Curriculum Vitae

Nama :Prof. dr. H. Sofyan Ismael, SpA(K)

Pendidikan : Dokter Umum FK UI, tahun 1961
Pendidikan Spesialis:
- Dokter Spesialis Anak FK UI, tahun 1964
- Dokter Spesialis Anak Konsultan, tahun 1987
Pendidikan Tambahan:
- Post graduate Peiatric Neurology Training, Montreal
Neurological Institute/Montreal Children Hospital,
Montreal, Canada
- Refresher Course on the Care of the Newborn
Pekerjaan : Staf Divisi Neurologi Anak FK. UI
Jabatan lain : Ketua Badan Penerbit PP. IDAI 2005-2008
 CPD
CME

KOMPETENSI

PELATIHAN KEJANG PADA BAYI DAN ANAK

STANDAR
PELAYANAN
KEDOKTERAN

Sofyan Ismael
Subdivisi Saraf Anak FKUI-RSCM

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 PROFESI KEDOKTERAN •Pekerjaan berdasarkan
keilmuan
•Kompetensi diperoleh
melalui pendidikan
berjenjang
•Kode etik
•Melayani masyarakat

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UUPK 29/2004, Pasal 1 ayat 11
 MELAKSANAKAN
PRAKTIK KEDOKTERAN

• Wajib mengikuti standar pelayanan kedokteran

• Standar pelayanan kedokteran dibedakan
menurut jenis dan strata pelayanan
• Diatur oleh Peraturan Menteri

• Strata pelayanan adalah tingkatan pelayanan

yang standar tenaga dan peralatannya sesuai
dengan kemampuan yang diberikannya
(kompetensi)
UUPK 29/2004, Pasal 44 ayat 1,2,3
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 PROFESI DALAM MELAKSANAKAN
PRAKTIK KEDOKTERAN
Profesi
Standar Profesi

dis
Standar

e
Standar Pelayanan M
m
Kedokteran a EEQ
ek
R
Standar Fasilitas
INPUT OUTPUT OUTCOME
PROCESS

CPD CME

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 STANDAR PELAYANAN KEDOKTERAN
(Standar Asuhan Medis)

A. Yang bersifat normatif

1. Melakukan penilaian yang adekuat
keadaan pasien berdasarkan tanda dan
gejala melalui anamnesis, pemeriksaan
fisik serta bila diperlukan pemeriksaan
diagnostik sesuai indikasi.
2. Merencanakan dan melakukan tindakan
pengobatan yang tepat.

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 … PELAYANAN KEDOKTERAN

3. Melakukan tindakan yang cepat bila

terdapat kondisi pasien yang
memerlukan intervensi medis yang
mendesak.
4. Merujuk pasien kepada dokter lain
yang sesuai, bila ada indikasi.

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 … PELAYANAN KEDOKTERAN

B. Yang bersifat teknis

1. Clinical Guidelines
2. Clinical Pathways
3. Standard Operating
Procedures
4. Algorithms
5. Protocols
6. Standing Order

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 Kejang pada Neonatus

MASALAH
1. Manifestasi kejang sulit dikenal
2. Kejang merupakan tanda adanya kelainan
pada SSP (keadaan kedaruratan)
3. Peran EEG
4. Menentukan prognosis
5. Menetapkan pengobatan

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 KEJANG PADA NEONATUS

PROGNOSIS
BANGKITAN
CT Scan
MRI
Metabolik ETIOLOGI “SPELL” EEG
Genetik
Biomolekular
KEJANG

PENATALAK-
SANAAN

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 DIFERENSIAL DIAGNOSIS BANGKITAN
PADA NEONATUS
Menyerupai kejang

Non Epileptogenic

Epileptogenic

Sindroma Epilepsi Neonatal

Focal Clonic, Focal Tonic,

Myoclonic
Subtle, Generalized Tonic,
Myoclonic
“Jitteriness”,”Benign Neonatal Myoclonus”

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 Perbedaan Jitteriness dan Kejang pada BBL

Gambaran Klinis Jitteriness Kejang

Gerakan abnormal bola

_ +
mata/kelopak mata

Peka terhadap rangsangan + -

Gerakan dominan Tremor Kejang klonik

Gerakan dapat dihentikan dengan

+ -
fleksi pasif

Perubahan fungsi otonom - +

Mizrahi & Kallaway, 1997

Volpe, 2000

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 Prinsip penatalaksanaan kejang
Ventilasi & Perfusi

Klasifikasi

Patofisiologi

Epileptik
Epileptik Klinik/Elektroklinik Non
Non Epileptik
Epileptik

Menilai
Menilai Kejang
Kejang Penyebab Mengobati
Mengobati

•Lama
Lama •Sebentar
Sebentar
•Sering
Sering •Jarang
Jarang
•Berat
Berat •Ringan
Ringan
Spesifik
Spesifik
OAE
OAE (+)
(+) OAE
OAE (-)
(-)

Rumat
Rumat

Stop
Stop Observasi
Observasi

Mizrahi EM and Kellaway R. Diagnosis and management of Neonatal Seizures, 1998

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 Correlation between type of seizures, clinical and EEG

Clinical Findings EEG Seizures

• Provoked by stimulation
Type of seizures discharge
• Suppressed by restrain
(Epileptogenic)
(Non Epileptogenic)

Subtle +/- +/-

Focal-clonic - +
Multifocal-clonic - +
Focal-tonic - +

Generalized tonic + -

Multifocal myoclonic + -

Focal myoclonic +/- +/-

Generalized myoclonic +/- +/-

Mizrahi EM and Kellaway R. Neurology 1987; 37:1837-1844

Mizrahi EM and Kellaway R. Diagnosis and management of Neonatal Seizures, 1998

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 Etiologic Distribution of Clinical Neonatal Seizures
(n=89)
(n=89)

Etiology n (%)
 Global cerebral HI 36 (40)
 Focal cerebral HI 16 (18)
 Intracranial hemorrhage 15 (17)
 Cerebral dysgenesis 4 (5)
 Transient metabolic disturbance 3 (3)
Hypoglycemia 2
Hypocalcemia + hypomagnesemia 1
 Infection 3 (3)
Bacterial meningitis 1
Herpes simplex encephalitis 1
Enterovirus encephalitis 1
 Inborn error metabolism 1 (1)
Pyridoxine dependency 1
 Etiology unknown 11 (12)

Tekgul H et al. Pediatrics 2006;117;1270-1280

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 Etiologic Distribution

Tekgul H et al. Pediatrics 2006;117;1270-1280

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 Etiologic Distribution

Widiastuti D et al. Pediatr Indones 2006

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 Etiologic Distribution

Taksande AM et al. 2005

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 Relationship of etiology Versus type of seizure

Taksande AM. et.al. 2005

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 Outcome by Etiology of Neonatal Sizures
Neurologic Cognitive Impairement
Overall Outcome
impairement (MDI),
Seizures After n (%)
n (%) n (%)
ICU
Etiology
Discharge
Mild- Mild-MDI Severe MDI n (%)
Severe Favorable Poor*
Moderate 70-84 <70

Global HI (36) 15 (42) 13 (36) 6 (20) 13 (43) 11 (31) 18 (50) 18 (50)

Focal HI (16) 6 (37) 0 3 (19) 0 0 16 (100) 0
Hemorrhage (15) 4 (27) 2 (13) 5 (50) 1 (10) 3 (20) 13 (87) 2 (13)
Cerebral dysgenesis
0 4 0 4 3 0 4 (100)
(4)
Transient metabolic
1 0 1 0 1 2 1
disturbance (3)
Infection (3) 0 1 0 1 0 2 1
Inborn error of
0 0 0 0 0 1 0
metabolism (1)
Unknown etiology (11) 2 0 0 0 9 11 (100) 0

* The proportion of infants with poor outcome differs by etiologic subgroup (P<.001)
Tekgul H et al. Pediatrics 2006;117;1270-1280
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 Epilepsy Outcome

Epilepsy
n=27/79 34%

Epilepsy without Epilepsy with

MR/CP MR/CP
n=4 15% n=23 85%

Survivors Deaths Deaths Survivors

n=4 n=0 n=10 N=13

Active Epilepsy In Remission Active Epilepsy In Remission

n=1 n=3 n=10 n=3

MR=mental retardation; CP=cerebral palsy Ronen GM.Neurology 2007

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 Prevalence of Epilepsy, mental retardation (MR), and Cerebral
Palsy (CP) in The Cohort

Ronen GM.Neurology 2007

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 Relationship Among Neonatal EEG, Neuroimaging
(CT, MRI), and Overall Outcome at 1 Year of Age
Total Favorable Outcome Poor Outcome
P
N (%) n n
EEG background (n=89) <.001
Normal 21 (24) 17 4
Mildly abnormal 26 (29) 25 1
Moderately abnormal 31 (35) 20 11
Severely abnormal 11 (12) 2 9
Neuroimaging (n=89) <.001
Normal 19 (21) 18 1
Extraparenchymal 11 (12) 10 1
Parenchymal 59 (66) 35 24
MRI alone (n=73) <.001
Normal 16 (23) 16 0
Extraparenchymal lesion 5 (7) 4 1
Parenchymal: cerebral
vortex 14 (19) 14 0
Focal cortical 19 (26) 7 12
Multifocal/diffuse 19 (26) 8 11
cortical
Parenchymal: deep gray
matter nuclei
SI-310508 Tekgul H et al. Pediatrics 2006;117;1270-1280
 HUBUNGAN ANTARA EEG DAN PROGNOSIS

49

36
34

13

Rose dan Lambroso, 1970

Gambaran EEG
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 Epilepsy Syndromes in Early Life
Age of
Syndrome Clinical EEG
onset
Benign familiar Early onset Focal clonic/focal tonic Flattening, spike &
neonatal convulsion Autosomal transmission sharp waves
Benign idiopathyc 2-7 days Partial/clonic/apnea Theta pointu alternant
neonatal seizures (5th day fits) No family history (75%)
Early myoclonic First month Myoclonus, partial motor, tonic Burst suppression
epilepsy (EME) of life spasms
Early infantile 1-3 months Tonic spasms, maybe focal motor, Burst suppression
epileptic encepha- MJ, GTCS
lopathy (EIEE/
Otahara Syndrome)
Severe myoclonic Within first Febrileafebrile seizure, Generalized SW
epilepsy of infancy year myoclonus, atypical absence photosensitivity (40%)
(Dravet Syndrome)
West Syndrome 4-7 months Infantile spasms Hypsarrhytmia
(Infantile Spasms)
Smith SJM. J. Neurol. Neurosurg. Physiatry, 2005

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 EPILEPTIC SYNDROMES IN NEONATES
I. BENIGN FAMILIAL and NON-FAMILIAL NS
1.Benign Familial and Neonatal Seizures (BFNS)
2.Benign Idiopathic Neonatal Seizures (BINS)/
(Fifth day fits)

II. SEVERE NEONATAL EPILEPSIES

with SUPPRESSION-BURST PATTERN
1.Early (Neonatal) Myoclonic Encephalopathy
(EME/NME)
2.Early Infantile Epileptic Encephalopathy (EIEE)

Plouin P and Anderson E. Epileptic Syndromes in Infancy, Childhood and Adolescence, 2005

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 EPILEPTIC SYNDROMES
• Benign Familial Neonatal Seizures (BFNS)
 2-4 months phenobarbital, sodium valproate, dilantine
 Risk febrile convulsion 5%
 Risk secondary epilepsy 11%

• Benign Idiopathic Neonatal Seizures (BINS)/(Fifth day fits)

 Stop without treatment

• Early (Neonatal) Myoclonic Encephalopathy (EME/NME)

 Infantile spasm

• Early Infantile Epileptic Encephalopathy (EIEE)

 West syndrome
 Lennox-Gastaut
Plouin P and Anderson E. Epileptic Syndromes in Infancy, Childhood and Adolescence, 2005
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 Specific Pathophysiologic Defects
Leading to Epilepsy
Level of Brain
Condition Pathophysiologic Mechanism
Function

Synapse Neonatal seizures Many possible mechanism, including

development either development of excitatory
synapsis and along in development of
inhibitory synapsis

Ionic channels Benign infantile Potassium channels mutation: impaired

neonatal repolarization
convulsion

Neurotransmitter Pyridoxin (Vit B6) Abnormal GABA receptor subunits

synthesis dependency

Statstorm CE. Pediatr. Rev. 1998;19;342

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 Hubungan Genotip dan Fenotip pada
Epilepsi Sindrom

KANAL
KANAL ION
ION

Ion
Ion Na
Na++ Ion
Ion KK++
SCNIA
SCNIA SCNIB
SCNIB SCN2A
SCN2A KCNAQ
KCNAQ22 KCNAQ
KCNAQ33

Infantile
Infantile Feb
Feb Seizure
Seizure BFNC
BFNC
GEFS
GEFS++ BFNIS
BFNIS BFNC
BFNC
Spasm
Spasm Afebrile
Afebrile Myokimia
Myokimia

FENOTIP
FENOTIP

Graves T.D Q J Med 2006

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 KEJANG PADA BAYI & ANAK

Bangkitan
“Spell”

Kejang

Epilepsi

Sindroma Epilepsi

Fokal/Umum/Klasifikasi (-)

Kejang Demam

Menyerupai kejang/“NES”

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 CLINICAL MANIFESTATION OF
NON EPILEPTIC SEIZURES
• Modes of presentation of seizure
includes:
– Collapse and loss of conciousness
– Staring & altered behaviour
– Limb movements & postures
– Nocturnal events

Mackay M. Austr Fam Physician. 2005;34:1003-8

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 DIFFERENTIAL DIAGNOSIS
Episodic collapse & loss Limb movements and Nocturnal episodes
of consciousness posturing

Syncope Neonatal & infants Parasomnias

• Jitteriness • Confusional arousals
Breath-holding spells
• Excessive startle • Sleepwalking
Psychogenic seizures • Benign neonatal myoclonus • Narcolepsy
• Migraine variants • Night terrors
• Shuddering attacks
Physiological
• Sandifer syndrome (GER) phenomenon
Episodic staring • Sleep Myoclonus
Older children
• Tics
Daydreaming • Self stimulation
• Migraine variants, vertigo
• Paroxysmal dystonia
• Episodic ataxia

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Mackay M. Austr Fam Physician. 2005;34:1003-8
 Stool withholding

Case report
presenting as a cause of
non-epileptic seizures
Anthony Cohn MBBS MRCP MRCPH,
Department of Pediatric, Watford General
Hospital, Watford, UK

Developmental Medicine & Child Neurology 2005;47:703-705

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 Bangkitan
“Spell”

Kejang

DEFINISI
Epilepsi

Sindroma Epilepsi

Fokal/Umum/Klasifikasi (-)

Kejang Demam

KEJANG
Menyerupai kejang/“NES”

 Kejang adalah suatu manifestasi klinik dari lepas muatan

listrik berlebihan dari sel-sel neuron di otak yang

terganggu fungsinya.
 Gangguan tersebut dapat disebabkan oleh kelainan

fisiologis, anatomis, biokimia atau gabungan dari ketiga

kelainan tersebut

EPILEPSI
 Kejang tanpa pencetus (tidak ada kelainan yang

bersamaan) yang terjadi 2 kali atau lebih.

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 PENDEKATAN KLINIS
FUNGSIONAL ANATOMI ETIOLOGI
Tergantung neuron yang Letak neuron yang • Idiopatik
berlepas muatan listrik berlepas muatan listrik
Klasifikasi • Simptomatik
1. ILAE 1981
• Fokal • Kriptogenik
• Umum
• Tidak terklasifikasi

2. ILAE 1989
• Sindroma

3. Kelainan yang • EEG • Genetik

menyerupai epilepsi • CT Scan • Biologi molekuler
(non epileptic • MRI • Imunologi
seizures) • Neurofarmakologi • Metabolisme
• Biokimia • Nutrisi
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SI-310508
 Correlation between CT Scan and MRI
in the same patient

• Left CT Scan had an apparently normal computer tomogram

• Magnetic resonance image (right) was obviously pathological
(right hemispheric glioma)
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 Medical Treatment of First Seizure(s)
• Whether to treat first seizure is controversial
 16-62% will recur within 5 years
 Relapse rate for second seizure is reduced by AEB
BUT long term prognosis of whether the patient will have
refractory epilepsy is not
 Increased risk of relapse
Abnormal neurological exam
Abnormal EEG
Abnormal imaging
Family history of epilepsy

 Quality of life issues are important

• Currently, most patient are not treated for the first seizure unless
there is an increased risk for relapse
Canfield P et al. Neurology 1989
Pollman-Eden B et al. BMJ 2006
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 Factors predicting outcome in childhood epilepsy

Lower probability of Predictive of

remission intractability

• Multiple seizures type

• Mental retardation at onset

• Seizure recurrence in the first 6 to 12 months of treatment

Oskoui M et al. J Child Neurol, 2005

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 Outcome in patients according to the number of
seizures before treatment
(P<0.001)

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 Bangkitan

EPILEPTIC SYNDROME
“Spell”

Kejang

Epilepsi

1. Infancy & Early Childhood Sindroma Epilepsi


Fokal/Umum/Klasifikasi (-)

- Febrile Seizures Kejang Demam

- Benign Myoclonic Epilepsy in Infancy Menyerupai kejang/“NES”

- Infantile Spasm and West Syndrome

- The Lennox – Gastaut Syndrome
- Severe Myoclonic Epilepsy in Infancy
2. Childhood
- Epilepsy with Centro-temporal Spikes and Related Syndrome
- Childhood Abscence Epilepsy and Related Syndrome
- The Syndrome of Myoclonic Abscence

3. Older Children & Adolescence

- Juvenile Abscence Epilepsy
- Juvenile Myoclonic Epilepsy
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 HUBUNGAN GENOTIP DAN FENOTIP EPILEPSI IDIOPATIK UMUM

KANAL ION

Ion Na++ Ion Ca 2+

2+ Ion K ++ Ion Cl --

SCN1A
SCN1A SCN1B
SCN1B SCN2A
SCN2A CACNA
CACNA 1 H CACN B4 KCNA1
KCNA1 KCNQ2-3
KCNQ2-3 KCNMA1
KCNMA1 CLCN
CLCN 22

G
GABRG 2
(R43Q)
A

GABRA 1
B

GABRD
A (R220H)

GEFS ++ CAE JME JAE BFNC EGMA

FENOTIP: EPILEPSI IDIOPATIK UMUM (IDIOPATHIC GENERALIZED EPILEPSY)

Wallace et al, 1998

Baulac et al, 1999
Sugawara et al, 2001
Graves TD. QJ Med 2006;99:201-17

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 KEJANG YANG DISERTAI DEMAM

BUKAN KEJANG
KEJANG DEMAM
DEMAM
• Sederhana • Meningitis
• Kompleks • Meningoensefalitis
• Ensefalitis

Gejala Klinis
Pungsi Lumbal

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 KEJANG DEMAM
Kontroversi Konsensus

Diagnosis Prognosis Penatalaksanaan

• LP • Terulangnya • Akut
• EEG kejang • Profilaksis
• Pencitraan • Epilepsi – Profilaksis
• Kejang lama intermiten
• Biokimia darah
– Profilaksis
• Perkembangan kontinyu
kognitif
• Antipiretika

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 Investigations in Children with Febrile Seizures

Features LP EEG Neuroimaging Biochemistry

• Febrile status epilepticus Yes No No None

• Age < 18 moths Consider No No None
• Complex febrile
seizures, otherwise Consider No No None
normal
• Simple febrile seizures,
No No No None
otherwise normal
• Neurodevelopmental
Possibly
abnormality and complex No No None
non-urgently
febrile seizures
• Symptoms and signs
Yes No No None
suggestive of meningitis
Sadleir LS and Scheffer IE. Febrile Seizures. BMJ 2007:334;307-11

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 ANGKA KEJADIAN KEJANG BERULANG DAN
KEJANG TANPA DEMAM

Kejang tanpa
demam
3%
Kejang
demam
berulang 34%

N=1708

Ellenberg dan Nelson (1981)

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 FAKTOR RISIKO TERULANGNYA KEJANG

• Riwayat keluarga dengan kejang demam

• Umur < 18 bulan waktu kejang pertama
• Temperatur berkisar 38oC saat kejang
• Kejang timbul, setelah demam < 1 jam

Risiko (-) 4%

• Faktor risiko (1+) 23% Faktor risiko (3+) 62%

• Faktor risiko (2+) 32% Faktor risiko (4+) 76%
Berg et al. Predictors of recurrent seizures: A prospective cohort study.
Ach Pediatr Adolesc Med 1997;151:371-8 (II-2,B)
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 KEJADIAN EPILEPSI DIHUBUNGKAN DENGAN
FAKTOR RISIKO
Faktor Risiko Kejadian Epilepsi
13% I. Tidak faktor risiko
• Keluarga : kejang tanpa demam
• Sebelum kejang demam : kelainan II. 1 Faktor risiko
saraf III III. > 2 faktor risiko
• Kejang lama, fokal, berulang 6%

3% II
34% I
60% 2%

N=1708

Ellenberg dan Nelson (1981)

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 Risk Factors for Afebrile Seizures Following
Initial Febrile Seizures

154 hospitalized children, follow-up 7 years 2 months, 19

patients (12,3%) developed subsequent epilepsy

• Complex features OR: 6.53, CI, 2.41-17.7 (p=0.0002)

• Family Hx Epilepsy OR: 5.64, CI, 1.36-20.8 (p=0.02)
• Neuro Dev Abn OR: 5,56, CI, 1.58-20.3 (p=0.01)
• EEG OR: 3.68, CI, 1.42-9.18 (p=0.02)

Tsai ML, Hung Al. Internation Symposium on Febrile Seizures, Japan 2008

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 HUBUNGAN KEJANG DISERTAI DEMAM DENGAN EPILEPSI

Manifestasi Klinik
Fenotip  Kejang disertai demam Genotip Ket.
 Kejang tanpa demam
SCN1A
FS GABRG2
S<G

SCN1A
FS+ GABRG2
S>G

SCN1A, 1B, 2A
GEFS+ GABRG2, GABRD
S>G

Sehat Myoclonic SCN1A

SMEI Status Kognitif  GABRG2 S»G

CAE Abscance GABRG2

Umur 0 6 bln 6 thn

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 Ion Channels Implicated on Epilepsy
Genotype Phenotype

Voltage-gated

Channel Sodium channel GEFS +

Protein Type 1 1 subunit

Febrile Seizures
Gene SCN1A
SMEI

Infantile Spasme

Ligand-gated ICEGTCS

Channel GABA receptor

GEFS +
Protein 2 subunit

Gene GABRG2 Febrile Seizures

SMEI

CAE

Graves TD. QJ Med 2006;99:201-17

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 HUBUNGAN GENOTIP DAN FENOTIP PADA KEJANG DISERTAI DEMAM

KANAL ION

Ion Na+

G SCN1A SCN1B SCN2A

A
GABRG 2  
(R43Q)

B

GABRD
(R220H)
 Infantile FS
A GEFS ++ FS SMEI CAE BFNIS
Spasm Afebrile

FENOTIP

Baulac et al, 1999

Sugawara et al, 2001
Graves TD. QJ Med 2006;99:201-17
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 Comparison of Phenotypes between Patients with SCN1A and
those with The GABRG2 Mutation

p<0.01

p<0.001
Patients (%)

p<0.01

Baulac et al. Lancet Neurol 2004;3:421-30

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 “All substance are poisons;
there is none which is not a poison.
The right dose differentiates a
poison from a remedy”
Paracelsus (1493-1541)

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SI-310508