TREATMENT OF NEWLY

DIAGNOSED EPILEPTIC
PATIENT
Margono IS
Bagian/SMF. Neurologi
FK. Unair/RSU. Dr. Soetomo
Surabaya
1

INTRODUCTION
Epilepsy is a common, sometimes chronic,
condition with physical risk, psychological and
socio economic consequences which impair
quality 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, selection
of optimal treatment, and counseling appropriate
to individual needs.
2

 Until recently, clinicians had a relatively limited

therapeutic armamentanium with which to treat
epilepsy. With the global introduction of nine new
anti epileptic drugs (AEDs) since the late 1980s,
the choice has been substantially widened and the
number of possible commbination as now almost
limitless.
Before starting the treatment, the patient (and
carer/family) should be sufficiently will informed
to make decisions about choices of treatment, the
need for long term treatment, and options for
dealing with the drug resistant conditions and its
consequences.
3

DIAGNOSIS

 The paroxysmal nature of epilepsy can be

mimicked by a variety of events. The dicision
whether the paroxysmal event is a seizure or a non
epileptic event is crucial and many errors both
positive and negative are inevitiable unless careful
consideration is placed.
Data from epilepsy clinics reveal that 20 to 25
percent of patients referred as epilepsy do not have
epileptic seizures. Jitteriness, benign neonatal
sleep myoclonus in the neonatal breath holding
spells in infants, syncope, cardiac arythmias,
pseudoseizures and migraine variants beyond
inafancy and reaction conversion in adult are
common confounders. A witnessed event, EEG,
video EEG and neuroimaging are very helpful in
5
making clear cut the diagnosis of epilepsy.

TREATMENT
The goal of epilepsy treatment is freedom
from seizure with no or minimal side
effects. The decision to start treatment is
much more straight forward in patient with
recurrent seizures and an clear cut diagnosis
of epilepsy.

There are three key principles of treatment

1. A single drug is cautiously introduced to
minimise risk of acute idiosynmatic and
dose related toxicity.
2. When seizures continue, the dose should
be increased to the maximum tolerated
before switching to alternative
monotherapy.
3. It is only when seizures continue despite
adequate trials of two appropriate drugs,
that combination/dual therapy should be
employed.
7

10

11

PRINCIPLES OF ANTIEPILEPTIC
DRUG SELECTION
Since the chance of remission is hihgher
with the first AED, substantial attention
should be given to choosing the most
effective first drug for the newly diagnosed
patient.

12

Table Efficacy of AEDs for common seizure types.

Partial +/secondary
GTCS

Primary
tonic-clonic

Absence

Myoclonic

Atonic/tonic

Phenobarbital

?+

Phenytoin

Carbamazepine

Sodium
valproate

Ethosuximide

Benzodiazepine
s

Gabapentin

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

GTCS = generalized tonic-clonic seizures

* Worsening of myoclonic seizures in some cases has been reported

13

 Choosing the most suitable AED for an

individual patient requires in depth
knowledge of the characteristics of the
epilepsy, the patient and the available
AEDs.

14

Table Factor to be considered when

choosing an AED regimen
Patients

Epilepsy

Drugs

Efficacy
Toxicity/adversed
effect
Pharmacokinetics
Interactions
Teratogenicity
Mechanisms
Cost

Age
Sex
Pregnancy
Body weight
Comorbidities
Learning disabled
Social

First seizure
Newly diagnosed
Idiopathic
Localizationrelated syndrome
Refractory

Dikutip dari Patrick Kwan, MRCP, PhD. Medical Progress, October 2004.
15

Table Clinical properties of established AEDs.

Drug

Primary
model(s)
of action

Indication

Carbamaze
pin

Sodium
channel
blockade

Partial and
GTCS

Clobazam

GABAergi
c

Partial and
generalized
seizure

GABAergi
c
Clonazepam

Partial and
generalized
seizure

Calcium
Ethosuximid
channel
e
blockade

Absence
seizure

Protein Eliminat
Binding ion halflife
(%
bound) (hours)

Routes of
elimination

Pharmac
okinetic
interactio
n

70-80

24-45
(single)
Hepatic
CYP
metabolism
enzyme
8-24
(chronic Active metabolite induction
)

87-90

Hepatic
No
metabolism
significan
t
Active metabolite

80-90

10-30

30-40

20-60

Hepatic
metabolism

No
significan
t

No
Hepatic
metabolism 25% significan
t
excreted
unchanged

Common/rare but
Important side
effect

Skin rash
Neurotoxicity
Hyponatraemia

Sedation
Tolerance

Sedation
Tolerance

Gastrointestinal
upset
Neurotoxicity
Skin rash
16

Phenobarb
ital

GABAer
gic

Partial,
GTCS,
myoclonic,
tonic, clonic
seizure,
status
epilepticus

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

17

Table Clinical properties of newer AEDs.

Primary
model(s) of
action

Indication

Felbamate

Multiple

Partial onset
seizures
LennoxGastaut
syndrome

Gabapentin

Neuronal
calcium
channel
binding

Partial onset
seizures

Sodium
channel
blockade

Partial
seizures
All
generalized
seizures

Drug

Lamotrigin
e

Levetiracet
am

Unknown

Partial onset
seizures

Protein
Bindin Eliminat
ion halfg
life
(%
(hours)
bound)

22-36

55

<10

13-23

Pharmacokinet
ic interaction

Common/rare but
Important side
effect

Hepatic
metabolism
CYP inhibitor
Renal excretion

Aplastic anaemia
Hepatotoxicity

Routes of
elimination

5-7

Not
metabolized
Renal excretion

22-36

Glucoronidatio
n

7-8

Nonhepatic
hydrolisis
Renal excretion

None known

Affected by
other AEDs

None known

Neurotoxicity
(mild)
Weight gain

Skin rash
Neurotoxicity

Neurotoxicity
Behavioural
problems
18

Oxcarbazep
ine

Sodium
channel
blockade

Partial and
GTCS

40

8-10

Hepatic
conversion to
active moiety

Pregabalin

Neuronal
calcium
channel
binding

Partial onset
seizures

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,
LennoxGastaut
syndrome

9-17

20-24

Hepatic
metabolism
Renal excretion

Affected by
other AEDs
At daily dose
>200 mg induces
metabolism of
oral
contraceptive
pill

Neurotoxicity
Paresthesia
Word- finding
problem
Renal stones

Vigabatrin

GABAergic

Partial onset
seizures

5-7

Not metabolized
Renal excretion

Reduces serum
phenytoin level

Psychiatric
problems
Visual field defect

Zonisamide

Multiple

Partial and
GTCS

40-60

50-68

Hepatic
metabolism
Renal excretion

Affected by
other AEDs

Neurotoxicity
Renal stones

Induces
metabolism of
oral cotraceptive
pill

Neurotoxicity
Skin rash
Hyponatraemia

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

19
Dikutip dari Patrick Kwan, MRCP, PhD. Medical Progress, October 2004.

Table Recommended first-line and second-line AEDs

for common seizures types.
Seizure type

First line
Carbamazepine
Phenytoin

Lamotrigine*
Gabapentin*
Oxcarbamazepine*
Topiramate*
Valproate
Levetiracetam
Pregabalin
Tiagabine
Zonisamide

Valproate
Carbamazepine
Phenytoin

Oxcarbamazepine*
Topiramate*
Lamotrigine*

Valproat

Ethosuximide
Lamotrigine

Valproat

Lamotrigine
Topiramate

Partial

Tonic clonic
Absence
Myoclonic

Second line

*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

20

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
21

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

newer antiepilrptic drugs fulfill desirable pharmacokinetic properties.
Long
half-life

Significant
renal
excretion in
unchanged
form

Absence of
oxidation or
conjugation

Absence of
active
metabolite

yes
no
yes
no
yes
yes
no

no*
yes
yes
yes
no
yes
no*

no
no
no
no
yes
yes
no

no
no
no
no
no
no
no

yes
yes
yes
yes
yes
no
yes
yes
yes

yes
no
yes
no
no
no
yes
no
yes

yes
yes
no
yes
no
no
yes
yes
yes

no
yes
no
yes
no
no
no
yes
no

Drug

High
oral
bioavaila
bility

LOW
plasma
protein
binding

Carbamazepine
Clobabazam
Ethosuximide
Phenytoin
Primidone
Phenobarbital
Valproic acid

yes
yes
yes
yes
yes
yes
yes

Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Tiagabine
Topiramate
Vigabatrin
Zonisamide

yes
no
yes
yes
yes
yes
yes
yes
yes

Linear
kinetics

Uncommo
n target of
drug
interactio
ns

Uncommon cause
of drug
interactions

no
no
yes
yes
no
yes
yes

no
yes
yes
no
yes
yes
no

no
no
no
no
no
no
no

no (inducer)
yes
yes
no (inducer)
no (inducer)
no (inducer)
no (inhibitor)

yes
yes
yes
yes
yes
yes
yes
yes
yes

yes
no
yes
yes
yes
yes
yes
yes
yes

no
yes
no
yes
yes S
no
no
yes
no

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-life allows twice-daily dosing
S The plasma levels of MHD are moderately reduced by enzyme-inducing comedicafion.

22

Poly Pharmacy Therapy (Poly

Therapy) :
When monotherapy fails, poly therapy is
often tried, but when and which AED
combination should be employed has not
been well studies.
Generally speaking combination therapy
should be considered after failure of two
monotherapy regiments.
23

Co Morbidities :
In In addition of controlling seizures, some AEDs
have also demonstrated efficacy for the treatment
of the neurological conditions, which may coexist
with epilepsy. For instance valproate has
traditionally been used in Bipolar affective
disorder. Gaba pentine is effective for the
treatment of certain neuropathic pain syndromes
and topiramate has been approved as prophylaxis
for migraine.
With the wide spectrum of indication, the
selection of AEDs may betailor made according to
the patients neurological co morbidities.
24

Pharmacogenetics
The influence of genetic variation in drugmetabolizing genes, in particular those endoding
the CYP enzymes, on susceptibility to drug
toxicity has long been recognized.
There is recent evidence that variants of the
ABCB1 (or MDR1) gene, which codes for the
efflux transporter P-glycoprotein at blood brain
barrier, maybe associated with resistance to AED
therapy in epileptic patients.
A Brazilian study should showed that a variant
allele of the cellular prion protein gene was more
common in patients underwent surgery and
conferred a poorer outcome after temporer
25
lobectomy.

 In conclusion, as the complexity of genetics

influence on treatment responsiveness
become better understood, pharmacogenetic
profiling may, in the future, be redognized
as a practical determinant of drug selection.

26

Patophysiology and Genetics

Ideally, the aim to treat epileptic patients is
to understand how epilepsy develops and to
prevent it rather than one that merely
suppresses seizure.

27

Table Epilepsy Syndromes Associated with Single-Gene Mutations.

Gene

Epilepsy
Syndrome

Gene Product*

Study

Generalized epilepsy
with febrile seizures plus

SCNI8
SCN1A
SCN2A
GABRG2

Sodium-channel subunit
Sodium-channel subunit
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

Potassium channel

KCNQ3

Potassium channel

Biervert et al.,35
Singh et al.36
Charlier et al.37

CHRNA4

Neuronal nicotinic
acetylcholine-receptor
subunit
Neuronal nicotinic
acetylcholine-receptor
subunit

Steinlein et al.38

Autosomal dominant
nocturnal frontal-lobe
epilepsy

CHRNB2

Fusco et al.39

Childhood absence
epilepsy and febrile
seizures

GABRG2

GABAA-receptor subunit

Wallace et al.40

Autosomal dominant
partial epilepsy with
auditory features

LGI1

Leucine-rich
transmembrane protein

Kalachikov et al.41

*GABAA denotes gamma-aminobutyric acid type A.

28

Table Some of the genes that are involved in epilepsy

Subtypes

Gene Symbol

Phenotype

Ion channel genes in idiopathyc epilepsy

Nicotinic acetylcholine receptors
Potassium channel
Sodium channel
Chloride channel
GABAA receptors

CHRNA4/CHRNB2
KCNQ2/KCNQ3
SCN1A/SCN2A/SCN1B
CLCN2
GABRG2/GABRA1

ADNFLE
BFNC
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

EPM2A/EPM2B(NHLRC1)
CSTB

Lafora disease
Unverricht-Lundborg ds.

MTTK/MTTL1
PPT
CLN2
CLN3
CLN5
CLN6
CLN8
NEU1

MERRF
Infantile NCL
Late infantile NCL, Indian variant
Juvenile NCL
Late infantile NCL, Indian variant
Late infantile NCL, Indian variant
Northern epilepsy
Sialidosis metabolism

Respiratory chain
Lipidoses

Glycopeptide/Oligosaccharide

29

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 glutamate

receptors (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+

Mutation voltage-gated K+ channel (benign familial

neonatal convulsion
Reduced Ach-mediated Ca flux (nocturnal frontal
lobe epilepsy)

Reduced of T-type Ca++ currents

(ethosuximide, valproate)

Increased membrane excitability

Decreased membrane excitability

Ca+

30

Conclusion
Treating childhood seizure and epileptic
syndrome should be pay attention on many
factors including the patient, the disease and
the AED.
The The optimal management of patients
with epilepsy requires cooperation between
neurologist pediatric neurologist, general
practitioners and care giver.
31

 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 as
monotheraphy or adjunctive treatment.
Patients too are not all the same.
32

 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 of
the suitable AEDs.
Such a strategic and individualized approach will
optimize the chance of attaining remission and
help many more patients enjoy a fulfilling life.

33

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37