pediatrics neuromuscular disorders...

PEDIATRICS NEUROMUSCULAR DISORDERS (NMD)

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Disorders of the lower motor neuron anatomical approach

AnteriorHorn CellHereditary

Spinal Muscular Atrophy

Acquired

Poliomyelitis

Nerve FibreNeuropathies

a) Demyelinating eg GBS.

b) Axonal, eg lead.

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Neuromuscular JunctionMyasthenia gravis

Muscle

Hereditary

1. Muscular Dystrophy

2. Congenital Myopathies

Acquired

1. Dermatomyositis.

2. Endocrine myopathies.

Symptoms of Neuromuscular Disease

1. Abnormal gait

a. Steppage

b. Toe-walking

c. Waddle

2. Easy fatigability

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2. Easy fatigability

3. Frequent falls

4. Slow motor development

5. Specific disability

a. Arm elevation

b. Climbing stairs

c. Hand grip

d. Rising from floor

Signs of Neuromuscular Disease

Observation1. Atrophy and hypertrophy

2. Fasciculations

3. Functional ability

Palpation

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Palpation1. Muscle texture

2. Tenderness

Examination1. Joint contractures

2. Myotonia

3. Strength

4. Tendon reflexes

Parental Concern not Weakness

� Trouble with walking and running

� Poor at sports

� Cannot keep up with peers

� Poor coordination

� Tires easily� Tires easily

� Falls frequently

� Delay milestones

� Difficulty climbing stairs

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NMD in Dept of Childhealth Cipto-Mangunkusumo tHospial

� Duchenne muscular dystrophy (DMD)

� Spinal muscualar atrophy (SMA)

� Guillain-Barre syndrome (GBS)

� Myastenia gravis (MG)

� Chronic inflammatory demyelinating polyneuropathy (CIDP)

� Periodic paralysis� Periodic paralysis

� Myotonia congenita

� Congenital myopathies

� Peroneal muscular atrophy

� Hereditary motor sensory neuropathy

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Differentiation between upper motor and lower motor unit disease

Upper motor unit Lower motor unit

Tone Hypotonia (infants)or spasticity Hypotonia

(infants and older children)

Strength Weakness (normal or minimal) Weakness (usually profound)

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Reflexes Increased tendon reflexes Decreased or absent tendon reflexes

Persistance of infantile reflexes

Babinski’s sign No Babinski’s sign

Ankle or knee clonus No clonus

Muscle mass Usually no atrophy Atrophy (usually not detectable in

infants)

Fasciculations (usually not detectable

in infants except in tongue)

A Nerve

terminal

Axon

Mitochondria

Vesicle

Acetylcholine

Acetylcholine

Release

Site

10

Acetylcholinereceptor

Acetylcholine

sterase

Basal lamina

Muscle

(end-plate)

Postsynaptic Alterations in MG

1. Reduction of AChR number

2. Destruction and simplification of junctional fold

3. Attachment of antibody to AChR and blocking of

its function

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its function

4. Increase the gap between nerve terminal and

postsynaptic

FIG.3. Neuromuscular Junction. A, Normal human neuromuscular

Junction. B, Neuromuscular junction of a patient with myasthenia

gravis

Clinical classification

� Group I : ocular

� Group II : Mild generalized

� Group IIB: Mild restricted bulbar

� Group III : Moderate generalized

� Group IIIB: Moderate restricted bulbar

� Group IV : Severe generalized –myastenic crisis

� Group IVB: Severe restricted bulbar

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Bedside clinical clues in the diagnosis of MG *

History

Onset of fluctuating ptosis or diplopia that worsens with repeated use

and improves with rest

Onset of fluctuating dysarthria, dysphagia, dysphonia with or without

ocular symptoms or generalized weakness that worsens with repeated

use and improves with rest

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Physical examination

Weakness referable to ocular, bulbar, or limb muscle

Limb Weakness prominent in proximal flexor groups

Normal muscle tone and bulk

Normal reflexes and sensation

Induction of muscle weakness with exercise when weakness is subtle

* For otherwise healthy persons

Clinical feature

� Ocular symptoms (53%)

� 25% ptosis, 25% diplopia, 3 % blurred visio

� Bulbar symptoms 16%

� 6% difficulty swallowing, 5% slurred, 4% difficulty chewing,

1% dyspnea

� Most patients exhibit progession of disease 86%� Most patients exhibit progession of disease 86%

� 40% purely ocular, 35% generalized, 15% bulbar or ocular-bulbar

� If an ocular MG is going to develop general symptoms

� 56% by 6 months

� 78% by the first years

� 85% by the second years

� 92% by the third years

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Symtomps and Signs in 35 Patients WithJuvenile Myasthenia Gravis

Symptom or Sign Number of patients

Ptosis 32

Diplopia 30

Facial weakness 29

Dysphonia 29

16

Dysphonia 29

Weakness of arms 29

Weakness of legs 29

Chewing weakness 22

External opthalmoplegia 18

Respiratory difficulties 12

After Millichap and Dodge (69)

TABLE 3. Diagnostic tests *

Studies to demonstrate neuromuscular transmission defectsPharmacologic

Edrophonium (Tensilon)

Neostigmine (Prostigmin)

Electrophysiologic

Repetitive nerve stimulation

Needle electromyography

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Needle electromyography

Single-fiber electromyography

Studies to demonstrate an abnormal immune respons against the endplate

and muscleAcetylcholine receptor antibodies

Anti-strational muscle antibodies

* Diagnostic test that are currently used in practice

Clinical test for MG

� Edrophonium chloride (Tensilon) (IV)

� Full dose 0,2 mg /kg (maximum dose 10 mg). A small

test 1/10 dose initially is needed

� Should not be given to young infant

� Neostigmine (IM)� Neostigmine (IM)

� Initial test 0,02-0,04 mg/kg is negative, retested 4 hr

later with 0,08 mg/kg

� 0,5 – 1,5 mg IM

� 0,01 mg/kg of atropine before neostigmine

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TABLE . Therapeutic steps in ocular myasthenia gravis

1. Begin by optimizing the response to pyridostigmine2. If a satisfactory response is obtained, continue pyridostigmine

with lowest effective dose

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with lowest effective dose3. If the response to pyridostigmine is unsatisfactory, consider

alternate-day low-dose prednisone or immunosuppressive drug

Table 2. Commonly Used Drugs in the Treatment of Myasthenic Disorders

Drug Available Dose Dosage Frequency

Endrophonium chloride (Tensilon) 10 mg/ml 0.2 mg/kg iv

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Endrophonium chloride (Tensilon) 10 mg/ml 0.2 mg/kg iv

Neostigmine bromide (Prostigmin) 15-mg tablet 7.5-15 mg/dose po 3-4 hours

Neostigmine methylsulfate (Prostigmin) 0.25, 0.5, 1.0 mg/ml 0.04 mg/kg im 3-4 hours

0.02 mg/kg iv

Pyridostigmin bromide (Mestinon) 60-mg tablet 30-60 mg/dose po 4-6 hours

Prednisone 1-, 2.5-, 5-, 20-, 2-3 mg/kg/day alternate day

20-, 50-mg tablets

TABLE 7. Therapeutic options in myasthenia gravis

Symptomatic therapy

Short-acting cholinesterase inhibitors

Pyridostigmine bromide (Mestinon)

Longer-acting cholinesterase inhibitors

Neostigmine (Prostigmin)

Mestinon Timespan

Long-term immunosuppressive drug therapy

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Long-term immunosuppressive drug therapy

Corticosteroids

Immunosuppressive drugs

Azathioprine (Imuran)

Long-term surgical Immunosuppression

Thymectomy

Short-term Immunosuppression

Plasma exchange

Intravenous administration of immune globulin

Duchenne muscular dystrophy

� Commonest and most serious type of muscular dystrophy

� 30 per 100,000 live born male affected

� Inheritance is as a sex-linked recessive but mutation are frequent (30%)mutation are frequent (30%)

� Symptoms appear in the first five years

� Prominence of the calf muscle is an early feature (pseudo-hypertrophy).

� Unable to walk by the age of 8 to 11 years

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Duchenne muscular dystrophy� Often develop scoliosis and an equinus deformity.

� Genetic counselling is important, and carriers may be detected by finding a moderately raised serum creatine kinase.

� The serum creatine kinase is always very elevated before clinically evidence.before clinically evidence.

� The diagnosis: serum creatine kinase 30 to 200 times higher, myopathic changes on EMG, characteristic muscle biopsy feature.

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Blood creatine kinase

� The Serum CPK is always elevated to 50 to 300 times normal. Characteristically is 15.000 –45.000 IU/L (normal, < 150 IU/L).

� Elevations have been demonstrated in placental blood of affected male fetuses of 16-20 weeks gestation.

� The CK level is decreased in pregnancy by as much as 30%.

� About 70% of genetically definite carriers will show a raised CPK

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Dystrophin

� Is a protein which is found on the inner side of

the membrane surrounding each muscle

fibres.

� If dystrophin is missing the muscle fibres � If dystrophin is missing the muscle fibres

break down (degenerated).

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Duchenne Normal

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40 50 60 70 80 90 100 110 120 130 140

IQ

Figure 2-17. Stylized distribution curve of IQ in Duchenne dystrophy showing normal bell-shape but a shift to the left.

Guillain-Barre syndrome

� Commonest cause of acute generalised paralysis

� 0.6 – 1.1 per 100,000 (<15 yrs)

� Any time during childhood (4 and 9 yrs)

� Core symptoms

� Progresive symmetric weakness

� Cease by 4 weeks

� areflexia

� Considerable clinical variability

� Untreated mortality 15% (at least)

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Guillain-Barre Syndrome

� Postinfectious polyneuropathy that causes

demyelination in mainly motor but sometime

also sensory nerves.

� This syndrome affects people of all ages and � This syndrome affects people of all ages and

is not hereditary.

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Guillian-Bare Syndromes

AcuteInflammatoryDemyelinatingpolyneuropathy

AcuteMotor axonalNeuropathy(AMAN)

Fishersyndrome

Acute motor-

IncreasingSeverity

Of the immune

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AIDP withSecondaryAxonal

degeneration

Acute motor-Sensory axonalNeuropathy (AMSAN)

Of the immuneattack

Fig. 22-3. Proposed interrelationships of the forms of GBS. (Reprinted with permission

From Griffin et al., Pathology of the motor-sensory axonal Guillian-Barre syndrome,

Ann Neurol 39:17 – 28, 1996 [41].)

Clinical Characteristics of 56 children with GBS

� Antecedent infection 70%

� Distal weakness predominantly 44%

� Cranial nerve weakness 43%

� Paresthesia and pain 43%� Paresthesia and pain 43%

� Meningeal irritation 17%

� CSF protein > 45 mg/dl 88%

� Asymmetry of involvement 9%

� Full recovery or mild impairment 77%

� Relapses 7%

� Mortality 4%

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Diagnostic Features of Guillain-Barre Syndrome

Features strongly supportive of the diagnosis :� Progression over days to a few weeks

� Relative symmetry

� Mild sensory loss

Features required for diagnosis :• Progressive motor weakness of more than one limb

• Areflexia or marked hyporeflexia

� Mild sensory loss

� Onset with extremity pain or discomfort

� Cranial nerve involvement

� Onset of recovery 2 to 4 weeks after halt of progression

� Autonomic dysfunction

� Initial absence of fever

� Elevated CSF protein level after 1 week of symptoms

� Abnormal electrodiagnosis with slowed conduction or prolonged F Waves

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weeks

weeks

ACUTE

MONOPHASIC GBS

ACUTE MONOPHASIC

GBS WITH

LIMITED RELAPSE

RELAPSING ACUTE

MONOPHASIC GBS

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weeks years weeks

weeks Months/years

weeks Months/yearsFigure 10-1.Possible temporal courses following acute GBS

CIDP STARTING

AS GBS

ACUTE GBS

FOLLOWED BY CIDP

APPROACH TO TREATMENT IN ACUTE STAGES OF GBS

Severity of Illness

Mild

� Able to walk

� No cardiovascular dysautonomia

Moderate

Treatment

� Observe : treat with plasma exchange if still worsening

� Active physical therapy

Moderate

� Unable to walk, but lifts limbs from bed or chair

� Oropharyngeal weakness but swallows safety

Severe

� Unable to lift limbs

� Aspiration risk

� Blood pressure fluctuations

� Begin plasma exchange / IVIG

� Passive physical therapy

� Plasma exchange/IVIG if hemodynamically stable

� Passive physical therapy

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Definisi

� Poliomyelitis is an acute infectious disease

which affects the motor neurons of the

spinal cord and brain and results in an spinal cord and brain and results in an

asymmetric flaccid paralysis of the

voluntary muscles

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Poliomyelitis

� Is a generalized viral infection with an affinity

for lower motor neurons

� Polios, meaning gray, reflecting the

involvement of the anterior horn gray matter involvement of the anterior horn gray matter

in the spinal cord.

� The paralytic rate also varies with the

virulence of the strain of poliovirus

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Pathophysiology

� There are 3 polioviruses (1,2 and 3), which have antigenic

differences

� Poliovirus receptor is present in high concentration on

LMN cell bodies in the spinal cord and brain stem

� The route of entry into the CNS may be from the blood,

or alternatively, from the muscle endplate through the

peripheral nerve

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Spread of infection Gut

Viremia Along nerves

Virus in spinal cord and

Bulbar motor neurones

Chronic persistence

In immunodeficiency

1000 : 1

Asymptomatic Symtomatic :

Acute paralyticProgressive CNS

Pathology

Clinical

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AsymptomaticAcute paralytic

Poliomyelitisdisorder

Recovery with

Residual deficits

Post poliomyelitis progressive

muscular atrophy

?? Amyotrophic

lateral

sclerosis

25 %?

Clinical

Late effects

Figure 1. Schematic depiction of natural history of poliomyelitis.

Epidemiology

� In infancy the illness was usually benign and

only rarely produced paralysis

� The potensial for paralysis increases with age

� 90-95% of cases asymptomatic; in 4-8% is � 90-95% of cases asymptomatic; in 4-8% is

nonspesific viral syndrome; only 1-2% of

cases are associated with paralysis

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DAYS AFTER EXPOSURE

01 5 10 15 20

MINOR ILLNESS

(NON SPECIFIG)MAJOR ILLNESS

(CNS INVOLVED)

1-2%

4-8%

FRANK CASES

ABORTIVE

PE

R C

EN

T O

F A

LL IN

FE

CT

ED

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90-95% INAPPARENT

VIRUS PRESENT IN

BLOCO

THROAT

FECES

CNS (FRANK CASES)

MAY PERSIST 12-17 WKS

ANTIBODIES PRESENT

NEUTRALIZING

COUP, FIXING

PERSIST FOR LIFE

PERSIST 1-5 YEARS (?)

01 5 10 15 20

DAYS AFTER EXPOSURE

PE

R C

EN

T O

F A

LL IN

FE

CT

ED

Table . Distribution of paralysis of acute anterior

poliomyelitis

Location Precentage of cases

Leg 78,6

Arm 41,4

Trunk 27.8

Throat and neck 5.8

Cranial nerves 13.8

Facial muscles 40.9

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Facial muscles 40.9

Pharyngeal 31.9

Ocular 30.1

Palatal 15.8

Glossal 5.6

Masticatory 2,9

Ergebn Inn Med Kinderheilk 1924; 26:248.

Paralytic Poliomyelitis

� Spinal form

� Bulbar form ( paralysis of motor cranial nerve

with or without involvement vital centre)

� Bulbospinal form� Bulbospinal form

� Encephalitic form

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DIAGNOSIS BANDING

POLIOMIELITIS GUILLAIN - BARRE

1. Akut Subakut

-- paralisis perifer ----

(motor neuron) (radix, difus)

2. Asimetrik Simatrik

3. Otot terkena Kelumpuhabn naik

tak tentu distal proksimal

(ascending)

4. Hanya motorik . Sensorik

. Motorik

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. Motorik

. Otonom

5. Tanda infeksi (+) (-)

6. Masa laten (-) (+)

7. L.P sel / N < 30/3

Protein / N

9. EMG giant

potensial (> 10 hari) -KHS N

10. Gejala sisa (+) paresis (-) “self limiting disease”sembuh 2 mg – 4 mg – 2 th

Spinal Muscular Atrophies

� SMA are degenerative disease of motor

neurons that begin in fetal life and continue

to be progressive in infancy and childhood

45

Classification SMA

� SMA type I, severe infantile form (Werdnig-

Hoffmann disease)

� SMA type 2, a late infantile form (more slowly

progressive form)progressive form)

� SMA type 3, juvenile form

(Kugelberg-Welander disease)

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SMA type I (in utero or 2-3 months)� Severe hypotonia, general weakness

� The lower limbs are more severely affected

than the upper

� Fasciculation and atrophy of the tongue� Fasciculation and atrophy of the tongue

� Intercostal muscles are severely affected ‘a

bell-shaped appearance’

� Contracture occurs in about 10%

� More than 2/3 die by 2 yr of age.

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SMA type 2 ( 3 to 15 months)

� Never achieves the ability to stand or walk

� Symmetrical, proximal muscles are more affected than the distal

� Tendon reflexes are usually depressed or � Tendon reflexes are usually depressed or absent

� Fasciculation and atrophy of the tongue and tremor of the hand are common

� The disastrous complication is scoliosis

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SMA type 3 ( > 24 months)

� Normal milestones in the first years and

achieves the ability to walk

� Muscular dystrophy fashion: waddling gait,

Gowers’ manouver, walk flat-footedGowers’ manouver, walk flat-footed

with eversion of the feet. In contrast to

tendency to inversion in Duchenne

� Reflexes may be normal or depressed

49

Age of First Clinical Manifestations in

Infantile Muscular Atrophy

Age Percent of cases

Newborn 37

0-1 month 10

1-3 months 12

3-6 months 6

50

3-6 months 6

6-9 months 12

9-12 months 9

More than 1 year 8

Modified from Brandt ((15

Creatine kinase (CK) test

� An enzyme (protein) that is important for

energy production within muscle fibres.

� Normally there is only small amount in the

bloodblood

52

2000

1000

53

Normal range

0 5 10 15 20

70

Age (years)

Figure 2-18. CPK level in early stages of

Duchenne dystrophy and gradual Decline with progression of disease

Electromyo/neurography (EMG/ENG)� Diagnostic aids in detecting NMD

� To determine and to differentiate axonal or myelin disorder

� Not pathognomonic, when present � Not pathognomonic, when present strongly suggest the diagnosis

� Motor conduction, sensory conduction, F wave and H wave.

� Needle electromyography.

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Muscle and nerve biopsy

Muscle biopsy is essential for any patient with

a suspected neuromuscular disorder in order

to establish a definitive diagnosis

55

Cerebrospinal fluid (CSF)

� Poliomyelitis

� Pleositosis, 20-300 WBC/mm3 lymphocytic,

the cell drops within the first 2-3 weeks

� Total protein increases in the first weeks, < 200 mg/dl. � Total protein increases in the first weeks, < 200 mg/dl.

� Guillain Barre syndrome

� Dissociation between high CSF protein and a lack of

cellular response.

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GB Protein

57

MG I II III IV

GB SEL < 30

3

Polio Protein

Polio SEL

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