TX Epilepsi Baru Dr Margono

8/10/2019 TX Epilepsi Baru Dr Margono

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TREATMENT OF NEWLYDIAGNOSED EPILEPTIC

PATIENT

Margono IS

Bagian/SMF. NeurologiFK. Unair/RSU. Dr. Soetomo

Surabaya


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INTRODUCTION

Epilepsy is a common, sometimes chronic,

condition with physical risk, psychological and

socio economic consequences which impairquality of life. Affecting approximately 1% of the

worlds population, it is among the most common

serious neurological disorders. The prime

requirements are a complete diagnosis, selectionof optimal treatment, and counseling appropriate

to individual needs.


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Until recently, clinicians had a relatively limitedtherapeutic armamentanium with which to treat

epilepsy. With the global introduction of nine newanti epileptic drugs (AEDs) since the late 1980s,the choice has been substantially widened and thenumber of possible commbination as now almost

limitless. Before starting the treatment, the patient (and

carer/family) should be sufficiently will informedto make decisions about choices of treatment, the

need for long term treatment, and options fordealing with the drug resistant conditions and itsconsequences.


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DIAGNOSIS


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The paroxysmal nature of epilepsy can bemimicked by a variety of events. The dicision

whether the paroxysmal event is a seizure or a nonepileptic event is crucial and many errors bothpositive and negative are inevitiable unless carefulconsideration is placed.

Data from epilepsy clinics reveal that 20 to 25percent of patients referred as epilepsy do not haveepileptic seizures. Jitteriness, benign neonatalsleep myoclonus in the neonatal breath holdingspells in infants, syncope, cardiac arythmias,

pseudoseizures and migraine variants beyondinafancy and reaction conversion in adult arecommon confounders. A witnessed event, EEG,video EEG and neuroimaging are very helpful in

making clear cut the diagnosis of epilepsy.


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TREATMENT

The goal of epilepsy treatment is freedomfrom seizure with no or minimal side

effects. The decision to start treatment is

much more straight forward in patient withrecurrent seizures and an clear cut diagnosis

of epilepsy.


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There are three key principles of treatment

1. A single drug is cautiously introduced tominimise risk of acute idiosynmatic anddose related toxicity.

2. When seizures continue, the dose shouldbe increased to the maximum toleratedbefore switching to alternativemonotherapy.

3. It is only when seizures continue despiteadequate trials of two appropriate drugs,that combination/dual therapy should beemployed.


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PRINCIPLES OF ANTIEPILEPTIC

DRUG SELECTION Since the chance of remission is hihgher

with the first AED, substantial attention

should be given to choosing the mosteffective first drug for the newly diagnosed

patient.


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Table Efficacy of AEDs for common seizure types.

Partial +/-

secondary

GTCS

Primary

tonic-clonic

Absence Myoclonic Atonic/tonic

Phenobarbital + + 0 ? + ?

Phenytoin + + - - 0

Carbamazepine + + - - 0

Sodium

valproate

+ + + + +

Ethosuximide 0 0 + 0 0

Benzodiazepine

s

+ + ? + +

Gabapentin + + - - 0

+ = effective; ?+ = probably effective; 0= ineffective; - = worsen seizure; ? = unknown

GTCS = generalized tonic-clonic seizures* Worsening of myoclonic seizures in some cases has been reported


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Choosing the most suitable AED for anindividual patient requires in depth

knowledge of the characteristics of the

epilepsy, the patient and the availableAEDs.


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Table Factor to be considered when

choosing an AED regimen

Patients Epilepsy Drugs

Age

Sex

Pregnancy

Body weight

Comorbidities

Learning disabled

Social

First seizure

Newly diagnosed

Idiopathic

Localization-

related syndrome

Refractory

Efficacy

Toxicity/adversed

effect Pharmacokinetics

Interactions

Teratogenicity

Mechanisms

Cost

Dikutip dari Patrick Kwan, MRCP, PhD. Medical Progress, October 2004.


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Table Clinical properties of established AEDs.

Drug

Primary

model(s)

of action

Indication

Protein

Binding

(%

bound)

Eliminat

ion half-

life

(hours)

Routes of

elimination

Pharmac

okinetic

interactio

n

Common/rare but

Important side

effect

Carbamaze

pin

Sodium

channel

blockade

Partial and

GTCS70-80

24-45

(single)

8-24

(chronic

)

Hepatic

metabolism

Active metabolite

CYP

enzyme

induction

Skin rash

Neurotoxicity

Hyponatraemia

ClobazamGABAergi

c

Partial and

generalized

seizure

87-90 10-30

Hepatic

metabolism

Active metabolite

No

significan

t

Sedation

Tolerance

Clonazepam

GABAergi

cPartial and

generalized

seizure

80-90 30-40Hepatic

metabolism

No

significan

t

Sedation

Tolerance

Ethosuximid

e

Calcium

channel

blockade

Absence

seizure 0 20-60

Hepatic

metabolism 25%

excreted

unchanged

No

significan

t

Gastrointestinal

upset

Neurotoxicity

Skin rash


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Phenobarb

ital

GABAer

gic

Partial,

GTCS,

myoclonic,

tonic, clonic

seizure,

statusepilepticus

48-54 72-144 Hepatic

metabolism 25%

excreted

unchanged

CYP

enzyme

inductio

n

Hypersensitivity

Sedation

Behavioural

problems

Phenytoin Sodium

channel

blockade

Partial and

GTCS status

epilepticus

90-93 9-40 Saturable hepatic

metabolism

CYP

enzyme

inductio

n

Hypersensitivity

Neurotoxicity

Dysmorphic effects

Primidone GABAer

gic

Partial and

GTCS

20-30 4-12 Hepatic

metabolism

Active metabolite

40% excreted

unchanged

CYP

enzyme

inductio

n

Sedation

Behavioural

problems

Valproate Multiple Partial

seizures

all

generalized

seizures

88-92 7-17 Hepatic

metabolism

Active metabolite

CYP

enzymeinductio

n

Weight gain

Hair loss(

transient)

Hepatotoxicity

(mainly children

AED =Antiepileptic drug; CYP= hepatic cytochrome P450; GABA= gamma-aminobutyric acid; GTCS=

generalized tonic-clonic seizures


bl li i l i f


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Table Clinical properties of newer AEDs.

Drug

Primary

model(s) of

action

Indication

Protein

Bindin

g

(%

bound)

Eliminat

ion half-

life

(hours)

Routes of

elimination

Pharmacokinet

ic interaction

Common/rare but

Important side

effect

Felbamate Multiple

Partial onset

seizures

Lennox-

Gastaut

syndrome

22-36 13-23

Hepatic

metabolism

Renal excretion

CYP inhibitorAplastic anaemia

Hepatotoxicity

Gabapentin

Neuronal

calcium

channel

binding

Partial onset

seizures0 5-7

Not

metabolized

Renal excretion

None known

Neurotoxicity

(mild)

Weight gain

Lamotrigine

Sodium

channel

blockade

Partial

seizures

All

generalized

seizures

55 22-36 Glucoronidation

Affected by

other AEDs Skin rashNeurotoxicity

Levetiracet

amUnknown Partial onset

seizures


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Oxcarbazep

ine

Sodium

channel

blockade

Partial and

GTCS

40 8-10 Hepatic

conversion to

active moietyInduces

metabolism of

oral cotraceptive

pill

Neurotoxicity

Skin rash

Hyponatraemia

Pregabalin Neuronal

calcium

channel

binding

Partial onset

seizures

0 6 Not metabolized

Renal excretion

None known Neurotoxicity

Weight gain

Tiagabine GABAergic Partial onset

seizures

96 5-9 Hepatic

metabolism

Affected by

other AEDs

Neurotoxicity

Topiramate Multiple Partial

seizures,GTCS,

absence,

myoclonus,

Lennox-

Gastaut

syndrome

9-17 20-24 Hepatic

metabolismRenal excretion

Affected by

other AEDsAt daily dose

>200 mg induces

metabolism of

oral

contraceptive

pill

Neurotoxicity

Paresthesia

Word- finding

problem

Renal stones

Vigabatrin GABAergic Partial onset

seizures

0 5-7 Not metabolized

Renal excretion

Reduces serum

phenytoin level

Psychiatric

problemsVisual field defect

Zonisamide Multiple Partial and

GTCS

40-60 50-68 Hepatic

metabolism

Renal excretion

Affected by

other AEDs

Neurotoxicity

Renal stones

AED =Antiepileptic drug; CYP= hepatic cytochrome P450; GABA= gamma-aminobutyric acid; GTCS= generalized tonic-clonic

seizures



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Table Recommended first-line and second-line AEDs

for common seizures types.

Seizure type First line Second line

Partial

Carbamazepine

Phenytoin

Lamotrigine*

Gabapentin*

Oxcarbamazepine*

Topiramate*

Valproate

Levetiracetam

Pregabalin

TiagabineZonisamide

Tonicclonic

Valproate

Carbamazepine

Phenytoin

Oxcarbamazepine*

Topiramate*

Lamotrigine*

Absence

Valproat Ethosuximide

Lamotrigine

MyoclonicValproat Lamotrigine

Topiramate

*First line in some countries

*Worsening of myoclonic seizures in some cases has been reported

Note: Readers are advised to refer to local national formularies for monotherapy indications


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Pharmacokinetics and drug-drug

Interaction

Table. Showed the Desirable Pharmacokinetics Properties of

an antiepileptic drugs.

High oral bioavailability

Low plasma protein binding

Ready penetration across the blood-brain barrier

Long half-life

Significant renal elimination

Elimination by routes not involving oxidation or conjugation

Linear kinetics

No active metabolites

Low vulnerability to drug interactions

Low propensity to cause drug interactions


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Table Mention a comparative assessment of the extend to which older and

newer antiepilrptic drugs fulfill desirable pharmacokinetic properties.

Drug

High

oral

bioavaila

bility

LOW

plasma

protein

binding

Long

half-life

Significant

renal

excretion in

unchanged

form

Absence of

oxidation or

conjugation

Absence of

active

metabolite

Linear

kinetics

Uncommo

n target of

drug

interactio

ns

Uncommon cause

of drug

interactions

Carbamazepine

Clobabazam

Ethosuximide

Phenytoin

Primidone

Phenobarbital

Valproic acid

Felbamate

Gabapentin

Lamotrigine

Levetiracetam

Oxcarbazepine

Tiagabine

Topiramate

Vigabatrin

Zonisamide

yes

yes

yes

yes

yes

yes

yes

yes

no

yes

yes

yes

yes

yes

yes

yes

yes

no

yes

no

yes

yes

no

yes

yes

yes

yes

yes

no

yes

yes

yes

no*

yes

yes

yes

no

yes

no*

yes

no

yes

no

no

no

yes

no

yes

no

no

no

no

yes

yes

no

yes

yes

no

yes

no

no

yes

yes

yes

no

no

no

no

no

no

no

no

yes

no

yes

no

no

no

yes

no

no

no

yes

yes

no

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

no

yes

yes

no

yes

yes

no

yes

no

yes

yes

yes

yes

yes

yes

yes

no

no

no

no

no

no

no

no

yes

no

yes

yes S

no

no

yes

no

no (inducer)

yes

yes

no (inducer)

no (inducer)

no (inducer)

no (inhibitor)

no (inhibitor) +

yes

yes

yes

no+

yes

yes+

yes

yes

* Sustained-release formulations suintable for twice-daily dosing are available.

+ Oxcarbazepine, topiramare (>200 mglday), and felbama(e (in addition to phenyioin, cavbamazepine, phenobarbital, and primidone) stimulate

the metabolism of the contraceptive pill.

Prolonged effect despite short half-lifeallows twice-daily dosing

S The plasma levels of MHD are moderately reduced by enzyme-inducing comedicafion.


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Co Morbidities :

In In addition of controlling seizures, some AEDshave also demonstrated efficacy for the treatmentof the neurological conditions, which may coexistwith epilepsy. For instance valproate has

traditionally been used in Bipolar affectivedisorder. Gaba pentine is effective for thetreatment of certain neuropathic pain syndromesand topiramate has been approved as prophylaxis

for migraine. With the wide spectrum of indication, theselection of AEDs may betailor made according tothepatientsneurological co morbidities.


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Pharmacogenetics The influence of genetic variation in drug-

metabolizing genes, in particular those endodingthe CYP enzymes, on susceptibility to drugtoxicity has long been recognized.

There is recent evidence that variants of theABCB1 (or MDR1) gene, which codes for theefflux transporter P-glycoprotein at blood brain

barrier, maybe associated with resistance to AEDtherapy in epileptic patients.

A Brazilian study should showed that a variantallele of the cellular prion protein gene was morecommon in patients underwent surgery andconferred a poorer outcome after temporer

lobectomy.


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In conclusion, as the complexity of genetics

influence on treatment responsivenessbecome better understood, pharmacogenetic

profiling may, in the future, be redognized

as a practical determinant of drug selection.


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Patophysiology and Genetics

Ideally, the aim to treat epileptic patients is

to understand how epilepsy develops and to

prevent it rather than one that merelysuppresses seizure.


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Table Epilepsy Syndromes Associated with Single-Gene Mutations.

Epilepsy

Syndrome

Gene Gene Product* Study

Generalized epilepsy

with febrile seizures plus

SCNI8

SCN1A

SCN2A

GABRG2

Sodium-channel subunit



GABAA-receptor subunit

Wallace et al.31.

Escayg et al.32

Sugawara et al 33

Baulac et al.34

Benign familial neonatal

convulsions

KCNQ2

KCNQ3

Potassium channel

Potassium channel

Biervert et al.,35

Singh et al.36

Charlier et al.37

Autosomal dominant

nocturnal frontal-lobe

epilepsy

CHRNA4

CHRNB2

Neuronal nicotinic

acetylcholine-receptor

subunit

Neuronal nicotinic

acetylcholine-receptor

subunit

Steinlein et al.38

Fusco et al.39

Childhood absenceepilepsy and febrile

seizures

GABRG2GABAA-receptor subunit Wallace et al.

40

Autosomal dominant

partial epilepsywith

auditory features

LGI1 Leucine-rich

transmembrane protein

Kalachikov et al.41

*GABAAdenotes gamma-aminobutyric acid type A.

T bl S f th th t i l d i il


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Table Some of the genes that are involved in epilepsy

Subtypes Gene Symbol Phenotype

Ion channel genes in idiopathyc epilepsy

Nicotinic acetylcholine receptorsPotassium channel

Sodium channel

Chloride channel

GABAA receptors

CHRNA4/CHRNB2KCNQ2/KCNQ3

SCN1A/SCN2A/SCN1B

CLCN2

GABRG2/GABRA1

ADNFLEBFNC

GEFS*

IGE

GEFS*/IGE

Non-ion channel genes in idiopathic

epilepsy

Function unknown

G-protein coupled receptors

LGI1

MASS1/VLGR1

ADLTE

FS

Progressive myoclonus epilepsies

Polyglucosan metabolism

Cysteine protease inhibition

Respiratory chain

Lipidoses

Glycopeptide/Oligosaccharide

EPM2A/EPM2B(NHLRC1)

CSTB

MTTK/MTTL1

PPT

CLN2

CLN3

CLN5

CLN6

CLN8

NEU1

Lafora disease

Unverricht-Lundborg ds.

MERRF

Infantile NCL

Late infantile NCL, Indian variant

Juvenile NCL



Northern epilepsy

Sialidosis metabolism

T bl C l ti b t h i f il t i d


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Table Correlation between mechanisms of epileptogenesis and

mechanisms of action of AEDs.

Mechanism of epileptogenesis Mechanism of action of AEDs

GABA Reduced GABA in microgyric cortex

Reduced benzodiazepine receptor binding in medial

thalamic nucleus (mesial temporal lobe epilepsy)

Reduced GABA levels and GAD activity (epileptic

foci)

Auto-antibodies to GAD (Stiff-man syndrome)

Increased functional pool of GABA

(vigabatrin, tiagabine)

Enhanced GABA-ergic inhibition

(benzodiazepine)

GABA agonistic effect (progabide)

(Weaker) GABA-ergic properties

(phenobarbital, gabapentin, topiramate,

valproate, zonisamide)

Glu

Upregulation of hippocampal ionotropic glutamatereceptors (temporal lobeepilepsy)

Anti-gluR3 antibodies (Rasmussen encephalitis)

Increased plasma glutamate levels (absence seizures)

Inhibition of glutamate release(lamotrigine)

Block of glycine site at NMDA receptor

(felbamate)

Na+ Mutation voltage-gated Na+ channel (generalized

epilepsy with febrile sizures)

Reduction of voltage-gated Na+ current

(carbamazepine, felbamate, lamotrigine,

oxcarbazepine, phenytoin, topiramate,

valproate, zonisamide)

K+

Ca+

Mutation voltage-gated K+ channel (benign familialneonatal convulsion

Reduced Ach-mediated Ca flux (nocturnal frontal

lobe epilepsy)Reduced of T-type Ca++ currents

(ethosuximide, valproate)

Increased membrane excitability Decreased membrane excitability


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Conclusion

Treating childhood seizure and epileptic

syndrome should be pay attention on many

factors including the patient, the disease andthe AED.

The The optimal management of patients

with epilepsy requires cooperation betweenneurologist pediatric neurologist, general

practitioners and care giver.


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Most patients with a first seizure do not need

treatment. When initially treatment start slow go slow

approach reduces risk of intolerance.

It must also bear in mind that AEDs from each

other greatly in many respects including mode of

action, range efficacy, interaction profile, all of

which should be considered when assessing drug

choice for the individual patient, whether asmonotheraphy or adjunctive treatment.

Patients too are not all the same.


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The presence of co morbidities may also influence

drug choice. The selection of treatment should,

therefore, involve careful assessment of individual

patient-related factors accurate classification of

seizure type and syndrome, combined with an

understanding of the pharmacology and toxixity ofthe suitable AEDs.

Such a strategic and individualized approach will

optimize the chance of attaining remission and

help many more patients enjoy a fulfilling life.


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Reference

1. Chongtrakul, S : Managing Childhood Epilepsy

Adapted from : Drug & Therapeurics Bulletin,

Febr, 2001.2. Chang BS. : Mechanisms of Disease Epilepsy. N

Engl J. Med 349;13. www.NEJM.orgSeptember

25, 2003.

3. Engelborghs, R. : Pathophysiology of Epilepsy.Acta Neurol, belg, 2000, 100, 301-213.
http://www.nejm.org/http://www.nejm.org/


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4. Frech, JA et al : Efficacy and Tolerability of TheNew Antileptic Drugs, III : Treatment of New-

Onset Epilepsy : Report of The TTA and QSSSubcommittee of the American Academy of

Neurology and The American Epilepsy Society.Epilepsia, 45, 5, 2004, 401-423.

5. Hirtz, D et al : Practice Parameter : Treatment ofThe Child with a first unprovoked seizure. Reportof the Quality Standards Subcommittee of theAmerican Academy of Neurology and The

Practice Committee of The Child NeurologySociety. American Academy of Neurology, Jan2003, 166-175.


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6. Kwan, P. : Principles of Drug Selection for The

Treatment of Epilepsy Medical Progress, Oct.

2004, 476-848.

7. Kalra, V. : Management of Childhood Epilepsy.

Indian J of Paediatrics, 70, Febr, 2003, 147-151.

8. Moshe, SL. : Special Consideration in TreatingChildren with Epilepsy. Pharmacotherapy, 20,

2000, 171S177S.

9. National Institute for Clinical Excellence : Newer

drugs for epilepsy in children Technology

Appraisal 79, April 2004.


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10. Perucca, E and Johannessen, SI : TheIdeal Pharmacokinetic Properties of anAntiepileptic Drugs : how closed doeslevitiracetam come ? Epileptic Discord2003, 5(supll 1), S 17-S26.

11. Smith, D and Chadwick, D. : TheManagement of Epilepsy. J. NeurolNeurosurg Psychiatry, 2001, Supll II, ii15-ii21.

12. Steinlein, OK : Genetic Mechanisms ThatUnderlie Epilepsy.

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TX Epilepsi Baru Dr Margono