seizures and epilepsy: an overview for...

Seizures and Epilepsy: An Overviewfor Neuroscientists

Carl E. Stafstrom1 and Lionel Carmant2

1Division of Pediatric Neurology, Departments of Neurology and Pediatrics, Johns Hopkins University Schoolof Medicine, Baltimore, Maryland 21287

2Division of Neurology, Department of Pediatrics, Sainte-Justine Hospital, Universite Montreal, Montreal,Quebec H3T 1C5, Canada

Correspondence: [email protected]; [email protected]

Epilepsy is one of the most common and disabling neurologic conditions, yet we have anincomplete understanding of the detailed pathophysiology and, thus, treatment rationale formuch of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with thegoal of providing neuroscientists an introduction to aspects that might be amenable toscientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed,various clinical syndromes are discussed, and aspects of differential diagnosis, treatment,and prognosis are considered to enable neuroscientists to formulate basic and translationalresearch questions.

This article provides an overview of seizuresand epilepsy for neuroscientists. We focus on

broad concepts, rather than clinical details, andraise questions related to mechanisms, epilepto-genesis, and therapeutic approaches that mightgenerate interest among basic researchers. Fur-ther information about differential diagnosis,drug doses, and clinical management are avail-able from numerous resources (Engel and Ped-ley 2008; Duchowny et al. 2012; Engel 2013).

We first define seizures and epilepsy andsummarize their classification, pathophysiolo-gy, and genetics. Diagnostic methods are thenconsidered, including the importance of an ac-curate historical description of an event suspect-ed to be a seizure and the appropriate use ofancillary/confirmative tests, such as electro-encephalogram (EEG), neuroimaging, and ge-netic studies. These modalities enable the clini-

cian to differentiate epilepsy from numerousclinical conditions that mimic seizures, buthave a nonepileptic pathophysiological basis.Examples of epilepsy syndromes are then de-scribed, selected based on their frequency inthe population or because they embody scien-tific questions that warrant elucidation. Finally,we provide an overview of treatment optionsand prognosis, including a consideration ofconditions that accompany epilepsy (comor-bidities) and complicate the daily lives of peo-ple with epilepsy. Subsequent articles in thiscollection explore the scientific basis of manyof the clinical concepts introduced here.

DEFINITIONS AND EPIDEMIOLOGY

A “seizure” is a paroxysmal alteration of neuro-logic function caused by the excessive, hyper-

Editors: Gregory L. Holmes and Jeffrey L. Noebels

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synchronous discharge of neurons in the brain.“Epileptic seizure” is used to distinguish a sei-zure caused by abnormal neuronal firing froma nonepileptic event, such as a psychogenicseizure. “Epilepsy” is the condition of recurrent,unprovoked seizures. Epilepsy has numerouscauses, eachreflecting underlying brain dysfunc-tion (Shorvon et al. 2011). A seizure provoked bya reversible insult (e.g., fever, hypoglycemia)does not fall under the definition of epilepsybecause it is a short-lived secondary condition,not a chronic state.

“Epilepsy syndrome” refers to a group ofclinical characteristics that consistently occurtogether, with similar seizure type(s), age of on-set, EEG findings, triggering factors, genetics,natural history, prognosis, and response to an-tiepileptic drugs (AEDs). The nonspecific term“seizure disorder” should be avoided.

Epilepsy is one of the most common neuro-logic conditions, with an incidence of approxi-mately 50 new cases per year per 100,000 pop-ulation (Hauser and Hersdorffer 1990). About1% of the population suffers from epilepsy, andabout one-third of patients have refractory ep-ilepsy (i.e., seizures not controlled by two ormore appropriately chosen antiepileptic medi-cations or other therapies). Approximately 75%of epilepsy begins during childhood, reflectingthe heightened susceptibility of the developingbrain to seizures.

CLASSIFICATION OF SEIZURESAND EPILEPSIES

The most recent International League AgainstEpilepsy (ILAE) classification of epileptic sei-zures and epilepsies (epilepsy syndromes), pub-lished in 2010, revises past classifications usingterminology and concepts appropriate for themodern era (Berg et al. 2010; Berg and Milli-chap 2013; Muro and Connolly 2014). Seizuresare divided into three categories: generalized,focal (formerly called partial), and epilepticspasms. Focal seizures originate in neuronal net-works limited to part of one cerebral hemi-sphere. Generalized seizures begin in bilateraldistributed neuronal networks. A seizure canbegin focally and later generalize. Seizures can

originate in the cortex or in subcortical struc-tures. Using a detailed history, EEG findings,and ancillary information, a physician can oftencategorize the seizure/epilepsy type, after whichan appropriate diagnostic evaluation and treat-ment plan is formulated.

The main subtypes of generalized seizuresare absence, generalized tonic–clonic (GTC),myoclonic, and atonic (Table 1). Absenceseizures (formerly called petit mal) involve star-ing with unresponsiveness to external verbalstimuli, sometimes with eye blinking or headnodding. GTC seizures (formerly called grandmal) consist of bilateral symmetric convulsivemovements (stiffening followed by jerking) ofall limbs with impairment of consciousness.Myoclonic seizures consist of sudden, brief(“lightning-fast”) movements that are not asso-ciated with any obvious disturbance of con-sciousness. These brief involuntary muscle con-tractions may affect one or several muscles;therefore, myoclonic seizures can be generalizedor focal. Atonic seizures involve the loss of bodytone, often resulting in a head drop or fall.

The clinical manifestations of a focal seizuredepend on the area of cortex involved. For ex-ample, a focal seizure arising from the occipitallobe may present with visual phenomena; fromthe precentral gyrus, with rhythmic clonic ortonic motor activity; and from the postcentralgyrus, with sensory symptoms, such as pares-thesias. When consciousness is impaired duringa focal seizure, that is, the patient is unable torespond normally to verbal or tactile stimuli,the seizure is classified as dyscognitive (former-ly called complex partial); seizures arising fromthe temporal lobe are often dyscognitive. Some

Table 1. Epileptic seizures

Generalized seizuresTonic–clonicAbsence

TypicalAtypical

MyoclonicAtonic

Focal seizuresEpileptic spasms

C.E. Stafstrom and L. Carmant

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seizures are preceded by an aura, which is a focalseizure wherein a patient retains awareness anddescribes motor, sensory, autonomic, or psy-chic symptoms. An aura precedes a focal dys-cognitive or generalized seizure by seconds orminutes and is most often experienced by pa-tients with temporal lobe epilepsy.

The origin of the third category of seizuretype, epileptic spasms, is uncertain. Epilepticspasms are manifest by sudden extension orflexion of extremities, held for several seconds,and then recur in clusters. Epileptic spasms canoccur at any age; when they begin in the firstyear of life, they comprise a syndrome calledinfantile spasms (IS) (West syndrome [WS];see below).

Epilepsies (epilepsy syndromes) (Table 2)were previously classified according to their on-set site (generalized or related to a specific corti-cal localization) and etiology, that is, whetherthe cause was known (symptomatic) or notknown (idiopathic). Here, we use the 2010 re-vised guideline for classification of seizures andepilepsy (Berg et al. 2010). The updated systemtakes into account expanding knowledge ofstructural and genetic causes, and includes theictal semiology (seizure type), syndrome diag-nosis (if present), and degree of functional im-pairment. New classification schemes will con-tinue to evolve as knowledge about epilepsypathophysiology, and genetics emerges.

PATHOPHYSIOLOGY AND GENETICS

A seizure can be conceptualized as occurringwhen there is distortion of the normal balancebetween excitation (E) and inhibition (I) in thebrain (Stafstrom 2010). This E/I imbalance canresult from an alteration at many levels of brainfunction, from genes and subcellular signalingcascades to widespread neuronal circuits. Thefactors that alter E/I balance can be genetic oracquired. Genetic pathologies leading to epilep-sy can occur anywhere from the circuit level(e.g., abnormal synaptic connectivity in corticaldysplasia) to the receptor level (e.g., abnormalg-aminobutyric acid [GABA] receptor subunitsin Angelman syndrome) to abnormal ionicchannel function (e.g., potassium channel mu-tations in benign familial neonatal epilepsy[BFNE]). Similarly, acquired cerebral insultscan alter circuit function (e.g., structural alter-ation of hippocampal circuitry following pro-longed febrile seizures or head trauma). Thedeveloping brain is particularly prone to sei-zures for a variety of physiological reasons (seeBerkovic 2015). Even in the normal developingbrain, excitatory synaptic function develops be-fore inhibitory synaptic function, favoring en-hanced excitation and seizure generation. In ad-dition, early in life, the neurotransmitter GABAcauses excitation rather than inhibition (Ben-Ari 2002; Pitkanen et al. 2015). These observa-tions partly explain why the very young brain isespecially susceptible to seizures. However, sei-zures cause less structural damage in the devel-oping brain than in the adult brain (Holmesand Ben-Ari 1998).

There has been a recent explosion of newinformation about the genetic basis of epilepsysyndromes. Both monogenic and polygenicmutations can lead to epilepsy (Poduri andLowenstein 2011). Many epilepsies have a com-plex genetic basis with multiple gene defectscontributing to a state of altered cellular excit-ability, which underlies epilepsy. For example,copy number variants, which are de novo orinherited deletions or duplications .1 kb, areincreasingly recognized as a source of geneticmutations in patients with epilepsy (Mullenet al. 2013; Olson et al. 2014). As genetics knowl-

Table 2. Examples of epilepsy syndromes accordingto age of onset

NeonatalBenign familial neonatal epilepsy (BFNE)

InfancyWest syndromea

Dravet syndromea

ChildhoodGeneralized epilepsy with febrile seizures plus

(GEFSþ)Childhood absence epilepsyLennox–Gastaut syndromea

Landau–Kleffner syndromea

Adolescence and adulthoodJuvenile myoclonic epilepsyaConsidered an “epileptic encephalopathy,” whereby

seizures themselves contribute to cognitive impairment.

Seizures and Epilepsy: An Overview

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edge expands, there is hope that syndrome-spe-cific therapeutic interventions can be designed(Thomas and Berkovic 2014).

DIAGNOSTIC EVALUATION

History and Examination

The history and neurologic examination are thecornerstones of the diagnosis of seizures andepilepsy, whereas laboratory evaluations serveas adjunctive tests. Important historical featuresinclude the clinical context in which the seizureoccurred, including premonitory signs, detailsof the seizure itself, such as phenomenology,responsiveness, focal features, and the postictalstate. Further inquiry centers on whether anepilepsy syndrome is present, guides the natureand extent of the evaluation, and determinestreatment and prognosis.

The neurological examination assesses focalsigns that might implicate or localize cerebralpathology. For example, increased tone on oneside of the body could indicate pathology in thecontralateral hemisphere, such as a cortical dys-plasia. The general physical examination is alsoimportant to determine whether the patient hasan underlying condition. For example, abnor-mal skin markings could indicate a neurocuta-neous disorder in which epilepsy is common,such as tuberous sclerosis or neurofibromatosis.

EEG

An EEG is a recording of the brain’s electricalactivity. It can detect abnormal electrical activ-ity, such as focal spikes or waves (consistent withfocal epilepsy), or diffuse bilateral spike waves(consistent with generalized epilepsy). A routineEEG will, preferably, include wakefulness, drow-siness, and sleep because the prevalence of epi-leptiform abnormalities varies in these differentstates of consciousness. Hyperventilation andphotic stimulation are activation proceduresperformed during an EEG to increase the yieldof epileptic activity. Having a patient hyperven-tilate for 3 min has a high yield of leading to anabsence seizure, related to the seizure-provokingeffect of alkalosis (Schuchmann et al. 2006).

Photic stimulation may elicit paroxysmal epi-leptiform activity or even a generalized seizurein a person susceptible to generalized epilepsy(Verrotti et al. 2012). Simultaneous video-EEGmonitoring for hours to days can increase thediagnostic yield or differentiate an epileptic sei-zure from a nonepileptic event. The EEG can berepeatedly normal in someone with epilepsy, es-pecially if seizures begin in the frontal or tem-poral lobe. In such cases, intracranial EEG mon-itoring, usually in the context of presurgicalevaluation, may be necessary to define a seizurefocus. The diagnosis of epilepsy is based on clin-ical information and the EEG should be regard-ed as confirmatory, not diagnostic. The standardteaching is “treat the patient, not the EEG.” Anexception to this guideline is absence epilepsy inwhich brief generalized bursts of spike-wave ac-tivity, even if not associated with obvious clini-cal changes, imply a high likelihood of absenceseizure recurrences that can go unrecognized.

Neuroimaging

Computed tomography (CT) and magnetic res-onance imaging (MRI) scans are important ad-juncts to the clinical examination and EEG inthe evaluation of a person with seizures. Neu-roimaging techniques are especially sensitive forcentral nervous system (CNS) structural lesions.Focal neurologic findings on examination (e.g.,unilateral weakness, asymmetric reflexes) man-date neuroimaging.

MRI is more likely to show an abnormalityin a patient with focal seizures, abnormal neu-rologic findings, or focal discharges on EEG.MRI is more sensitive than CT and is there-fore preferred, especially for the detection ofcortical malformation, dysgenesis, or hippo-campal sclerosis. Quantitative, computer-assis-ted volume analysis of the temporal lobes maydetect asymmetries that are not readily apparenton visual analysis of the scan. CT is valuable inthe acute setting to detect hemorrhage, calcifi-cation, or tumors.

Several new imaging techniques are availableto aid in the assessment of epilepsy (Kim et al.2010). MRI abnormalities can be correlated di-rectly with EEG activity. Functional MRI (fMRI)



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takes advantage of blood oxygen level depen-dence (BOLD) to image neuronal activationand map interictal or ictal epileptiform activityand localize language and memory. Magneticresonance (MR) spectroscopy measures the con-centrations of a variety of neurochemicals indifferent brain regions and can sometimes assistin localizing a seizure focus. Positron emissiontomography (PET) images the brain’s regionaluse of glucose with asymmetries suggesting areasof interictal or ictal abnormality. Single-pho-ton emission-computed tomography (SPECT)compares local blood flow discrepancies, infor-mation that is most useful when recorded dur-ing a seizure. Magnetoencephalography (MEG)assesses the brain’s dynamic electromagneticfields and can better localize epileptic dipoles,including those tangential to the scalp, whichcan be missed by conventional EEG (Caruso etal. 2013). These advanced modalities are usedmainly in epilepsy centers for presurgical evalu-ations (Kay and Szaflarski 2014).

Metabolic Evaluation

The type of seizure and syndrome dictates theextent of the metabolic workup (Pearl 2009).For example, a child with IS or Lennox–Gastautsyndrome is more likely to have a metabolic ordegenerative disorder than one presenting withsimple partial seizures. In metabolic disorders,seizures are typically accompanied by other ab-normalities, such as developmental delay, unex-plained vomiting, or coma. In neonatal seizures,a metabolic evaluation is mandatory, includinga screen of serum amino acids and urine organicacids, and blood lactate to screen for mitochon-drial disease. In addition to its more commonuse to evaluate CNS infection, cerebrospinalfluid can be analyzed for glucose transporterdefects (GLUT1 deficiency syndrome) (Pearsonet al. 2013) and rare (but sometimes treatable)neurotransmitter defects (Pearl et al. 2007).

Genetic Testing

As the genetic basis of epilepsies becomes pro-gressively unraveled, clinical testing will occupyan increasingly pivotal role in the clinic (Miche-

lucci et al. 2012; Olson and Poduri 2014). At thispoint, genetic testing is available for several sin-gle genes, as well as complex genetic disorders(see Coulter and Steinhauser 2015; Vezzani et al.2015). A basic karyotype can be performed toevaluate for a chromosomal anomaly, especiallyin a patient with dysmorphic features. If a spe-cific syndrome is suspected, an epilepsy panelof selected genes can be ordered (e.g., SCN1Afor Dravet syndrome [DS]). Comparative geno-mic hybridization (CGH) microarray evaluatestargeted chromosomal regions for copy numbervariants. When a genetic diagnosis is highly sus-pected, but other work up is unrevealing, theclinician can consider whole exome sequenc-ing of the patient and parents, a technique withrapidly expanding clinical use, especially in ep-ileptic encephalopathies of unknown etiology(Olson et al. 2014).

SELECTED EPILEPSY SYNDROMES

The most recent ILAE epilepsy classification dis-penses with the dichotomies used in the 1989classification (generalized vs. localization relat-ed, idiopathic vs. symptomatic) in favor of anorganization according to pathogenesis (genet-ic vs. structural/metabolic/autoimmune) andage of onset (Berg et al. 2010). Examples of ep-ilepsy syndromes are now provided. Details ofepilepsy syndromes not described here can befound elsewhere (Engel and Pedley 2008; Nab-bout and Dulac 2008).

Electroclinical Syndromes with Age-RelatedOnset

BFNE

BFNE is a neonatal epilepsy syndrome in whichseizures begin in the first week of life. Seizuresare focal clonic or focal tonic, often accompa-nied by apnea. They usually stop after a few daysor weeks. Except for seizures, the infants arenormal and evaluation fails to detect an etiolo-gy. The key to the diagnosis is a family historyof newborn or infantile seizures that resolved.The prognosis of BFNE is good, although�10%–15% of affected infants continue to



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have seizures beyond the neonatal period, eveninto adulthood (Steinlein et al. 2007).

BFNE is the first epilepsy syndrome to be ex-plained by a mutation in a voltage-gated ionchannel gene. BFNE has been linked to twogenes: KCNQ2 on chromosome 20q andKCNQ3 on chromosome 8q. These genes codefor voltage-gated potassium channel subunits,which regulate the M-current, a muscarine-ac-tivated neuronal current that turns off potassi-um channels (Rogawski and Bazil 2008). TheM-current stabilizes resting membrane poten-tial; its dysfunction leads to increased neuronalexcitability and seizures. It is not known whyseizures in BFNE affect neonates and then re-solve because the genetic defect is presentthroughout life.

WS

WS is characterized by the triad of epilepticspasms (usually during infancy, when it is calledIS), an interictal EEG pattern called hypsar-rhythmia, and intellectual disability. WS is anage-specific disorder, beginning primarily in thefirst year of life; the peak age of onset is between4 and 6 mo. The duration of an epileptic spasmis intermediate between a myoclonic jerk(which is briefer) and a tonic seizure (which ismore sustained). Spasms often occur in clustersof head nods, forceful flexion, or extension ofthe trunk and limbs. They frequently occur dur-ing sleep transitions, especially on awakening.

The interictal EEG pattern in WS is calledhypsarrhythmia, a disorganized, “chaotic” pat-tern of very high voltage slow waves and spikesover multiple cortical areas. The classic ictalEEG pattern is a generalized slow wave followedby background voltage attenuation in all chan-nels (“electrodecremental response”), accom-panied by a clinical spasm.

Most cases of WS have an identifiable cause,such as hypoxia-ischemia, intracranial hemor-rhage, CNS infection, developmental brainanomaly, or inborn metabolic error. Tuberoussclerosis complex (TSC) has an especially highincidence of IS (up to 50% of TSC patients).

Adrenocorticotrophic hormone (ACTH)and corticosteroids are the primary drugs used

to treat IS. The anticonvulsant mechanism ofACTH is not known; it may work via the hypo-thalamic-pituitary axis or directly affect neu-ronal membrane excitability (Stafstrom et al.2011). Vigabatrin, a GABA transaminase in-hibitor, is highly effective for spasms in childrenwith TSC. Infants with focal-onset spasms, suchas those caused by cortical dysplasia, may ben-efit from resective surgery.

WS is an epileptic encephalopathy with apoor prognosis. At least two-thirds of affectedchildren have intellectual disability. With age,the seizures often change from spasms to otherseizure types, such as those seen in Lennox–Gastaut syndrome (see below). Several animalmodels of IS have been reported recently, raisinghope that elucidating the pathophysiology of ISwill lead to more efficacious treatments (Staf-strom 2009; Swann and Moshe 2012; Lado et al.2013).

Febrile Seizures Plus

Children with febrile seizures plus (FSþ) (for-merly called generalized epilepsy with febrileseizures plus [GEFSþ]) have febrile seizures be-yond the age at which febrile seizures usuallystop (�5 yr). In addition, these children maydevelop additional afebrile seizure types, in-cluding GTC, absence, and myoclonic. There-fore, this syndrome differs from ordinary febrileseizures (see below) and represents a geneticpredisposition to epilepsy. In FSþ, the outcomeis variable; seizures resolve in some children, butpersist in others. In different families, geneticdefects have been identified in neuronal sodiumchannels (Escayg et al. 2000) and GABA recep-tors (Macdonald et al. 2010). Many patientswith FSþ have mutations in the a1 subunit ofthe voltage-gated sodium channel gene, SCN1A(Steinlein 2014).

DS

DS, previously called severe myoclonic epilepsyof infancy, is a rare epilepsy syndrome in whichchildren present with seizures before 18 mo ofage (Dravet et al. 2005). The initial seizure oftenoccurs with a fever and has a hemiclonic semi-



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ology. Later, other seizure types occur and thechild shows developmental regression. Seizurestend to be refractory to medications, althoughstiripentol has shown some efficacy; sodiumchannel blockers must be avoided.

About 70%–80% of patients with DS have amutation in the SCN1A gene, mostly sporadic,with haploinsufficiency causing nonfunctionalsodium channels. Therefore, the spectrum ofSCN1A mutations in epilepsy spans from mild(FSþ–missense mutations) to severe (DS–trun-cating mutations) (Escayg and Goldin 2010).The presence of SCN1A mutations in multipleepilepsy syndromes has generated considerableresearch interest. Mice with knockout of SCN1Areplicate many clinical features of DS (Oakleyet al. 2011). The cellular defect may be abnormalsodium channels in cortical interneurons, al-lowing increased firing of downstream excitato-ry pyramidal neurons, which are released frominhibitory control (Yu et al. 2006). Several lab-oratories are pursuing potential methods to re-mediate the effect of the SCN1A mutation (Liuet al. 2013; Lenck-Santini and Scott 2015).

Lennox–Gastaut Syndrome

Lennox–Gastaut syndrome (LGS) begins be-tween the ages of 1 and 6 yr. Patients developmedically intractable seizures (up to hundredsper day), constituting an epileptic encephalop-athy. LGS characteristics include: (1) slow spike-wave EEG pattern (1.5–2.5 Hz), (2) intellectualdisability, and (3) multiple seizure types (e.g.,tonic, GTC, atypical absence, atonic, tonic,myoclonic).

Tonic seizures consist of periods of sus-tained muscle contractions and are especiallyfrequent during sleep. Atonic (astatic) seizures,or drop attacks, occur without warning and of-ten result in head or face injuries. Atypical ab-sences occur frequently in children with LGS.These have a gradual onset and cessation duringwhich the child appears confused with behav-ioral arrest. It can be difficult to tell when oneseizure ends and the next one begins becausealertness and activity level may not improve be-tween epileptiform bursts, which occur in long

runs during wakefulness and even more fre-quently during sleep.

Children with LGS are already handicappedneurologically. The numerous LGS etiologiesoverlap those of WS and include hypoxic braininjury, cerebral dysgenesis, and neurocutaneousdisorders. The encephalopathy in the majorityof children with LGS is static, although a degen-erative disorder, such as neuronal ceroid lipo-fuscinosis, can present as LGS.

Seizures in LGS patients are notoriously re-fractory to AEDs. Drug therapy is individual-ized to seizure type and frequency (Hancockand Cross 2013). Patients may benefit from val-proate, clonazepam, lamotrigine, topiramate,rufinamide, lacosamide, clobazam, or felba-mate. Because of the intractability of the sei-zures, there is a tendency to place patients onmultiple AEDs. This polypharmaceutical ap-proach often causes drug toxicity with somno-lence, fatigue, nausea, ataxia, and rarely resultsin optimal seizure control.

Children with LGS have a poor neurologicprognosis. Over time, the atonic, myoclonic,and atypical absence seizures may decrease,but GTC seizures increase and partial seizuresemerge. In addition to debilitating seizures, in-tellectual impairment hinders children withLGS from leading independent lives. The lackof an experimental model hinders progress inthis disorder. One potentially informative ani-mal model mimics atypical absence seizures(Cortez et al. 2001).

Landau–Kleffner Syndrome

Landau–Kleffner syndrome (LKS) (acquiredepileptic aphasia) is a rare epilepsy in which achild loses previously acquired language abili-ties because of seizures or epileptiform abnor-malities on EEG. In its pure form, LKS occurs inpreviously normal children with normal lan-guage development who gradually lose the abil-ity to understand spoken language and producespeech (Landau and Kleffner 1957). More re-cently, the syndrome has expanded to includebehavioral and cognitive deterioration, includ-ing autistic symptoms. Regression of social andlanguage skills is frequently seen in children



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with autism, with or without accompanying sei-zures, so the differentiation of autism and LKScan be difficult. In LKS, compared with autism,social skills are better preserved. The pathophys-iology of LKS is unknown. Imaging studies aregenerally negative although PET studies haveshown bitemporal abnormalities, supportingthe hypothesis that language-related brain re-gions are dysfunctional in LKS (Issa 2014).

EEG abnormalities in LKS may include gen-eralized, focal, or multifocal spikes or spikewaves. If focal, discharges commonly involveone or both temporal or perisylvian regions.One hypothesis is that the epileptiform dis-charges interfere with language production;alternatively, both the language dysfunctionand EEG abnormalities might be independentconsequences of the same underlying brain pa-thology. Successful treatment of the seizures orEEG discharges is not usually accompaniedby language or behavioral improvement. Theoutcome is variable; some children recovercompletely, usually in adolescence, whereas oth-ers have persistent aphasia in adulthood. Theseizures usually respond readily to AEDs (e.g.,valproate, benzodiazepines), although the lan-guage impairment does not (Van Bogaert 2013).Treatment with steroids or subpial resection iscontroversial.

Childhood Absence Epilepsy (CAE)

Absence seizures, characterized by staring anddiminished responsiveness, can be part of sev-eral epilepsy syndromes, including CAE and ju-venile myoclonic epilepsy (JME). Note that “ab-sence” refers to both a seizure type and anepilepsy syndrome. CAE onset is between 4and 10 yr of age. The seizures start abruptlyand, generally, last from 5 to 20 sec. When aseizure ends, the patient immediately resumesprior conversation or activity. Because absenceseizures are brief and nonconvulsive, they can beeasily missed or misdiagnosed.

The frequency of absence seizures variesfrom a few to hundreds per day. Stress and fa-tigue increase their frequency. Most childrenwith typical absence seizures have a normal neu-rologic examination and intelligence, although

school performance may be impaired if seizuresare frequent.

The EEG background is normal, whereasthe seizure itself is accompanied by generalized3-Hz spike-wave complexes. This EEG abnor-mality is a marker for genetic susceptibility toabsence epilepsy. Hyperventilation is a potentactivator of absence seizures, and this simpletest is used in the clinic to diagnose absenceseizures and assess treatment effectiveness.

The pathophysiology of absence seizuresinvolves altered function of thalamocortical cir-cuits, with thalamic relay neurons firing abnor-mally owing to calcium channel dysfunction(Cain and Snutch 2013). Ethosuximide and val-proic acid (VPA) are effective for treating ab-sence seizures (Glauser-Menachem et al. 2013).Both drugs block low-threshold calcium cur-rents in thalamic neurons (Coulter et al. 1989).CAE (and other genetic generalized epilepsies)has a complex genetic basis with only a few per-cent transmitted monogenically. The prognosisof CAE is good with �75% of children outgrow-ing the absence seizures during adolescence.

JME

JME is an epilepsy syndrome that typically be-gins in adolescence and consists of myoclonic orGTC seizures in an otherwise normal individu-al. The myoclonic jerks may cause the patient todrop or fling objects, especially in the morning.GTC seizures occur in as many as 90% of pa-tients with JME, and the syndrome often pre-sents with these. The myoclonic and GTC sei-zures often occur soon after awakening. Up to35% of patients with JME also have absenceseizures. Seizures are exacerbated by fatigue,sleep deprivation, and alcohol use.

The neurologic examination and intelli-gence are usually normal in JME. Multifactorialinheritance is presumed. Some studies havelinked JME to chromosome 6p, a locus that ap-pears to be dominantly inherited, but a respon-sible gene has not yet been identified, and thismutation accounts only for a small fraction ofpatients (Michelucci et al. 2012).

The interictal EEG in JME shows charac-teristic bursts of fast (3.5- to 6-Hz) spike-wave



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complexes. Photic stimulation may activatethese epileptiform discharges. Valproate is themost effective AED, but, in females, otherbroad-spectrum AEDs are preferable (levetira-cetam, lamotrigine). Long-term treatment isusually required.

Epilepsy Syndromes Caused by Structural/Metabolic/Autoimmune Causes

Epilepsy syndromes, previously called “sympto-matic localization-related,” are those in whichseizures arise in a focal brain region caused by anacquired or congenital lesion. Etiologies includetumor, scar (e.g., hippocampal sclerosis), corti-cal dysplasia, porencephalic cyst, and vascularmalformation. The seizure semiology is relatedto the region of brain affected; seizures oftenbegin focally and then generalize. The interictalEEG will show focal spikes, sharp waves, orslowing, related to the area of brain involved.If neuroimaging results, EEG evidence of sei-zure onset, and ancillary data (e.g., neuropsy-chological findings) align, surgical interventionis considered.

Temporal Lobe Epilepsy

The syndrome of mesial temporal sclerosis is apertinent example of a structural lesion (hippo-campal scarring), in which seizures often be-come intractable and for which surgery is a vi-able option (Thom et al. 2010; Bernhardt et al.2013). Seizures originate in the medial temporalregion with such manifestations as posturing,altered responsiveness, and memory/behaviorchange. Spread of seizure discharges beyondthe hippocampus is common. Seizures often be-come intractable and affective comorbidities arefrequent. When two medications fail, a surgicalevaluation should be undertaken. Extensive lab-oratory investigation has been performed to un-derstand the mechanisms of seizure genesis andspread. Impaired GABAergic inhibition, en-hanced synaptic excitation via axonal sprouting,and changes in ion channel distribution andfunction have all been implicated in the patho-physiology of temporal lobe epilepsy, and genet-ic factors may also play a role (Liu et al. 1995;

Buckmaster 2004; Dudek and Sutula 2007; Joshiet al. 2013).

Childhood Hemispheric Epilepsy Syndromes

Some important childhood epilepsy syndromesinvolve an entire hemisphere. Rasmussen’s en-cephalitis is a focal encephalitis that affectsonly one hemisphere and results in progressivehemiparesis, intractable epilepsy (focal seizuresthat can progress to become continuous, calledepilepsia partialis continua), and cognitive de-cline (Varadkar et al. 2014). Rasmussen’s en-cephalitis might have an autoimmune basis, butthe exact etiology has not been defined. Theunilateral pathology may be a result of focalbreakdown of the blood–brain barrier. Neuro-imaging shows progressive unilateral cortical at-rophy. Another hemispheric syndrome, Sturge–Weber syndrome (SWS; encephalotrigeminalangiomatosis), consists of a hemispheric vascu-lar malformation, leading to intractable epilepsyand hemiparesis. Mutations in GNAQ, a genegoverning angiogenesis, have recently beenidentified in SWS (Shirley et al. 2013). Someauthorities feel that early surgery (hemispherec-tomy) affords a better prognosis in hemisphericepilepsy syndromes (Hartman and Cross 2014).

Metabolic, Mitochondrial, and AutoimmuneEpilepsies

Epilepsies caused by a metabolic, mitochondri-al, or autoimmune etiology are increasingly rec-ognized. Any alteration of neuronal energy me-tabolism or use could result in E/I imbalanceand seizures. The role of autoantibodies to avariety of cellular proteins in patients with here-tofore undiagnosed neurological deteriorationis shedding new light on the ways in whichepilepsy can manifest (Davis and Dalmau2013; Miya et al. 2014; Holmes 2015).

Other

Neonatal Seizures

Neonatal seizures, occurring in the first 30 d oflife or before 44 wk postconception in prema-



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ture babies, represent a special class because oftheir age-specific characteristics, wide range ofetiologies, and unique pathophysiology. Sei-zures may be the first and only sign of CNS dys-function in a newborn, so their recognition iscritical.

Four types of neonatal seizure semiologyare described based on behavioral observations:subtle, generalized tonic, focal or multifocalclonic, and myoclonic. Subtle seizures may in-clude repetitive oral-buccal-lingual movements,such as sucking, pedaling movements of the legsor arms, or eye deviation. Subtle seizures areoften associated with severe CNS insults. Neo-natal tonic seizures involve posturing with in-termittent tonic extension of the arms and legs;they are usually associated with severe brain le-sions and most often occur in preterm infants.Clonic seizures consist of rhythmic jerking ofgroups of muscles in a focal or multifocal pat-tern. In multifocal clonic seizures, movementsmigrate from one part of the body to another.Focal seizures may be seen with localized brainmalformations or insults, such as a perinatalstroke, as well as in disorders affecting the braindiffusely, such as asphyxia, metabolic derange-ment, or infection. As a result of immature mye-lination and cortical organization, the neonatalbrain is unable to sustain generalized epilepti-form discharges, so GTC and absence seizuresdo not occur.

Simultaneous video-EEG monitoring canhelp to differentiate behaviors with EEG corre-lates (“epileptic seizures”) from behaviors thatdo not have associated EEG changes. Focal clon-ic seizures have the highest correlation with EEGictal abnormalities. Many behaviors consideredto be subtle seizures on clinical grounds (e.g.,chewing or pedaling movements) have no asso-ciated EEG abnormalities, suggesting that thesebehaviors are not epileptic in nature. Subtle ortonic seizures may represent brainstem dysfunc-tion or epileptic seizures originating from deepsubcortical structures not recordable on surfaceEEG.

The neonatal EEG is usually not specific fora particular etiology, but it may supply cluesabout the severity and time course of a CNSinsult. Epileptic discharges often occur without

overt clinical manifestations (“uncoupling” ofelectrographic and clinical seizures). For prog-nostic purposes, EEG background patterns andsleep–wake cycles are especially important. Am-plitude-integrated EEG (aEEG) is a new tech-nique allowing continuous bedside samplingof a limited number of EEG channels; aEEG isproving to be quite reliable in documentingprobable seizure events (Glass et al. 2013).

Establishing the etiology of a neonatal sei-zure is critical because the cause determines thetherapy and is highly correlated with outcome.Major causes of neonatal seizures include hy-poxic-ischemia (H-I), hypocalcemia, hypogly-cemia, hyponatremia, intracranial hemorrhage,infection, congenital malformations, geneticfactors, inherited metabolic disorders, and drugwithdrawal. H-I, mostly occurring before deliv-ery, is the most common cause of neonatal sei-zures.

The decision to treat an infant with recur-rent seizures is based on the seizure durationand frequency, associated autonomic dysfunc-tion, etiology, and EEG abnormalities. If sei-zures are brief and not associated with auto-nomic instability, treatment may be deferredor the infant treated with a short-acting benzo-diazepine. Conversely, neonates with frequentseizures, especially if they interfere with ventila-tion, require prompt and vigorous treatment.

Phenobarbital has been the primary drugused to treat neonatal seizures, but it is effective,50% of the time (Painter et al. 1999). Pheno-barbital or phenytoin sometimes suppressesclinical seizures, but electrographic seizures con-tinue (“uncoupling”). Any drug that targetsGABA receptors (barbiturates, benzodiazepines)may be ineffective or even exacerbate seizuresbecause of the depolarizing action of GABA inthe neonatal brain (Staley 2006; Berkovic 2015;Pitkanen et al. 2015). Active research is attempt-ing to untangle the role of potassium-chloridecotransporters and their developmental profilein the GABA depolarizing-to-hyperpolarizingswitch; inhibitors of these cotransporters mighthave clinical utility (Loscher et al. 2013). NewerAEDs, such as levetiracetam, may be effective,but there is an urgent need for more effectiveneonatal seizure treatments.



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Febrile Seizures

Febrile seizures occur in children from �6 moto 5 yr of age. Although the exact pathophysi-ology is unknown, febrile seizures represent anage-dependent response of the developing brainto fever. There is a genetic association, with fe-brile seizures occurring 2–3 times more fre-quently in affected families than in the generalpopulation. Overall, febrile seizures occur in2%–5% of children in the susceptible age range.

The two main types of febrile seizures are:(1) simple, and (2) complex or complicated.Simple febrile seizures are brief (,15 min),generalized, and do not recur within 24 h of thefirst one. Complicated febrile seizures are eitherprolonged (.15 min), have focal components(e.g., begins on one side of the body or involveslateralized eye deviation), or recur within 24 h.Simple febrile seizures do not require treatment,nor do most complicated febrile seizures.

A child who has had a single simple febrileseizure has a 33% chance of another febrile sei-zure with a subsequent fever. If a child has hadtwo simple febrile seizures, there is a 50%chance of a third febrile seizure. The recurrencerisk for additional febrile seizures is greatest if achild has had a first febrile seizure ,12 mo ofage or there is a family history of febrile seizures.

The more concerning risk is for the devel-opment of afebrile seizures (epilepsy). A signifi-cant proportion of adults with temporal lobeepilepsy (caused by mesial temporal sclerosis)had a prolonged febrile seizure as a child (Pat-terson et al. 2014). After a simple febrile seizure,the risk for epilepsy later in life is only slightlyhigher than for the general population, �2%.The risk of developing epilepsy after febrile sei-zures varies up to �9% and is greatest if thechild has preexisting neurologic impairment,such as developmental delay or cerebral palsy,a family history of epilepsy, or a complicatedfebrile seizure (prolonged, focal, recurrent)(Pavlidou and Panteliadis 2013).

An ongoing multicenter study (FEBSTAT) isinvestigating the consequences of febrile statusepilepticus in a large cohort using longitudinalclinical and MRI data (Lewis et al. 2014). Acomplete understanding of febrile seizures will

also require animal models to gain greater in-sight into the effects of hyperthermia and fever-related immunological changes in the develop-ing brain (McClelland et al. 2011).

NONEPILEPTIC DISORDERS THAT MIMICSEIZURES

Numerous paroxysmal behaviors mimic epilep-tic seizures by history or clinical presentation(Obeid and Mikati 2007). A few of the morecommon disorders are mentioned here. It isimportant to distinguish epileptic from non-epileptic behaviors because some nonepilepticphenomena respond to medications other thanAEDs and others require no specific treatmentother than reassurance or avoidance of the cir-cumstances that precipitate the spell.

Nonepileptic Seizures (NES)

NES, also called psychogenic seizures or pseu-doseizures, are paroxysmal changes in motoractivity or behavior that resemble epileptic sei-zures, but have no EEG correlate. Although theyare not epileptic seizures, NES can be disablingand often reflect major underlying psychopa-thology (Lortie 2013).

NES present with a variety of clinical forms.Many resemble GTC seizures, but the two sidesof the body are more likely to jerk out of phasewith each other. GTC activity in the setting ofpreserved consciousness favors a nonepilepticevent. However, caution is warranted as somebehaviors previously thought to be NES are ac-tually epileptic events. For example, seizuresoriginating in the supplementary area (SMA)of the frontal lobe involve bilateral motor activ-ity with preserved consciousness. Comparedwith NES, SMA seizures are briefer, more ste-reotyped, and often occur during sleep. Sei-zures originating in the orbitofrontal regionare now recognized to include screaming, affec-tive changes, such as intense fear, bilateral non-rhythmic limb movements, and even sexual au-tomatisms, for example, pelvic thrusting. Suchbehaviors were previously considered to reflectNES. These observations underscore the diffi-culty of differentiating between epileptic sei-



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zures and NES on clinical grounds. Video-EEGmonitoring is helpful to separate the two enti-ties. Of note, NES and epileptic seizures maycoexist in the same patient.

The patient and family are assured that thesymptom (seizure) is “real,” but does not in-volve abnormal neuronal discharges, so therapyis designed to address the underlying psycho-logical issues. The main therapeutic goal is toteach the patient alternative coping skills, so thatanxiety or psychological stress does not mani-fest in such a maladaptive fashion (LaFranceet al. 2013). The pathophysiology of NES is un-certain, and an important research question ishow and why psychological stress results in sei-zure-like behaviors.

Breath-Holding Spells (BHS)

Despite their name, BHS are involuntary reflexresponses. BHS are maximal in preschoolersand are, typically, outgrown by school age.Two types of BHS are cyanotic (also called cya-notic infantile syncope) and pallid (also calledpallid infantile syncope or reflex anoxic sei-zures).

Cyanotic BHS, the more common type, areprecipitated by anger or frustration. The hall-mark is crying, during which the child will stopbreathing (in expiration), become cyanotic, andlose consciousness. At that point, the child maybecome rigid, limp, or even shake, raising con-cern about a seizure. The pathogenesis of cya-notic BHS is complex, probably involving aninteraction between hyperventilation, Valsalvamaneuver, expiratory apnea, and intrinsic pul-monary mechanics.

Pallid BHS are more likely to be provoked byfright or an unpleasant stimulus (such as mildtrauma). A gasp is followed by loss of conscious-ness, pallor, bradycardia, diaphoresis, and limp-ness. Pallid BHS result from vagus nerve-medi-ated cardiac inhibition, causing diminishedcerebral blood flow.

Neither type of BHS is associated with anincreased predisposition to epilepsy, althoughseizure activity can occur at the end of a BHS.These “seizures” manifest as tonic stiffening ofthe extremities, sometimes with brief clonic

jerking, and are not epileptic. Instead, they rep-resent the brain’s response to acute hypoxia.They terminate spontaneously and do not re-quire anticonvulsant treatment. Evaluation withan EEG is usually not needed. An electrocar-diogram is obtained to rule out prolonged QTsyndrome. Management of BHS consists main-ly of reassurance that the spells will be out-grown.

Syncope

Syncope (fainting) can usually be distinguishedfrom an epileptic seizure by history. Attacks maybe preceded by warning (presyncopal) signs,such as lightheadedness, blurred vision, pallor,nausea, or diaphoresis. These warning signs arefollowed by a loss of consciousness and slowslump to the ground, as opposed to a moreabrupt fall seen with a myoclonic or atonic sei-zure. Late in a syncopal spell, there may be abrief tonic or clonic seizure secondary to cere-bral hypoperfusion and hypoxia; these are notepileptic seizures. Consciousness is regainedrapidly, compared with a more prolonged post-ictal state after an epileptic seizure. The seizurethat follows BHS or syncope engages neural cir-cuitry that produces GTC activity, but themechanisms underlying this hypoxia-relatedseizure activity warrant further clarification.

Syncope is caused by transient reduction ofcerebral blood flow as a result of an irregularheart rate (an arrhythmia causing decreasedcardiac output), decreased venous return (or-thostasis or Valsalva), or vasovagal mechanism(fright, pain, emotional upset). Vasovagal at-tacks often occur in a hot environment. TheEEG is usually normal. The key to treatment isthe avoidance of precipitating factors.

Parasomnias

Parasomnias are sleep disorders that sometimesmimic seizures. Night terrors, a common para-somnia, occur in children from 18 mo to 8 yr ofage. In early (non-REM) sleep, the child awak-ens with inconsolable screaming, sweating, andnonrhythmic flailing of extremities, followed byreturn to sleep and no memory of the episode.



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There is often a family history of night terrors.The diagnosis is based on clinical history; vid-eo-EEG is rarely needed. The main differentialdiagnosis is nightmares (that occur during REMsleep) and nocturnal epileptic seizures of frontallobe origin. The predisposition to epileptic sei-zures during sleep-state transitions, increasedepileptiform activity in sleep, and risk of sei-zures with sleep deprivation all indicate an in-timate relationship between sleep and epilepsythat is in need of further research.

COMORBIDITIES

Epilepsy is more than spontaneous recurrentseizures and should be considered a spectrumdisorder. For many patients and families, theburden of the disease is largely caused by co-morbid conditions, including behavioral andpsychiatric disorders, such as depression, anxi-ety, learning disabilities, attention-deficit hy-peractivity disorder, intellectual disability, andautism. These comorbidities, previously con-sidered to be secondary to uncontrolled seizuresor medication adverse effects, are now recog-nized as an integral part of the disorder, some-times even preceding the seizures and attribut-able to an underlying disorder of neuronalnetworks (Brooks-Kayal et al. 2013). Even a sin-gle seizure can alter neurodevelopment by mod-ifying receptor expression and distribution inthe absence of neuronal death, leading to cogni-tive and behavioral changes (Cornejo et al.2007). Understanding the pathophysiologicallink between these associated conditions andthe epilepsies could have a major impact onthe life of people living with epilepsy, and shouldbe considered a research priority.

Depression is the most frequent psychiatriccomorbidity and, interestingly, is associatedwith hippocampal and limbic dysfunction,structures commonly implicated in epilepticcircuits. The association between epilepsy anddepression is described as bidirectional: epilep-sy patients with depression are more frequentlyrefractory and people with epilepsy are morelikely to develop depression. About 10% ofadults with epilepsy have bipolar disorder andup to 30% have depression (Kanner 2013).

These symptoms are also associated with an in-creased suicide risk. This is also the case in chil-dren when symptoms are even less recognizable,but studies have shown that children with newlydiagnosed epilepsy are almost three times morelikely to have a mood disorder than controls.Anxiety is also difficult to diagnose clinicallyin patients with epilepsy because of the unpre-dictable nature of the disease, leading to someform of anxiety.

Nonpsychiatric comorbidities also affectthis population. In the Centers for Disease Con-trol and Prevention (CDC) National HealthInterview Survey, adults with epilepsy had ahigher prevalence of cardiovascular and respi-ratory disorders, diabetes, inflammation, obesi-ty, and other disorders (e.g., headache, mi-graine, arthritis) (Strine et al. 2005). Personswith epilepsy are also at increased risk for earlymortality and sudden unexplained death in ep-ilepsy (SUDEP) (Surges and Sander 2014).

Recently, the impact of seizure medicationon bone health has become a major concern.Patients with epilepsy are at high risk for frac-tures because of lower bone mineral density(BMD) (Beerhorst et al. 2013). Phenytoin, phe-nobarbital, and carbamazepine appear to be theantiseizure medications that lead to a reductionin BMD via induction of the CYP450 enzymesystem results, but osteopenia has also been re-ported with non-enzyme-inducing AEDs.

TREATMENT: GENERAL PRINCIPLES

With an armamentarium of .20 drugs, up to70% of newly diagnosed people living with ep-ilepsy can be successfully treated. Drugs used totreat epilepsy work by decreasing the electricalactivity of the brain, either by preventing neuro-nal depolarization by blocking sodium channelsor calcium channels, enhancing potassiumchannel function, inhibiting excitation mediat-ed by the neurotransmitter glutamate, or pro-moting inhibition mediated by GABA (Table 3)(see Bui et al. 2015). The efficacy of these med-ications varies based on etiology. Patients withno identified etiology are most likely to be con-trolled, especially if they have a normal develop-mental history and neurological examination.



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A neurologist’s decision to begin one seizuremedication over another is based on seizuretype, age, other medical conditions, and poten-tial side-effect profile. Often, a wide-spectrummedication is used as seizure description by awitness may be lacking. Levetiracetam has be-come very popular in recent years as first-linetherapy because of its efficacy, easy titration,and well-recognized side-effect profile. Previ-ously, carbamazepine was the first choice forfocal seizures, whereas valproic acid was the firstchoice for generalized seizures.

As a general principle, medication should bestarted at a low dose to avoid side effects. Doseincreases can be performed at regular intervals ifneeded. The goal is to control seizures with thelowest dose. When a first drug fails, most clini-cians will choose to add on a second drug, laterdeciding whether or not to withdraw the initialmedication. A proper trial is considered to be2 mo at a therapeutic, well-tolerated dose. Be-cause of drug interactions, combination thera-py has the potential of high toxicity; however,some combinations display particular efficacy,such as lamotrigine plus valproic acid for gen-eralized seizures.

Because of their mechanism of action, allseizure medications have CNS side effects. Forexample, sleepiness is a common side effect ofalmost all AEDs. Lamotrigine is fairly well tol-erated, but requires a very slow dose titration.Some physicians consider stopping a medica-tion if seizures have not recurred over the pre-vious 2 yr or more. If medication fails to controlseizures, other options include dietary therapy(ketogenic diet), resective epilepsy surgery (le-sionectomy, hemispherotomy), and palliativeepilepsy surgery (stimulation therapy, callosot-omy). The role of immune therapy for refracto-ry epilepsy is still being defined.

Lifestyle adjustment is a crucial aspect ofepilepsy management. Optimizing sleep, im-proving medication compliance, and reducingstress can significantly improve epilepsy out-come. Also important are prevention efforts toreduce causes of symptomatic epilepsies, suchas head trauma, perinatal injury, and brain in-fections like neurocysticercosis.

Finally, health professionals need to advocatefor people with epilepsy. Even today, stigmaand discrimination represent significant barriersto a normal life for people living with epilepsy.

PROGNOSIS

Of persons with epilepsy, 60%–70% will seetheir seizures controlled by medication. In mostcases, treatment is deferred until a second sei-zure occurs. The overall risk of recurrence fol-lowing a single seizure varies between 27% and

Table 3. Mechanisms of action of selected AEDs

Mechanism Antiepileptic drugs

Block repetitiveactivation of sodiumchannels

Phenytoin,carbamazepine,oxcarbazepine,lamotrigine,topiramate

Enhance slowinactivation of sodiumchannels

Lacosamide, rufinamide

Enhance activity ofg-aminobutyric acid(GABAA) receptors

Phenobarbital,benzodiazepines,clobazam

Block N-methyl-D-aspartate (NMDA)receptors

Felbamate

Block a-amino-3-hydroxy-5-methyl-4-isoxazole propionicacid (AMPA)receptors

Perampanel, topiramate

Block T-calciumchannels

Ethosuximide, valproate

Block N- and L-calciumchannels

Lamotrigine, topiramate,zonisamide, valproate

Modulate H-currents Gabapentin, lamotrigineBlock unique binding

sitesGabapentin,

levetiracetamInhibit carbonic

anhydraseTopiramate, zonisamide

Open potassiumchannels (KCNQ[Kv7])

Retigabine

Inhibit GABAtransaminase

Vigabatrin

Inhibit GABA reuptake Tiagabine



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71%. A meta-analysis found that the averagerisk of seizure recurrence was 40% in prospectivestudies versus 52% in retrospective studies (Bergand Shinnar 1991). Of these recurrences, 80%occur within the first 2 yr of the initial seizure.Similar numbers are observed in children (Shin-nar et al. 2000). As medical treatment has thepotential for significant adverse events, the ben-efits for treatment are clearer after a second un-provoked seizure when the risk of recurrencewithin 1 yr is doubled (Hauser et al. 1998; Shin-nar et al. 2000). There is no evidence that earlytreatment affects long-term prognosis, but theoutcome of children who have experiencedmore than 10 unprovoked seizures before treat-ment appears worse (Camfield et al. 1996).

About 70% of children will achieve a pe-riod of remission of at least 2 yr without aseizure. At that time, one can consider stop-ping medication, especially if there is no iden-tified underlying etiology and the child is de-veloping well. Of those, 20%–25% will recureither when seizure medication is being with-drawn (50%) or spontaneously (Sillanpaa andSchmidt 2009). Of all patients, 37% will haveeasily controlled seizures from the onset, 25%will have refractory seizures from the onset,and 38% will have a remitting relapsing pat-tern. Patients with no identified etiology havea better outcome than those with a structural,metabolic, or genetic etiology.

An analysis of 14 AED withdrawal studiesfound that the recurrence rate following AEDdiscontinuation ranged from 12% to 66%(mean 34%), and reinstatement of treatmentwas successful in obtaining further remissionin �80% with no significant differences be-tween age groups. A second remission may, how-ever, take many years to achieve, whereas, in19%, the reintroduction of medication didnot control the seizures as well as before. Up to23% of those discontinuing treatment go on todevelop intractable epilepsy. Risk factors forsubsequent poor treatment outcome are symp-tomatic focal epilepsy and cognitive deficits(Chadwick et al. 1996; Schmidt and Loscher2005). Finally, �5% of those with refractory ep-ilepsy will achieve a remission of 12 mo whenmedication is adjusted, although about one-

half will subsequently relapse (Neligan et al.2012).

CONCLUSIONS

This review introduced the concepts of clinicalepilepsy to allow neuroscientists to assess thestate of the field and formulate relevant researchquestions. Many clinical conundrums in needof attention by researchers were discussed in arecent opinion paper in which the followingtopics were deemed ripe for neuroscientific in-vestigation: the roles of genes versus acquiredfactors in seizure predisposition; how epilepsydevelops in an otherwise normal brain and howto prevent the consequences of seizures, for ex-ample, following a brain injury (epileptogene-sis, neuroprotection); methods to better localizeseizure onset and identify at-risk circuits with agoal of surgical intervention; how to predict(and thereby avert) seizure occurrence; optimi-zation of medication for specific ages and epi-lepsy syndromes; novel methods of drug deliv-ery to vulnerable circuits; and interventions torelieve comorbidities during postictal and inter-ictal periods, which comprise the majority of apatient’s daily function, but disproportionatelyaffect the quality of life (Fisher 2009). Consid-erable progress has been made, but there is ob-viously much work remaining.

REFERENCES�Reference is also in this collection.

Beerhorst K, van der Kruijs SJ, Verschuure P, Tan IY, Alden-kamp AP. 2013. Bone disease during chronic antiepilepticdrug therapy: General versus specific risk factors. J NeurolSci 331: 19–25.

Ben-Ari Y. 2002. Excitatory actions of GABA during devel-opment: The nature of the nurture. Nat Rev Neurosci 3:728–739.

Berg AT, Millichap JJ. 2013. The 2010 revised classification ofseizures and epilepsy. Continuum (Minneap Minn) 19:571–597.

Berg AT, Shinnar S. 1991. The risk of seizure recurrencefollowing a first unprovoked seizure: A quantitative re-view. Neurology 41: 965–967.

Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, vanEmde Boas W, Engel J, Glauser TA, Mathern GW, MosheSL, et al. 2010. Revised terminology and concepts fororganization of seizures and epilepsy: Report of the



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



ILAE Commission on Classification and Terminology,2005–2009. Epilepsia 51: 676–685.

� Berkovic SF. 2015. Genetics of epilepsy in humans. ColdSpring Harb Perspect Med doi: 10.1101/cshperspect.a022400.

Bernhardt BC, Hong S, Bernasconi A, Bernasconi N. 2013.Imaging structural and functional brain networks in tem-poral lobe epilepsy. Front Hum Neurosci 7: 624.

Brooks-Kayal AR, Bath KG, Berg AT, Galanopoulou AS,Holmes GL, Jensen FE, Kanner AM, O’Brien TJ, Whitte-more VH, Winawer MR, et al. 2013. Issues related tosymptomatic and disease-modifying treatments affectingcognitive and neuropsychiatric comorbidities of epilepsy.Epilepsia 54: 44–60.

Buckmaster PS. 2004. Laboratory animal models of tempo-ral lobe epilepsy. Comp Med 54: 473–485.

� Bui A, Kim H, Moroso M, Soltesz I. 2015. Microcircuitsin epilepsy: Heterogeneity and hub cells in networksynchronization. Cold Spring Harb Perspect Med doi:10.1101/cshperspect.a022855.

Cain SM, Snutch TP. 2013. T-type calcium channels inburst-firing, network synchrony, and epilepsy. BiochimBiophys Acta 1828: 1572–1578.

Camfield C, Camfield P, Gordon K, Dooley J. 1996. Does thenumber of seizures before treatment influence ease ofcontrol or remission of childhood epilepsy? Not if thenumber is 10 or less. Neurology 37: 19–23.

Caruso PA, Johnson J, Thibert R, Rapalino O, Rincon S,Ratai EM. 2013. The use of magnetic resonance spec-troscopy in the evaluation of epilepsy. NeuroimagingClin N Am 23: 407–424.

Chadwick D, Taylor J, Johnson T. 1996. Outcomes afterseizure recurrence in people with well-controlled epilepsyand the factors that influence it. The MRC AntiepilepticDrug Withdrawal Group. Epilepsia 37: 1043–1050.

Cornejo BJ, Mesches MH, Coultrap S, Browning MD, BenkeTA. 2007. A single episode of neonatal seizures perma-nently alters glutamatergic synapses. Ann Neurol 61:411–426.

Cortez MA, McKerlie C, Snead OC. 2001. A model of atyp-ical absence seizures: EEG, pharmacology, and develop-mental characterization. Neurology 56: 341–349.

� Coulter DA, Steinhauser C. 2015. Role of astrocytes in epi-lepsy. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a022434.

Coulter DA, Huguenard JR, Prince DA. 1989. Specific petitmal anticonvulsants reduce calcium currents in thalamicneurons. Neurosci Lett 98: 74–78.

Davis R, Dalmau J. 2013. Autoimmunity, seizures, and sta-tus epilepticus. Epilepsia 54: 46–49.

Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. 2005.Severe myoclonic epilepsy in infancy: Dravet syndrome.Adv Neurol 95: 71–102.

Duchowny M, Cross JH, Arzimanoglou A. 2012. Pediatricepilepsy. McGraw-Hill, New York.

Dudek FE, Sutula TP. 2007. Epileptogenesis in the dentategyrus: A critical perspective. Prog Brain Res 163: 755–773.

Engel J Jr. 2013. Seizures and epilepsy. Oxford UniversityPress, Oxford.

Engel J Jr, Pedley TA. (ed.). 2008. Epilepsy: A comprehensivetextbook. Wolters Kluwer, Philadelphia.

Escayg A, Goldin AL. 2010. Sodium channel SCN1A andepilepsy: Mutations and mechanisms. Epilepsia 51:1650–1658.

Escayg A, MacDonald BT, Meisler MH, Baulac S, HuberfeldG, Gourfinkel-An I, Brice I, LeGuern E, Moulard B,Chaigne D, et al. 2000. Mutations of SCN1A, encodinga neuronal sodium channel, in two families with GEFSþ2.Nat Genet 24: 343–345.

Fisher RS. 2009. What clinicians want to know from epilepsyresearchers. Epilepsia 50: 364–367.

Glass HC, Wusthoff CJ, Shellhaas RA. 2013. Amplitude-integrated electro-encephalography: The child neurolo-gist’s perspective. J Child Neurol 28: 1342–1350.

Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guer-reiro C, Kalviainen R, Mattson R, French JA, Perucca E,Tomson T, et al. 2013. Updated ILAE evidence review ofantiepileptic drug efficacy and effectiveness as initialmonotherapy for epileptic seizures and syndromes. Epi-lepsia 54: 551–563.

Hancock EC, Cross JH. 2013. Treatment of Lennox–Gastautsyndrome. Cochrane Database Syst Rev 2: CD003277.

Hartman AL, Cross JH. 2014. Timing of surgery in Rasmus-sen syndrome: Is patience a virtue? Epilepsy Curr 14: 8–11.

Hauser W, Hersdorffer D. 1990. Epilepsy: Frequency, causesand consequences. Demos, New York.

Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE.1998. Risk of recurrent seizures after two unprovokedseizures. N Engl J Med 338: 429–434.

� Holmes GL. 2015. The neurobiology of epilepsy: Futuredirections. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a022749.

Holmes G, Ben-Ari Y. 1998. Seizures in the developing brain:Perhaps not so benign after all. Neuron 21: 1231–1234.

Issa NP. 2014. Neurobiology of continuous spike-wave inslow-wave sleep and Landau–Kleffner syndromes. Pe-diatr Neurol 51: 287–296.

Joshi S, Rajasekaran K, Kapur J. 2013. GABAergic transmis-sion in temporal lobe epilepsy: The role of neurosteroids.Exp Neurol 244: 36–42.

Kanner AM. 2013. The treatment of depressive disorders inepilepsy: What all neurologists should know. Epilepsia 54:3–12.

Kay B, Szaflarski JP. 2014. EEG/fMRI contributions to ourunderstanding of genetic generalized epilepsies. EpilepsyBehav 34: 129–135.

Kim H, Paige AL, Knowlton RC. 2010. Advances in struc-tural and functional neuroimaging: How are these guid-ing epilepsy surgery? In Epilepsy: Mechanisms, models,and translational perspectives (ed. Rho JM, Sankar R, Staf-strom CE), pp. 257–282. CRC, Boca Raton, FL.

Lado FA, Rubboli G, Capovilla P, Avanzini G, Moshe SL.2013. Pathophysiology of epileptic encephalopathies. Ep-ilepsia 54: 6–13.

LaFrance WC Jr, Reuber M, Goldstein LH. 2013. Manage-ment of psychogenic nonepileptic seizures. Epilepsia 54:53–67.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Landau WM, Kleffner FR. 1957. Syndrome of acquiredaphasia with convulsive disorder in children. Neurology7: 523–530.

� Lenck-Santini P-P, Scott R. 2015. Mechanisms responsiblefor cognitive impairment in epilepsy. Cold Spring HarbPerspect Med doi: 10.1101/cshperspect.a022772.

Lewis DV, Shinnar S, Hesdorffer DC, Bagiella E, Bello JA,Chan S, Xu Y, MacFall J, Gomes WA, Moshe SL, et al.2014. Hippocampal sclerosis after febrile status epilepti-cus: The FEBSTAT study. Ann Neurol 75: 178–185.

Liu Z, Mikati M, Holmes GL. 1995. Mesial temporal scle-rosis: Pathogenesis and significance. Pediatr Neurol 12:5–16.

Liu Y, Lopez-Santiago LF, Yuan Y, Jones JM, Zhang H,O’Malley HA, Patino GA, O’Brien JE, Rusconi R, GuptaA, et al. 2013. Dravet syndrome patient-derived neuronssuggest a novel epilepsy mechanism. Ann Neurol 74: 128–139.

Lortie A. 2013. Psychogenic nonepileptic seizures. HandbClin Neurol 112: 875–879.

Loscher W, Puskarjov M, Kaila K. 2013. Cation-chloridecotransporters NKCC1 and KCC2 as potential targetsfor novel antiepileptic and antiepileptogenic treatments.Neuropharmacology 69: 62–74.

Macdonald RL, Kang JQ, Gallagher MJ. 2010. Mutations inGABAA receptor subunits associated with genetic epilep-sies. J Physiol 588: 1861–1869.

McClelland S, Dube CM, Yang J, Baram TZ. 2011. Epilepto-genesis after prolonged febrile seizures: Mechanisms,biomarkers and therapeutic opportunities. NeurosciLett 497: 155–162.

Michelucci R, Pasini E, Riguzzi P, Volpi L, Dazzo E, NobileC. 2012. Genetics of epilepsy and relevance to currentpractice. Curr Neurol Neurosci Rep 12: 445–455.

Miya K, Takahashi Y, Mori H. 2014. Anti-NMDAR autoim-mune encephalitis. Brain Dev 36: 645–652.

Mullen SA, Carvill GL, Bellows S, Bayly MA, Trucks H, LalD, Sander T, Berkovic SF, Dibbens LM, Scheffer IE, et al.2013. Copy number variants are frequent in genetic gen-eralized epilepsy with intellectual disability. Neurology81: 1507–1514.

Muro VM, Connolly MB. 2014. Classifying epileptic sei-zures and the epilepsies. In Epilepsy (ed. Miller JW, Good-kin HP), pp. 10–14. Wiley, Chichester, UK.

Nabbout R, Dulac O. 2008. Epileptic syndromes in infancyand childhood. Curr Opin Neurol 21: 161–166.

Neligan A, Bell GS, Elsayed M, Sander JW, Shorvon SD.2012. Treatment changes in a cohort of people with ap-parently drug-resistant epilepsy: An extended follow-up.J Neurol Neurosurg Psychiatry 83: 810–813.

Oakley JC, Kalume F, Catterall WA. 2011. Insights into path-ophysiology and therapy from a mouse model of Dravetsyndrome. Epilepsia 52: 59–61.

Obeid M, Mikati MA. 2007. Expanding spectrum of parox-ysmal events in children: Potential mimickers of epilepsy.Pediatr Neurol 37: 309–316.

Olson HE, Poduri A. 2014. Epilepsy: When to perform agenetic analysis. In Epilepsy (ed. Miller JW, Goodkin HP),pp. 159–166. Wiley, Chichester, UK.

Olson H, Shen Y, Avallone J, Sheidley BR, Pinsky R, BerginAM, Berry GT, Duffy FH, Eksioglu Y, Harris DJ, et al.

2014. Copy number variation plays an important rolein clinical epilepsy. Ann Neurol 75: 943–958.

Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gard-ner JC, Paneth N, Minnigh B, Alvin J. 1999. Phenobar-bital compared with phenytoin for the treatment of neo-natal seizures. N Engl J Med 341: 485–489.

Patterson KP, Baram TZ, Shinnar S. 2014. Origins of tem-poral lobe epilepsy: Febrile seizures and febrile statusepilepticus. Neurotherapeutics 11: 242–250.

Pavlidou E, Panteliadis C. 2013. Prognostic factors for sub-sequent epilepsy in children with febrile seizures. Epilep-sia 54: 2101–2107.

Pearl PL. 2009. New treatment paradigms in neonatal met-abolic epilepsies. J Inherit Metab Dis 32: 204–213.

Pearl PL, Taylor JL, Trzcinski S, Sokohl A. 2007. The pedi-atric neurotransmitter disorders. J Child Neurol 22: 606–616.

Pearson TS, Akman C, Hinton VJ, Engelstad K, DeVivo DC.2013. Phenotypic spectrum of glucose transporter type 1deficiency syndrome (Glut1 DS). Curr Neurol NeurosciRep 13: 342.

� Pitkanen A, Lukasiuk K, Dudek FE, Staley KJ. 2015. Epilep-togenesis. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a022822.

Poduri A, Lowenstein D. 2011. Epilepsy genetics—Past,present, and future. Curr Opin Genet Dev 21: 325–332.

Rogawski MA, Bazil CW. 2008. New molecular targets forantiepileptic drugs: a2s, SV2A, and Kv7/KCNQ/Mpotassium channels. Curr Neurol Neurosci Rep 8:345–352.

Schmidt D, Loscher W. 2005. Uncontrolled epilepsy follow-ing discontinuation of antiepileptic drugs in seizure-freepatients: A review of current clinical experience. ActaNeurol Scand 111: 291–300.

Schuchmann S, Schmitz D, Rivera C, Vanhatalo S, SalmenB, Mackie K, Sipila ST, Voipio J, Kaila K. 2006. Exper-imental febrile seizures are precipitated by a hyperther-mia-induced respiratory alkalosis. Nat Med 12: 817–823.

Shinnar S, Berg AT, O’Dell C, Newstein D, Moshe SL, HauserWA. 2000. Predictors of multiple seizures in a cohort ofchildren prospectively followed from the time of theirfirst unprovoked seizure. Ann Neurol 48: 140–147.

Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP,Cohen B, North PE, Marchuk DA, Comi AM, PevsnerJ. 2013. Sturge–Weber syndrome and port-wine stainscaused by somatic mutation in GNAQ. N Engl J Med368: 1971–1979.

Shorvon SD, Andermann F, Guerrini R. (ed.). 2011. Thecauses of epilepsy. Cambridge University Press, Cam-bridge.

Sillanpaa M, Schmidt D. 2009. Early seizure frequency andaetiology predict long-term medical outcome in child-hood-onset epilepsy. Brain 132: 989–998.

Stafstrom CE. 2009. Infantile spasms: A critical review ofemerging animal models. Epilepsy Curr 9: 75–81.

Stafstrom CE. 2010. Pathophysiological mechanisms ofseizures and epilepsy: A primer. In Epilepsy: Mecha-nisms, models, and translational perspectives (ed. RhoJM, Sankar R, Stafstrom CE), pp. 3–19. CRC, BocaRaton, FL.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Stafstrom CE, Arnason BGW, Baram TZ, Catania A, CortezMA, Glauser TA, Pranzatelli MR, Riikonen R, RogawskiMA, Shinnar S, et al. 2011. Treatment of infantile spasms:Emerging insights from clinical and basic science per-spectives. J Child Neurol 26: 1411–1421.

Staley KJ. 2006. Role of the depolarizing GABA response inepilepsy. Adv Exp Med Biol 548: 104–109.

Steinlein OK. 2014. Mechanisms underlying epilepsies as-sociated with sodium channel mutations. Prog Brain Res213: 97–111.

Steinlein OK, Conrad C, Weidner B. 2007. Benign familialneonatal convulsions: Always benign? Epilepsy Res 73:245–249.

Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P,Balluz LS. 2005. Psychological distress, comorbidities,and health behaviors among U.S. adults with seizures:Results from the 2002 National Health Interview Survey.Epilepsia 46: 1133–1139.

Surges R, Sander JW. 2014. Sudden unexpected death inepilepsy: Mechanisms, prevalence, and prevention. CurrOpin Neurol 25: 201–207.

Swann JW, Moshe SL. 2012. On the basic mechanisms ofinfantile spasms. In Jasper’s basic mechanisms of the epi-lepsies (ed. Noebels JL, Avoli M, Rogawski MA, Olsen RW,Delgado-Escueta AV), pp. 272–285. Oxford UniversityPress, Oxford.

Thom M, Mathern GW, Cross JH, Bertram EH. 2010. Mesialtemporal lobe epilepsy: How do we improve surgical out-come? Ann Neurol 68: 424–434.

Thomas RH, Berkovic SF. 2014. The hidden genetics of ep-ilepsy—A clinically important new paradigm. Nat RevNeurol 10: 283–292.

Van Bogaert P. 2013. Epileptic encephalopathy with contin-uous spike-waves during slow-wave sleep including Lan-dau–Kleffner syndrome. Handb Clin Neurol 111: 635–640.

Varadkar S, Bien CG, Kruse CA, Jensen FE, Bauer J, PardoCA, Vincent A, Mathern GW, Cross JH. 2014. Rasmus-sen’s encephalitis: Clinical features, pathobiology, andtreatment advances. Lancet Neurol 13: 195–205.

Verrotti A, Beccaria F, Fiori F, Montagnini A, Capovilla G.2012. Photosensitivity: Epidemiology, genetics, clinicalmanifestations, assessment, and management. EpilepticDisord 14: 349–362.

� Vezzani A, Lang B, Aronica E. 2015. Immunity and inflam-mation in epilepsy. Cold Spring Harb Perspect Med doi:10.1101/cshperspect.a022699.

Yu FH, Mantegazza M, Westenbroek RE, Robbins CA,Kalume F, Burton KA, Spain WJ, McKnight GS,Scheuer T, Catterall WA. 2006. Reduced sodium currentin GABAergic interneurons in a mouse model of severemyoclonic epilepsy in infancy. Nat Neurosci 9: 1142–1149.



ww

w.p

ersp

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2015; doi: 10.1101/cshperspect.a022426Cold Spring Harb Perspect Med Carl E. Stafstrom and Lionel Carmant Seizures and Epilepsy: An Overview for Neuroscientists

Subject Collection Epilepsy: The Biology of a Spectrum Disorder

Research ChallengesThe Epilepsy Spectrum: Targeting Future

Gregory L. Holmes and Jeffrey L. Noebels EpilepsyEpileptogenesis and the Comorbidities of Common Mechanisms Underlying

Andrey Mazarati and Raman SankarRole of Sodium Channels in Epilepsy

David I. Kaplan, Lori L. Isom and Steven PetrouComorbiditiesImpact the Development of Epilepsy and

Epilepsy Model: How Past Events−The Diathesis

Christophe Bernard

the Ketogenic DietMechanisms of Action of Antiseizure Drugs and

M. RhoMichael A. Rogawski, Wolfgang Löscher and Jong

Potassium Channels in EpilepsyRüdiger Köhling and Jakob Wolfart

Epilepsy and AutismAshura W. Buckley and Gregory L. Holmes

GABAergic Synchronization in EpilepsyRoustem Khazipov

Immunity and Inflammation in Epilepsy

AronicaAnnamaria Vezzani, Bethan Lang and Eleonora

Status Epilepticus

ShinnarSyndi Seinfeld, Howard P. Goodkin and Shlomo

Nucleotide-Gated (HCN) Channels in EpilepsyHyperpolarization-Activated Cyclic

PoolosGary P. Brennan, Tallie Z. Baram and Nicholas P.

Genetic ModelsNeonatal and Infantile Epilepsy: Acquired and

Aristea S. Galanopoulou and Solomon L. Moshé

The Role of Calcium Channels in EpilepsySanjeev Rajakulendran and Michael G. Hanna

Epigenetics and EpilepsyDavid C. Henshall and Katja Kobow

EpilepsyInterneuron Transplantation as a Treatment for

Robert F. Hunt and Scott C. BarabanCells in Network SynchronizationMicrocircuits in Epilepsy: Heterogeneity and Hub

Anh Bui, Hannah K. Kim, Mattia Maroso, et al.

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