40751.ppt

8/20/2019 40751.ppt

1/60

Epilepsy: Prognosis and

TreatmentWilliam H Theodore MD

Chief, Clinical Epilepsy Section

National Institte of Nerological Disorders and Stro!eNational Instittes of Health

"ethesda, Maryland, #S$

8/20/2019 40751.ppt

2/60

Pre%alence and Incidence

& Third most common nerologic disorder

& 'irst sei(re incidence: )*+* - .**,***

& Epilepsy incidence: /*+0* - .**, ***

& Pre%alence: 0+.* - .***

1 2eported higher in some de%eloping contries

& Cmlati%e ad3sted lifetime ris!: .4/51/4/5

Hauser WA, Hesdorfer DC. Epilepsy: Frequency, Causes, and Consequences. New York,

Demos !""!:!.

8/20/2019 40751.ppt

3/60

8/20/2019 40751.ppt

4/60

$nnegers .66/

Etiology of Symptomatic Epilepsy

#S$

8/20/2019 40751.ppt

5/60

Epidemiology 7y Sei(re

Types

#eproduced wi$% permission &rom Hauser WA. Epilepsia. !""'(()suppl *+:

Comple /ar$ial)(01+

2nclassi3ed )(1+

4yoclonic )(1+

A5sence )01+/ar$ial 2nknown

)61+

7$%er 8enerali9ed)1+

imple /ar$ial)!*1+

8enerali9ed ;C)'(1+

8/20/2019 40751.ppt

6/60

/ro

8/20/2019 40751.ppt

7/60

AED Peak Plasmaconcentration

Protein binding

clearance T ½ Drug interactions Therapeutic level(μmol/L)

lamotrigine !"h ##$ hepatic #!%& AEDs &!%&

gabapentin '!"h

≈≈dose

& renal %!h minimal *&!'&

tiagabine !'h +% ,-P"A #!.h AEDs

vigabatrin !'h & #!h

Topiramate '!*h # mied .!'"h Lithium0 1,s0 some AEDs &!%&

1carba2epine

(34D metabolite)

!'h *& 5on!,-P

mediated

&!' hr

(34Dmetabolite)

AEDs

oral contraceptives

#&!*& (34D)

6elbamate '!%h ''!'# hepatic #!'"hr AEDs '&&!*&&

Phenobarbital !* h *&!## hepatic .&!"& etensive #&!"&

Phen7toin '!% hr +& 4epatic888 etensive *&!.&

,arbama2epine 9lo:0 variable &!# hepatic .!## hr8' hr88

etensive #!*#

Levetiracetam !' h & ;enal %!& hr minimal

8/20/2019 40751.ppt

8/60

Drug9odium

channels,alciumchannels

?A@As7stem

?lutamatereceptors

,linical Eicac7

L;E P?E 9?E

Phen7toin BB - 5 5

,arbama2epine BB - 5 5

1carba2epine BB - 5 5

Lamotrigine BB + - - -

8/20/2019 40751.ppt

9/60

Epilepsy Therapy in 0)0 Patients

89an and "rodie )***

8/20/2019 40751.ppt

10/60

eterans $dministration Cooperati%eStdy

#eproduced wi$% permission &rom 4a$$son #H, e$ al. N En

8/20/2019 40751.ppt

11/60

Marsan et al )**

Time to .) month remission 5 remaining on drg

S$N$D Stdy

8/20/2019 40751.ppt

12/60

Mattson et al .6;0

2easons for $ED 'ailre

$ Cooperati%e StdyCBZN

8/20/2019 40751.ppt

13/60

Callhagan et al )**;

Prognosis of ADrg+2efractoryB Epilepsy2e+e%alation of )=? patients

& Drg failre 7efore inde>date: 1 ma>imm tolerated dose in

0=5 1 idiosyncratic reaction in ?405 1 intolera7le side effect in .65

1 n!no9n reasons in ).54

& ?+month terminal sei(reremission: 1 14% of AED-treated patients

(about 5% per year of study) 1 52% of surgery patients

& persistent intracta7ility:& Dration .* years, mental

retardation, stats, ? $EDs

No drg seemed sperior

8/20/2019 40751.ppt

14/60

Some Emerging $EDs $ED CPS

place7o

PFE SFE to>icity

"ri%aracetam G ))5 ;5 Gphotosensitity

FI

Caris7amate G.;+)*5 CNS

Eslicar7a(epine G )*5 CNS, FI

acosamide G )*+)05 CNS, FI

2etiga7ine G )*+)05 CNS

2finamide G )*5 total

G =*5 atonic

CNS, FI

8/20/2019 40751.ppt

15/60

8/20/2019 40751.ppt

16/60

Why do $EDs 'ailJ

& $7ot /*5 of patients do not respond at all

& $7ot .*5 of patients 9ith good initial $ED

response cease to respond

& Pharmaco!inetic 1 Drg interactions

1 En(yme indction

& Tolerance to non+"KP $EDs J

1 2eceptor, channel response changes

& Drg effl> transporters

1 PgP, M2Ps,

8/20/2019 40751.ppt

17/60

$ED Tolerance

oscher L Schmidt )**?

& ong+term "KPs: G

allosteric F$"$+"KP

site interactions

& F" tolerance inMES model: G F$D

de to F$"$

feed7ac! inhi7ition

8/20/2019 40751.ppt

18/60

$ltered N$@ Channel

2esponsesJ

2emy et al )**/

No MTS

MTS

8/20/2019 40751.ppt

19/60

Mltiple Drg Transporters

p+glycoproteins& Pmp lipophilic drgs and

other >eno7iotics ot ofcells 1 2ole in cancer

chemotherapy resistance& May 7e o%ere>pressed in

hman epileptic tisse,especially TE

& #nreplicated lin! 7et9een

MD2 genepolymorphisms and

hman $ED resistance

oscher )**

8/20/2019 40751.ppt

20/60

oscher )**

PgP $ffects "rain Phenytoin

e%els

8/20/2019 40751.ppt

21/60

Possi7le Therapetic

Mane%ers

& Manage 9ith drg holidays, dosead3stmentsJ 1 $lternate $EDsJ

& o9er starting dosesJ& Cross+tolerance J

1 Choose drgs 9ith different mechanismsJ

& PgP inhi7ition

1 %erapamil

1 tariidar

8/20/2019 40751.ppt

22/60

Natral History of

Epilepsy

& Natral history ofntreated epilepsyn!no9n

1 "romides since .;0 1 P" a%aila7le since

.6.)

$ l f r e d H a p t m a n

C h a r l e s I o c o

c !

8/20/2019 40751.ppt

23/60

Natral History of Epilepsy

& Natral history ofntreated epilepsyn!no9n4 1 Corse may Aflctate4B

& No difference in sei(re+free rate if treatment7egn after .st or )dsei(re

& In Aresorce poorBcontries, spontaneos

remission rate /*5 1 prognosis not related

to pretreatment FTCS

4auser et al ++.

8/20/2019 40751.ppt

24/60

"erg et al )**/

Early onset 2E may not 7ecome clearly

intracta7le for many years

& centers: /// patients e%alated forresecti%e srgery for locali(ation+relatedepilepsy prospecti%ely identified at initiale%alation

& atency from epilepsy onset to ) $EDfailre 64. years

& )?5 reported at least . yr remission& ;405 0 year remission

8/20/2019 40751.ppt

25/60

Intracta7le Epilepsy:

Comparison of Diagnostic Criteria

"erg et al Epilepsia )**?

8/20/2019 40751.ppt

26/60

Kwan et al Epilepsia 2009

I$E Epilepsy Otcome Categories

Sei(re Control Side Effects Otcome

Sei(re+free No .$

Qes ."

ndetermined .C

Treatment failre No )$Qes )"

ndetermined )C

#ndetermined No /$

Qes /"

ndetermined /Cat least .) months $ND three times the longest intersei(re inter%al in .) months

prior to ne9 inter%ention

8/20/2019 40751.ppt

27/60


Drg 2esistant Epilepsy

I$E )**6

& 'ailre of informati%e trials of t9o tolerated

and appropriately chosen and sed $ED

schedles 9hether as monotherapies or in

com7ination to achie%e sstained sei(refreedom4

8/20/2019 40751.ppt

28/60


Data Needed to Determine if a Therapetic

Inter%ention is RInformati%e

& Mode of application (e.g., formulation, dose,dosing interval)

& Compliance

& Duration of eposure& !as t"ere #as effort to optimi$e dose%& Reason(s) for discontinuation

1 &nsatisfactor' sei$ure control 1 dverse effects

1 Ps'c"osocial reasons, for eample, planning forpregnanc'

1 dministrative reasons, for eample, lost to follo# up 1 inancial issues, for eample, cannot afford drug 1 *t"er reasons

8/20/2019 40751.ppt

29/60

Berg et al 2003

Early onset 2E may not 7ecome clearly

intracta7le for many years & centers: /// patients e%alated for

resecti%e srgery for locali(ation+relatedepilepsy prospecti%ely identified at initiale%alation

& atency from epilepsy onset to ) $EDfailre 64. years

& )?5 reported at least . yr remission& ;405 0 year remission

8/20/2019 40751.ppt

30/60

Predicting Intracta7le Epilepsy

& Epilepsy !attern"# & 2emittent

1 8CN) or 8CN/ 7enignfamilial con%lsions

1 Some a7sence

& Non+remittent Adrgresponsi%eB 1 UME

& Non drg+responsi%e 7ttreata7le 1 ocali(ation+related

& Poorly responsi%e 1 FS

& $linical eatures at &nset"

& Early age of onset

& presentation in stats

epileptics J

& a7normal nerological e>am

& partial sei(res at diagnosis

& mi>ed sei(re types

de%elopmental delay

& mltiple sei(res prior totreatment

& sei(re clstering, AdensityB

& Strctral lesion

8/20/2019 40751.ppt

31/60

Spooner et al )**?

Ne9 onset TE in Children: M2I and Prognosis

Prospecti%e Stdy of 'innish

8/20/2019 40751.ppt

32/60

Sillanpaa et al .666

Prospecti%e Stdy of 'innish

Children

.6?=+.66)

8/20/2019 40751.ppt

33/60

Drg Therapy: Prognosis 7y

Sei(re Type n

8/20/2019 40751.ppt

34/60

What is Intracta7le EpilepsyJ

modified after DC Taylor

& The esion or Disease: 1 mesial temporal sclerosis, malformation

& The Illness:

1 intermittent sei(res& The Predicament:

1 social

1 psychological

1 economic& $EDs treat the illness, not the disease

1 Is that importantJ

8/20/2019 40751.ppt

35/60

Progression of Epilepsy& RThe interparo>ysmal

mental state of epilepticsoften presents gra%edeterioration4

& REach fit apparently lea%esa change in the ner%e

centers, facilitating theoccrrence of other fits4 1 Fo9ers .;6*

& RMental deteriorationfollo9s relentlessly4BB 1 CecilBs Te>t7oo! of Medicine .6)6

Ed9in F Ka7ris!ie $ssociate Professor of Nerology, Colm7ia#ni%ersityPhysician to the Nerological Institte

8/20/2019 40751.ppt

36/60

Silanpaa et al .66;V Uo!eit et al)***V Helmstaedter et al )**/

+europs'c"ological and functional

Prognosis in T-

& Srgery accelerates

decline if nsccessfl

& Stops or re%erses it if

sccessfl& In 'innish pediatric

stdy, ad%erse socio+

economic effects e%en

in patients 9ho enteredadlt life in remission

off $EDs

8/20/2019 40751.ppt

37/60

Cramer et al )**/, Ettinger et al)**=, )**0, 8o7a et al )**?

Depression and Epilepsy

& Depression in Poplation .; sr%ey data

1 /?405 epilepsy

1 )4;5 asthma

1 ..4;5 control

1 $dlts e%er told of epilepsy: 22 )40

1 $dlts 9ith acti%e epilepsy: 22 /4*

& 2edced ality of life

& Increased medical resorce se

8/20/2019 40751.ppt

38/60

ality of ife

& Sei(re control sally considered most

important measre

& Complete sei(re+freedom sally has a mch

greater effect on H2O measres than simplyredced freency

& Depression has greater ad%erse impact than

sei(re freency itself in some stdies

& Drg side effects and nemployment

1 Isse of 9hen to 9ithdra9 drgs after sccessfl

srgery

8/20/2019 40751.ppt

39/60

De%ins!y et al Nerology )**0V"a!er Nerology )**?

Sei(re Control, Depression, and

$n>iety

& Se%eral stdies sggest

sei(re freency

predicts an>iety and

depression symptoms

& Mlticenter srgery

stdy

1 G depression sei(re

control

1 ?4.5 ne9 depression in

non+sei(re free patients

8/20/2019 40751.ppt

40/60

Silanpaa et al .66;V Sperling et al.666

Death

& Standardi(ed mortality ratio is increased in epilepsy,

e%en if no nderlying illness& Mar!ed increase in sdden ne>plained death

1 S#DEP related to: 1 FTCS 1 ) $EDs

& Death after TE 1 SM2 for patients 9ith recrrent sei(res =4?6 1 sei(re free patients: no difference %s age+ and se>+

matched poplation of the #nited States

& Persistent sei(res death in 'innish pediatric stdy& Deat' is due to uncontrolled epilepsy

8/20/2019 40751.ppt

41/60

$pproaches to Intracta7le

Epilepsy

& Srgery

1 ocal resection

1 hemispherectomy 1 Callosotomy palliati%e

& 8etogenic Diet

& E>perimental Drgs

& "rain Stimlation

8/20/2019 40751.ppt

42/60

Wie7e et al )**.

One year )+.* years

Helmstaedter et al )**/

Controlled Temporal o7ectomy Trial

AIntracta7leB TE:

Comparison of Medical and Srgical Otcome

Non+randomi(ed Clinical Series

8/20/2019 40751.ppt

43/60

The 8etogenic Diet

/0 at

1/0 Car2s

3/0 Protein

410 at

10 Car2s5/0 Protein

P t ti l M h i f $ ti

8/20/2019 40751.ppt

44/60

Potential Mechanisms of $ction

& 8etosis& $cetone& $spartate, F$"$& Polynsatrated

fatty acids& Mitochondrial

ncopling& Flcose modlation& Enhanced

gltamate transport& Opening 8 $TP

channels& $cidosis

& Caloric restriction& Decreased I+.& Nerosteroids

8/20/2019 40751.ppt

45/60

8etogenic Diet

& Traditionally started gradally inthe hospital after a )=+=; horfast 1 'amilies edcated daily

& 2atio fat: car7s and protein 1 =:. more strict 1 /:. for infants, adolescents

& Calories ?*+.**5& 'lids ;0+.**5& Solid foods and-or formla& 2eires dietician spport& Strong family committment

8/20/2019 40751.ppt

46/60

Side Effects

& Constipation& Slo9ed 9eight gain& $cidosis 9hen ill

& itamin deficiency if nspplemented& 2enal stones& Impaired height and 9eight& Dyslipidemia& Fastrointestinal pset

8/20/2019 40751.ppt

47/60

8etogenic Diet 2andomi(ed Controlled Stdy

Neal et al ancet Nerology )**;

5/671 #"o stopped diet not included in anal'sis

8/20/2019 40751.ppt

48/60

"rain Stimlation for Epilepsy& agal Ner%e Stimlation

& Transcranial Magneticstimlation

& Intracranial stimlation 1 Srface electrodes

Aresponsi%eB

1 Deep "rain Stimlation& Hippocamps

& Thalams

& Cere7ellm

orpedo fuscomaculata

http://upload.wikimedia.org/wikipedia/commons/1/13/Torpedo_fuscomaculata2.jpg

8/20/2019 40751.ppt

49/60

NS

& 2eires srgery, 7te>tracranial

& Effects 7roadly compara7leto ne9 $ED trials

& /*+=*5 X 0*5 sei(re

freency redction& In open la7el e>tension

effect sstained X .) months

& ery rare patients sei(re+free

& Only consider 9hen nochance for resecti%e srgery

2efractory Fenerali(ed EpilepsyNei et al Epilepsia )**?

8/20/2019 40751.ppt

50/60

Transcranial Magnetic Stimlation

TMS i E il

8/20/2019 40751.ppt

51/60

TMS in Epilepsy

& TE: 1 Case reports and open

trials:& /*+*5 sei(re decreases

reported

1 "linded controlled trial

& .?5 redction place7o*4*0YpY*4.*

& Effect lasted )+= 9ee!s

& Cortical Dysplasia

1 significantly decreasedthe sei(res in acti%ecompared 9ith shamrTMS grop

~4 cm

8/20/2019 40751.ppt

52/60

Thalamic Stimlation

& Centromedian 1 #ncontrolled stdies reported impro%ement

1 Small controlled stdy: no effect

& $nterior 1 2ecent controlled stdy sho9ed sei(re G

& .=405 in the control grop

& =*4=5 in the stimlated grop

& S7thalamic

1 Impro%ement in ncontrolled stdies

8/20/2019 40751.ppt

53/60

ong8term follo#8up of patients #it" t"alamic

deep 2rain stimulation for epileps'

& ong+term follo9+p mean, 0 years

1 ? patients 9ith anterior $N

1 ) centromedian thalamic deep 7rain stimlation

& 'i%e patients all $N had 0*5 sei(re redction 1 7enefit 9as delayed in t9o ntil years 0 to ?

1 after changes in antiepileptic drgs4

& Sei(re redction . to / months 7efore acti%e

stimlation

1 Possi7ility of a 7eneficial microthalamotomy effect4

$ndrade et al Nerology )**?

8/20/2019 40751.ppt

54/60

Hippocampal Stimlation

& 2edced CPS freency reported in se%eral ncontrolledstdies

& One small controlled stdy:

& 'or patients 9ith refractory MTE

1 2is! to memory contraindicated temporal lo7e resection

& Do7le+7lind stimlation randomly trned ON . month andO'' . month for ? months

& Median redction in sei(res of .05 1 Effects seemed to carry o%er into the O'' period

1 Possi7le implantation effect4

& No ad%erse effects4

& One patient treated for = years has s7stantial long+termimpro%ement4

Telle(+Kenteno et al NE#2OOFQ )**?V??:.=6*1.=6=

8/20/2019 40751.ppt

55/60

Sei(re Prediction

-nerg' level (red)

decision t"res"old (2lue)

prediction output (green)

sei$ure onset (2lac9)

Positive outputs

("ig" level in greencurve)

o2served : 3 "

2efore sei$ures4

Esteller et al Clin Nerophysiol )**0

8/20/2019 40751.ppt

56/60

2NSZ Placement

Cortesy of Martha Morrell

8/20/2019 40751.ppt

57/60

nterior ead ()

Posterior ead (P)

Para"ippocampal

ongitudinal

;trip (not connected)

Cortesy of Martha Morrell

8/20/2019 40751.ppt

58/60

Preliminary 2NS Efficacy n

8/20/2019 40751.ppt

59/60

2is!s of "rain Stimlation& TMS

1 2are sei(res at 'ig' .*h( freency& Epilepsy therapy trials are at [ . h(

1 Mild headache, scalp discomfort

& NS 1 Cogh, Hoarseness 9hen stimlator on

1 dyspnea, pain, paresthesia, and headaches 1 respond to alteration of stimlation settings

1 ery rare %ocal cord paralysis, 7radycardia dring implant

& D"S 1 "leeding

1 infarction 1 intracranial infection 1 $ll less li!ely 9ith srface 2NS

8/20/2019 40751.ppt

60/60

Documents

40751.ppt