review article - l.s. neuro · 2014-09-22 · cure: citizens united for research in epilepsy, the...

Management ofChildhood Epilepsy

Tracy A. Glauser, MD; Tobias Loddenkemper, MD

ABSTRACTPurpose of Review: This article outlines a diagnostic and management approachto pediatric seizures and epilepsy syndromes, and delineates pharmacologic andnonpharmacologic treatment options.Recent Findings: Progress in tracking of seizures, identifying and addressing medi-cation nonadherence, treatment with novel devices, and clinical decision support al-gorithms will provide additional management options in the future.Summary: The management of pediatric seizures and epilepsies presents multiplechallenges to the clinician because of nonepileptic imitators, evolving classificationapproaches, clinical presentations, limited clinical trial data for medications, and thetoxicities of therapies. While certain pediatric seizures and epilepsy syndromes respondbest to certain medications, early identification of pharmacologically resistant patientswhomay be candidates for epilepsy surgery is important. Alternative treatment optionsmay include ketogenic diet or vagus nerve stimulation.

Continuum (Minneap Minn) 2013;19(3):656–681.

DIAGNOSTIC EVALUATIONOVERVIEWThemanagement of childhood epilepsybegins with four sequential diagnosticsteps that precede any therapeuticdecisions. The answers to these funda-mental questions help to shape treat-ment approaches and strategies. Thediagnostic questions are as follows:

1. Seizure confirmation: ‘‘Are the eventsseizures?’’

2. Seizure classification: ‘‘Where onthe surface of the brain does theseizure probably originate?’’

3. Epilepsy classification: ‘‘What is theetiology for these seizures?’’

4. Syndrome identification: ‘‘Do theseizures and other patient-specificsymptoms (eg, age of onset, EEGpattern, developmental status) fit arecognizable pattern?’’

SEIZURE CONFIRMATIONThe first step in approaching a childwith suspected epilepsy is to confirm

that the reported spells are actuallyseizures rather than another conditionsuch as syncope, migraines, tics, orbehavioral events (Table 5-11). Thisdifferentiation is crucial because non-epileptic events usually do not respondwell to antiepileptic medications, andmisdiagnosis leads to delay in initiat-ing appropriate therapy. Confirming orruling out epilepsy not only preventsunnecessary treatment and exposure tointerventions but also reduces patientand family anxiety and possibly unnec-essary stigma (Case 5-1).

A detailed history is often all that isneeded to differentiate nonepilepticevents fromepileptic seizures in children.Although individual symptoms can beshared between seizures and nonepilep-tic events, it often is the ‘‘constellationof symptoms’’ (with special attention tothe sequential progression of symptomsfrom beginning to end of the event andthe overall time course) that helps con-firm or refute a diagnosis of seizures.

Address correspondence toDr Tracy Glauser, CincinnatiChildren’s Hospital MedicalCenter, 3333 Burnet Avenue,ML2015, Cincinnati,OH 45229,[email protected].

Relationship Disclosure:

Dr Glauser serves as aconsultant or speaker for EisaiCo, Ltd, GeneDx, Lundbeck,Questcor Pharmaceuticals,Inc, Sunovion Pharmaceuticals,Inc, Supernus Pharmaceuticals,Inc, UCB, and Upsher-SmithLaboratories, Inc. Dr Glauserreceives royalty payments for apatent license from AssureRxHealth, Inc, has receivedpersonal compensation formedical record reviews, andreceives multiple grants fromthe NIH. Dr Loddenkemperserves on the American Boardof Clinical Neurophysiology, theCouncil of the American ClinicalNeurophysiology Society, andthe Laboratory AccreditationBoard for Long Term (Epilepsyand ICU) Monitoring (ABRET).Dr Loddenkemper serves asassociate editor for SeizureVEuropean Journal of Epilepsyand received investigator-initiatedresearch support from Eisai andLundbeck. Dr Loddenkemperreceives research and fundingsupport from the AmericanEpilepsy Society, the Center forIntegration of Medicine andInnovative Technology/Department of Defense,Children’s Hospital Boston,CURE: Citizens United forResearch in Epilepsy, theEpilepsy Foundation of America,Epilepsy Therapy Project,Harvard Medical School, theNIH, and Translational ResearchProject.

Unlabeled Use ofProducts/Investigational

Use Disclosure:Drs Glauser andLoddenkemper discuss theunlabeled use of epilepsymedications and epilepsytreatment options, all of whichare limited to certain ageranges including infantsand/or children.

* 2013, American Academyof Neurology.

656 www.ContinuumJournal.com June 2013

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

[email protected]

An abrupt onset of symptoms maybe shared between epileptic seizuresand syncope, but the auras of seizures(eg, funny taste in mouth, funny smell,warmth in stomach) tend to be differ-ent than those in syncope (eg,lightheadedness, dizziness, and visualloss as if a curtain was being pulleddown). Involuntary and uncontrollableactivity during the event is moresuggestive of an epileptic seizure.Usually, when witnesses or parentsreport that an activity can reliably bestopped or modified by intervention,nonepileptic events need to be con-sidered. Postictal manifestations suchas drowsiness or amnesia are alsomore consistently reported after epi-leptic seizures.

Overall, a complex stereotyped clin-ical pattern with recurring featuresand evolution (the ‘‘constellation ofsymptoms’’) more likely indicates ep-ileptic seizures. Note that some be-haviors in children can be a responseto a seizure and not an ictal manifes-tation, eg, crying as a response to anuncomfortable aura or painful seizure.Although most childhood epilepsiespresent with one stereotyped clinicalpattern, some severe epilepsies canhave multiple seizure types even atinitial presentation. Lastly, when indoubt, diagnostic video-EEG confirma-tion can help differentiate suspiciousnonepileptic events from epilepticseizures (Table 5-11).

This review will only discuss man-agement of pediatric epilepsy patients,specifically of patients with two or moreunprovoked epileptic seizures.

PEDIATRIC SEIZURE/EPILEPSYCLASSIFICATION ANDSYNDROMESSeizure classification uses the Interna-tional League Against Epilepsy’s (ILAE)1981 Clinical and Electrographic Clas-sification of Epileptic Seizures. This

classification approach used clinicalseizure symptoms and interictal/ictalEEG expressions to divide seizures intothree categories: partial (focal, local), gen-eralized (convulsive or nonconvulsive),and unclassified. The partial seizureswere divided into simple, complex, andsecondarily generalized, while the gen-eralized seizures included absence,atypical absence, myoclonic, clonic,tonic, tonic-clonic, and atonic. Thesesubcategories are important since forthe past 30 years antiepileptic medica-tion clinical trials focused on pre-venting seizures (not epilepsy) haveused this classification scheme to de-termine subject eligibility and medica-tion efficacy and/or effectiveness. Inaddition to history and EEG, at timesphysical examination and neuroimag-ing can be helpful to classify seizures.

Classification of pediatric epilepsiesfollows the ILAE’s still-valid 1989 Re-vised Classification of Epilepsies andEpileptic Syndromes approach. Thisclassification uses two categories toclassify epilepsies (etiology and sei-zure localization). This classification isstill the current classification system,and all subsequent updates have beenproposals. The seizure localizationcomponent is already determined inthe seizure classification step de-scribed above. The etiology categoriesinclude idiopathic, symptomatic, andcryptogenic (added in order to char-acterize epilepsies with a presumedbut unknown cause). Additional toolsand techniques that can help addressetiology include structural neuroimag-ing, functional and metabolic neuro-imaging, and laboratory testingincluding genetic, metabolic, and his-topathologic studies.

Criteria for classification of epilepsysyndromes were described within thesame 1989 document as the epilep-sies. While this two-dimensional 1989classification of epilepsies is still valid,

KEY POINTS

h The first step inapproaching a childwith suspected epilepsyis to confirm that thereported spells areactually seizures ratherthan another conditionsuch as syncope,migraines, tics, orbehavioral events.

h Seizure classificationuses the InternationalLeague AgainstEpilepsy’s 1981 Clinicaland ElectrographicClassification ofEpileptic Seizures. Thisclassification approachused clinical seizuresymptoms andinterictal/ictal EEGexpressions to divideseizures into threecategories: partial(focal, local),generalized (convulsiveor nonconvulsive), andunclassified.

657Continuum (Minneap Minn) 2013;19(3):656–681 www.ContinuumJournal.com


TABLE 5-1 Description of Nonepileptic Paroxysmal Events in Children Mimicking EpilepticSeizure Featuresa

Seizure Types Potentially Mimicked

Nonepileptic event Peak AgeTonicSeizure

ClonicSeizure

Tonic-ClonicSeizure

MyoclonicSeizure

ComplexMotorFeatures

Acute life-threatening event Neonate, infant + + +

Jitteriness and startle Neonate, infant + + +

Hereditary hyperekplexia Neonate, infant + +

Paroxysmal tonic upward gaze Neonate, infant +

Benign neonatal sleep myoclonus Neonate + +

Shuddering attacks Infant, child + + +

Breath-holding spells Infant, child + + +

Benign paroxysmal vertigo Infant, child,adolescent

+

Movement disorders Infant, child,adolescent

+ + + +

Sandifer syndrome Infant +

Rumination Infant

Benign myoclonus of infancy Infant + + + +

Infantile masturbation Infant + + +

Spasmus nutans Infant + +

Opsoclonus Infant + +

Rhythmic movementdisorder of sleep

Infant, child + + +

Alternating hemiplegia Child, infant

Stereotypies Child, infant +

Stool withholding Child, infant + +

Hyperventilation Child, adolescent + +

Daydreaming Child

Parasomnias Child +

Pavor nocturnus Child +

Nightmares Child +

Munchausen syndrome by proxy Child, infant b b b b b

Migraine and variants Adolescent, child,infant

Syncope Adolescent, child +

Psychogenic nonepileptic seizures Adolescent, child + + + + +

Narcolepsy/cataplexy Adolescent, child

Hallucinations Adolescent, child

Normal behavior or sensationmistaken for seizure

All age groups + + + + +

a Modified from Loddenkemper T, Wyllie E, Cambridge University Press.1 B 2010 Cambridge University Press. Reprinted with permission.b Semiology is not reliable and based on parental report.


Management of Childhood Epilepsy


Automatisms Akinetic HypomotorFluctuatingConsciousness

AtonicSeizure Aura

AutonomicFeatures

+ + + +

+ + + +

+

+

+

+

+

+

+ +

+ + +

+

+ +

+ + +

+ + +b b b b b b b

+ + +

+ + + +

+ + + + + + +

+ +

+ + +

+ + + + + + +



other classifications of seizures andepilepsies have been proposed andremain a work in progress. The latest2010 classification proposal now per-mits a multidimensional diagnosticapproach with determination of (1)epilepsy localization, (2) clinical seizurepresentation, (3) etiology of epilepsy,and (4) inclusion of related medicalconditions, paralleling the informationacquisition process in clinical practice.This new classification/organization fur-ther bridges the gap toward a clinicallyuseful classification approach thatadapts to increasing knowledge andclinical approach and, importantly forpediatric epilepsies, considers age ofonset.2 Additional information is alsoavailable in the article ‘‘The 2010Revised Classification of Seizures andEpilepsy’’ by Drs Berg and Millichap inthis issue of . In partic-ular, the presentation of electroclinicalsyndromes by age at onset is helpful inmanaging pediatric epilepsies (pleaserefer to Table 1-6 in ‘‘The 2010Revised Classification of Seizures and

Epilepsy’’ in this issue), as the age ofonset is usually easy to obtain andprovides important clues regardingsyndromic presentation.

PHARMACOLOGIC TREATMENTOPTIONSIndications for TreatmentAfter a first unprovoked seizure, thechances of a second seizure rangefrom 30% to 55% over the next 2 to5 years. Seizure recurrence is higherin patients with a known etiology forseizures, with abnormal examinationfindings, occurrence during sleep, andabnormal EEGs with interictal epilep-tiform discharges. While treatmentafter a first unprovoked seizure mayreduce the risk of seizure recurrenceby half, it does not modify the long-term prognosis. As such, chronicantiepileptic drug (AED) therapy isnot started after a first unprovokedseizure. However, some clinicians mayelect to initiate treatment if risk ofinjury and harm from seizures isextremely high.

KEY POINT

h After a first unprovokedseizure, the chances of asecond seizure rangefrom 30% to 55% overthe next 2 to 5 years.Seizure recurrence ishigher in patients witha known etiology forseizures, with abnormalexamination findings,occurrence duringsleep and abnormalEEGs with interictalepileptiform discharges.

Case 5-1A 7-year-old girl presented with occasional staring spells, which started3 months ago and now occurred 5 to 10 times per day, lasting 10 to20 seconds each. Her responsiveness appeared to be decreased duringspells. She stared and did not respond; occasionally minimal mouthmovements were seen. After each spell, she quickly reoriented and wasat baseline, but did not remember the episode. Birth, development, andmedical history were otherwise unremarkable, and the patient was an Aor B student, but her staring spells were also recently noted in school, andher teachers questioned whether she had attention deficit hyperactivitydisorder. A routine EEG showed generalized 3-Hz spike-and-wavecomplexes, and hyperventilation provoked a generalized absence seizurewith unresponsiveness associated with 3-Hz spike-and-wave complexes.Childhood absence epilepsy was diagnosed, ethosuximide was initiated,and the patient became seizure free. Of interest, up to 30% of clinicalabsence seizures may present with additional symptoms, such as mouthautomatisms.

Comment. This case illustrates a frequent clinical presentation andworkup in pediatric epilepsy: the diagnostic workup of staring spells.Ethosuximide has been shown to be the most effective treatment withthe fewest side effects in patients with childhood absence epilepsy.




After a second unprovoked seizure,the chances of a third unprovoked sei-zure are 80% to 90% within 2 years iftreatment is not initiated. Therefore,treatment after the second (rather thanthe first) unprovoked seizure is recom-mended.3 By the same token, delayingtreatment until a second seizure occurscan increase diagnostic certainty andprevent unnecessary treatment ofnonepileptic events.

Goals of TherapyIdeally, the three goals of epilepsytherapy are complete seizure control,no adverse events, and the best qual-ity of life. Realistically, many childrencan reach seizure freedom with agood to excellent quality of life butmay do so at the cost of some adverseevents. These side effects are usuallymild in nature and tolerable and mayonly be recognized in hindsight oncean AED has been weaned. The goalsof therapy often change when com-plete seizure control becomes elusive.In children with treatment-resistantepilepsy, defined as ‘‘failure of ade-quate trials of two tolerated, appropri-ately chosen and used antiepilepticdrug schedules (whether as mono-therapies or in combination) to achievesustained seizure freedom,’’4 the goalsof therapy shift to be fewest seizures,fewest adverse events, and best qualityof life.

Medication Selection andManagementThe selection of the first (or subsequent)antiepileptic medication is affected by acombination of patient-specific and AED-specific factors. Patient-specific factorsinclude the child’s disease characteristics(eg, seizure type, epilepsy type, andepilepsy syndrome) along with theircomorbidities, comedications, age, gen-der, and ability to swallow pills. AED-specific factors include the drug’s effec-

tiveness and/or efficacy for a specificseizure type or epilepsy syndrome, itspharmacokinetic characteristics, dose-dependent adverse effects, idiosyn-cratic reactions, chronic toxicities, ter-atogenicity, and carcinogenicity.Among these factors, pediatric epilepsyexperts show agreement that thechild’s disease characteristics, theAED’s drug-toxicity profile, and thechild’s comorbidities/comedicationsare the most important features theyconsider whenmatching the AED to thepatient.5 An AED’s effectiveness for aspecific seizure type (Table 5-2) can beassessed by multiple approaches. USFood and Drug Administration (FDA)indications (based solely on regulatoryfocused clinical trials), internationalsystematic reviews (based on pre-specified criteria for specific clinical sit-uations such as initial monotherapy6),and expert opinion represent threecomplementary approaches. Althoughexpert opinion is the most impreciseof the three, it can be useful since itincorporates the complexities and va-garies of real-life clinical practice acrossa wide range of patients. The practic-ing clinician can use these three ap-proaches to judge the overall strengthof evidence for a specific AED for aspecific seizure type.

In addition to seizure type, seizurefrequency and severity may have animpact on AED selection. For example,between two equally effective AEDs, apatient with daily, prolonged general-ized tonic-clonic seizures may be startedon the AED that can be titrated moreswiftly to a therapeutic dose. Lastly,while some AED efficacy results in chil-dren parallel those in adults,7 this com-parison may not apply to all pediatricepilepsy patients,8 and individualizedmedication selection is vital to success.

Age at onset, longitudinal course,and related medical information mayprovide information on an underlying

KEY POINTS

h After a secondunprovoked seizure,the chances of a thirdunprovoked seizure are80% to 90% within2 years if treatment isnot initiated. Therefore,treatment after thesecond (ratherthan the first)unprovoked seizureis recommended.

h Ideally, the three goalsof epilepsy therapy arecomplete seizurecontrol, no adverseevents, and the bestquality of life.Realistically, manychildren can reachseizure freedom witha good to excellentquality of life but maydo so at the cost ofsome adverse events.

h In children withtreatment-resistantepilepsy, defined as‘‘failure of adequatetrials of two tolerated,appropriately chosenand used antiepilepticdrug schedules(whether asmonotherapies or incombination) toachieve sustainedseizure freedom,’’ thegoals of therapy shift tobe fewest seizures,fewest adverse events,and best quality of life.



TABLE 5-2 Antiepileptic Medications and Pediatric Dosing Information (as of April 2013)

MedicationaUSFDA LabeledEpilepsy Indication

Initial Monotherapy:ILAE Level of Efficacyor EffectivenessEvidence

Authors’ Opinion of AEDPotential Utility (Weak,Strong, Unknown,Avoid) By Seizure Type

Acetazolamide Adjunctive treatment ofgeneralized epilepsies

Partial, generalizedtonic-clonic (GTC), andabsence seizures:No data available

Partial: Weak

GTC: Weak

Myoclonic: Weak

Absence: Weak

Spasms: Unknown

Adrenocorticotropichormone

Infantile spasmsin patients G2 y old

Partial, GTC, and absenceseizures: No data available

Partial: Unknown

GTC: Unknown

Myoclonic: Unknown

Absence: Unknown

Spasms: Strong

Carbamazepineb Partial, GTC, and mixedtypes of seizures: allpediatric age groups

Partial seizures: Level CGTC seizures: Level C

Partial: Strong

GTC: Strong

Myoclonic: Avoid

Absence: Avoid

Spasms: Avoid

Clobazam Lennox-Gastaut syndrome:adjunctive (in patientsQ2 y old)

Partial seizures: Level D Partial: StrongGTC and absence seizures:No data available

GTC: Weak

Myoclonic: Weak

Absence: Weak

Spasms: Unknown

Clonazepam Seizures (in patients upto 10 y old or weighingup to 30 kg)

Partial seizures: Level D Partial: WeakGTC, and absence seizures:No data available

GTC: Weak

Myoclonic: Weak

Absence: Weak

Spasms: Unknown




Target Dose andDose Interval Target AED Blood Level

Common Side Effects, ClinicalChallenges, and Black Box Warnings

G12 y old: 10Y20 mg/kg/d

912 y old: 250Y1000 mg/d

10Y14 mg/L or 45Y63 2mol/L Side effects: Paresthesias, drowsiness, ataxia,blurred vision, frequent urination, nausea,vomiting, diarrhea, metabolic acidosis, rash

Daily or twice dailyBlack box warnings: Severe dermatologicreactions, fulminant hepatic necrosis,agranulocytosis, and aplastic anemia andother blood dyscrasias; use caution withconcomitant high-dose aspirin

150 IU/m2/d for 2 wk n/a Side effects: Cushingoid features,hypertension, hyperglycemia/glycosuria,electrolyte disturbance, irritability,immunosuppression and infection,congestive heart failure, cardiomyopathy

30 IU/m2/d for 3 d

Clinical challenges: IM injection

15 IU/m2/d for 3 d

10 IU/m2/d for 3 d

10 IU/m2 every other dayfor 3 doses

Daily or twice daily

G6 y old: 20Y35 mg/kg/d 4Y12 mg/L or 17Y51 2mol/L Side effects: Sedation, dizziness, confusion,nausea, vomiting, diarrhea, blurred vision,leukopenia, neutropenia, rash, hyponatremia,aplastic anemia; increases PR interval

6Y15 y old: 600Y1000 mg/d

Clinical challenges: Drug interactions throughP450 enzyme induction; autoinduction

915 y old: 800Y1200 mg/d

Black box warnings: Severe dermatologicreactions in patients of Asian descent whohave the human leukocyte antigen-B*1502allele; aplastic anemia and agranulocytosis

2 to 3 times daily

(4Y12 mg/L or 17Y51 2mol/L)

G12 y old: 0.4Y0.8 mg/kg/d n/a Side effects: Sedation, drowsiness, dry mouth,constipation, restlessness or excitation,dependence

912 y old: 20Y40 mg/d

Twice daily

G12 y old: 0.1Y0.2 mg/kg/d n/a Side effects: Sedation, drowsiness,dizziness, ataxia, hyperexcitability,dry mouth

912 y old: 4Y10 mg/d


Continued on next page



TABLE 5-2 Antiepileptic Medications and Pediatric Dosing Information (as of April 2013)(continued )




Diazepam Seizures (in patientsQ6 mo old)


Partial: Weak

GTC: Weak

Myoclonic: Weak

Absence: Weak

Spasms: Unknown

Ethosuximide Absence epilepsy Absence seizures: Level A Partial: Avoid

Partial and GTC seizures:No data available

GTC: Unknown

Myoclonic: Weak

Absence: Strong

Spasms: Unknown

Ezogabinec Partial seizures: adjunctive(in patients Q18 y old)


Partial: Unknown

GTC: Unknown

Myoclonic: Unknown

Absence: Unknown

Spasms: Unknown

Felbamate Partial seizures: monotherapy,adjunctive, with and withoutgeneralization


Partial: Strong

Partial and generalized seizuresassociated with Lennox-Gastautsyndrome: adjunctive (inpatients Q2 y old)

GTC: Strong

For use only in patientswho respond inadequatelyto alternative treatments

Myoclonic: Weak

Absence: Weak

Spasms: Weak

Gabapentin Partial seizures: adjunctive(in patients 3Y12 y old)

Partial and GTC seizures:No data availableAbsence seizures: Level F

Partial: Weak

GTC: Weak

Myoclonic: Unknown

Absence: Avoid

Spasms: Unknown

Lacosamide Partial seizures: adjunctive(in patients Q17 y old)


Partial: Strong

GTC: Unknown

Myoclonic: Unknown

Absence: Unknown

Spasms: Unknown






0.5Y2 mg/dose

2 to 4 times daily

n/a Side effects: Sedation, dizziness,ataxia, hyperexcitability, dry mouth,respiratory depression (overdoseor with other CNS depressants)

G12 y old: 20Y30 mg/kg/d (40Y100 mg/L or300Y700 2mol/L)

Side effects: Vomiting and diarrhea,abdominal discomfort, hiccups,headaches, sedation

912 y old: 600Y1200 mg/d

Twice daily

Adolescents:

600Y1200 mg/d

n/a Side effects: Dizziness, somnolence, fatigue,confusional state, vertigo, tremor, abnormalcoordination, diplopia, disturbance inattention, memory impairment, asthenia,blurred vision, gait disturbance, aphasia,dysarthria, balance disorder

3 times daily

Clinical challenges: Urinary retention, QTprolongation potential, 3 times per day dosing


Side effects: Nausea and vomiting, anorexia,insomnia, dizziness, headache, diplopia,aplastic anemia, hepatic failure, weight loss

912 y old: 2400Y5000 mg/d

Clinical challenges: Drug interaction,inhibition of phenytoin and valproic acidmetabolism

Twice daily

Black box warnings: Aplastic anemia,hepatic failure


Side effects: Somnolence, dizziness, ataxia,fatigue, nausea, vomiting, diarrhea, blurredvision, diplopia, rash, acne, impotence,aggressive behavior, weight gain

912 y old: 900Y3600 mg/d

Clinical challenge: 3 times daily dosing

3 times daily

Adolescents: 200Y400 mg/d (10Y20 mg/L or40Y80 2mol/L)

Side effects: Dizziness, headache, somnolence,tremor, diplopia, vertigo, nausea andvomiting; increases PR intervalTwice daily








Lamotrigineb Partial seizures: monotherapy,adjunctive

Partial seizures: Level D Partial: Strong

Primary GTC seizures: adjunctive(in patients Q2 y old forimmediate release andQ13 y old for delayed andimmediate release)

GTC seizures: No dataavailable

GTC: Strong

Lennox-Gastaut syndrome:adjunctive (in patients Q2 y old)

Absence seizures: Level CMyoclonic: Avoid

Absence: Weak

Spasms: Weak

Levetiracetamb Partial seizures: adjunctive (inpatients Q1 mo old: oral solutionand immediate release; Q16 y old:extended release and IV)


Partial: Strong

Primary generalized tonic-clonicseizures: adjunctive (in patientsQ6 y old)

GTC: Strong

Myoclonic seizure: adjunctive(in patients Q12 y old)

Myoclonic: Strong

Absence: Weak

Spasms: Unknown

Lorazepam Status epilepticus (injection) Partial, GTC, and absenceseizures: No data available

Partial: Weak

No US FDA approved indicationfor tablet form in epilepsy

GTC: WeakMyoclonic: WeakAbsence: WeakSpasms: Unknown

Methsuximide Absence epilepsy: refractory Partial, GTC, and absenceseizures: No data available

Partial: Unknown

GTC: Unknown

Myoclonic: Unknown

Absence: Weak

Spasms: Unknown

Oxcarbazepineb Partial seizures: monotherapy(in patients Q4 y old)

Partial seizures: Level A Partial: Strong

Partial seizures: adjunctive(in patients Q2 y old)

GTC seizures: Level D GTC: Strong

Absence seizures: No dataavailable

Myoclonic: Avoid

Absence: Avoid

Spasms: Unknown

Perampanel Partial seizures: adjunctive(Q12 y old)


Partial: Unknown

GTC: Unknown

Myoclonic: Unknown

Absence: Unknown

Spasms: Unknown






G12 y old: 1Y5 mg/kg/dd (3Y15 mg/L or12Y58 2mol/L)

Side effects: Rash, diplopia, dizziness, ataxia,headache, tremor, insomnia, nausea,vomiting, diarrhea, rarely Stevens-Johnsonsyndrome; increases PR interval

912 y old: 100Y400 mg/d

Clinical challenge: Slow titration to minimizerisk of severe dermatologic reaction

Twice daily

Black box warning: Severe dermatologicreactions

G12 y old: 30Y40 mg/kg/d (12Y46 mg/L or 70Y270 2mol/L) Side effects: Somnolence, ataxia,dizziness, behavioral difficultiesand aggression, emotional lability

912 y old: 1000Y3000 mg/d

Twice daily

0.05Y0.15 mg/kg/dose;maximum 4 mg/dose

n/a Side effects: Sedation, fatigue, nausea,ataxia, dizziness, respiratory depression,agitation, drooling or dry mouth3 to 4 times daily

G30 kg: 20 mg/kg/d (Normethsuximide: 10Y40 mg/Lor 52Y211 2mol/L)

Side effects: vomiting and diarrhea,abdominal pain, drowsiness, dizziness,headache, hiccups, insomnia, rarely rash

Q30 kg: 14 mg/kg/d

Adults: 1200 mg/d

2 to 4 times daily

G12 y old: 20Y40 mg/kg/d (3Y35 mg/L or 12Y137 2mol/L) Side effects: Somnolence, dizziness,headache, diplopia, blurred vision,nausea and vomiting, hyponatremia,rash, fatigue; rarely anemia and hepatitis

912 y old: 600Y2400 mg/d

Twice daily

Q12 y old: 4Y12 mg/d n/a Side effects: Dizziness, somnolence, fatigue,irritability, falls, nausea, ataxia, balancedisorder, gait disturbance, vertigo, weight gain

Black box warnings: Serious or life-threateningpsychiatric and behavioral reactions such asaggression, hostility, irritability, anger,homicidal ideation/threats








Phenobarbital Epilepsy: all pediatricage groups

Partial seizures: Level C Partial: Strong

GTC seizures: Level C GTC: Strong

Absence seizures:No data available

Myoclonic: Strong

Absence: Weak

Spasms: Unknown

Phenytoin GTC and complex partial(psychomotor and temporallobe) seizures: all pediatricage groups



Absence seizures:No data available Absence: Avoid

Myoclonic: Avoid

Spasms: Unknown

Pregabalin Partial seizures: adjunctive(Q18 y old)


Partial: Weak

GTC: Unknown

Myoclonic: Unknown

Absence: Unknown

Spasms: Unknown

Rufinamide Seizures associated with

Lennox-Gastaut syndrome:adjunctive (Q4 y old)


Partial: Weak

GTC: Weak

Myoclonic: Weak

Absence: Weak

Atonic/Tonic: Strong

Spasms: Unknown

Stiripentol Not approved in the UnitedStates


Partial: Unknown

GTC: Unknown

Myoclonic: Strong

Absence: Unknown

Spasms: Unknown

Tiagabine Partial seizures:adjunctive (Q12 y old)


Partial: Weak

GTC: Avoid

Myoclonic: Avoid

Absence: Avoid

Spasms: Unknown






2 moY1 y old: 4Y11 mg/kg/d (10Y40 mg/L or 43Y172 2mol/L) Side effects: Sedation, drowsiness,nausea and vomiting, hyperactivity,irritability, dysarthria, cognitiveimpairment, hypersensitivity reaction

1Y3 y old: 3Y7 mg/kg/d

Clinical challenge: Drug interactionsthrough P450 enzyme induction

3Y6 y old: 2Y5 mg/kg/d

96 y old: 1.5Y4 mg/kg/d

Daily

G12 y old: 5Y10 mg/kg/d (10Y20 mg/L or 40Y80 2mol/L) Side effects: Rash, ataxia, slurred speech,decreased coordination, paresthesia, nauseaand vomiting, constipation,hepatitis, gingival hyperplasia, hirsutism

912 y old: 200Y400 mg/d

Clinical challenges: Nonlinearpharmacokinetics, drug interactionsthrough P450 enzyme induction

2 to 3 times daily

Adolescents: 150Y600 mg/d n/a Side effects: Somnolence, dizziness,ataxia, fatigue, paresthesias, vomiting,dry mouth, constipation, blurred vision,diplopia, erectile dysfunction, weight gain

Twice daily

G12 y old: 20Y40 mg/kg/d (10Y20 mg/L or 40Y80 2mol/L) Side effects: nausea and vomiting, dizziness,fatigue, diplopia, somnolence, hypersensitivitysyndrome, decreases QT interval

912 y old: 1800Y3200 mg/d

Twice daily

50 mg/kg/d; may beincreased to 4 g/d

n/a Side effects: Anorexia, loss of appetite,nausea and vomiting, drowsiness, ataxia,hypotonia, dystonia, hyperkinesias, insomnia,aggressiveness, irritability, weight gain

2 to 3 times daily

Clinical challenges: Nonlinear pharmacokinetics,drug interactions through P450 enzymeinhibition

G12 y old: 0.2Y2 mg/kg/d (20Y200 ng/mL or53Y532 nmol/L)

Side effects: Sedation, dizziness, depression,nausea, vomiting, diarrhea, bruising912 y old: 15Y45 mg/d;

higher doses withenzyme inducer

Twice daily








Topiramateb Partial seizures: monotherapy(Q2 y old)


Partial seizures: adjunctive(2Y16 y old)


Primary GTC seizures:monotherapy (Q2 y old)

Absence seizures:No data available

Myoclonic: Strong

Primary GTC seizures:adjunctive (2Y16 y old)

Absence: Unknown

Lennox-Gastaut syndrome:adjunctive (Q2 y old)

Spasms: Unknown

Valproic acidb Complex partial seizure (Q10 y old) Partial seizures: Level C Partial: Strong

GTC: StrongAbsence seizure (Q10 y old) GTC seizures: Level CMyoclonic: StrongMultiple seizure types:

adjunctive (Q10 y old)Absence seizures: Level A

Absence: Strong

Spasms: Unknown

Vigabatrin Refractory complex partialseizures: adjunctive (only adults)


West syndrome (1 moY2 y old)GTC and absence seizures:No data available

GTC: Unknown

Myoclonic: Unknown

Absence: Unknown

Spasms: Strong (forspasms associatedwith tuberous sclerosis)

Zonisamide Partial seizures: adjunctive(Q16 y old)

Partial seizures: Level D Partial: Strong

GTC seizures: No dataavailable

GTC: Strong

Absence seizures: No dataavailable

Myoclonic: Strong

Absence: Weak

Spasms: Unknown

US FDA = US Food and Drug Administration; ILAE International League Against Epilepsy; AED = antiepileptic drug; n/a = not applicable;IM = intramuscular; IV = intravenous.a Please note that suicidal ideation and depression as a side effect in many AEDs has been reported.b Extended-release formulation available allowing once-per-day dosing.c United States Adopted Name; known in rest of world as retigabine.d Higher doses with enzyme inducer and lower doses with valproic acid.






G16 y old: 3Y9 mg/kg/d;higher doses withenzyme inducer

(3Y29 mg/L or 9Y86 2mol/L;lower in older children)

Side effects: Psychomotor slowing,fatigue, slurred speech, anorexia, nausea,weight loss, metabolic acidosis, hypohidrosis,sedation, dizziness, ataxia, blurred vision916 y old: 200Y600 mg/d

Twice daily

(50Y100 mg/L or350Y700 2mol/L)

Side effects: Tremor, drowsiness, lethargy,dizziness, alopecia, nausea, vomiting,diarrhea, constipation, hyperammonemia,hypocarnitinemia, rare hepatotoxicityand pancreatitis, rare neutropenia, rarepolycystic ovary syndrome, weight gain

G20 kg: 20Y30 mg/kg/d

Adolescents: 500Y3000 mg/d

Clinical challenge: Drug interaction throughinhibition of some medications metabolism

2 to 3 times daily

Black box warnings: Hepatotoxicity,teratogenicity, pancreatitis

Infants: 150Y200 mg/kg/d (0.8Y36 mg/L or 6Y279 2mol/L) Side effects: Visual field defects (irreversible),diplopia, nystagmus, sedation, dizziness,ataxia, cognitive and behavioraldisturbances, paresthesia, nausea, fatigue

Children: 2000Y3000 mg/d

Clinical challenges: Restricted distributionthrough Support, Help And Resources forEpilepsy (SHARE) program in the United States

Adolescents: 1000Y3000 mg/d

Black box warnings: Vision loss (permanent)


G12 y old: 1Y2 mg/kg/d

912 y old: 100Y600 mg/d

(10Y40 mg/L or 47Y188 2mol/L) Side effects: Drowsiness, fatigue, ataxia,psychomotor slowing, aggression,irritability, anorexia, nausea and vomiting,weight loss, abdominal pain,metabolic acidosis, hypohidrosis, rash,rarely aplastic anemia, nephrolithiasis


Clinical challenges: Long half life(950 hours) may result in slow titration



pediatric epilepsy syndrome, and thismay result in even better targetedtreatment options (Table 5-3).

Side Effects and MonitoringAll medications carry the risk of adverseevents, commonly referred to as sideeffects. The most common dose-dependent side effects and idiosyncraticreactions associated with specific AEDsare listed in Table 5-2. Matching thepatient to the best potential AED forthem requires attention to both theseside effects and the patient’s comor-bidities and concomitant medications.For example, AEDs associated withweight loss may not be ideal in patientswith preexisting eating disorders orweight problems.

Dose-dependent side effects aremost common in the first 4 to 8 weeksof therapy as a medication is titratedto its initial target dose. To decreasethe risk of these types of side effects,AED dosages are usually slowly in-creased. These initial side effects, suchas gastrointestinal symptoms or nau-sea, warrant clinical follow-up andmonitoring but are usually not severeenough to lead to discontinuation ofthe medication. Taking medicationsafter meals, shifting the timing ofmedication doses, changing the dos-ing schedule, or slowing the medica-tion titration may help overcome theseinitial adverse effects. A validated pedi-atric epilepsy side-effect questionnaireis now available that can help cliniciansmeasure and follow medication sideeffects longitudinally.9 This question-naire covers the most common dose-dependent side effects and takes patients/parents approximately 5 to 6 minutesto complete.

Currently, the only reliable bio-marker that predicts idiosyncratic re-actions of epilepsy medications isHLA-B*1502. This marker helps toidentify patients of specific Asian back-

grounds at risk for Stevens-Johnsonsyndrome from carbamazepine.10

Tracking Treatment ResponseIn order to assess response to treat-ment, information on baseline seizurefrequency and intervals between initialseizures is crucial. Tracking responseto seizures is important, either withpaper diaries or with online seizure-tracking tools, such as those availableat www.epilepsy.com or www.seizuretracker.com, among others. Inthe future, portable seizure monitors,possibly connected to electronic seizurediaries, may provide additional informa-tion on treatment response.11,12 In ap-proximately one-third to one-half ofchildren with newly diagnosed epilepsy,the first antiepileptic drug fails and thepatients continue to have seizures13,14;this is similar to adult data.15

Adjusting Medications Basedon Seizure Timing(Chronopharmacology)In selected patients, medication treat-ment may be adjusted to times ofgreatest seizure susceptibility.16 Whilethere is no independent parameter topredict the timing of seizures, histor-ical seizure data as tracked in diariesor recorded during video EEG may bea start to identify times when seizuresoccur most frequently. For example,some patients solely have seizures atnight. In these patients, a higher night-time dose of epilepsy medications maylead to a decrease in daytime side ef-fects while improving control of night-time seizures.17

Polypharmacotherapy andInteractionsUp to 40% of patients may requirepolypharmacotherapy if their seizurecontrol is unsatisfactory with mono-therapy. Factors involved with selectinga second or third AED are similar to

KEY POINTS

h The selection of thefirst (or subsequent)antiepileptic medicationis affected by acombination ofpatient-specific anddrug-specific factors.Patient-specific factorsinclude the child’sdisease characteristics(eg, seizure type,epilepsy type, andepilepsy syndrome) alongwith their comorbidities,comedications, age,gender, and abilityto swallow pills.Drug-specific factorsinclude the drug’seffectiveness and/orefficacy for a specificseizure type or epilepsysyndrome, itspharmacokineticcharacteristics,dose-dependent adverseeffects, idiosyncraticreactions, chronictoxicities, teratogenicity,and carcinogenicity.

h Matching the patientto the best potentialantiepileptic drugfor them requiresattention to both theseside effects and thepatient’s comorbiditiesand concomitantmedications.

h In order to assessresponse to treatment,information on baselineseizure frequency andintervals between initialseizures is crucial.Tracking response toseizures is important,either with paperdiaries or with onlineseizure-tracking tools.




www.sciencedirect.com/science/article/pii/S1556407X12000070

www.seizuretracker.com

www.seizuretracker.com

those employed for the initial AEDselection. Efficacy and adverse-eventprofile are always important, but therisk of untoward interactions betweenAEDs and other medications is in-creased with polytherapy. Typically,treatment with more than three AEDsis discouraged, as cumulative side ef-fects frequently outweigh benefits.

A decision for polypharmacother-apy also needs to be preceded by ananalysis of why monotherapy failed,including questioning the diagnosis ofepilepsy, evaluation for nonepilepticseizures, reassessment of nonadher-ence, and trigger prevention. Seizurereduction is likely with the addition ofa second anticonvulsant but much lesslikely with the addition of a third AED.18

Knowledge of enzyme-inducing andenzyme-inhibiting properties is impor-tant when combining different medica-tions, because these properties mayinterfere with dose optimization.

AdherenceNonadherence to recommended med-ication regimens is an underappreciat-ed problem for children with epilepsy.Electronic medication monitors re-vealed that during the first 6 monthsof therapy, 58% of children with newlydiagnosed epilepsy demonstrated per-sistent nonadherence.19 Lack of iden-tifying nonadherence in these childrenoften leads to uninformed and incor-rect medication changes in responseto seizures.20 Patients and families areusually more adherent right beforeand after office appointments,20 andmedication levels may therefore notalways provide adequate adherenceinformation. A medication level at thetime of presentation for breakthroughseizures may help detect nonadher-ence. While more detailed adherencemonitoring, such as electronic medi-cation monitors, is not yet available ona routine basis, the tools for epilepsy

medication monitoring are now inplace and have been used in selectedpatients.21 Although these electronicmonitors may not be easily imple-mented, a correction factor for inter-preting parent-reported adherencemaybe a more accessible and reliable tool inthe near future.21 These tools are an-ticipated to become more widely ac-cessible as electronic solutions becomecheaper and more easily available.

Medication DiscontinuationA trial of epilepsy medication dis-continuation is usually recommendedafter 2 seizure-free years. Medicationsshould be discontinued over at leasta 6-week period, and if the patient ison polytherapy, only one medicationshould be weaned at a given time.Before discontinuing medications, it isimportant to discuss with the familyand patient that seizure recurrencecan occur, and in a small number ofchildren reintroduction of previouslyeffective AEDs after relapse may nothave the same effect. Consideration ofthe underlying etiology or epilepsysyndrome is also important whendiscussing weaning options with pa-tients and families. For example, med-ication weaning may be considered atthe 2-year seizure-free mark in patientswith benign focal epilepsy of childhoodor childhood absence epilepsy and inpatients without MRI lesions, whileweaning may be deferred in patientswith juvenile myoclonic epilepsy or inthose with progressive intracranial le-sions such as brain tumors.

NONPHARMACOLOGICTREATMENT OPTIONSPediatric Epilepsy SurgeryChildren with pharmacologically resis-tant epilepsy are potential candidatesfor epilepsy surgery. Children withongoing seizures due to a focal abnor-mality in the setting of an otherwise

KEY POINTS

h A trial of epilepsymedicationdiscontinuation isusually recommendedafter 2 seizure-freeyears. Medicationsshould be discontinuedover at least a 6-weekperiod, and if thepatient is on polytherapy,only one medicationshould be weaned at agiven time.

h Children withpharmacologicallyresistant epilepsy arepotential candidates forepilepsy surgery.



TABLE 5-3 Selected Pediatric Epilepsy Syndromes and Treatment Choices

Syndrome Peak Age of Onset Clinical Presentation and EEG Findings

Ohtahara syndrome(early infantile epilepticencephalopathy)

First months of life Clinical presentation: Tonic, focal motorand generalized tonic-clonic (GTC) seizuresEEG findings: Burst suppression

West syndrome 4Y9 mo old Clinical presentation: Epileptic spasmsEEG findings: Hypsarrhythmia andhypsarrhythmia variants

Dravet syndrome (severemyoclonic epilepsy of infancy)

First year of life Clinical presentation: Initially unilateral(hemi)clonic and GTC seizures, frequentlyin the setting of fever, later multipleseizure typesEEG findings: Generalized and multifocalspikes

Benign rolandic epilepsy 3Y12 y old Clinical presentation: Unilateral face andarm tonic or clonic nocturnal seizures,drooling, inability to speakEEG findings: Centrotemporal spikes withfrontal dipole

Panayiotopoulos syndrome(early-onset benignchildhood occipital epilepsy)

3Y7 y old Clinical presentation: Prolongedautonomic seizures and status epilepticus,abdominal discomfort, headacheEEG findings: occipital and multifocal spikes

Lennox-Gastaut syndrome 3Y7 y old Clinical presentation: Tonic, atypicalabsence, myoclonic, atonic, and GTCseizuresEEG findings: Slow spike-and-wavecomplexes, also generalized andmultifocal spikes and polyspikes

Continuous spike and waveduring slow-wave sleep,Landau-Kleffner syndrome

2Y4 y old Clinical presentation: Absences (atypical),partial motor and GTC seizures;developmental regressionEEG findings: electrical status epilepticusin sleep

Childhood absence epilepsy 5Y8 y old Clinical presentation: Absence seizures,occasionally associated with automatisms,and myoclonic, tonic or clonic features

Juvenile absence epilepsy 10Y12 y old EEG findings: 3 Hz spike-and-wavecomplexes

Juvenile myoclonic epilepsy 12Y16 y old Clinical presentation: Myoclonic and GTCseizures, frequently in the morning,occasionally absence seizuresEEG findings: generalized 4Y5 Hzspike-wave complexes and polyspikes

a Lamotrigine may work well in some patients with juvenile myoclonic epilepsy, but may lead to myoclonic seizure exacerbation in others.




First Choice Alternate ChoiceLimited Indication orPotential Worsening

Phenobarbital, benzodiazepines,topiramate, zonisamide

Lamotrigine, levetiracetam Valproate

Adrenocorticotropic hormone,vigabatrin (for tuberous sclerosis)

Steroids, topiramate, lamotrigine,pyridoxine, zonisamide, felbamate

Phenobarbital,benzodiazepines

Stiripentol (in combinationwith clobazam and valproic acid)

Adrenocorticotropic hormone/steroids,topiramate, lamotrigine, pyridoxine,zonisamide, felbamate, phenobarbital

Lamotrigine, carbamazepine

No antiepileptic drug;oxcarbazepine, carbamazepine

Levetiracetam, zonisamide,valproic acid

No antiepileptic drug;oxcarbazepine, carbamazepine

Levetiracetam, zonisamide,valproic acid

Valproic acid, clobazam,topiramate, lamotrigine,rufinamide

Felbamate

Diazepam, steroids,levetiracetam, valproic acid

Clobazam/clonazepam,zonisamide, lamotrigine,IV immunoglobulin G

Tiagabine

Ethosuximide Valproic acid, lamotrigine Oxcarbazepine,carbamazepine, tiagabine,gabapentin, vigabatrin

Levetiracetam (girls),valproic acid (boys)

Valproic acid (girls), levetiracetam(boys), topiramate, clobazam/clonazepam, felbamate

Lamotrigine,a

oxcarbazepine,carbamazepine, tiagabine,vigabatrin



normal brain should also be consid-ered candidates for surgery.

Once a child is identified as a can-didate, potential deficits resulting froma resection need to be acceptable forthe family and the child. Functionaldeficits may be seen after resectionsclose to eloquent areas. In children,earlier surgery may also provide aprolonged window of developmentalplasticity after epilepsy resolution, andmay therefore render improved cogni-tive outcomes. For pediatric patients12 years and older, an online tool toevaluate appropriateness for an epi-lepsy surgery evaluation is now available,including assessment of seizure typesand frequency, epilepsy duration, seizureseverity, previous medication trials,medication side effects, and previousevaluations including MRI and EEG.22

All tests performed during thesurgical evaluation aim to estimate

either the epileptogenic zone or elo-quent areas, and their relationship toeach other (Figure 5-1). The surgicalworkup algorithm aims to identify thearea of cortex that needs to be re-sected in order to make the childseizure free (ie, epileptogenic zone)while leaving eloquent cortical areasintact (Figure 5-223).

Preoperative workup of the epilep-togenic zone entails a detailed history,EEG and video-EEG monitoring, high-resolution MRI, and (if clinically indi-cated) additional techniques includingpositron emission tomography (PET)and single-photon emission com-puted tomography (SPECT), as well asmagnetoencephalography (MEG).Functional workup entails neuropsy-chological testing and functional MRI(fMRI) or, if clinically indicated,intracarotid amobarbital testing. In se-lected cases, subdural grid recordings or

KEY POINT

h The surgical workupalgorithm aims toidentify the area ofcortex that needs to beresected in order tomake the child seizurefree (ie, epileptogeniczone) while leavingeloquent cortical areasintact.

FIGURE 5-1 Steps and evaluations in the presurgical workup of pediatric epilepsy surgerycandidates. First steps include a detailed history and EEG and/or video-EEGmonitoring. Based on findings, the decision for a high-resolution MRI of the

brain may be made. Next steps include nuclear medicine evaluation of the seizure focus,neuropsychological testing, and assessment of eloquent areas followed by discussion in aninterdisciplinary epilepsy surgery patient management conference. In this conference, candidacyfor surgery and surgical interventions will be discussed, including the need for invasivemonitoring and mapping.




electrocorticography and cortical stimu-lation may also provide additional in-formation on seizure onset, interictalspiking, and function.

The extent of the epileptogenic zone(as estimated by these techniques), thelocation of eloquent areas, and po-tential overlap are subsequently esti-mated to assess tentative deficits afterresection.

Types of pediatric epilepsy surger-ies are age dependent. While infantsand younger children are more likelyto undergo hemispherectomies andextratemporal and multilobar resec-tions, older children are more likelyto undergo temporal lobectomies.Seizure freedom after resection ranges

from 60% to 70%.24 Children under-going mesial temporal resections usu-ally have better outcomes (58% to78% seizure free) than patients withlateral temporal (59% to 70%) or extra-temporal resections (54% to 66%).Based on pathology, patients withtumors and hippocampal sclerosistend to do better than patients withmalformations of cortical develop-ment. Completeness of the resectionof the epileptogenic lesion, particularlyin patients with malformations of corti-cal development, predicts better out-come.25 Other factors indicating goodoutcome include history of febrile sei-zures, mesial temporal sclerosis, abnor-mal MRI, concordant MRI and EEG

FIGURE 5-2 An approach to pediatric epilepsy patients. As a prerequisite, pharmacologicintractability needs to be demonstrated. The presence or absence of an MRIlesion and EEG findings provide additional guidance on surgical candidacy andtentatively appropriate surgical interventions.

MRI = magnetic resonance imaging; EEG = electroencephalograph; SPECT =single-photon emission computed tomography; FDG-PET = fluorodeoxyglucosepositron emission tomography; SDG = subdural grids; ECoG = electrocorticography.

Modified from Vendrame M, Loddenkemper T, Sleep Med Clin, 2012:7(1):59Y73.23 B 2012, withpermission from Elsevier. www.sciencedirect.com/science/article/pii/S1556407X12000070.



www.sciencedirect.com/science/article/pii/S1556407X12000070

features, and larger resection. Mortalityof epilepsy surgery is about 1%. Pediat-ric epilepsy surgery may also improvedevelopmental outcome, in particular ifseizure control is achieved.26 Addition-ally, pediatric epilepsy surgery may bemore cost-effective than medical ther-apy in selected patients.27

Vagus Nerve StimulationVagus nerve stimulation (VNS) wasapproved in 1997 by the FDA as anadjunctive treatment of intractableepilepsy for patients aged 12 yearsand older with partial epilepsy. VNSconsists of an implanted device thatprovides retrograde stimulation to theleft vagus nerve. In addition to contin-uous stimulation, on-demand stimula-tion can be achieved by swiping amagnet over the implanted generator,usually over the left chest or in the leftaxilla, and programming can be com-pleted through a transcutaneous de-vice. Baseline stimulation settings areusually at 20- to 30-Hz frequency, 250-to 500-2s pulse width, 0.25- to 0.5-mAcurrent, 7- to 30-second on-time and0.2- to 10-second off-time, with amagnet current of 0.25 to 0.5 mA andmagnet stimulus duration of 30 to 60seconds. For a detailed review on set-ting management refer to the article byValencia and colleagues.28

VNS is indicated in pediatric patientswith pharmacologically resistant sei-zures who are not candidates for surgi-cal resection. Specific pediatric patientsreported to experience improvementwith VNS therapy include those withLennox-Gastaut syndrome, epilepticencephalopathies, tuberous sclerosiscomplex, hypothalamic hamartomas,and Landau-Kleffner syndrome.29

In one VNS trial, 60 patients under 18years of age experienced a 23% seizurereduction at 3 months and 40% seizurereduction after 6 months. Other serieshave reported similar rates of 50% or

greater seizure reduction in 19% to53% of pediatric patients after 3 to24 months of treatment initiation, withthe best results in patients with Lennox-Gastaut syndrome. Most recently, a ran-domized, controlled, double-blindedadd-on study in children revealed 50%or greater reduction of seizure fre-quency in 16% of the high-stimulationgroup and in 21% of the low-stimulationgroup. During the open-label follow-upphase of this study, 26% of the chil-dren were deemed responders (ie,seizure frequency reduction of 50%or more).30

Infection after VNS surgery is oneof the most frequent complications.Additionally, hardware defects, vocalcord paralysis or dysfunction, hoarse-ness and coughing, throat pain, phar-yngitis, headaches, paresthesia at theinsertion site, and dyspnea are com-mon. Interestingly, mood stabilizationand improvement of behavior andmood have at times been reported.30

Ketogenic DietSeveral variations of the ketogenic diethave been developed, including thelow glycemic index diet or the modi-fied Atkins diet. The main goal of allthese diets consists of reduction ofcarbohydrate intake and increase ofcaloric intake through fat, thereby in-creasing ketogenesis. The ratio offat to protein and carbohydrates istherefore usually 3:1 or 4:1. Monitor-ing parameters include urine ketonesand plasma "-hydroxybutyric acid(target is usually a "-hydroxybutyricacid level of 30 to 100 mg/dL or 2 to12 nmol/L).

The ketogenic diet is considered inchildren who have pharmacologicallyresistant seizures and who are not sur-gical candidates or in whom epilepsysurgery failed.31 In children with glu-cose transporter (GLUT1) deficiencyor pyruvate dehydrogenase deficiency,




the ketogenic diet is a first-line treat-ment choice.

In some pediatric epilepsy syndromesVincluding infantile spasms, myoclonic-astatic epilepsy (Doose syndrome),Dravet syndrome, tuberous sclerosiscomplex, Rett syndrome, and infantilespasmsVand certain variants of statusepilepticus (including febrile infectionYrelated epilepsy syndrome [FIRES]),sooner treatment with ketogenic diet isalso recommended by some authors.32,33

However, certain metabolic conditionsmay be exacerbated by the diet, suchas carnitine deficiency or beta-oxidationdefects, pyruvate carboxylase deficien-cy, and porphyria32 and are thereforecontraindications to starting the diet. Adetailed evaluation should be done torule out these metabolic conditions be-fore diet initiation. Further details onthe ketogenic diet are available in thearticle ‘‘Dietary Treatment of Intrac-table Epilepsy’’ by Drs Cervenka andKossoff in this issue of .

Steroids and ImmunomodulatoryTreatmentsImmunomodulatory treatments, in-cluding steroids, plasmapheresis, andIV immunoglobulin, have been tried inselected pediatric epilepsy syn-dromes.34 Specifically, adrenocortico-tropic hormone (ACTH) is a first-linetreatment option for infantile spasms.35

Steroids and other immunomodulatorytreatments have also been used inepileptic encephalopathies, includingcontinuous spike-wave during slow-wave sleep, Landau-Kleffner syndrome,severe refractory pediatric epilepsy syn-dromes, and Rasmussen encephalitis.Whereas some authors highlight theanti-inflammatory effect of steroids,34

others suggest that response to ste-roids may also be related to GLUT1deficiency.36 With the identification ofadditional autoimmune-mediated en-cephalitides in children, treatment

with rituximab, cyclophosphamide,and other long-term immunomodula-tory treatments such as azathioprinemay also be considered.37

Pyridoxine-Dependent SeizuresPyridoxine-dependent seizures are theresult of antiquitin deficiency andpresent with early-onset seizures andepileptic encephalopathy, which isresponsive to pyridoxine treatment. Adefect leads to lack of the aldehydedehydrogenase ALDH7A in lysine me-tabolism, and resulting accumulatingmetabolites include pipecolic acid (amarker in the urine, plasma, and CSF),among others. While seizures arefrequently controlled with pyridoxine,patients often remain cognitively de-layed on long-term follow-up.38 Differ-ential diagnoses include pyridoxamine5¶-phosphate oxidase deficiency, neo-natal/infantile hypophosphatasia, andfamilial hyperphosphatasia. Treatmentis 100 mg of pyridoxine given intrave-nously, or orally/enterally at a dose of30 mg/kg/d. Respiratory arrest mayoccur during the first dose, and there-fore precautions should be taken.39

Other Management andTreatment OptionsAdditional work on detection devicesbased on wearable or at times implantedEEG, accelerometry tracking movementin three dimensions over time and otherbiological signal detectors, and relatedprediction algorithms is ongoing. Simul-taneously, treatment approaches such asdeep brain stimulation, transcranial mag-netic stimulation, and trigeminal nervestimulation have not been approved inthe United States but are undergoinginvestigation. Multimodal data acquisi-tion and processing, including genomicdata, may provide further information inthe future.40 A closed-loop responsiveneurostimulation is being investigated.Cooling in selected cases, optogenetics



allowing modulation of specific genet-ically altered neuronal populations bylight, and drug delivery systems arealso experimentally pioneered.41 Whileepilepsy and seizures are most frequentlyseen in young children and early treat-mentmay lead to a larger impact, many ofthese experimental methods focus solelyon adults.

CONCLUSIONPrompt and accurate identification ofseizure type and epilepsy syndromeprovides important information that,when coupled with patient-specificfactors, can help optimize the initialand ongoing pharmacologic andnonpharmacologic management of pe-diatric epilepsies.

ACKNOWLEDGMENTSDrGlauser is funded byNIH/NINDS (U01NS045911, U10-NS077311, R01NS062756,R01LM011124, and R01NS065840). DrLoddenkemper is funded by a facultydevelopment award by Harvard MedicalSchool and Children’s Hospital Boston.We apologize to the many authorswhose work could not be cited becauseof space limitations.

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review article - l.s. neuro · 2014-09-22 · cure: citizens united for research in epilepsy, the...

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