Curriculum Vitae

• Irawan Mangunatmadja
• Tempat/tgl lahir: Martapura, 28 Februari
• Status: Menikah + 2 anak wanita
• Pendidikan:
• SMA 8 Jakarta - 1977
• Dokter umum – FKUI 1984
• Dokter anak – FKUI 1993
• Spesialis Anak Konsultan – IDAI 2002
• DOKTOR – FKUI 2012
• Pendidikan tambahan
• Fellow Clinical Neurophysiology – UMC Utrecht The Netherlands 1999 – 2000
• Training of Epilepsy – UMC Utrecht The Netherlands 2002
• Pekerjaan
• Ketua Divisi Neurologi Anak Departemen Ilmu Kesehatan Anak FKUI – RSCM Jakarta 1995 -
sekarang
 The Treatment Approach Epileptic Patients
who are Predisposed to Drug Resistent Epilepsy
Irawan Mangunatmadja
Department of Child Health
Medical School Uiversity of Indonesia
Cipto Mangunkusumo Hospital Jakarta
The authors declare
• No conflic of interest
• Precentation Indonesian - English
Introduction

Paradigm treatment

Risk factors

AED mechanism

Proposal treatment
Introduction
• The goal treatment epilepsy patient to seizure free with normal
development
• About 60% of patients with epilepsy become seizure-free with anti-
epileptic drugs [AED], and between 30–40% of patients continue to
have seizures despite pharmacological treatment
• Determining the risk factors of intractable epilepsy may be useful in
the early diagnosis, prognosis, and treatment of the disease.
• Managing patients with medically refractory epilepsy is challenging
and requires a structured multidisciplinary approach in specialized
clinics
Anak AP, wanita, usia 1 tahun 6 bulan, Pasien kejang klojotan seluruh tubuh dengan mata melihat
ke arah kiri. Perkembangan saat ini baru dapat duduk sendiri.

FOCAL-GENERAL
Developmental
delay

FOCAL

EPILEPSY NON SYNDROM

 TAHAPAN PERKEMBANGAN YANG HARUS SUDAH MAMPU DILAKUKAN

USIA MOTORIK BICARA KOGNITIF

(BULAN) KASAR
3 Angkat badan Cooing, ketawa Senyum spontan
6 Duduk sebentar Babbling Suka, tidak suka
9 Menarik, berdiri Mengikuti suara Ciluk - bak
12 Berjalan dituntun 1 – 2 kata Dipanggil menengok
18 Naik tangga di bantu 8 kata Mengikuti mimik
24 Berlari 2 – 3 kalimat Bermain
36 Berjalan bergantian, 75% bicara dimengerti Menggunakan sendok
lompat
48 Berdiri satu kaki Menyebutkan warna Menggosok gigi

Hazlam (2007) dan Levina (2011)

 Paradigm treatment epilepsy
Epilepsy Patient

47% seizure free

1st AED

13% seizure free

2nd AED
40%
Drug Resistant Epilepsy

Rational
Surgery
Polytherapy
Brodie MJ and Kwan P, CNS Drugs 2001;15:1-12
Drug-resistant epilepsy [DRE] is defined as a failure to adequate trials of
two tolerated and appropriately chosen and used AED scheduled as a
monotherapy or in combination to achieve sustained seizure freedom

Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy:
consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010 Jun;51(6):1069-77.
 Apa yang harus dikerjakan bila pasien
cendrung menjadi DRE

• 1. Pastikan faktor risiko yang ada pada pasien

• 2. Pemilihan OAE tambahan pada pasien sebaiknya OAE dengan
mekanisme kerja yang lebih dari satu
• 3. Naikkan dosis secara progresif

Expert Rev Neurother. 2009 ; 9: 1791–1802

 TREATMENT AED PREDISPOSED INITIAL FACTORS
DRUG RESISTENT EPILEPSY age of 1 year
daily seizures at onset,
motor, mental and behavior
abnormalities,
history of status epilepticus,
Early identification, risk factor symptomatic etiology SEIZURE
analysis and understanding in the abnormal neuroimaging ANTI FREE
dynamics of the disease helps the Abnormal EEG EPILEPTIC
physician in initiating the appropriate symptomatic etiology DRUG
treatment, thereby avoiding the multiple seizure types 1st and 2nd
wrong therapy, low dose therapy and febrile seizures PROGRES
EVOLUTION FACTORS SIVE DRUG
infrequent therapy. RESISTANT
Respons therapy
Gowrinathan TG et al. Int J Contemp Pediatr. Evolution of seizure EPILEPSY
2019; 6: 1432-8
Evolution of background EED

Kalilani,et.al. Epilepsia. 2018;59:2179–19

Xue-ping et al. Medicine (2019) 98:30
Öncü D, et.al. Eur J Ther 2021; 27(: 78-83.
Gowrinathan TG et al. Int J Contemp Pediatr.. 2019 ;6:1432-8
 Combining antiepileptic drugs—Rational polytherapy

Table.Guidance for combining antiepileptic drugs

-------------------------------------------------------------------------
Establish optimal dose of baseline agent
Some authors believe that the use
Add drug with multiple mechanisms
of drugs with different mechanisms
Avoid combining similar modes of action
of action appears to be more
Titrate new agent slowly and carefully progressively
effective than combining drugs with
Be prepared to reduce dose of original drug maximal dosage
similar mechanisms
Replace less effective drug if response still poor
Try range of different duotherapies Granata,et al. Expert Rev Neurother. 2009;
Add third drug if still sub-optimal control 9: 1791–802.
Devise palliative strategy for refractory epilepsy
-------------------------------------------------------------------------
Brodie and Sills Seizure.2011;20: 369–75
MECHANISM OF ANTI EPILEPTIC DRUGS
 Table. Different mechanistic groups suitable for combination therapy.
-----------------------------------------------------------------------------------------------------------
1. Sodium channel blockers
(a) Fast-inactivated state—phenytoin, carbamazepine, lamotrigine, oxcarbazepine,
eslicarbazepine (b) Slow-inactivated state—lacosamide
2. Calcium channel blockers
(a) Low voltage activated channel—ethosuximide (b) High voltage activated channel—
gabapentin, pregabalin
3, GABA-ergic drugs
(a) Prolongs chloride channel opening—barbiturates
(b) Increased frequency of chloride channel opening—benzodiazepines
(c) Inhibits GABA-transaminase—vigabatrin
(d) Blocks synaptic GABA reuptake—tiagabine
4.Synaptic vesicle protein 2A modulation—levetiracetam
5.Carbonic anhydrase inhibition—acetazolamide
6. Multiple pharmacological targets—sodium valproate, felbamate, topiramate,
zonisamide, rufinamide
----------------------------------------------------------------------------------------------------------------------
Brodie and Sills Seizure.2011;20: 369–75
 Pharmacokinetic of AED
AED Na Channel Ca Channal GABA Glutamat GABA turnover
Receptor Receptor
Valproic Acid ++ ++ - - ++

Carbama +++ - - - -
zepin
Phenobarbital - + +++ + -

Phenytoin +++ - - - -
Topiramate ++ ++ ++ ++
Lamo +++ ++ - - -
trigin
Levetira cetam - + + +++ -

+++: prinsip target, ++: probable +: possible target Epilepsia.2009.20.257-63

Principles AED Therapy

Perucca and Tomson T. Lancet Neurol.2011; 10: 446-56

PENELITIAN : EFEKTIVITAS OBAT LEVETIRASETAM DAN TOPIRAMAT
PADA EPILEPSI INTRAKTABEL

Penelitian Ginting dkk (2020),4 mendapatkan efektifitas obat LEV untuk terkontronya kejang
adalah 63.3 %, sedangkan TPM hanya 35,0%, sedangkan kombinasi keduanya 36,4% pada
pasien epilepsi intraktabel usia di bawah 3 tahun. Adapun faktor yang memengaruhi
terkontrolnya kejang adalah evolusi EEG yang baik .

Penelitian Fahlevi dkk (2020),5 efektifitas obat LEV 54,8%, TPM 34,1% dan kombinasi keduanya
adalah 58,3% pada epilepsi intraktabel usia 1 – 18 tahun. Adapun faktor risiko yang
memengaruhi terkontrolnya kejang adalah gambaran EEG awal normal, evolusi EEG yang baik
dan CT/MRI kepala normal.
Ginting, dkk. Tesis.2020 dan Fahlevi dkk. Tesis.2020
 The Treatment Approach Epileptic Patients who
are Predisposed to Drug Resistent Epilepsy
PROPOSAL

First
EPILEPSY PATIENT Second
Third
with LEVETIRACETAME
LINE 2
RISK FACTORS DRE or
AED
( CBZ / VA) TOPIRAMATE

MORE RISK FACTORS ---à DRUG RESISTEN EPILEPSY ??

Summary
• Determining the risk factors of intractable epilepsy may be useful in
the early diagnosis
• The use of drugs with different mechanisms of action appears to be
more effective
• Second line to DRE are Levetiracetame or Topiramate
• The goal treatment epilepsy patient are seizure free and
improvement of neurodevelopmental (AED + Physiotherapy)
THANK YOU 20