Curriculum

Vitae
• Nama Lengkap : Dwi Putro Widodo
• Pendidikan : Dokter Umum, FK Univ. Indonesia, tahun 1983
Dokter Spesialis Anak, FK Univ. Indonesia, tahun 1992
Dokter Spesialis Konsultan Neurologi Anak tahun 1998
Doktor Ilmu Kesehatan Anak FKUI, September 2012
• Pendidikan tambahan : Master of Medicine in Clinical Neuro science.
Univ. Melbourne, 1996 -1998
Course on Clinical Neurophysiology in Royal Children
Hospital, Melbourne, 1998
• Jabatan : Kepala Divisi Neurologi
Departemen Ilmu Kesehatan Anak 2011-2017
• Jabatan lain : Delegasi Indonesia untuk Asean Oceanian Child Neurologi
Assotiation (AOCNA) tahun 2010 – 2016
• Institusi : Divisi Neurologi
Dept. Ilmu Kesehatan Anak
FK. Univ. Indonesia – RS. Dr. Cipto Mangunkusumo
 Paralysis in children

Motor neuron

Brain

Spinal cord

Dwi Putro Widodod, MD, PHD, MMed (clin neurosci)

 Peripheral maturation
After
Gestational bird
Weeks
Embrionik

Adault hood
2 yrs
Weeks

12
mo
Conception

Delivery
neuraltubeclose

Neurons form

Gila cels form

Neuronal migration

Dendrites, synapses, reorganisation

Programed cell death

All organsformed

Myelination peripheral nerves

Myelination sensory nerves

Myelination cortico-spinal
tract
Myelination
association area
3

4
1

9
8
5
2

7
Months 3
Nerve
development
 Human muscle development (major events)

Differentiation (0-5 Week)

Proliferation myoblast
Formation of syncytian

Movement to periphery

Differentiation fiber type

Increase fiber type II

( > 34 weeks) Increase all muscle fiber

?

0 3 6 9 Post conception
 Major event in human brain development

Neurulasi
Prosensefalik
Proliferation

Migration
differentiation

Myelination ?

0 3 6 9 Pasca natal
 Development of the nervous systems

MYELINATIO
N
First in pyramidal tract , then in CNS
cerebral commissures & association
areas. PNS
First motor fibres, than sensory

Dendrite
Migration Formation &
synaptogenesis
PROLIFERATIO
N
CNS Neuroblast proliferation
PNS First motor fibres, then sensory

GA 5 10 15 20 25 30 35 40 LY
Features differentiating central and peripheral
problems

Central Peripheral

Developmental delay Developmental delay

Seizure Weakness
GCS CM
CK n CK
DTRs DTRs
Paresthesia Paresthesia

Fenichel’s clinical pediatric neurology’ 2013

Signs and Symptoms of weakness

Observation
1. Atrophy and hypertrophy 1. Abnormal gait
2. Fasciculations a. Steppage
3. Functional ability b. Toe-walking
c. Waddle
Palpation 2. Easy fatigability
1. Muscle texture 3. Frequent falls
2. Tenderness 4. Slow motor development
5. Specific disability
Examination a. Arm elevation
1. Joint contractures b. Climbing stairs
2. Myotonia c. Hand grip
3. Strength d. Rising from floor
4. Tendon reflexes
Fukuyama- type congenital muscular dystrophy

1. Symptoms
Delayed milestones (mostly can sit alone)
CNS abnormalities (MR, convulsion)
Contracture of multiple joint
Slowly progressive

2. Brain CT/MRI: polymicrogyria, delayed myelin

High CK: 10-20 times normal
 Neuromuscular disorder in pediatric
In CMH ‘2017
179 149

DMD GBS/CIDP
SMA (16)
(16)
(11)
O/GMG PP
7 Dermato-myositis 1 Myotonia
CMT
3 2
3
LGMD
Bell’s/Erb palsy
4 Other
5/4
Neuropathy
(68)

History and
neurological CK EMG DNA analysis
examination
Volpe J. Neurology of the Newborn
2008
 Conditions presenting as gait disorder
(mimic weakness)

• Acute Viral Myositis

• Chikungunya
• Arthritis post infectious streptococcus
• Henoch-Schonlein purpura
• Toxic transient Synovitis (hip)
• Diskitis (spine)
• Growing pain
• Hypotonia
• Conversion disorder atau malingering !
 Question !

1. Is neurologic disease present

2. Where is the lesion
3. What is the nature of the lesion

12
 Motor Neuron control muscles used for activities such as breathing, crawling, walking,
head and neck control, and swallowing. 2

MOTOR NEURONS SMA is characterised by

IN SMA LACK AN degeneration of motor neurons
ESSENTIAL in the spinal cord, caused by
PROTEIN CALLED poor availability of a protein
SURVIVAL OF called SMN 1,2
MOTOR NEURON
(SMN) Without proper input from
motor neurons, muscle cells
become much smaller, causing
muscle weakness 2

Motor neuron

Brain

Spinal cord
MOTOR NEURON IN THE SPINAL
ANTERIOR HORN
SPINAL MUSCULAR ATROPHY (SMA)
Severe neuromuscular disease characterized by the loss of motor neurons
leading to progressive muscle weakness and paralysis 1,2

SMA TYPE 1
SMA TYPE 1 Presents between six and 18
The #1 genetic cause of infant months of age 2
mortality, 2 SMA type 1 In natural history sudies ,
typically presents within the those affected will never walk
first six months of life and without support 2
those affected :
§ Never sit without support 2
§ Have poor head control 3
§ Have dificulty breathing & MORE THAN
Caused by a genetic defect in
swallowing 2,4

30%
the SMN1 gene that codes
SMN, a protein necessary for
survival of motor neurons1

MORE THAN

90% OF PATIENTS WILL DIE

BY 25 YEARS OF AGE 5

SMA TYPE 3 & 4

WILL DIE OR
NEED PERMANENT
VENTILATORY SUPPORT
1 IN 10,000 AFFECTED BY THE AGE OF 2 4
Presents between six and 18
Typically presents in early
childhood to early adulthood 2
Those affected may lose the
ability to walk over time 2

EPNS, Greece Athena, 2019

 SMN- Targeted therapies
AVXS-101 I Spiranza I Risdiplam I Bramaplam I Reldesemtiv

Mechanism SMN upregulating SMN independent

SMN gene Muscle

Strategy SMN2 splicing modified
replacement enhancer

Drug type Gene Therapy ASO Small molecule

Delivery
IV intrathecal Oral
method

Body
distribution Systemic CNS only Systemic

Patient
population Type 1-2 Type 1-3 Type 1 Type 2-4
Characteristics of Guillain-Barre syndrome :
• Commonest acute generalised paralysis
• Progressive weakness, cease by 4 weeks.
• Untreated mortality 15%
• Considerably clinical variably
• Affect people of all ages and is not hereditary

Motor neuron
NERVE FIBER

Brain

Spinal cord
BRAIN
DORSAL COLUMN
Grey Matter
Guillain-Barré syndrome in the 100 years since
its description by Guillain, Barré and Strohl
Richard A.C. Hughes,1 David R. Corblach2 and High J, William3

Table I Guillain-Barré syndrome subtypes, related Antiganglioside antibodies can activate

disorders and associated antiganglioside antibodies complement and induce disruption of

Syndrome Associated antiganglioside § Nodes of Ranvier

antibodies § Neuromuscular junction
§ Other neuronal and glial membranes

ACP None
AMSAN GMI, GMIb, GDIa nAChR C3c MAC
AMAN GMI, GMIb, GDIa, GaNac-GDIa
Active sensory neuropathy GDIb
Fisher syndrome GQIb, GTIa
Fisher GBS over bp syndrome GQIb, GMI, GMIb, GDIa
GaNac-GDIa
Carvico-brachial-cropharyngeal GTIa
syndrome

AMSAN + active motor and memory axomal neuropathy

Inherited peripheral
neuropathy

Classification
CMT 1 Demyelination (<38 m/s)
CMT 2 Axonal (> 38 m/)
CMT intermediate (25-45 m/s)

CMT Diagnosis: 2018

. Single gene analysis ( usually sanger)
. Targeted diseases specific gene panels
. Exome sequencing
. Whole genome sequencing

Harding and Thomas: Brain; 1980

CMT subtypes and disease burden in patients enrolled in the
Inherited Neuropathies Consortium natural history study: a
cross-sectional analysis
V Fridnan,1 B Bundy,2 M M Reilly,3 D Pareyson,4 C Bacon,5 J Burns,6 J
Day,7 S Feely,5,8 R S Finkel,9 T Grider,5 C A Kirk,2 D N Hermamm, on
behalf of the Inherited Neuropathies Consortium

J Neurol Neurosurg Pschiatry 2015,86:873-878

225 CMT1
36
CMT2
53
47 CMT4
61% CMT1A CMTX
107
910
CMTN
32
HSN

287 HNPP
UNKNOWN
Characteristics of Myasthenia Gravis :
• uncommon;
• Fluctuating of weakness;
• fatiguability;
• reflexs normal;
• positive response to anticholinesterase.

NEUROMUSCULAR
JUNCTION

Motor neuron

Brain

Spinal cord
Characteristics of Duchenne Muscular dystrophy:
• Progressive disease
• Many medical issue
• No cure, premature death
• Genetic implication.

MUSCLE
Motor neuron

Brain

Spinal cord
DIAGNOSIS OF DUCHENNE MAY BE DELAYED

A retrospective chart review of 20 patients in England found that the mean age at first reported
symtomps was 32.5 months (range 8-72 months).2
§ First contact with a healthcare professional occurred at a mean age of 42.9 months (range
10-90 months).2
§ Diagnosis was confirmed at a mean age of 51.7 months (range 16-90 months).2
§ Total delay from parental concern to diagnosis was 19.2 months (range 4-50 months).2

First reported symptoms 32.5 months

First contact with healthcare professional 42.5 months 19.2 months

First contact with healthcare professional 51.7 months

 DMD is caused by mutations in the DMD gene1

§ Several different Large deletions

mutation types can
prevent the creation ~15%
of a full-length, Nonsense mutations
functional dystrophin
10-15%
protein 2-4
60-80%
7-11% Other small mutations
§ It is important to
identify the type of
mutation to help
Large duplications
inform medical
management option
1,5
 Diagnosis Duchenne

Unexplained
DIAGNOSIS Family history of
increase in
DUCHENNE1 Duchenne
transaminases

STEP 1 Testing for serum creatine kinase ( CK)

Avoid diagnostic delay with
prompt referral to a
neuromuscular specialist

STEP 2 Testing for dystrophin gene deletion /

duplication
* if genetic testing does not
confirm a clinical diagnosis of
DMD then a muscle biopsy
STEP 3 Genetic sequencing* should be performed

Confirmed Duchenne diagnosis

 TIMING OF INITIATION OF CS1
The timing of CS initiation is an individualized decision, based on
functional state, age and risk factors for side effects.1

MOTOR
FUNCTION Making progress Plateau Decline

START
Recommended Recommended
Not recommended
CS* (age 4+) (age 8+)

• The child’s immunisation schedule should be complete before starting CS1

• Families should be provided with a steroid card (or similar)1
 Medical therapy
Mutation specific treatment

Recently 2 drugs (officially marketing approved)

Atalurent@ that induces dystrophin production
from the nonsense-encoding m RNA
Eteprilsen@ that induce skipping of dystrophin
exon 51 during splicing.

In Japan, have developed an anti-sense therapy for

DMD that induce dystrophin exon 45 skipping.

26
 Hypokalemic periodic paralysis

• CACNA1S calcium channel (2/3) • Frequency 8 attacks/month,

• SCN4A sodium channel (1/3) lasting from hours to days
• Prevalence about 1:100,000 • Carbohydrate-rich food, stress,
• AD or AR alcohol and rest after exercise
• Onset < 20 years • K+ can drops < 3.0 mmol/L
– Highest frequency of attacks • Transient elevation on serum CK
between 15 and 35 years • Patophysiology
– Attack frequency decreases with age – Abnormal gating pore current for
– Fixed limb girdle weakness later in both calcium and sodium mutation in
life the context of low K+
• Attacks range from mild – sustained depolarization
weakness to paralyzed – Sodium channel to an inactive
configuration
– Rarely involves ocular, bulbar, and
respiratory muscles

Dubai, 24th World Congress of Neurology 2019

 Hypokalemic periodic paralysis

Acute attacks Prevention

• Oral K+ 10 mEq to 20 mEq • Low carbohydrate and low
every 15 to 30 minutes over Na+ diets
1 to 3 hours not to exceed • K+ supplementation
200 mEq in 24 hours typically 10 mEq to 20 mEq
• IV K+ mixed with 5% up to 3x day
manitol NOT glucose or – Maintaining serum K+
sodium chloride approximately 4 mEq/L
– 35 mEq potassium in 1 L 5% • Carbonic anhydrase
monnitol, run at 250 ml/hour inhibitors eq.
– Not to exceed 200 mEq in 24 acetazolamide
hours
• Potassium-sparing diuretics

Dubai, XXIV World Congress of Neurology 2019

 Limb-girdle Muscular Dystrophies

LGMD type Gene product clinical features

2A Calpain 3 0nset at 8-15 years,

progression variable
2B Dysferlin adolescence, mild
weakness
2C Sarcoglican Duchenne -like
2D A-sarcoglican Duchenne -like
2E B-sarcoglican Duchenne-Becker like
2F Sarcoglican slowly progressive, growth
retardation

Fenichel’s clinical pediatric neurology’ 2013

 PRESENTATION
Evaluate the history and examination

Age of onset
Gender
Clinical symptoms
Rate of progression
Other organ involvement: hepatic, renal, musculoskeletal, brain
Localization: nerve, neuromuscular junction, muscle
Personal and family history: disorder?

ESTABLISH INITIAL DIFFERENTIAL DIAGNOSIS

Genetic or acquired conditions to consider
Motor Neuron Peripheral nerve NM Muscle
junction
Congenital SMA type 0 CMT variants Neonatal MG Congenital DM1, CM, CMD
Infancy SMA types 1 and 2 CMT variants Botulism, MG CM. DM1, CMD, MM,, DMD, LGMD
GBS EM, IM
Childhood SMA type 3 CMT variants GMG DMD/BMD, CM, LGMD, DM1, CMD, MM,
GBS/CIDP DM/PM, IM, EM
Adolescence Juvenile ALS CMT variants MG BMD, LGMD, DM1, DM2, MM,
GBS/CIDP DM/PM, IM, EM

Swaiman’s, Pediatric neurology principle and practice 2017

Perform non invasive first-tier and if needed, invasive second-tier testing to determine if:
1. Neuropathic, NMJ, muscle disorder
2. genetic

First tier: CK, Muscle or Brain imaging or other organ

second tier: NCS/EMG or LP

1. Create ‘final’ differential diagnosis and if acquired condition complete

diagnostic evaluation
2. If genetic, do disease specific testing, gene panel for neuromuscular disorder
subtype or whole genome or exome sequencing

Swaiman’s, Pediatric neurology principles and practice 2017