Update Pedi Epliepsy 2010 Dartmouth

8/8/2019 Update Pedi Epliepsy 2010 Dartmouth

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RichardP.Morse,MD

Chief,ChildNeurology

ChildrensHospitalatDartmouth

PediatricEpilepsyUpdate:2010 Overview:

Epilepsyfromvariousvantagepoints:

Molecularmechanisms:

pathophysiology

medications(pharmacogenomics)

thefuture

Medications:

newAEDs,otheroptionsfortreatment

Management:

statusepilepticus,emergencyactionplans

awarenessofcomorbidities

Epilepsy:aPediatricCondition

90%ofepilepsypresentsbyage20years

Affects2%ofpopulation

Commonchildhoodepilepsiesandepilepticencephalopathies/ thedevelopingbrain

Medicallyresistant

epilepsy:

30%

(Brodie

and

others)

MedicallyIntractableEpilepsy

Seizurefree1stdrug47%

seizurefree 2nddrug13%

seizurefree3rdormultipledrugs4%

pharmacoresistantepilepsy36% fromKwan,Brodie

NEJM2001

36% 47%

13%4%

Epilepsy:Definition,Classification Epilepsy:recurrent,unprovokedseizures

Seizure:excessivelysynchronizeduncontrolledneuronalbehavior

ILAE:classification schemes

Seizures:partial(simple,complex,2nd gen)

generalized(TC,absence,atonic)

TheEpilepsies:samebasicscheme,butwithadditionalfeatures(EEG,FH,medicationresponse)

Nametheseizuretype:A:PartialorGeneralized

B:

If

partial:

simple

or

complex

C:Ifgeneralized: TonicClonic

myoclonic

tonic

atonic

absence


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Rfrontalcortical

dysplasia


B:Ifpartial:simpleorcomplex


myoclonic

tonic

atonic

absence


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B:Ifpartial:simpleorcomplex


myoclonic

tonic

atonic

absence

Congenitalhemiplegiaepilepsy,hemiatrophy


B:

If

partial:

simple

or

complex


myoclonic

tonic

atonic

absence


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TuberousSclerosis

withepilepsy

PediatricEpilepsy

ThestoriesofCMandJandhowtheyillustratethechangesinpediatricepilepsy

DravetSyndrome:CM

LennoxGastautSyndrome:J

DravetSyndrome:CM Normalpregnancy,labor,delivery

Normaldevelopmentinitially

Febrileseizures,prolonged,partial(RUE,withpostictalparesis),2040minutes,beganat45months

PlacedonPB,evaluationincludednormalMRIandEEG

Nextseizure4monthslater,againfebrile;taperedoffPB;recurrentRUEseizures,OXCintroduced, seizureGTC,backonPB

ReferredforVEEGmonitoring

DravetSyndrome VEEGmonitoringat14monthsshowedfrequent

generalizedspikewavedischarges,headbobs,occasionalfallingifstanding


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EEGshowingfrequentgeneralizedspikewaveandpolyspikewaveDischargesinachildwithDravetSyndrome

DravetSyndrome GenetictestsentforDravet,positive(frameshift)

mutationdescribed,

disease

producing,

SMEI

or

B

(borderline) phenotype

Whattotelltheparents?

DravetSyndrome:lesson1

Severemyoclonicepilepsyofinfancy:catastrophic,medicallyrefractory,agedependentepilepticencephalopathy

Generallypooroutlook,repeatedstatusepilepticus, developmentalregression,mentalretardation

DravetSyndrome Onsetusuallyinthefirstyearoflifewithprolonged

febrileconvulsions,oftenhemiclonic

Inthesecondyear,mixedseizureswithdrops,absence,GTC,anddevelopmentalregression(encephalopathy)

EEGfromnormaltospike,polyspikeandslowwave

Medicallyrefractoryepilepsy

IncreasedincidenceofSUDEP

DravetSyndrome:Genetics

Duetoasodiumchannelgenemutation,SCN1A

SCN1A,asubunit

protein

(alpha

1)

of

aneuronal

voltage

gatedsodiumchannel

Mutationsassociatedwithseveraloverlappingepilepsysyndromes,spectrumfrommildtosevere

AllelicwithGEFS+,andnewlydescribedfebrileseizuresusceptibilityassociatedwithcertainpolymorphisms


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DravetSyndrome:MolecularGenetics

ClinicalCorrelationsofMutationsintheSCN1AGene:

FromFebrile

Seizures

to

Severe

Myoclonic

Epilepsy

in

Infancy Bertenetal,2004PediatrNeurol

Mutationanalysisin60patients: truncating95%hadclassicSMEI

missenseinporeforming:75%SMEI

missenseinvoltagesensor:spectrum

missenseelsewhere:usuallyGEFS+

DravetSyndrome

Naturalhistory,presenceinadults

Seizurespersistintoadulthood

Mentalretardationistherule

Highmortalityrate(SUDEP)

Studyinadults:GTCnocturnalseizures,frequent,andmixedseizures(myoclonic,absence,partial)inmostaswell

DravetSyndrome:Integration Moleculargenetics

Whatwelearnfrommousemodel

Conceptofinterneuronopathy

Targetingmedications

Outcomestudies

Modelforepilepticencephalopathy,pharmacogenomics, pathophysiology,careorganization(IDEALeague)

LennoxGastaut:Jeffrey NormalP/L/D

ALLat14months,treatedwithMTXIT

Seizures

began

at

3yo,

initially

considered

symptomatic(settingoffebrileillness),nottreateduntilage4yearswhenseizuresoccurredunprovoked

Developedmixedseizuretypes,slowspikewaveonEEG,significantdevelopmentalregression

Giventoepisodicspikewavestatusandfrequentdropattacks


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ElectrodecrementalEEGchanges:correlateoftonicspasm

SlowSpikeWaveofLenoxGastaut

LennoxGastaut Dropattacksresultedinbrokenteeth,lacerations,

frequentheadinjury

Unabletoleftunattended

Declineinfunction

Medicallyrefractory

VNSplaced

Corpuscallosotomyperformed(2stages)

LennoxGastaut ConsideredforDBS

Chronicmedicationeffects,PHT

Rufinamide

Epilepsycontinueswithtypicallydailymultipleseizures,withdrawn,littleinteraction, occasionalbrightmomentswhenseizurescontrolled

VNSmagnetresponsive

LennoxGastautSyndrome Triadofmixedseizuretypes,MR,slowspikewaveon

EEG

Agedependentepilepticencephalopathy,onset16years,typically24years

Poorprognosis:somestartoffnormalormildlydelayed,butwithin5yearsofonset7595%havesignificantcognitiveimpairments

LennoxGastautSyndrome

TonicseizuresmostcharacteristicinLGS

Tonic

refers

to

a

sustained

increase

in

muscle

contractionlastingafewsecondstominutes

Atypicalabsencesecondmostcommon,involvebrieflapseinconsciousness; oftenhardtoidentify

Highincidenceofdropattacks,headinjury

spikewavestuporoccursin5075%


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LennoxGastautSyndrome

EEG:slow

spike

wave;

58minutes

Shinnar,SandtheBronxlongtermepilepsystudy

Febrileseizuresusceptibilityprovidesamodelapproachtoseizuresusceptibilityingeneralandunderscoresthelikelypolygenicaspectsofmanyoftheepilepsies

PediatricEpilepsy:Medications

Epilepsymedications:

Historical New(er)developments

Levetiracetam

Rufinamide

Stiripentol

Lacosamide

Clobazam

Vigabatrin

Treatment:AEDgenerations FirstGenerationAEDs:

carbamazepine,ethosuximide,phenobarbital,phenytoin,primidone,valproicacid

SecondGenerationAEDs:felbamate,gabapentin,lamotrigine,

levetiracetam, oxcarbazepine,tiagabine,topiramate,vigabatrin,zonisamide,pregabalin

NewAEDs:lacosamide,rufinamide,stiripentol


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Treatment:NewAEDs Rufinamide

Lacosamide

Vigabatrin

Treatmentconsiderations:choosingamedication:guidelines Moreanissueofsideeffects,tolerability

Cost

Likelihoodofefficacy,experienceintreatmentoftheparticulartypeofepilepsy

PediatricEpilepsy:other

treatments

Dietarytherapy:ketogenicdiet,LGIT

VNS

Othersurgery:earlyinterventiontrueforepilepsyasmuchasforotherthingspediatric

DBS,RNS

MRIandfocalcorticaldysplasia

Treatment:EvidenceBased

Guidelines ProblemswithEvidenceBasedGuidelines

J.French(2007):CanEvidenceBasedGuidelinesandClinicalTrialsTellusHowtoTreatPatients?

Evidencebasedguidelinesareabletoinformclinicalpracticeonlyifthebest studiescandoso,astheyareusuallybasedonexpertsdeterminingthebest studies

AANandILAEhavedifferentdefinitionsofclassIstudies,havelimitedevidence,limitedquantityof

evidence

to

work

with.

Treatment:EvidenceBased

Guidelines Becauseofstudycriteria(inclusion,exclusion),the

resultsofstudiesareoftennoteasilygeneralizable(complexities ofreallifeareoftenexcludedforstudypatients)

Clinicaltrialscanonlyanswerthequestionthattheyaredesignedtoaddress,sointerpretingdatadifficult(needtolookattrialdesign,howmedicationused,populationusedin,endpointsoftrialwhichincludeduration,dropoutrate,tolerability)

Treatment:EvidenceBased SANAD(StandardandNewAntiepileptic Drugs)trial

ILAEguidelinetreatedthisasaclassIIIduetoopennatureoftrial(nonblinded,leadingtobias)

Smallnumbersofpublishedrandomizedtrials,difficultyinidentifyinggooddata,selectionofendpointsthatdonotfullyinformtreatmentchoice,lackofgeneralizabilityofstudies,toolittleattentiontomodeofuse

Treatment:Guidelines AAN,AES,CNS,ILAEguidelinessupportsecond

generationAEDsduetobettertolerance,equalefficacy,simplerpharmacokinetics, lessinteractions,

safer,less

lab

monitoring

Thoughmoreexpensive,costbenefitanalysesnotdone

NationalInstituteforHealthandClinicalExcellence(NICE)inUKinterpretsdatatosupportuseoffirstgenerationAEDsastheyareequallyeffective,lessexpensive,notshowntoaffectqualityoflife


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PediatricEpilepsy:Lesson3 Organization:EpilepsyProjectatCHaD:

Examinationofthesystemofcareforchildrenwithepilepsy:developmentofguidelines

Identification ofkeyissues

Creationofactionplans,resourcesforinformation

Assignmentofroles,whentorefer,studiestoobtain

Recognitionofcomorbiditieswithepilepsy:thenextsteps

PediatricEpilepsy:ActionPlans

SeizureActionPlan

PediatricEpilepsy

Comorbidities:

Incidenceofpsychiatric comorbidity

Learningandcognition

BRE:notsobenign?

sideeffectsofAEDs

PediatricEpilepsy:2010

Newtreatments:medications, diet,surgery,?genetic

Newunderstanding: pathophysiology,pharmacogenomics

Newconcerns:susceptibility,neonatalseizures

Newsystemsofcare,emergentandchronic

Shapingthefutureofcare:sophisticated, rational,evidencebasedapproachtomanagement

PediatricEpilepsy:2010

Ittakes

avillage

Update Pedi Epliepsy 2010 Dartmouth

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