CHILDHOOD

NEUROMUSCULAR DISORDERS
CHILDHOOD NEUROMUSCULAR
DISORDERS (NMD)

I.Definition

II.Classification

III.Diagnostic
 I. NMD. Definition
 Disorders of MOTOR UNIT:
motor neurons
axons peripheral nerves
neuromuscular junction
muscular fibers
 MOTOR UNIT DISORDER

 Segmentary motor deficit

 Hypotonia

 Muscular atrophy

 /absent DTR ( deep tendon reflexes )

 Specific EMG
 II. NMD. Classification

 Topography

 Onset and evolution

 Etiology
 MAIN DISORDERS OF THE MOTOR UNIT

ANTERIOR HORN NERVE NM JUNCTION MUSCLE FIBER

SPINAL NEUROPATHIES MYASTHENIAS DYSTROPHIES

MUSCULAR Duchenne / Becker
ATROPHIES H.S.M.N. Myasthenia Limb girdle (LGMD)
(SMA) gravis sarcoglycanopathies
(Charcot- Emery-Dreifuss / FSH
Types 1-4
Marie-Tooth, Congenital
Djerine-Sotas, MYOTONIC Sd
(Werdnig-Hoffman) myasthenic Steinert / Thomsen
(Kugelberg-Welander) others) syndromes
MISCELLANEOUS
H.M.N.
Mitochondrial
A.L.S. H.N.A. Congenital
Metabolic
Dysimmune
 1. Anterior horn

 Proximal, progressive motor deficit

 Hypotonia, amiotrophy of involved muscles
 Abolished DTR in affected territory
 Fasciculations
 Lack of sensitive anomalies
 Neurogenic EMG (fibrilations at rest, . in repaus,
traseu sarac si accelerat cu prez de pot polifazice largi si
ample)
 Normal conduction studies
 2. Peripheral nerve

 Predominantly distal motor deficit

 Hypotonia
 Amyotrophy,
 Abolished DTR
 Objective, subjective sensitive disorders
 Neurogenic EMG.(fibrilatii in repaus, traseu sarac
fara aspect interferential la contractie,cu amplitudine
mai mare a PUM)
 Modified ( ) conduction velocities (motor+/- sensitive)
 3. Neuromuscular Junction
 Time& effort variable motor deficit
 Fatigability
 Muscles predominantly involved: facial, proximal
muscles, deglutition, phonation
 Normal DTR
 Normal muscular enzymes (CK)
 Normal EMG normal, but decrement at repetitive
stimulare repetitive
 + antibodies against Ach receptors
 4. Muscular disorder

 Proximal motor deficit

 +/- or diminished DTR
 Muscular atrophy/pseudohypertrophy
 No sensory loss Absente tulb senzitive
 EMG - myogenic
 Muscular enzymes elevated (CK, LDH)
 EKG, cardiac ultrasound - cardiomyopathy
 NMD. Classification

 Topography

 Onset and evolution

 Etiology
The diagnostic of NMD can be suspected at any age !!!

 PRENATAL

 diminished fetal movements

 hydramnios

 arthrogryposis
The diagnostic of NMD can be suspected at any age !!!

 NEONATAL

 hypotonia

 weak cry

 deglutition difficulties

 respiratory distress
The diagnostic of NMD can be suspected at any age !!!

 INFANT

 delayed motor milestones

 loss of previous acquistions

 respiratory problems
The diagnostic of NMD can be suspected at any age !!!

 SCHOOL AGED CHILD AND ADULT

 gait abnormalities

 fatigability

 muscular pain
 NMD classification
onset, evolution, etiology

Genetic: AD, AR, X linked

Acquired inflammatory
infectious
autoimmune
Acute chronic paraneoplastic,
metabolic
vasculitis,
toxic
 III. NMD. Evaluation & diagnostic

 History

 Clinical examination

 Investigations

 Genetic testing
 III. NMD. Evaluation & diagnostic

 History

 complaints & symptoms:

deficits, myalgias, falls, gait abnormalities, cramps
 age at onset ( prenatal, newborn, child, adult )
 motor milestones
 acute/progressive onset
 slow/ fluctuating/ rapid course
 family history + for NMD
 III. NMD. Evaluation & diagnostic

 Clinical examination
 General
 Neurological examination

 Clues:

Children < 2 yrs DIFFUSE HYPOTONIA

Children > 2 yrs MUSCULAR DEFICIT

 Clinical examination - kids< 2yrs
Hypotonic syndrome

History: pre-, peri-, postnatal

Lack of movements in postural
postural reflexes reflexes
Fasciculations
CNS involvement (cognitive, Absent/ + DTR
seizures, dysmorphism) , Arthrogriposis
Absent pathological reflexes
DTR ++ cranial nerves (oculomotricity,
deglutition)
Pathological reflexes Muscular atrophy

CENTRAL PERIPHERAL
 FLOPPY INFANT

consistent with : SMA, congenital myopathies, congenital myotonic

dystrophy, congenital muscular dystrophies, others
 Clinical examination kids> 2yrs

1. Gait
2. Muscular deficit
3. DTR
4. Muscle response to percution
5. Muscular mass modifications
6. Muscles intrinsec movements
7. Sensitive deficit
8. trophicity
9. Other organs involvement (heart, CNS)
 PARACLINICAL INVESTIGATIONS
 EMG
 neuropathic vs. myopathic
 neuromuscular junction blocks
 myotonic discharge
 decremental response
 nerve conduction velocities (M & S)
 sensory potentials
 Routine biochemistry and myology
 Creatine-kinase (CK)
 much inter-individual variability
 if highly elevated, suggest muscular dystrophy
EMG

normal pattern

myopathic pattern

neuropathic pattern
 PARACLINICAL INVESTIGATION
 Imaging: muscles ultrasound tomography/Computerized
Tomography (CT-scan)/Magnetic Resonance Imaging (MRI)
 to select the site of muscle biopsy
 to demonstrate some selectivity
 to follow up disease progression

 EKG, echocardiography
 Muscle/nerve biopsy
 Western Blotting
 on muscle specimen, mainly
 semi-quantitative method
 reduction of protein level or
 size/weight abnormalities
 for a limited number of proteins
PRIMITIVE MUSCULAR
DISORDERS
 PRIMITIVE MUSCULAR DISORDERS
CLASSIFICATION
 I. PROGRESSIVE MUSCULAR DYSTROPHIES
 II. CONGENITAL MUSCULAR DYSTROPHIES
 with involvement of CNS
 without involvement of CNS = Classical CMD

 III. CONGENITAL MYOPATHIES

 IV. METABOLIC MYOPATHIES
 V. CHANNELOPATIES - muscular contraction abnormalities
 Cl channels
 Na
 Ca
 Acetilcholine receptors
 Acetazolamide receptors
 Behavioral distrubances of incompletely known etiology
 VI INFLAMMATORY MYOPATHIES
 VII MYOPATHIES IN SYSTEMIC DISEASES
 CHILDHOOD MUSCULAR DYSTROPHIES

 Dystrophinopathy: disorders involving dystrophin

 Dystrophin is a very large gene on the X-chromosome, ubiquitous in the human

body
 Locus : at Xp21.2
 Huge : 2.7 Mb (50% of the genome size of E coli)

 Muscular Dystrophies: group of genetic disorders that are characterized by

progressive loss of muscle integrity, wasting, and weakness. Characterized by
chronic degeneration and regeneration of muscle fibers (in contrast with static or
structural myopathies)

 Diagnostic: clinical picture+genetic testing+investigations ) neuroradiology,

muscle biopsy (for dystrophin, glicoproteins, merosine)
CHILDHOOD MUSCULAR DYSTROPHIES

 PROGRESSIVE

 CONGENITAL
PROGRESSIVE MUSCULAR DYSTROPHIES (PMD)
Classification

 PMD affecting predominantly the girdles

 Dystrophynopathies
 Limb-girdle muscular dystrophy
 Emery - Dreyfuss
 PMD with muscular involvement other than girdle
muscles
 Facioscapulohumeral dystrophy Landouzy - Dejerine
 Distal PMD
 Ocular & oculopharyngeal myopathy
 Myotonic dystrophies
 1. DYSTROPHYNOPATHIES
a) PMD Duchenne ( DMD Duchenne muscular dystrophy )
 INCIDENCE: 1/3500-6000 live male births.
 The most frequent PMD
 X-linked - Xp21.2. :
 mother carries the recessive gene and passes it to her child
 trait is usually expressed in males only
 1. DYSTROPHYNOPATHIES
a) DMD
 CLINICAL PICTURE:
 Insidious onset, progressive course

 Motor developmental delay:

 Gait difficulties waddling gait difficulties in rising from the floor
and climbing stairs - toe-walking( tendinous retractions)
 Gowers sign

 Articular deformities hyperlordosis (fascia lata tensor retraction ),

 pseudo-hypertrophy (calves) from age of 3-4
 DTR diminishing slowly
 Scoliosis and respiratory muscles involvement respiratory failure.
 Progressive muscular deficit nonambulatory by 12 yrs
 1. DYSTROPHYNOPATHIES
a) DMD
CLINICAL PICTURE:

 Smooth muscle involvement :

 Cardiac:

 initial EKG modifications ( high amplitude in precordial

right derivations), then clinical signs ( dilatative
cardiomyopathy )
 INVESTIGATE CAREFULLY!!

 Digestive acute gastric dilatation, megacolon,

paralytic bladder
 Mental retardation ( IQ<70).
1. DYSTROPHYNOPATHIES
a) DMP Duchenne
1. DYSTROPHYNOPATHIES
a) DMP Duchenne
 1. DYSTROPHYNOPATHIES
a) DMP Duchenne

 + DIAGNOSTIC

 Characteristic clinical picture

 High levels of muscular enzymes - CPK (>5000 UI) la debut ,
 EMG myogenic
 Genetic testing - demonstration of deletion in the dystrophin gene
 Muscular biopsy
 Dosing dystrophin ( absent or 3-5%)
 Lack of immunostaining of dystrophin in muscle biopsy specimen

 Prenatal diagnostic
 >10 wks gestational age
 Chorionic villi

 Neonatal screeningul neonatal: CK > 15th day

 1. DYSTROPHYNOPATHIES
a) DMP Duchenne
 EVOLUTION & OUTCOME
- Progressive course :
 Imobilization > 6yrs ,

 Life expectancy - they die by the 2nd-3rd decade:

 Respiratory failure ( weak patients)
 Cardiomyopathy ( better muscular representation)
- General anesthesia should be avoided
( tachycardia, fever, elevated CPK ).
 Pathologyof
Pathology ofthe
theDYSTROPHIN
DYSTROPHINGENE
GENE

direct stop
Detection : difficult frame-shifting ins/del
splice
SMALL MUTATIONS missense

28%

63%
9%
DELETIONS
DUPLICATIONS
Detection : easy
Detection : special

D959-8/H
From DMD to dystrophinopathies
Take-home messages
1. DIAGNOSTIC (positive and differential)
relies upon molecular evidence :
Dystrophin analysis : protein  gene defect
is mandatory because
 atypical forms of dystrophinopathies
may be confused with other muscle diseases
metabolic, congenital, dilated cardiomyopathies
 other MD (LGMD ) may be confused with DMD or BMD

 importance to identify precisely the gene mutation

for genetic counseling ( prenatal, female carriers)
for allele-based therapy
Dystrophin is at the sarcolemma and is absent in DMD

NORMAL DMD
When to suspect DMD
 1. DYSTROPHYNOPATHIES
a) DMP Duchenne
TREATMENT - no efficient curative treatment
 Profilactic:
 Weight control( tendency for obesity)
 Preserving the ambulation
 Nocturnal intermittent positive pressure

 Corticotherapy :
 Prednisone - Dubowitz 0,75 mg/kg/zi 10 days/mo vs continue
therapy
 Deflazocort less adverse reactions
 Ciclosporine, coenzime Q10, creatine
 DYSTROPHYNOPATHIES
a) DMP Duchenne
 Modern therapies:
 Myoblasts transfer unsatisffactory
 Genic therapy research human trial !!!
 concept of gene-based therapy (GBT)
 BRING dystrophin (by the gene)
 REPAIR the gene :
 allele-based therapy (exon skipping)
 READTHROUGH of nonsense mutations
 STIMULATE a substitute (utrophin)
 REPRESS secondary troubles
 ENHANCE regeneration
 Genetic counselling.
 1. DYSTROPHYNOPATHIES
b) DMP Becker
Main clinical and paraclinical features

 incidence: lower than Duchenne, but equal prevalence ( higher life expectancy)
 Clinical presentation:
 later onset (late childhood or adolescence) : > 5yrs
 Ambulation + - 16 yrs
 Less evident pseudohypertrophy
 exertional myalgia in calves + cramps
 Preserved DTR
 rare cardiomyopathy
 Testicular atrophy reduced fertility
 Normal intelect
 slower progression

 Investigations: similar to DMD

 CPK ~ Duchenne
 Myogen EMG
 Muscular CT to differentiate from spinal amiotrophy
 Muscular biopsy 20% dystrophin +
 X-linked , but believed to be at another locus
 NEUROMUSCULAR
JUNCTION DISORDERS
 Myasthenic Syndromes
 topography of of the lesion: neuromuscular junction

disorder of neuromuscular transmission ( neuromuscular blockade)

 clinically characterized by :
 Weakness of skeletal muscles

 Fatigability on exertion
 ! Reminder: Normal physiology
 Neuromuscular Junction (NMJ) The NMJ is a type of synapse, a site of
 Components:
cell-to-cell communication, where a
 Presynaptic membrane
nerve cell can stimulate a muscle cell
 Postsynaptic membrane
to contract and produce movement.
 Synaptic cleft
The nerve cell, or presynaptic side
of the NMJ, stimulates the muscle cell
by releasing a chemical signal called
acetylcholine (ACh). The ACh
travels across a synaptic space to
reach the postsynaptic surface of the
muscle cell, where it triggers
contraction by opening pores (or
"channels") called ACh receptors.
To shut off the signaling process, an
enzyme called acetylcholinesterase
(AChE) breaks down ACh in the
synaptic space.
 Myasthenic Syndromes - Classification

ETIOLOGY : PATHOPHYSIOLOGY:

AUTOIMMUNE PRESYNAPTIC
Myasthenia Gravis i.e. Lambert-Eaton syndr.;
Lambert-Eaton syndrome botulism, ChAT deficiency

TOXIC and/or DRUG- SYNAPTIC

INDUCED i.e. Endplate AChE deficiency
Botulism, venoms
Penicillamine, curare, quinines, POSTSYNAPTIC
procainamide i.e. Myasthenia Gravis,
penicillamine intoxication, curare
GENETIC intoxication, RAPSN...
Congenital myasthenic syndromes
 MYASTHENIA GRAVIS,
autoimmune myasthenia
EPIDEMIOLOGY:

ETIOPATHOGENY:
 Autoantibodies that binds and
reduce the number of AchR at
postsynaptic membrane (90%)
 Cellular immune mechanism (10%)
 Frequency
 Worldwide prevalence 125/1 000
000
 7-9 / 100 000 inhab in Northern
Europe
 Sex & incidence
 F-M (3:2) in young people age
peak 15-30
 F-M (1:1) > 50yrs Mean age of
onset 15-30
 Incidence peaks- M- 6-7th decade
F- 3rd decade).
 10-15% - onset <15 yrs
 MYASTHENIA GRAVIS -CLASSIFICATION
 Clinical forms
 Ocular:
 10-15%
 AChR(50%) and anti-MuSK (40-60%) antibodies
 frequent in children
 favorable evolution
 resistance to treatment
 Generalized MG (anti-AChR antibodies 65-85%)
 Ocular forms with later generalization ( frequent adult type)

 Age of onset :
 Adult type
 Juvenile MG , debut dup 10 ani, niciodat sub 1 an, cu frecven mai
mare la fete mai ales postpubertar
 Transient neonatal myasthenia:
 Result of placental transfer of maternal AChR antibodies
 10-18% of infants with AMG affected mothers
 No relationship between maternal and infant disease severity
 TRANSIENT NEONATAL MYASTHENIA

CLINICAL FEATURES
 Poor sucking and feeding
 Weak cry
 Paucity of movements
 Possibly respiratory distress (need for ventilatory support)

TREATMENT

Spontaneous resolution of symptoms occurs within weeks

Neostigmine can be transiently effective

Exchange transfusion may be required in severe cases
 MYASTHENIA GRAVIS CLINICAL PRESENTATION

 Fluctuating, painless weakness increased by exertion

 Weakness increases during the day and improves with rest.

 Topography:
 extraocular muscles:
 strabismus,
 diplopia, uni-/bilateral ptosis,ophtalmoplegia- frequent initial presentation
 facial muscles & bulbar involvement common eventually
 dysphonia, dysphagia, dysarthria, jaw weakness
 head extension and flexion weakness
 related to respiratory difficulties/ exertional dyspnea
 limb muscles:
 proximal weakness more common, symmetric
 Arms more affected than legs
 preserved DTR
 MYASTHENIA GRAVIS + DIAGNOSTIC

 characteristic fluctuating weakness,

 + Miostin test,

 Electrodiagnostic studies
 Repetitive nerve stimulation DECREMENT
(reproducible 10% decremental in amplitude when the first stimulus is
compared to fourth or fifth)
 Single fiber electromyography (SFEMG),

 AChR and anti-MuSK antibodies dosage

 80% in generalized myasthenia
 50% of patients with pure ocular myasthenia
 Anti-striated muscle antibodies
 Present in 84% of patients with thymoma < 40 yrs

 Chest CT/MRI scan is mandatory to identify thymoma

MG - CLINICAL PRESENTATION
 Muscle strength
 Facial muscle weakness
 Bulbar muscle weakness
 Limb muscle weakness
 Respiratory weakness
 Ocular muscle weakness
 Modified Osserman MG severity
classification
 Clinical Classification
 Class 1: ocular symptoms only
 Class 1A: ocular symptoms with EMG evidence of peripheral
muscle involvement
 Class 2A: mild generalized symptoms
 Class 2B: more severe and rapidly progressive symptoms

 Class 3: acute and presenting in weeks to months with

severe bulbar symptoms
 Class 4: late in the course of disease with severe bulbar
symptoms and marked generalized weakness
 TREATMENT:
1. AntiAChE used routinely
1. neostigmine (2mg/kg/day),piridistigmine(1-7 mg/kg)
2. CORTICOSTEROIDS
3. THYMECTOMY recommended for patients with generalized
diseases ( 80% - thymic anomalies)
4. plasmapheresis (in severely weak)
5. IV Ig (2g/kg 2-5 days or 0,4 g/kg 5 days)
6. Azathioprine not used except for refractory cases
7. The risk of decompensation determine energic treatment of
infections, limiting surgery, avoiding contraindicated drugs

 PROGNOSTIC :
 variable
 depending on clinical form + response to treatment
MYASTHENIA GRAVIS
PERIPHERAL NERVE
DISORDERS
 PERIPHERAL NERVOUS SYSTEM DISORDERS

Classification - depending on localization :

 Radiculopathy affects one nerve root

 Polyradiculopathy affects more nerves roots

 Plexopathy affects a network of nerves

 Mononeuropathy -affects a single nerve.

 Mononeuritis multiplex (mononeuropathy multiplex) affects multiple

several different nerves

 Polyneuropathy affects symmetric, bilateral many peripheral nerves

 Polyradiculoneuropathy is a condition which is both radiculopathy and a

neuropathy affecting multiple nerve roots.
POLYNEUROPATHIES CLASSIFICATION CRITERIA

 onset : acute, subacute, chronic

 the affected functions : motor/ sensitive/ vegetative/ mixt

 pathophysiology : axonal, demyelinating

 etiology : infections, autoimmune reaction , systemic vasculitis,cancer,

toxic substances , drugs

 distribution : symmetric/asymmetric, proximal/distal

 ACUTE INFLAMMATORY DEMYELINATING
POLYNEUROPATHY
GUILLAIN - BARR SYNDROME
DEFINITION:

an acute inflammatory demyelinating polyneuropathy (AIDP)

an autoimmune disorder affecting the peripheral nervous system - rapidly ascending

and progressive weakness oil patch

the most common cause of acute flaccid motor deficit in childhood (rare, but
present even in infancy)

EPIDEMIOLOGY:

 the annual incidence rates : 1.9 / 100,000,

 all parts of the world, in all seasons, usually sporadic
 "Epidemic" - was described in 1976 in the US associated with flu vaccination
 M>F
 4-15% mortality rate, 25% mechanical ventilation, 20% persistent disability, 67% persistent
fatigue
 ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
GUILLAIN - BARR SYNDROME

ETIOLOGY:
 It is not clear yet if a trigger factor is involved
 frequently preceded by viral infection(C. Jejuni, herpes, Citomegalvirus, HIV, B.Lyme), vaccinations or
surgery ( after 1-4 weeks)
 associated with :
 metabolic disease : diabetes mellitus, dysglobulinemia, porphyrias
 systemic disease: disseminated lupus erythematosus
 paraneoplastic syndrome

PATHOPHYSIOLOGY:
etiology unknown - may be cell-mediated immunological reaction directed at the peripheral nerves

CLINICAL STAGES:

 Rapid progression - rapidly progressive weakness is reached within 12 hours (3 to 30 days),

 Plateau stage - maximum level of disability is reached within 4 weeks

 Recovery phase - remission of symptoms is reached within 1 week - 28 months

 ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
GUILLAIN - BARR SYNDROME
CLINICAL PRESENTATION:

 2 4 wk after a benign febrile respiratory / gastrointestinal infection (2/3 of cases) or

immunization
 Paresthesias in toes + fingers + lower limbs weakness, (a)symmetric, ascending to upper limbs,
respiratory muscles and cranial nerves (VII, IX, X), with diminished /absent reflexes
 In children frequently pain (back and lower limbs) radicular characteristics (elongation signs +)
 Fishers variant: opthalmoplegia without midriasis, ataxia, areflexia

 MOTOR DEFICIT :
 asymetric/ symetric limb weakness
 respiratory muscle weakness
 cranial nerves palsies VII IX, X
 diminihed/ absent DTR
 SENSORY DYSFUNCTION:
 Myalgia
 Parasthesia
 loss in proprioception and vibration sensibility
 AUTONOMIC DYSFUNCTION : cardiac arrhythmias, blood pressure fluctuations,
abnormal haemodynamic responses to drugs, sweating abnormalities, pupillary
abnormalities, and bladder and bowel dysfunction.
 ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
GUILLAIN - BARR SYNDROME

INVESTIGATIONS:
 CSF :
 albumino-cytologic dissociation

 protein level

 <10 mononuclear cells/mm3

 Electrophysiological tests:
 EMG neurogenic findings

 Nerve motor action potentials

 conduction block

 delay of the F-wave

 absent or low H-reflex

 ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
GUILLAIN - BARR SYNDROME

DIAGNOSTIC CRITERIA (Asbury si Cornblath 1990):

 REQUIRED CRITERIA

 Progressive motor weakness of more than one limb.

 Areflexia or hyporeflexia (loss of ankle jerks and diminished knee

and biceps reflexes)

 will suffice if other features are consistent with the diagnosis

 ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
GUILLAIN - BARR SYNDROME

 SUPPORTIVE DIAGNOSTIC CRITERIA

 1.progression : weakness may develop rapidly but cease to progress
after 4 weeks
 relative symmetrical motor deficit

 mild sensory symptoms and/or signs, cranial nerve involvement,

autonomic dysfunction.
 2.recovery :begins 24 weeks after progression ceases; occasionally it
is delayed for months.
 3.absence of fever at the onset of neurological symptoms.

 4.CSF : elevated protein after the first week of symptoms

<10 mononuclear leucocytes/mm3
 5.electrodiagnostic features : NCS -slowing or conduction block
(80%)
ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY

GUILLAIN - BARR SYNDROME

Diagnosis

 Clinical data  Other required

investigations:
 Laboratory findings
 HIV serology
 Albumino-cytologic
dissociation in CSF  B. burgdorferi serology
in selected cases

 Electrodiagnostic findings  Studies related to other

 NCV <80%, blocks
possible causes /
general medical care /
 Prolonged distal latencies
for understanding
 Prolonged/absent F causation
response
 ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
GUILLAIN - BARR SYNDROME
TREATMENT
 PDIA medical EMERGENCY!
 Specific treatment ( immunomodulatory):
 intravenous immune serum globulin (IV IG) 0.4 g/kg for 5 days or 1 g/kg for 2 days
or plasmapheresis :
 are treatment options for severe GBS in children shortens the clinical course
in children
 Indications:
 Non-ambulant patient at the time of diagnosis
 Evidence of bulbar or respiratory dysfunction
 Clinical deterioration
 2 4 wks after the onset

 Supportive treatment
 Management of cardiovascular and respiratory functions
 Management of pain
 Prevention of complications
 Physiotherapy
 Psychological support
 Prevention of relapses : special recommendations regarding vaccination not recommended
during the acute phase & 1 year after the onset
ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
GUILLAIN - BARR SYNDROME
FOLLOW-UP

 Short term complications :

- Respiratory failure, mechanical ventilation

- deglutition disorders
- Cardiac arhytmia
- Complicatii de decubit thromboebolism,

 Long term complications:

 80% - full recovery in weeks- months, no neurologic sequelae

 20 %- mild- sever neurologic sequelae
 HEREDITARY NEUROPATHIES
HEREDITARY MOTOR AND SENSORY NEUROPATHIES
(HMSN)

 Chronic polyneuropathies
 Genetic transmission
 Distal motor >sensory deficit
 Slowly progressive
 Axonal/myelinic nervous fibers degeneration
 Hereditary motor and sensory neuropathies
DYCK (1975)

In common :
- peroneal muscular atrophy phenotype
Type I :
- nerve hypertrophy
- reduced nerve conduction velocities
- onion bulbs autosomal dominant
inheritance
Type II :
- no nerve hypertrophy
- normal or slightly reduced nerve conduction velocities
- loss of myelinated fibers
Type III :
- nerve hypertrophy
- reduced nerve conduction velocities
- autosomal recessive inheritance
 Current classification of CMT disease

Mode of transmission
Autosomal dominant or recessive ;
X-linked.

Electrophysiological examination
Demyelinating CMT: MNCVs 30 m/s ;
Axonal CMT: MNCVs > 40 m/s ;
Intermediate forms : 30 MNCVs < 40 m/s.

Molecular genetics
 CHARCOT- MARIE - TOOTH MYELINIC TYPE
CMT 1

 Sensory & motor neuropathy not due to an acquired or identified

disorder (! primarily motor disorder)

 the most common type CMT 1 demyelinating form

 prevalence CMT 1 - 15 \ 100 000 ( CMT 1A reprezinta 70 -80 % of all

types of CMT1 )
 CMT 1
GENETICS

 Heterogenous group of disorders various myelin protein

gene encoding mutation

 Subtypes - clinically the same, different molecular genetic

tests

 4 forms (depending on the mutated gene):

 CMT1 A - gena PMP22 ( peripheral myelin protein)
 CMT1 B - gena MPZ (P0) (protein zero)
 CMT1 C - gena LITAF(lipopolysaccharide-induced tumor
necrosis factor- alpha factor)
 CMT1 D - gena EGR2 (early growth response)
 CMT

Dominant forms

MNCV <30m/s 25<MNCV<40m/s(males) MNCV>40m/s

30 <MNCV(females)

CMT1A CMT1B CMT1C CMT1D ? CMTX CMT2 Spinal

17p11.2 1q23 16p13 10q21 Xq13-21

CMT2A CMT2B CMT2C CMT2D CMT2E CMT2F
7p14
12q23
1p35 3q13 ? 7p14 8p21 7q11 ? 2q14
?

PMP22 P0 LITAF EGR2 Cx32 RAB7

KIF1B GARS NF-L
 CMT TYPE 1
CLINICAL PRESENTATION

 onset at the first or second decade of life

 slowly progressive weakness and atrophy of distal limbs
 symmetrical weakness and wasting is found in intrinsic foot,
peroneal, and anterior tibial muscles, pes cavus and hammer toe
 decreased or absent DTR
 absent ankle reflexes are universal
 distal sensory loss;
 Pes cavus;
 scoliosis
 sensory loss
 Proprioception
 Pain and touch
 CMT 1A
ELECTROPHISIOLOGY
 Marked and uniform slowing of MNCVs (motor nerve conduction
velocities) in all nerves
 MNCVs frequently unrecordable on peroneal nerve
 Small CMAPs due to axonal loss; degree of reduction correlated
with disease severity
 Absence or marked reduction of SNAPs
 Absence of conduction block
 Intrafamilial variability of MNCVs
 Stability of MNCVs throughout the life in a given patient

Very sensitive method for the detection of asymptomatic mutation

carriers
 CMT 1A
ANATOMOPATHOLOGY

 Demyelinating CMT
 onion bulbs ( demyelinization
& remyelinization )
 hypomyelination

 NOT NECESSARY FOR

THE DIAGNOSTIC OF
FAMILIAL CASES !
 CMT 1A
SPECIAL DIAGNOSTIC TECHNIQUES
 molecular genetics (mutations)

 PRENATAL DIAGNOSTIC
 possible for:
 CMT 1A,

 CMT 1B,

 chorionic villi biopsy in wks 10-12 or amniocentesis in wks 16-18

 first: identification of mutant allele in the family!
 EVOLUTION

 Slowly progressive

 Active period undefined ; clinically stationary for long periods

 Foot deformities worsening with time

 Early onset more severe course

 Early diagnostic in a parents similar expression in his child

 TREATMENT
 No curative treatment

 Symptomatic treatment

 Multidisciplinary team:

 neurologist
 orthoped
 physical therapist
 occupational therapist
 Psychiatrist

SPINAL MOTONEURON
DISORDERS
 CLASSIFICATION
 ACUTE
 ACQUIRED
 INFECTIOUS
POLIOMYELITIS
ECHO VIRUSES
COXSACKIE VIRUSES
ENTEROVIRUSES

 NON-INFECTIOUS
SPINAL TRAUMA
SPINAL VASCULAR DISORDERS
 CHRONIC
 GENETIC
 SPINAL MUSCULAR ATROPHY
 AMIOTROPHIC LATERAL SCLEROSIS
 ACQUIRED
 CHRONIC GENETIC DISORDERS
SPINAL MUSCULAR ATROPHY ( SMA)
Definition:

 Pure Motor Neuron Disease (or Anterior Horn Cell disease)

 Spinal muscular atrophy (SMA) is a genetic, motor neuron disease caused by
progressive degeneration and apoptosis of motor neurons in the entire spinal
cord and in select brainstem motor nuclei (nuclei of cranial nerves V, VII, IX,
and XII).

 The disorder causes weakness and wasting of the voluntary muscles.

 SMA is the second most common autosomal recessive disease in the US after
cystic fibrosis

 Genetic locus 5q12.2-13.3

 mutations in the Survival Motor Neuron (SMN) gene
result in a loss of function of the SMN protein.
 CHRONIC GENETIC DISORDERS
SPINAL MUSCULAR ATROPHY ( SMA)

Classification:

 ISMAC (International Spinal Muscular Atrophy

Consortium):

 Type I (Werdnig-Hoffman disease, severe infantile form)

 Type II (Dubowitz disease, intermediate)
 Type III (Kugelberg-Welander disease, mild juvenile form)
 Type IV
 CHRONIC GENETIC DISORDERS
SPINAL MUSCULAR ATROPHY ( SMA)

 SMA I (Werdnig-Hoffmann, infantile onset SMA)

ONSET: < 6 mo (30% in utero);

CLINICAL PRESENTATION:
I. Peripheral motor neuron syndrome :
- weakness and profound hypotonia ( axial + limbs) first few months of life;
- absent DTR ;
- bilateral, symmetric severe motor deficit, predominantly proximal (limited
spontaneous movement just fingers), progressive
- generalized muscle atrophy;
- fasciculations (often present in the tongue);
II. skeletal anomalies (pectus excavatum, spine deformities, arthrogriposis)
III. paradoxical breathing (abdominal);
IV. normal social awareness and interaction;
V. sphincter tone and sensation are intact

EVOLUTION:
Respiratory insufficiency + feeding difficulties, deglutition problems die by complications
< 18 mo; nonsitters
SMA tip I
 CHRONIC GENETIC DISORDERS
SPINAL MUSCULAR ATROPHY ( SMA)

 SMA tip II (chronic infantile)

ONSET: 6 18 mo; most common form

CLINICAL PRESENTATION:
I. Peripheral motor neuron syndrome :
 Axial & limbs hypotonia;
 Absent DTR;
 Most common manifestation is developmental motor delay. Infants with SMA
type II often have difficulties with sitting independently or failure to stand by 1
year of age
 may learn to sit but will never be able to stand or walk
II. Less skeletal deformities (lordosis, tendinous retractions);
III. Tremor of upper extremities - postural tremor affecting the fingers - thought to be
related to fasciculations in the skeletal muscles ;

EVOLUTION:
Rapid regression stabilization ( 1-2 yrs after onset) respiratory failure,
speaking and deglutition difficulties die by a mean age of 20
sitters
 CHRONIC GENETIC DISORDERS
SPINAL MUSCULAR ATROPHY ( SMA)

 SMA III (Kugelberg-Welander, chronic juvenile)

ONSET: > 18 mo - adult

CLINICAL PRESENTATION:
I. Peripheral motor neuron syndrome :
 bilateral, symmetric absent DTR (some may have DTR +, but diminished);
 bilateral, symmetric, predominantly proximal motor deficit( Gower sign +), slowly
progressive
 most can stand and walk but have trouble with motor skills, such as going up and down
stairs.
 muscular atrophies (! gastrocnemian pseudohypertrophy)
II. Tremor of upper extremities ;
III. Bulbar dysfunction - late in the disease
IV. Musculoskeletal deformities - rare;

EVOLUTION:
 Slowly progressive slowly - the overall course is mild - +/- dysarthria/ dysfagia
 Many patients have normal life expectancies.
walkers
 CHRONIC GENETIC DISORDERS
SPINAL MUSCULAR ATROPHY ( SMA)

 Diagnostic:
I. Clinical presentation + onset type of SMA;
II. Electrophysiological studies:
 Nerve conduction studies normal or slightly decreased velocities, the sensory nerve
action potentials are normal.
 Electromyography abnormal spontaneous activity with fibrillations and positive
sharp waves. The mean duration and amplitude of motor unit action potentials are
increased; rhytmic action potentials ( 5-15c/sec)
III. Anatomopathology: no patognomonic findings
- medular: degeneration and loss of motor neurons form anterior horn and also bulbar
- spinal nerves roots: loss of myelinated axons
- muscular: modifications secondary to denervation;
IV. Molecular genetics: deletion of exon 7, 8 - gene 5q12.2-13.3;

 Treatment: supportive ( respiratory infections, nutrition, orthopedic, physical

therapy) only improves the quality of life !
 Dont forget
Muscle Physiology

Muscle

Motor Neuron

Motor Unit

Muscle Fibres
Dont forget
localization