EPILEPSY SYNDROMES AND THEIR TREATMENTS: AN UPDATE

Howard P. Goodkin, MD, PhD

University of Virginia
Charlottesville, VA
"The seizure is only the symptom that brings the patient to the physician. The epileptic
syndrome of which the seizure is a symptom is the determinant of the prognosis and is the
product of the underlying disease. Thus, the family history, age at onset, rate of progression,
presence or absence of neurological abnormalities, presence or absence of interictal
electroencephalographic (EEG) abnormalities, and response to medication all contribute to the
diagnosis of the syndrome. (Dreifuss and Ogunyemi, 1992)
Modern-day attempts to classify the epilepsies date back to 1969 (Gastaut, 1969), with the International League
Against Epilepsy (ILAE) publishing its first official proposed classification of the epilepsies in 1970 (Merlis, 1970).
Subsequent clarifications or revisions were published in 1985, 1989, 2001, 2006, and, most recently, 2010 (See
section E. References for ILAE Classifications). The continued need to modify the initial proposal represents an
evolution necessitated by advances in genetics, imaging, and basic science (Berg et al, 2010).
The changes proposed in the 2010 report of the ILAE Commission on Classification and Terminology (Berg et al,
2010) represent a major transformation from the previous classification schemes. Lost is the prior dichotomy of
localization-related vs. generalized epilepsy. In the newly proposed system, the epilepsies are subdivided into
electroclinical syndromes (i.e. clinical entities that are identifiable on the basis of a typical age onset, specific
EEG characteristics, seizure type, and often other features which, when taken together, permit a specific
diagnosis; Berg et al, 2010) sorted based on age of onset; constellations (clinically distinctive entities on the
basis of specific lesions or other causes; many of these constellations are amenable to epilepsy surgery);
structural/metabolic epilepsies (epilepsies secondary to structural or metabolic lesions or conditions not fitting
electroclinical syndromes); and epilepsies of unknown cause. For an ongoing discussion of the proposed changes
and possible revisions, please refer to the following website hosted by the ILAE (last accessed on February 2,
2014): http://www.ilae.org/Visitors/Centre/Organization.cfm
A. The Causes of Epilepsy.
The 2010 Commission report recommends that the terms that have been used to separate the epilepsies based
on cause (idiopathic, cryptogenic, and symptomatic) be removed from the epilepsy lexicon as these words were
frequently misused and are no longer relevant given recent advances in genetics. The 2010 report proposed that
etiology should be classified as genetic, structural-metabolic, and unknown cause. More recently, it has been
recommended that the etiological categories been expanded to six non-exclusive etiological causes: genetic,
structural, metabolic, immune, infectious, and unknown
(www.ilae.org/Visitors/Centre/Documents/OrganizationEpilepsy.pdf).
Of the prior terms, idiopathic created the most confusion over the years. Prior to the 19th century, the term
idiopathic described any epilepsy of cerebral origin in contrast to those epilepsies which may arise from another
part of the body (e.g. stomache). The intended purpose of this term within the ILAE classification system was to
differentiate the idiopathic or primary epilepsies from the symptomatic or secondary epilepsies. The idiopathic
epilepsies were those that occurred in the absence of a structural lesion or cognitive/psychiatric comorbidities,
were frequently self-limited, and of presumed genetic etiology (Committee on Classification and Terminology of
the ILAE, 1989). Based on these features, the implication was that an idiopathic epilepsy was benign, in contrast
to the symptomatic epilepsies that tend to persist, be resistant to medication, and often had obvious
cognitive/psychiatric comorbidities (Dreifuss and Henriksen, 1992; see Section B. Old Labels for further
discussion of the term benign).
However, these prior concepts no longer hold. First, the idiopathic epilepsies are not necessarily void of cognitive
and behavioral dysfunction (e.g. Wirrell et al, 1997; Wirrell, 2003;Trinka et al, 2006; Moschetta et al, 2011).
Second, there are increasing examples in which a genetic etiology can be associated with difficult-to-treat

2014 The American Academy of Neurology Institute.

epilepsy and a poor developmental outcome. (Note: Although genetic and inherited are not synonymous,
replacement of idiopathic with genetic has been criticized due to the potential negative psychological and social
impact that being diagnosed with a genetic epilepsy may have on the patient or their family).
An example of a recently described genetic epilepsy associated with moderate-to-profound intellectual disability is
KCNQ2 encephalopathy (Weckhuysen et al, 2012; Saitsu et al, 2012; Kato et al, 2013; Milh et al, 2013;
Weckhuysen et al, 2013) that results from mutations of KCNQ2, which encodes for potassium voltage-gated
channel, KQT-like subfamily, member 2. This protein is a subunit of the M channel, a slowly activating and
deactivating potassium channel involved in regulation of neuronal excitability.
Mutations of KCNQ2 were first linked to benign familial neonatal seizures (BFNS; Biervert et al, 1998; Singh et al,
1998). This familial electroclinical syndrome (Wirrell and Nickels, 2010) consists of focal, multifocal, as well as
generalized seizures in an otherwise healthy full term newborn. Frequently, these events are described as brief
(seconds to minutes) episodes of tonic posturing of the limbs that can be associated with a shrill cry and apnea.
Untreated the seizure can occur frequently throughout the day and status epilepticus has been observed. The
interictal EEG is often normal; although focal epileptiform discharges may be present. Electrographically, the ictal
event is associated with generalized suppression. Imaging should be normal.
Typically age of onset BFNS is the first week of life (day 2 to 8); however, onset can occur as late as 4 months.
The epilepsy is self-limited with most children seizure free by 18 months and developmental outcome is good.
However, upwards of 15% may develop epilepsy later in life with generalized tonic or tonic-clonic seizures.
Given reports of unfavorable outcome associated with KCNQ2 mutations and BFNS (Dedek et al, 2003; Borgatti
et al, 2004; Steinlein et al, 2007; Schmitt et al, 2005), Weckhuysen and colleagues (2012) screened a cohort of
80 children with intellectual disability in the setting of neonatal or early infantile onset (<3 months of age) seizures
for mutations in KCNQ2 and KCNQ3, which had also been linked to BFNS (Charlier et al, 1998).
Of the 80 children, 8 (10%) had novel heterozygous missense mutations of KCNQ2. These mutations lead to a
reduction of the M-current as the result of a dominant-negative mutational effect (Orhan et al, 2013). These 8
children had seizure onset within the first week of life. The seizure semiology was similar to that of BFNS (tonic
accompanied by motor and autonomic features). However, the initial interictal EEG was abnormal due to the
presence of a burst suppression pattern and early MRI of the brain demonstrated the presence of basal ganglia
and thalamic hyperintensities, an MRI pattern that would typically be attributed to hypoxia-ischemia or potentially
a metabolic disorder.
During the first year, seizures can be frequent and difficult to treat but self-limited in 7 patients (resolution age 9
months to 4 years) with 1 child continuing to have frequent tonic seizures at 5.5 years of age and 1 child with a
recurrence at 8 years. In contrast to BFNS, all children tend to develop moderate to profound intellectual
disabilities despite eventual improvement in the EEG (normal or mild slowing) and MRI.
B. OLD LABELS
BENIGN. The benign epilepsies are those that are either easily treated or require no treatment and remit without
sequelae (Engel, 2001). Those epilepsy syndromes which have been considered benign include benign neonatal
familial seizures, benign infantile epilepsy, benign familial infantile epilepsy, benign childhood epilepsy with
centrotemporal spikes (BECTS), Panayiotopoulos syndrome, childhood absence epilepsy, late onset-childhood
occipital epilepsy (Gastaut type), juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with
generalized tonic-clonic seizures alone (Vigevano et al, 2009).
As noted above in A. Causes of Epilepsy, designating a syndrome benign does not exclude the possibility of
comorbid behavioral or cognitive difficulties. Indeed, the authors of the 2010 Committee report have
recommended against the use of this term based on the argument that it belies the growing understanding of the
relationship between the epilepsies and a wide variety of brain disorders including cognitive, behavioral, and
psychiatric illness as well as sudden death and suicide. Benign can be misleading and leave physicians,
patients, and families unaware of and unprepared to address these associated disorders.
In this regard, BECTS, which represents approximately 15% of childhood epilepsies, can serves as a prototype
(Wirrell et al, 2011). In this syndrome, the seizures arise from the lower Rolandic region and are characterized by
drooling, dysarthria, tingling or clonic movements of the unilateral lower half of the face. At night, the parents are
2014 The American Academy of Neurology Institute.

typically alerted to the seizure by a guttural sound prior to rapid secondary generalization. The majority of
seizures are short; however, status epilepticus has been reported. The pathognomic interictal EEG demonstrates
the presence of a centrotemporal dipole. Imaging of the head is typically normal.
The peak age of onset of BECTS is approximately 6-7 years of age, with the majority of cases presenting
between 5 and 10 years of age. However, rare cases as young as 1 year and as old as 16 years have been
reported. Some choose not to treat BECTs as it is unusual for these children to have more than 3 seizures and
there is often spontaneous remission within 2 to 4 years of presentation. Antiseizure medications that have been
used to treat this condition include carbamazepine, valproate, gabapentin, levetiracetam, and oxcarbazepine
(Glauser et al, 2013)
In the report that proposed the benign designation for this syndrome, Blom and colleagues (1972) reported on the
long term outcome of 23 patients older than 18 years of age. It is stated that none of them had experienced any
difficulty in school or choosing a profession because of their seizures. Although more modern studies have
demonstrated good long term cognitive outcome (e.g. Lindgren et al, 2004; Callenbach et al 2010), there is
increasing evidence for cognitive and learning difficulties during the years that the epilepsy is active (e.g.
Northcott et al, 2007; Kramer, 2008; Genizi et al, 2012; Besseling et al, 2013).
As alternative to benign (and idiopathic when the intent was to imply a favorable outcome), the Committee has
proffered self-limited and pharmacoresponsive. The attempt to limit the use of benign is not without its critics (e.g.
Panayiotopoulos, 2012). However, despite the Committees recommendation, it is suspected that many will
continue to designate these syndromes as benign, especially as the syndromic names in this category have not
yet been changed.
CATASTROPHIC. The 2010 Committee report also recommends that the term catastrophic be shed due to its
strong emotional overtones. For the epilepsies previously designated catastrophic, the 2010 Committee report
endorses the concept of epileptic encephalopathy, which was originally introduced in 2006.
The distinctive feature of an epileptic encephalopathy is the presence of severe cognitive and behavioral
impairments that commence and/or worsen after the onset of the epilepsy. For these syndromes, it is proposed
that that the epileptic activity may contribute to the encephalopathy. The electroclinical syndromes that fall under
this rubric include Ohtahara syndrome, Early Myoclonic Encephalopathy, West Syndrome, Dravet Syndrome,
Lennox-Gastaut syndrome, and Landau-Klefner syndrome. As a group, these disorders tend to be difficult to treat
(i.e. pharmacoresistant).
A prototypic epileptic encephalopathy is West syndrome (Tuxhorn, 2011). West syndrome is characterized by the
triad of epileptic spasms, an interictal EEG demonstrating the presence of hypsarrhythmia, and a severe
intellectual disability. The spasms consist of brief, massive flexion, extension, or mixed contraction of the axial
musculature typically shortly after awakening, tending to occur in clusters, and coincident with an
electrodecrement on the EEG. The majority of children present between 3 and 7 months of age. The causes of
West Syndrome are multiple and include neurocutaneous syndromes, brain malformations and tumors, acquired
injuries, inborn errors of metabolism, and an expanding list of genetic mutations (e.g. ARX, CDKL5, FOXG1).
Standard initial treatment for West Syndrome includes hormonal therapies (ACTH or prednisolone) or vigabatrin.
Options for refractory epileptic spasms have included the ketogenic diet, valproate, and potentially surgery when
a focal lesion is identified. The recent evidenced-based guideline from the American Academy of Neurology and
the Practice Committee of the Child Neurology Society (Go et al, 2012) recommended hormonal therapy in
preference to vigabatrin for children with infantile spasms of undetermined etiology. Although a low dose ACTH
protocol was recommended, a recent survey of Child Neurology Society members (Mytinger and Joshi, 2012)
found that the majority of respondents (n=222; 18.5% of those polled) continue to use high dose ACTH protocols
of 150 IU/m2/day.
An important question with respect to any epileptic encephalopathy is whether early treatment can affect outcome
(Riikonen, 2010). OCallaghan and colleagues (2011) evaluated developmental outcome at 4 years of age of a
cohort of 77 children previously medically treated for infantile spasms as part of the United Kingdom Infantile
Spasms Study (UKISS; Lux et al, 2004). They found that children who were promptly diagnosed and received
prompt treatment had a better developmental outcome. Similarly, Mathern and colleagues (Jonas et al, 2005)
demonstrated that early surgical intervention for children with medically refractory infantile spasms was
2014 The American Academy of Neurology Institute.

associated with a better developmental outcome. These findings provide support to the hypothesis that early
identification and treatment of an epileptic encephalopathy can alter the developmental trajectory of these
children.
C. NEW SYNDROMES
Three new syndromes are included in the 2010 Committee report: genetic epilepsy with febrile seizures plus
(GEFS+), autosomal dominant frontal lobe epilepsy (ADNFLE), and autosomal dominant lateral temporal lobe
epilepsy (ADLTE; a.k.a. autosomal dominant partial epilepsy with auditory features, ADPEAF).
GEFS+ (Scheffer et al, 2009) is a heterogeneous electroclinical syndrome characterized by the presence of both
febrile seizures, which persist beyond 6 years of age, and afebrile seizures (generalized tonic-clonic, myoclonic,
absence, astatic, and focal-onset seizures). The interictal EEG may be normal or demonstrate nonspecific
findings that include typical 3 Hz generalized spike waves and focal discharges. Imaging is typically normal.
Treatment is determined by seizure type with the majority of children with this syndrome remitting by
adolescence.
The diagnosis of GEFS+ is dependent on a family history of epilepsy that can range from simple febrile seizures
to Dravet syndrome. Inheritance occurs in an autosomal dominant pattern with penetrance ranging from 60-90%.
The initial family described by Scheffer and Berkovich (1997) were later found to have a mutation in the voltagegated sodium channel 1 subunit gene (SCN1B). In the interim, mutations of SCN1A, SCN2A, SCN9A ,
GABARG2, and GABRD have all been correlated with a GEFS+ phenotype.
ADNFLE (Steinlein, 2001) is characterized by focal seizures of frontal lobe onset consisting of brief dystonic
posturing followed by complex hypermotor activity and moaning. An aura of fear may also be described. Clusters
of brief (5 to 30 seconds) seizures may occur during non-REM sleep. Daytime seizures are rare. Seizure onset is
typically around 11-12 years of age with a range of 1 to 30 years. ADNFLE is often initially misdiagnosed as
nightmares or other parasomnias. Abnormalities that have been observed on interictal EEG include focal slowing
or attenuation over the anterior head regions and frontally dominant paroxysmal epileptiform discharges. Ictally,
bifrontal, high-voltage sharp and slow waves or low-amplitude, paroxysmal fast activity may be observed. Head
imaging is normal. Cognitive comorbidities are rare but can occur. The seizures typically respond well to
treatment and reduce in frequency as the patient ages.
A family history of nocturnal frontal lobe epilepsy may be present or affected family members may have been
previously misdiagnosed with a parasomnia or behavioral problem. Inheritance is autosomal dominant with
incomplete penetrance (~30 to 100%). ADNFLE has been linked to mutations of genes encoding the
2
(CHRNA2), 4 (CHRNA4), and 2 (CHRNB2) subunits of the nicotinic acetylcholine receptors (nACHR).
Mutations of KCNT1, which encodes the sodium-activated potassium channel subunit KCNT1 (a.k.a, KCa4.1),
have been found in families and a sporadic case in which there were comorbid psychiatric features that
accompanied the nocturnal frontal lobe seizures (Heron et al, 2012).
ADLTE/ADPEAF (Nobile et al, 2009) is characterized by focal seizures that arise from the cortex of the lateral
temporal lobe and frequently have a prominent auditory aura that manifests as ringing, whistling, or
humming/singing. Associated features have included reports of ictal aphasia as well as other sensory symptoms
such as complex visual hallucinations, psychic auras, olfactory hallucinations and vertigo. Secondary
generalization can occur. These seizures can be triggered by sounds. Seizure onset is typically during
adolescence but can be variable (typically 18 years of age, range 1 year to 60 years). Diagnosis may be delayed
as the symptoms can be mild. Interictal EEG findings may demonstrate focal temporal slowing. MRI of the brain is
usually normal. The seizures are responsive to standard antiseizure medications but may recur when the drug is
discontinued.
ADLTE is inherited in an autosomal dominant pattern with penetrance rates ranging from approximately 50 to
85%. In several families with ADLTE, this syndrome was associated with a mutation of the LGI1 (leucine-rich,
glioma-inactivated 1) gene. Unlike other electroclinical syndromes for which a gene mutations have been
identified, ADLTE is unique in that LGI1 does not encode for an ion channel or receptor subunit. LGI1 is
expressed during neural development and associated with both presynaptic potassium channels and the
postsynaptic protein complex. Yet, how this mutation triggers epileptogenesis remains unknown.

2014 The American Academy of Neurology Institute.

D. PUTTING CLASSIFICATION OF EPILEPSY SYNDROMES TO THE TEST

Classification schemes provide for data simplification and a universal language. In terms of epilepsy, the
classification system must be accurate if it is to be used for providing prognostic information and assisting in
antiseizure medication choice (Glauser et al, 2013) while also creating a framework upon which clinical trials and
other epilepsy research can be performed.
As demonstrated by Berg and colleagues (Berg et al, 1999; Berg et al, 2000), the 1989 classification system had
a high degree of accuracy for the syndromic diagnosis of new onset epilepsy in children. In their study, Berg et al.
were able to classify the majority of a prospectively attained cohort of 613 children with new onset epilepsy using
the 1989 classification system (Berg et al, 1999). Two years later, the cohort was re-examined (Berg et al, 2000).
In the majority of cases (~86%), the initial syndromic diagnosis was correct. For those children who required
reclassification, an expected syndromic evolution (e.g. evolution of West syndrome to Lennox-Gastaut syndrome)
occurred in 24 children (~4%). Only approximately 10% (n=60; 9.8%) required rectification of the initial syndrome
diagnosis. For many of these, classification to a more specific syndrome occurred, often as the result of findings
on EEG.
Although no similar study is available for the 2010 revision, van Campen and colleagues (2013) found high
interobserver agreement between the 1989 classification and the 2010 revision suggesting that results similar to
those of Berg and colleagues could be expected using the 2010 revised syndrome format.
D. SUMMARY
The individual epileptic seizure is, as it were, but one of the pigments with which the illness is
painted, the picture of the illness itself is made up of a large number of such individual pigments
and an arrangement that is specific for the condition under consideration. (Dreifuss and
Ogunyemi 1992)
It is important to recognize that no classification system is perfect. As we make advances in our understanding of
each individual pigment within the arrangement that is the epilepsy syndrome, revisions will be required. As
correct classification is necessary for guiding decisions regarding the evaluation and management of the
epilepsies, it is imperative that the informed physician be aware of evolution within the internationally proposed
epilepsy classification system, the rationale for the changes, and the imperfections that still exist.
E. REFERENCES FOR THE ILAE CLASSIFICATIONS OF EPILEPSY
1970: Merlis JK. Proposal for an international classification of the epilepsies. Epilepsia 1970;11:114-119.
1985: Commission on Classification and Terminology of the International League against Epilepsy. Proposal for
classification of epilepsies and epileptic syndromes. Epilepsia, 1985;26:268-278.
1989: Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for
revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-399.
2001: Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the
ILAE Task Force on Classification and Terminology. Epilepsia 2001;42:796-803.
2006: Engel J. Report of the IALE Classification Core Group. Epilepsia 2006;47:1558-1568.
2010: Berg At, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and
epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 5:676685.
F. NOTE
For a clear and precise description the pediatric epilepsy syndromes and their treatment, the following reference
is recommended:
Wirrell E and Nickels KC. Pediatric Epilepsy Syndromes. Continuum. 2010;16:57-85.

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TABLE. Electroclinical syndromes and other epilepsies (modified from Berg et al, 2010)
Electroclinical syndromes
Electroclinical syndrome commencing during the neonatal period:
Benign familial neonatal epilepsy, early myoclonic encephalopathy, Ohtahara syndrome
Electroclinical syndromes commencing during infancy:
Epilepsy of infancy with migrating focal seizures, West Syndrome, Myoclonic epilepsy in infancy, Benign
infantile epilepsy, Benign familial infantile epilepsy, Dravet syndrome, Myoclonic encephalopathy in
nonprogressive disorders
Electroclinical syndromes commencing during childhood:
Febrile seizures plus (can start in infancy), Panyiotopoulos syndrome, Epilepsy with myoclonic atonic
seizures, Benign epilepsy with centrotemporal spikes, Autosomal-dominant frontal lobe epilepsy, Late
onset childhood occipital epilepsy (Gastaut type), Epilepsy with myoclonic absences, Lennox-Gastaut
syndrome, Epileptic encephalopathy with continuous spike-and-wave during sleep, Landau-Klefner
syndrome, Childhood absence epilepsy
Electroclinical syndromes commencing during adolescence or older:
Juvenile absence epilepsy, Juvenile myoclonic epilepsy, Epilepsy with generalized tonic-clonic seizures
alone, Progressive myoclonus epilepsies, Autosomal dominant epilepsy with auditory features, Other
familial temporal lobe epilepsies
Electroclinical syndromes with less specific age relationship:
Familial focal epilepsy with variable foci (childhood to adult), Reflex epilepsies
Distinctive Constellations
Mesial temporal lobe epilepsy with hippocampal sclerosis, Rasmussen syndrome, Gelastic seizures with
hypothalamic hamartoma, Hemiconvulsion-hemiplegia-epilepsy, Other
Structural metabolic
Malformations of cortical development, Neurocutaneous syndromes, Tumor, Infection, Trauma, Angioma,
Perinatal insults, Stroke, etc
Epilepsies of unknown cause
Conditions with seizures not traditionally considered epilepsy
Benign neonatal seizures, Febrile seizures.

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