmacoresponsive. Carba-
scores the need for maintaining a high mazepine, oxcarbazepine, tiagabine,
level of suspicion of this diagnosis. vigabatrin, and possibly phenytoin
may exacerbate absence seizures and
Childhood Absence Epilepsy should be avoided.
Childhood absence epilepsy presents Prognosis. Over two-thirds of chil-
at a peak age of 5 to 7 years and dren with childhood absence epilepsy
accounts for 5% to 10% of all epilepsies will achieve seizure control with their
beginning in childhood. The condition first or second AED, and medication
is slightly more common in girls and should be weaned after a seizure-free

Pediatric Epilepsy
FIGURE 4-7 EEG of a 7-year-old girl with staring spells shows abrupt onset of 3-Hz generalized spike-wave discharge with
staring, consistent with an absence seizure.
period of 1 to 2 years if the EEG family history is frequently positive for

normalizes. While most cases ultimately either epilepsy (15% to 37%) or febrile
remit and do not require medication seizures (50%). Myoclonic-atonic epi-
into adulthood, a minority evolve to lepsy is one of the syndromes that can
juvenile myoclonic epilepsy in late ado- be seen in GEFS+ families.
lescence or early adulthood, or patients Clinical features. The initial pre-
may continue to have brief, often infre- sentation of myoclonic-atonic epilepsy
quent, absence seizures in adulthood. is usually with febrile or afebrile gen-
Even with remission of epilepsy, social eralized tonic-clonic seizures, followed
outcomes can be problematic with by other generalized seizures after weeks
academic and behavioral concerns to months.26 The myoclonic-atonic sei-
persisting into adulthood. zure is characteristic, seen in nearly all
cases, consists of a brief generalized
Myoclonic-Atonic Epilepsy myoclonic jerk affecting proximal mus-
(Doose Syndrome) cles, and is followed by an atonic com-
Myoclonic-atonic epilepsy, or Doose ponent that can be very subtle (head
syndrome, is a rare syndrome (1% to nod) or more prominent (abrupt fall)
2% of childhood epilepsy) that has (Figure 4-8). Myoclonic, atonic, atypi-
onset between 2 and 5 years of age cal absences, and, rarely, tonic seizures
and has a male preponderance. Most may also occur. One or more periods
children are developmentally normal of nonconvulsive status epilepticus can
prior to the onset of seizures, and be seen in 40% of patients and may be

FIGURE 4-8 EEG of a 3-year-old boy with myoclonic-atonic epilepsy who presented with sudden onset of staring and falls
showing a generalized spike-wave discharge in association with a head drop. Some head drops are
preceded by a brief jerk and minor vocalization, consistent with myoclonic-atonic seizures.
induced by inappropriate AEDs such Prognosis. Outcome is variable in

as carbamazepine. patients with myoclonic-atonic epilepsy.
Investigations. The initial EEG back- Seizures remit in 54% to 89% of cases,
ground is normal, but over time, cen- and half of children have normal devel-
troparietal theta rhythms emerge, opment long term or only mild cogni-
amplitude increases, and a 2-Hz to 3-Hz tive delay.27 However, other cases fare
generalized spike, polyspike, and wave poorly, with persisting seizures and cog-
discharge is seen interictally, which nitive regression. Poorer outcome is
increases with sleep. Photosensitivity predicted by prolonged or recurrent
is common. nonconvulsive status epilepticus and
Treatment. Medications that may be by the presence of tonic seizures.
beneficial in myoclonic-atonic epilepsy Myoclonic-atonic epilepsy is impor-
include valproic acid, ethosuximide, tant to differentiate from Lennox-Gastaut
lamotrigine, topiramate, levetiracetam, syndrome. Useful distinguishing features
zonisamide, and, in refractory cases, include family history of epilepsy (often
ACTH. However, seizures are frequently positive in myoclonic-atonic epilepsy ver-
pharmacoresistant, and the ketogenic sus usually negative in Lennox-Gastaut
diet is one of the most efficacious ther- syndrome), past history of neuro-
apies, providing a greater than 50% re- developmental delay (usually absent in
duction in seizures in 55% of cases and myoclonic-atonic epilepsy versus often
seizure freedom in 18%. present in Lennox-Gastaut syndrome),

Pediatric Epilepsy
KEY POINTS
h Myoclonic-atonic presence of tonic seizures (uncommon 3 years, frequent seizures, and recurrent
epilepsy is important and usually late in the course of nonconvulsive status epilepticus. Hyper-
to distinguish from myoclonic-atonic epilepsy versus the kinetic behaviors, autistic features, and
Lennox-Gastaut prominent seizure type in Lennox- perseverative behaviors are common.
syndrome, as Gastaut syndrome), and interictal EEG Investigations. Interictally high-
myoclonic-atonic pattern (2-Hz to 3-Hz generalized spike- amplitude 1.5-Hz to 2.5-Hz general-
epilepsy usually has a wave with 4-Hz to 7-Hz centroparietal ized and multifocal polyspike and
much more benign rhythms in myoclonic-atonic epilepsy spike-wave discharges on a slow back-
long-term prognosis. versus 1-Hz to 2-Hz generalized spike- ground are seen, which increase dur-
h Lennox-Gastaut wave and fast anterior rhythms in ing sleep (Figure 4-9A). However, this
syndrome typically affects Lennox-Gastaut syndrome). pattern may take months to evolve
neurodevelopmentally and is present in less than 30% of
abnormal children with Lennox-Gastaut Syndrome patients early on. Low-voltage frontally
characteristic features, Lennox-Gastaut syndrome is a relatively predominant greater than 10-Hz gen-
including tonic and
rare epilepsy syndrome with an inci- eralized paroxysmal fast activity is seen
atonic seizures. Interictal
dence of 1.9 to 2.1 per 100,000 children in slow-wave sleep (Figure 4-9B) and is
EEG shows both slow
spike-wave discharge
but accounts for approximately 6% to suggestive of the diagnosis of Lennox-
and characteristic 7% of children with intractable epilepsy. Gastaut syndrome, even if other EEG
generalized paroxysmal Onset is typically in the preschool years, features have not yet fully evolved.
fast activity in sleep. and males are preferentially affected. Treatment and prognosis. The
Two-thirds of cases occur in children seizures in Lennox-Gastaut syndrome
with preexistent brain abnormalities, are pharmacoresistant. Valproic acid
one-third of whom have a history of and its derivatives are commonly used,
West syndrome. and lamotrigine, topiramate, rufinamide,
Clinical features. Lennox-Gastaut clobazam, and felbamate have all been
syndrome typically evolves over months shown to be superior to placebo in
to include a triad of symptoms: (1) randomized controlled studies.28 Carba-
multiple generalized seizure types, in- mazepine may lessen tonic seizures but
cluding tonic, atonic, myoclonic, and worsen atypical absences. Ethosuximide
atypical absence; (2) an interictal EEG may be helpful for refractory atypical
pattern of diffuse slow spike-wave com- absences. Given the poor response to
plexes; and (3) cognitive dysfunction.26 AEDs, the ketogenic diet should be
Nocturnal tonic events are most considered early in the course of
characteristic of Lennox-Gastaut syn- Lennox-Gastaut syndrome.29 Approxi-
drome but are often subtle and diffi- mately half of children experience
cult to recognize without video-EEG significant seizure reduction with rare
recording. Daytime tonic and atonic cases achieving seizure freedom.
seizures often lead to problematic Children with Lennox-Gastaut syn-
falls. Nonconvulsive status epilepticus drome are generally not candidates for
is also common but often difficult to resective surgery. Corpus callosotomy
detect in a timely manner. is a possible treatment for intractable
Intellectual disability ultimately af- drop seizures. Section of only the
fects nearly all children with Lennox- anterior two-thirds limits severity of
Gastaut syndrome but is not always disconnection symptoms compared
evident early in the course. Factors pre- to complete callosotomy but is less
dictive of poorer cognitive outcome effective. Retrospective studies have
include delayed development prior to demonstrated vagus nerve stimulation
seizure onset, history of infantile spasms, to reduce seizures by approximately
onset of symptoms before the age of 50% in nearly half of children.29

FIGURE 4-9 EEG of a 5-year-old boy with a remote history of West syndrome, global developmental delay, and multiple
seizures. A, Interictal EEG shows high-amplitude frontally predominant slow spike waves characteristic of
Lennox-Gastaut syndrome. B, Generalized paroxysmal fast activity is shown during sleep.
ADOLESCENT-ONSET EPILEPSIES Juvenile Absence Epilepsy

The following syndromes have their on- Juvenile absence epilepsy, one of the
set in adolescence or young adulthood. less-common genetic generalized

Pediatric Epilepsy
KEY POINT
h While a generalized epilepsies, accounts for 1% to 2% of which they attributed to nervousness
tonic-clonic childhood epilepsy. or clumsiness. Of patients with juve-
seizure is the most Clinical features. Juvenile absence nile myoclonic epilepsy, 30% to 40%
common seizure type epilepsy presents in otherwise healthy have a history of brief and infrequent
leading to diagnosis of children at a peak age of 10 to 12 years absences that were often disregarded.
juvenile myoclonic with relatively infrequent absences (of- Investigations. The interictal EEG
epilepsy, most patients ten less than daily). Generalized tonic- usually shows paroxysmal generalized
have a history clonic seizures occur in approximately 4-Hz to 6-Hz polyspike-and-wave dis-
of early morning 80% of patients, usually after onset of charge and irregular spike-and-wave
myoclonic jerks, the absences, and minor myoclonic jerks on a normal background (Figure 4-10).
significance of which
may coexist in 20% of cases. Focal changes and a photoparoxysmal
had gone unrecognized.
Investigations. While the EEG is response are each seen in up to half of
similar to childhood absence epilepsy, cases. The characteristic ictal finding is
spike-wave frequency is slightly faster a frontally predominant polyspike-
(greater than or equal to 3.5 Hz), and and-wave discharge that correlates with
polyspikes may be seen. Discharges are a myoclonic jerk.
commonly induced by hyperventilation; Treatment and prognosis. Although
however, photosensitivity is unusual. most cases are pharmacoresponsive,
Treatment and prognosis. First-line remission is rare and lifelong therapy is
medications include valproic acid or usually needed.30 Valproic acid has ex-
lamotrigine. While ethosuximide may be cellent efficacy, but the potential adverse
efficacious for absences, monotherapy is effects of weight gain, polycystic ovary
not advised as it is ineffective for gener- syndrome, teratogenicity (neural tube
alized tonic-clonic seizures. Juvenile ab- defects in up to 6% of pregnancies),
sence epilepsy is usually a lifelong and cognitive concerns in offspring
condition. Approximately 60% of patients limits its use in women of childbearing
achieve complete seizure control with age. Lamotrigine is often the therapy of
medication, while the remainder have first choice, although it rarely may
ongoing infrequent generalized tonic- exacerbate myoclonic seizures. Other
clonic or absence seizures. therapeutic options include topiramate,
levetiracetam, and zonisamide. Carba-
Juvenile Myoclonic Epilepsy mazepine, phenytoin, and vigabatrin
Juvenile myoclonic epilepsy is the most should be avoided as they typically
common of the genetic generalized worsen seizures. Counseling regarding
epilepsies, accounting for approximately avoidance of common provoking fac-
5% to 10% of all epilepsies. It most tors, such as sleep deprivation, exces-
commonly begins between 12 and sive alcohol use, and exposure to photic
18 years of age in neurodevelop- stimulation, should be provided.
mentally normal individuals and has a
slight female predilection (60%). VARIABLE-ONSET EPILEPSIES
Clinical features. Patients with ju- The following syndromes may present
venile myoclonic epilepsy typically at a variety of ages.
present with a generalized tonic-
clonic seizure (often provoked by Focal Epilepsy of Unknown Cause
sleep deprivation, alcohol ingestion, Nonlesional focal epilepsy that does not
exposure to flashing lights, or stress), meet criteria for a known electroclinical
but most patients have had myoclonic syndrome comprises approximately
jerks (predominantly early morning) 20% to 30% of new-onset epilepsy in
often triggered by sleep deprivation, children.31 In these children, a variety

FIGURE 4-10 EEG, showing generalized polyspike and atypical spike-wave discharge, of a developmentally normal 16-year-old
boy who presented with a single early morning generalized tonic-clonic seizure triggered by photic
stimulation. The patient also has a history of myoclonus, exacerbated by sleep deprivation. These findings
are characteristic of juvenile myoclonic epilepsy.
of focal-onset seizures are seen, and Lesional Focal Epilepsy KEY POINT
the majority are developmentally and Lesional focal epilepsy also accounts for h Focal epilepsy of
neurologically normal. These epilep- unknown cause in
approximately 20% to 30% of new-onset
sies have an overall benign course, neurodevelopmentally
epilepsies in children and can present at
with a much better seizure prognosis normal children
any age. Common lesional causes in-
accounts for 20% to
than those with lesional focal epilepsy; clude malformations of cortical devel- 30% of all pediatric
approximately two-thirds will remit and opment, tuberous sclerosis, perinatal epilepsy and overall has
be able to discontinue AEDs, while brain injury or other remote brain a very benign course.
only 7% to 13% will develop intractable insult, hippocampal sclerosis, develop-
epilepsy. Although terminal remission mental tumors, or vascular causes.
rates are high, many children go Pharmacoresistant epilepsy is a signifi-
through a relapsing and remitting cant concern in this group, and only
pattern before achieving that state. approximately one-third will achieve
Despite their relatively mild epilepsy, long-term seizure remission. For those
many have social concerns and with intractable seizures, resective sur-
comorbidities, including school, behav- gery should be strongly considered in
ior, and psychiatric concerns that can eligible cases once pharmacoresistance
persist into adulthood. has been established.

Pediatric Epilepsy
Important Genetic and includes a summary of several of the

Metabolic Causes currently recognized more frequent
Genetic etiologies are being recognized causal genes. Important metabolic etiol-
as causal for many early-onset epileptic ogies, including treatable causes, are
encephalopathies (Case 4-3).32 Table 4-1 listed in Table 4-2.
Case 4-3
A 34-month-old boy presented with a history of intractable generalized epilepsy that began at 12 months
of age. He had myoclonic-atonic seizures as well as isolated myoclonic, atypical absence, and atonic
events. His EEG showed mild slowing of the background, bursts of generalized polyspike, and spike-wave
discharges as well as recorded seizures with a generalized correlate (Figure 4-11). Seizures had been
medically intractable to levetiracetam, lamotrigine, oxcarbazepine, and valproic acid. His development was
mildly delayed, and he had just started combining words. His neurologic examination was unremarkable,
and head circumference was concordant with weight and height. On further investigation, he had low CSF
glucose (35 mg/dL), low CSF-to-plasma glucose ratio (36.8%), and a borderline low CSF lactate (1.2 mEq/L).
Genetic testing revealed a pathogenic mutation in the glucose transporter gene (SLC2A1), and he was
initiated on the ketogenic diet with resolution of seizures and improvement in his developmental trajectory.
FIGURE 4-11 EEG of the patient in Case 4-3 showing a recorded myoclonic-absence seizure. Further metabolic evaluation
revealed low CSF glucose, and a diagnosis of glucose transporter deficiency was made. His seizures resolved
on the ketogenic diet.

Comment. Significant phenotypic heterogeneity is present in disorders of glucose transport. This
diagnosis should be considered in cases of early-onset epilepsy (particularly early-onset absence epilepsy)
with mild to severe developmental delay with or without microcephaly. Expedient diagnosis and
treatment with a ketogenic diet allows the child to maximize his or her developmental potential.
TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies
Gene or Other Clinical Interictal EEG

Syndrome Chromosome Findings Seizure Type Findings Course
SCN1A 2q24.3 Severe cases: Severe cases: Generalized or Severe cases:
Developmental Dravet syndrome focal/multifocal Medically
delay, crouch with prolonged discharges intractable,
gait, ataxia, hemiconvulsive lifelong
Photoparoxysmal
pyramidal signs seizures triggered epilepsy
response may
by fever prior to
be seen Mild cases:
18 months of age;
Remission
later on, other
generalized and
focal seizures
Mild cases: Genetic
epilepsy with
febrile seizures
plus (GEFS+) with
febrile seizures
and generalized
or focal seizures
Wolf- Partial Prenatal growth Focal, myoclonic, High-voltage Severity
Hirschhorn monosomy 4p failure, severe generalized spike wave or slow decreases
syndrome delay, cleft lip tonic-clonic, or waves or sequences with time
or palate, atypical absence of sharp waves in
beaked nose, seizures the centroparietal
hypertelorism, or occipital regions
low-set ears
HCN1 5p12 Mild to severe Onset of febrile Multifocal or Medically
intellectual or afebrile generalized intractable
disability, autistic generalized or discharges
features, behavior focal seizures in
disturbances, first year of life,
ataxia followed by
absence or
myoclonic
seizures
STXBP1 9q34.1 Severe to Early-onset tonic Suppression-burst Seizures often
profound delay, seizures, spasms, or hypsarrhythmia intractable
MRI may show or tonic-clonic although
hypomyelination, seizures rarely remit;
global atrophy, severe to
or thinning of profound
the corpus developmental
callosum delay

Pediatric Epilepsy
TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies Continued from page 81

SPTAN1 9q33Y9q34 Progressive Spasms, Hypsarrhythmia Medically
microcephaly, generalized intractable
spastic quadriplegia, seizures
severe intellectual
disability,
hypomyelination
and diffuse brain
atrophy on MRI
DNM1 9q34 Hypotonia Infantile spasms Hypsarrhythmia, Severe to
evolving to slow spike wave profound
Lennox-Gastaut intellectual
syndrome disability,
intractable
epilepsy
SLC25A22 11p15.5 Hypotonia, Myoclonic Suppression-burst, Medically
microcephaly, seizures, spasms hypsarrhythmia intractable
abnormal
electroretinogram
Trisomy 12p 12 Severe delay, short Myoclonic or 3-Hz spike and Seizures often
neck, prominent myoclonic polyspike respond to
forehead, absence, antiepileptic drugs
flat occiput, generalized
hypertelorism, tonic-clonic
micrognathia, seizures
low-set ears
SCN8A 12q13.1 Movement disorder Clusters of focal Multifocal or Often intractable
or generalized generalized
seizures discharges
triggered by
fever, spasms
Ring 14 Severe delay, Symptomatic Multifocal or Often intractable
chromosome microcephaly, generalized generalized
14 narrow face, epilepsy with discharges
high-arched onset in first
palate, short year of life
palpebral
fissures, flat nasal
bridge, retrognathia,
ocular anomalies
FOXG1 14q11Y14q13 Severe delay without Focal and Slowing of Often refractory
microcephaly, generalized background,
“congenital Rett” seizures focal and
multifocal
discharge


Inversion- 15 Moderate to Epileptic Hypsarrhythmia, Often
duplication severe delay, encephalopathy slow spike wave refractory
15 syndrome autism, microcephaly, resembling West
mild occasional syndrome or
dysmorphic features Lennox-Gastaut
syndrome,
occasional focal
seizures
Angelman Partial Ataxia, tremor, Atypical High-amplitude, Valproic
syndrome monosomy 15q minimal speech, absence, symmetric, acid and
severe delay, myoclonic, synchronous benzodiazepines
happy demeanor tonic-clonic, notched 2-Hz helpful
unilateral polyphasic slow
clonic, focal waves or Seizure severity
dyscognitive slow and decreases
seizures sharp waves, over time
particularly
during slow-
wave sleep
POLG1 15q24 Cerebral atrophy, Myoclonic, Multifocal Refractory
liver dysfunction other focal and discharge
generalized with slowing
seizures
CHD2 15q26 Intellectual Fever-sensitive Generalized Mild to severe
disability, may generalized polyspike- intellectual
have microcephaly tonic-clonic and-wave disability
seizures usually discharges
after age 1; later initially, later
with prominent on may see
myoclonus focal or
and atypical multifocal
absences discharge
GRIN2A 16p13.2 Intellectual Focal seizures Centrotemporal Seizures resolve
disability, affecting the spikes, which around puberty,
speech delay lower face or may be nearly but intellectual
secondarily continuous disability and
generalized in sleep speech delays
seizures from may persist
sleep; onset in
late preschool
to early
school years

Pediatric Epilepsy

Miller-Dieker 17p13.3 Four-layered In first weeks Prominent fast Seizures are
syndrome deletion lissencephaly; to months, activity, although refractory
microcephaly; massive slowing is
bitemporal myoclonus and common in the
narrowing; small, epileptic spasms first year of life
anteverted nose; are seen; over
micrognathia; time, focal and
high forehead; tonic seizures
cardiac, renal, emerge as
and sacral predominant
anomalies seizure types
KCNQ2 20q13.33 Usually normal Severe cases: Severe cases: Most cases are
infants but Early-onset Suppression-burst mild with
rarely may have tonic spasms, or hypsarrhythmia self-limited
moderate to focal seizures, seizure disorder
profound delay; myoclonic Mild cases: and normal
severely affected seizures Normal or focal development
infants may have discharges
reversible T2 Mild cases: Rarely, may
signal changes in Focal epilepsy present as
the thalami and in infants a severe
basal ganglia early-onset
epileptic
encephalopathy
with refractory
seizures
Ring 20 Mild to moderate Runs of atypical Ictal: High-voltage, Seizures are
chromosome delay, restlessness, absence or 2-Hz to 3-Hz refractory and
20 aggression, myoclonic slow activity with do not remit
nondysmorphic status superimposed spikes with age
epilepticus maximal over
frontal regions
Interictal: Normal
or mild slowing/
sharp waves
DEPDC5 22q12.3 Autosomal Focal epilepsy Focal or multifocal Heterogeneous:
dominant (often frontal discharges Some cases have
inheritance with or temporal) well-controlled
incomplete epilepsy, others
penetrance (50% are intractable
to 82%); may be
associated with Rarely, individuals
cortical dysplasias, may have
often bottom of intellectual
the sulcus disability, autism,
and psychiatric
features


CDKL5 Xp22 More common in Generalized Interictal EEG Intractable
girls but also seen tonic seizures normal early on, generalized
in boys, severe beginning then see slowing seizures
developmental in first 10 weeks, of background
delay with followed by and modified
hypotonia, acquired spasm, atypical hypsarrhythmia
microcephaly absences, and
in some cases, myoclonic
impaired eye seizures
contact, gaze
avoidance
PCDH19 Xp22.1 Girls only, intellectual Generalized Generalized or Intellectual
disability, autism tonic-clonic or focal discharge disability,
focal seizures, autism
typically occurring
in clusters with Seizures
febrile illness often
medically
intractable
Rett Xq28 Normal early Generalized Slowing of Often
syndrome development tonic-clonic background with refractory
(MECP2) followed by seizures, other multifocal and
acquired generalized generalized
microcephaly, and focal epileptiform
autistic features, seizures discharge
lack of purposeful
hand movement
with characteristic
hand wringing
ARX Xp22.3 Severe developmental Spasms, other Suppression-burst, Usually
delay and seizures generalized hypsarrhythmia refractory
in boys; often seizures
associated cerebral
malformations
including
lissencephaly,
agenesis of corpus
callosum; may
have dystonia,
spasticity
SLC35A2 Xp11.23-p11.22 Moderate to Spasms, Hypsarrhythmia, Often
severe intellectual focal electrical status intractable
disability, language epilepsy epilepticus in
impairment, slow sleep
early pubertal onset
EEG = electroencephalogram; MRI = magnetic resonance imaging.

86
TABLE 4-2 Selected Metabolic Causes of Epileptic Encephalopathies
Metabolic Age at Clinical

Disorder Onset Presentation Diagnostic Test Prognosis Treatment
Pyridoxine Birth to Refractory seizures Increased Variable, depending Pyridoxine 50Y200 mg/d
dependency33,34 1 year that may begin in !-aminoadipic on duration of IV or orally
utero, progressive semialdehyde in CSF, symptoms prior to
encephalopathy, serum, and urine; supplementation
www.ContinuumJournal.com
clinical and EEG confirm with ALDH7A1
response to pyridoxine genetic analysis
Pyridoxal phosphate Neonatal Refractory seizures, Low pyridoxal Variable, depending Pyridoxal 5¶-phosphate
dependency33,34 often in preterm 5¶-phosphate on duration of 30 mg/kg/d orally
infant, encephalopathy, in CSF; confirm with symptoms prior to
clinical and EEG response PNPO genetic analysis supplementation
to pyridoxal phosphate
Folinic acidYresponsive Neonatal Refractory seizures, Increased Variable, depending Folinic acid 3Y5 mg/kg/d
seizures33,34 encephalopathy, clinical !-aminoadipic on duration of orally
and EEG response to semialdehyde in CSF symptoms prior to
folinic acid, incomplete and increased supplementation
Pediatric Epilepsy
response to pyridoxal serum pipecolic acid,

phosphate and abnormal peaks on
pyridoxine CSF neurotransmitter
analysis
Serine deficiency Neonatal and Microcephaly, cognitive Decreased serine in Variable, depending Serine 500Y700 mg/kg/d
disorders33,34 childhood disability, failure to thrive, CSF and plasma on duration of with or without glycine
spasticity, hypomyelination amino acids symptoms prior to supplementation orally
and brain atrophy on MRI, supplementation
neonatal or absence seizures
Creatine deficiency33 Neonatal and Developmental delay, Screen with urine testing Poor, majority with Creatine monohydrate
infancy seizures, autistic features, for creatine and GAA, moderate to severe 5Y20 g/d orally
movement disorder, followed by definitive developmental
poor growth genetic testing for disability
AGAT, GAMT, or

creatine transporter
Untreated Neonatal and Growth failure, Increased phenylalanine Good if diagnosed Phenylalanine-restricted
phenylketonuria infancy microcephaly, seizures, in plasma amino acids and treated early diet, consider
developmental delay, tetrahydrobiopterin trial to
mousy odor rule out deficiency
February 2016
Urea cycle Neonatal, later Vomiting, lethargy, Increased serum Variable, depending Removal of
disorders if partial coma, seizures, ammonia, abnormal on severity ammonia with dialysis
enzyme developmental delay, serum amino acids and duration (if hyperammonemic
deficiency protein avoidance, and urine organic acids of symptoms crisis); treat with
diffuse white matter sodium benzoate,
changes on MRI sodium phenylacetate,
arginine supplementation,
high-carbohydrate and
low-protein diet with
provision of essential
Continuum (Minneap Minn) 2016;22(1):60–93

amino acids
Nonketotic Neonatal and Lethargy, hypotonia, Increased CSF and Poor, death Sodium benzoate
hyperglycinemia33 infancy hiccups, intractable plasma glycine with usually within 250Y750 mg/kg/d orally
seizures, apnea CSF/plasma glycine the first year and dextromethorphan;
90.08 avoid valproate
and vigabatrin
GABA transaminase Neonatal and Intractable seizures, lethargy, Increased GABA Poor, death Symptomatic only
deficiency infancy irritability, severe delay, in serum and CSF usually within
hypotonia, hyperreflexia, the first 5 years
accelerated growth
Sulfite oxidase Neonatal and Intractable seizures, Elevated sulfite Poor Some patients
deficiency and infancy progressive neurocognitive levels in fresh urine; may improve with
molybdenum decline, acquired low plasma vigabatrin or
cofactor deficiency33 microcephaly, MRI homocysteine; dextromethorphan;
demonstrating confirm with specific some may improve
leukoencephalomalacia enzyme analysis with dietary restriction
and atrophy; later-onset of fibroblasts of methionine
forms may present with
encephalopathy, focal
findings, and seizures
after a febrile illness
Peroxisomal Neonatal and Hepatic disease, Abnormal very long Variable, depending Symptomatic only
disorders33 infancy developmental delay, chain fatty acids or on phenotype
retinopathy, deafness, phytanic acid
seizures, cortical

migration defects
87
88
TABLE 4-2 Selected Metabolic Causes of Epileptic Encephalopathies Continued from page 87
Metabolic Age at Clinical

Disorder Onset Presentation Diagnostic Test Prognosis Treatment
Menkes disease33 Infancy Developmental regression; Low serum copper Poor, with Copper histidine
seizures, particularly and ceruloplasmin; progression supplementation
spasms; hypopigmentation confirm with ATP7A to death typically and supportive
of skin and hair; mutation analysis within 5 years treatment
hypothermia; characteristic
“kinky” hair
Glutaricaciduria type 1 Infancy and Macrocephaly; Increased urinary Poor, although Low-protein
childhood acute neurologic glutaric acid detection and diet (low lysine
decompensation with treatment prior to and tryptophan)
infection or febrile decompensation may with carnitine
illness, characterized by improve outcome supplementation
hypotonia, opisthotonic
posturing, dystonia or
dyskinesia; seizures;
encephalopathy; MRI
shows widening of
sylvian fissures
Pediatric Epilepsy
Biotinidase deficiency33 Neonatal through Seizures, hypotonia, Low serum biotinidase Outcome can be Biotin
childhood developmental delay, good if diagnosed supplementation
ataxia, dermatitis, and treated early 5Y40 mg/d
hair loss, autistic
behavior, optic atrophy
Succinic semialdehyde Infancy and Developmental delay, Increased GABA in Variable, Symptomatic
dehydrogenase childhood ataxia, hypotonia, seizures, urine; confirm with treatment targeted
deficiency hyperactivity, behavior enzymatic analysis at symptoms
problems; increased or ALDH5A1
T2 signal in globus pallidus, gene sequencing
dentate nucleus, and
subthalamic nucleus with
cerebral atrophy
Congenital Infancy and Epilepsy, Postprandial Outcome can be Protein restriction,

hyperinsulinism childhood intellectual disability hypoglycemia, good if diagnosed diazoxide
and hyperammonemia hyperammonemia; and treated early
confirm by mutation
analysis in glutamate
dehydrogenase gene
February 2016
Tetrahydrobiopterin 2 to 12 months Cognitive regression, Elevated phenylalanine Outcome can be Tetrahydrobiopterin
deficiencies34 microcephaly, in plasma amino acids, good if diagnosed supplementation;
generalized seizures, abnormal pterins and and treated early may need additional
irritability, dystonia, neurotransmitters supplementation with
rash, basal ganglia in CSF neurotransmitter
calcifications precursors based on type
Glucose transporter Birth to early Seizures (infantile- Low CSF/plasma glucose Variable, Ketogenic diet
deficiency33Y35 childhood onset focal or with normal or low depending
generalized, or lactate; confirm with on duration of
early-onset absence SCL2A1 genetic testing symptoms prior
epilepsy), microcephaly, to treatment with
developmental ketogenic diet
Continuum (Minneap Minn) 2016;22(1):60–93

delay, acquired ataxia,
paroxysmal dyskinesia
Cerebral folate Childhood to Intractable epilepsy, Low CSF Variable, Folinic acid
deficiency adolescence intellectual disability methyltetrahydrofolate; depending supplementation
or regression, further testing requires on exact etiology 0.5Y5 mg/kg/d orally
microcephaly, mutation analysis in and duration of
dyskinesias, autism FOLR1 gene, assessment symptoms prior
for antibodies to folate to treatment
receptors, and if these
are negative, a workup
for secondary causes of
cerebral folate deficiency
should be undertaken
Mitochondrial Infancy to Focal or generalized Elevated plasma Variable, Avoid valproate; treat
disorders33 adulthood seizures, spasms, and CSF lactate; may depending with mitochondrial
deafness, myopathy, have evidence of on specific type cocktail (L-carnitine,
lactic acidosis, cardiac, renal, or coenzyme Q, riboflavin);
ataxia, optic atrophy, hepatic dysfunction; ketogenic diet may be
hepatic dysfunction elevated lactate peak on MR helpful in some conditions
spectroscopy, muscle biopsy,
and specific genetic analysis
Congenital Infancy to Developmental Abnormalities in Variable Symptomatic
disorders of childhood delay, hypotonia, carbohydrate deficient depending
glycosylation failure to thrive, transferrin analysis; on cause

multisystem disease, confirm with specific
inverted nipples or genetic analysis
abnormal fat pads,
cerebellar hypoplasia
CSF = cerebrospinal fluid; EEG = electroencephalogram; GABA = ,-aminobutyric acid; MR = magnetic resonance; MRI = magnetic resonance imaging.
89
Pediatric Epilepsy
TABLE 4-3 Progressive Myoclonic Epilepsy Syndromes
Disease or Age at Clinical

Condition Onset Presentation Investigations Prognosis
Tay-Sachs disease 4Y9 months Exaggerated Hexosaminidase Death in 2Y4 years
and Sandhoff startle reflex, A deficiency
disease developmental (Tay-Sachs disease)
regression, visual loss, and hexosaminidase
cherry red spot A and B deficiency
(Sandhoff disease)
Tetrahydrobiopterin 2Y12 months Cognitive regression, Urine for pterins May respond to
deficiencies microcephaly, tetrahydrobiopterin
generalized seizures,
irritability
Alpers disease 0Y5 years Progressive cognitive Genetic: POLG1 Death, usually
deterioration, mutation due to hepatic
peripheral neuropathy, failure or status
recurrent status epilepticus
epilepticus and
epilepsia partialis
continua,
hepatic failure
Juvenile Huntington 5Y20 years Myoclonic tremor, Genetic: expanded Slow progression
disease chorea, cognitive trinucleotide to death in
regression, CAG repeat on 10Y20 years
behavior change chromosome 4p16.3
Neuronal ceroid Infancy to Progressive seizures, Skin, rectal, conjunctival, Death within
lipofuscinosis adulthood, ataxia, myoclonus, or brain biopsy 1Y15 years,
depending dementia, visual loss demonstrating depending
on subtype with some subtypes, characteristic on subtype
cerebral atrophy, ultrastructural
pyramidal and pathology; genetic
extrapyramidal signs diagnosis available
for many subtypes
Sialidosis type 1 8Y15 years Decreased vision, !-Neuraminidase Profound impairment
cherry red spot, from myoclonus,
Urine
burning extremity death in third or
oligosaccharides
pain, progressive fourth decade
myoclonus, cognition
mildly impaired
Sialidosis type 2 0Y10 months Coarse features, !-Neuraminidase Often severe
in infantile visual deficits,
form or cherry red spot, Urine
adolescence generalized seizures, oligosaccharides
in juvenile burning extremity
form pain, dementia
Unverricht- 6Y18 years Ataxia, mild cognitive Genetic: EPM1 (21q22.3) Slow progression
Lundborg deterioration, with tendency
disease generalized to stabilize
tonic-clonic seizures in adulthood

TABLE 4-3 Progressive Myoclonic Epilepsy Syndromes Continued from page 90
Disease or Age at Clinical

Condition Onset Presentation Investigations Prognosis
Lafora disease 6Y19 years Generalized tonic-clonic Genetic: EMP2A Rapidly
and occipital seizures, or EMP2B progressive to
rapid cognitive Axillary skin biopsy death within
regression 2Y10 years
Myoclonic epilepsy 3Y65 years Partial or generalized Genetic testing of Variable
with ragged seizures, deafness, mitochondrial DNA
red fibers myopathy, lactic
Muscle biopsy for
acidosis, ataxia,
ragged red fibers
optic atrophy
Gaucher disease Childhood to Supranuclear gaze Glucocerebrosidase Variable but
early adulthood palsy, generalized deficiency often more
or partial seizures, severe if
rigidity, ataxia, younger onset
cognitive regression,
splenomegaly
Dentatorubral- 6Y69 years Choreoathetosis, CAG expansion Variable
pallidoluysian dementia, psychosis, at 12p13
atrophy (DRPLA) ataxia
DNA = deoxyribonucleic acid.
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Review Article

Infantile, Childhood, and

Continuum (Minneap Minn) 2016;22(1):60–93.

INTRODUCTION many children have a specific elec-

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FIGURE 4-2 Imaging of the patient in Case 4-1. Coronal

Comment. The asymmetric manifestations of this child’s clinical seizures

Children with West syndrome have by fever or hyperthermia. Classically,

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KEY POINT Treatment. Prophylactic medication Electrical Status Epilepticus in

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Continued from page 71

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period of 1 to 2 years if the EEG family history is frequently positive for

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induced by inappropriate AEDs such Prognosis. Outcome is variable in

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ADOLESCENT-ONSET EPILEPSIES Juvenile Absence Epilepsy

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Important Genetic and includes a summary of several of the

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TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies

Gene or Other Clinical Interictal EEG

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Gene or Other Clinical Interictal EEG

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Gene or Other Clinical Interictal EEG

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Gene or Other Clinical Interictal EEG

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Gene or Other Clinical Interictal EEG

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