This document provides an overview of neuromuscular junction disorders and myasthenia gravis. It discusses the anatomy of the motor unit and neuromuscular junction. Regarding myasthenia gravis, it covers the pathophysiology, clinical features, diagnosis, and management. Myasthenia gravis is an autoimmune disorder caused by antibodies that reduce acetylcholine receptors at the neuromuscular junction, leading to muscle weakness and fatigability. Diagnosis involves testing for autoantibodies, repetitive nerve stimulation, and response to treatment with cholinesterase inhibitors or immunosuppression. Management focuses on symptomatic control and immunosuppression with corticosteroids, plasma exchange, or intravenous immun

1. APPROACH TO NMJ DISORDERS &
MYASTHENIA GRAVIS
PRESENTER TSEHAY (R3)
MODERATORS DR NEBIYU B ( NEUROLOGIST)
DR SAMSON Y ( NEUROLOGIST)
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2. Outline
 Anatomy of motor unit and NMJ
 Clinical approach of NMJ disorders
 Myasthenia gravis
 Path physiology
 Clinical feature
 Diagnosis
 management
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3. Motor unit
 defined as a somatic motor
neuron and all the skeletal
muscle fibers it innervates.
 When this neuron is
stimulated, all the muscle
fibers it synapses will contract
as a unit.
 The number of muscle fibers
per motor unit may be as high
as several hundred or as few
as four.
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4. Neuromuscular Junction
 Region where the motor neuron
stimulates the muscle fiber
 Formed by
_ End of motor neuron axon
(axon terminal)
_ The motor end plate of a
muscle
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5.  Ach is synthesized in the
cytoplasm of the nerve
terminal & stored in the
synaptic vesicles.
 AchE
– In the synaptic space
– destroys Ach a few
msecs after it has been
released from the
synaptic vesicles
NMJ
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6.  During depolarization of nerve
terminal
• Voltage-gated calcium channels
open
 Exocytosis The vesicles fuse with
the neural membrane and empty
their acetylcholine into the synaptic
space.
NMJ
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8. Case
One evening after dinner, a 58 year old woman began to have swallowing
difficulties and double vision. Over the next few hours she developed ptosis, facial
weakness, and difficulty breathing so her family brought her to the emergency
room. Examination was notable for normal mental status, severely limited horizontal
and vertical eye movements with normally reactive pupils, facial diplegia,
dysarthria, weakness of the bilateral arms and legs worse proximally than distally, 1+
patellar reflexes but otherwise undetectable deep tendon reflexes, and a normal
sensory exam. Vital capacity was 600 cc ( low).
1. Where is the lesion?
2. What are possible differentials?
3. How do u investigate ?
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9. Clinical approach
 History
 symptoms
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10. Temporal pattern
Acute Progressive chronic weakness
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 Myasthenia crisis
 Boutlinum toxin
 Drugs
 Organophosphate poisoning
 Snake venom
 MG
 LEMS
 Inflammatory myopathies
_ DM,PM, Necrotizing myopathy
 Toxic myopathies
 Metabolic myopathies

11. Distribution of involvement
 proximal / Distal
 ocular weakness
 Oculopharyngeal muscular dystrophy
 myotonic dystrophy
 mitochondrial myopathies
 NMJ disorders
MG vs. other causes of ptosis
 asymmetric
 fluctuating
 Associated significant diplopia
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12.  Prominent bulbar weakness
E.g. MG, LEMS, oculopharyngeal muscular dystrophy , ALS
MG vs. ALS
 UMN signs , atrophy and fasciculation's in tongue & neck muscles
 Dysarthria
flaccid / spastic
 Ocular signs
 fluctuations
 NMJ disorders
 Metabolic abnormality
 Channel disorders
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13.  Triggering events
exercise
_ after brief or prolonged exercise
_ after exercise followed by rest
_ After a high-carbohydrate meal, potassium ingestion or
fasting state
_ related to internal/external temperature
 Past medical history
- small cell lung ca
- CTDs
- autoimmune conditions
 Family history
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14. Toxin and drug history
Neuromuscular Junction
 Botulinum toxin
 Snake venom
 Organophosphates
 Magnesium
(hypermagnesemia)
Myopathies
Inflammatory
 Cimetidine
 D-penicillamine
 Procainamide
 L-dopa
Non inflammatory necrotizing
 Cholesterol-lowering agents
 Chloroquine
 Cyclosporine and tacrolimus
 Alcohol
 steroids
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15. Level Lower motor
neuron
Nerve root,
plexus, pnerve
Neuromuscular
junction
muscle
Weakness Focal or
segmental,
bulbar
Focal or segmental Diffuse or proximal,
bulbar, ocular
Diffuse or proximal,
bulbar, ocular
Tone Flaccid Flaccid Usually normal Normal or flaccid
Volume and
contour
Atrophy common Atrophy common Usually no change Normal, atrophy,
hypertrophy,
pseudo hypertrophy
Fasciculation Common Occasional Due to anti
cholinesterase therapy
None
Deep tendon
reflex
Focally decreased or
absent
Decreased or
absent
Affect distal axons
Usually normal
Could be depressed in
postsynaptic NMJ
In presynaptic NMJ ,
depressed at rest and
return normal after brief
exercise
Normal unless
weakness is severe
sensory
disturbance
yes yes Normal except minor
sensory signs in LEMS
Normal except minor
sensory signs in IBM
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16. INVESTIGATIONS
 Auto-antibodies
 chest CT
 Toxin assay
 TFT
 Serum electrolytes
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17. ELECTRO DIAGNOSTIC EXAMINATION
NERVE CONDUCTION STUDIES
 To exclude mimics and to examine abnormalities associated
with particular muscle disease.
 SNAPs
_ normal in myopathies and NMJ diseases
_ exceptions in LEMS and IBM
 CMAPs
_ normal
_ low amplitude in LEMS, critical myopathy
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18. Needle EMG
 assess electrical waveforms both at rest and with activation.
 evaluate the integrity and function of the motor units.
 used to identify a suitable muscle for biopsy
 any spontaneous activity that persists beyond 3 seconds is
considered abnormal
Fibrillations and positive sharp waves
 Irritability of muscle membranes
 denervation
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19. Motor unit configuration and recruitment
 low amplitude
 short duration myopathic
 polyphasic morphology
 Low amplitude, short duration ,polyphasic and motor unit
instability seen in NMJ.
REPETITIVE STIMULATION
• MG
 normal amplitude baseline motor response.
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20.  Decremental response in 2 Hz to 3 Hz of repetitive
stimulation. (Post exercise facilitation /exhaustion)
Botulism and LEMS
 the baseline motor amplitudes are low.
 Decrement following low rates of repetitive stimulation
 Incremental response following 20 Hz to 50 Hz.
Single-fiber EMG measures
 “Jitter “between two single muscle fibers belonging to the
same motor unit.
 block
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21. Major disorders of the neuromuscular junction
Myasthenic Syndromes Causal Agent Or Gene Defect
Presynaptic
Botulism Peptide toxin from C. botulinum
Lambert-Eaton myasthenic syndrome Autoimmune reduction in calcium-
mediated quantal release
Synaptic
Insecticides Organophosphates (inhibits AchE)
Postsynaptic
Myasthenia gravis •Autoimmune attack on postsynaptic
membrane
•Antibodies to AchR or MUSK protein
Snake venom toxins Multiple peptide toxins that lyse muscle,
bind Na channels, K channels (acting both
post- and presynaptically)
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22. MYASTHENIA GRAVIS
 A neuromuscular disorder characterized by weakness and
fatigability of skeletal muscles.
 Antibody-mediated autoimmune attack resulting reduced
AchR on neuromuscular junction.
 Systemic autoimmune disorders are found with greater
incidence in patients with MG.
 Thyroid disorders are present in up to 15% of patients with
MG.
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23. EPIDEMIOLOGY
 MG may begin at any age from infancy to very old age.
 Gender and age influence the incidence of MG.
 MG is equally present in men and women older than the age
of 40 years
 three times more common in women than men under 40
years of age.
 the incidence is higher in males after age 50.
 MuSK myasthenia is also more common in women.
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24. PATHOPHYSIOLOGY
 An autoimmune response mediated by specific anti-AChR
antibodies.
 Auto antibodies reduce the number of available AChRs.
1. Accelerated turnover of AChRs by cross-linking and rapid
endocytosis of the receptors.
2. Damage to the postsynaptic muscle membrane by the
antibody.
3. Blockade of the active site of the AChR.
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25.  T lymphocytes role
– bind to the acetylcholine receptor and stimulate B cell
antibody production.
 Role of MuSK
 MuSK activation through agrin-Lrp4 binding triggers a
signaling pathway which includes Dok7 recruitment leading to
AChR clustering.
 An immune response to MuSK a protein involved in AChR
clustering at neuromuscular junctions can also result in MG.
 Double seronegative MG- Anti-LP4 antibodies
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26.  Role of thymus
 abnormal in ~75% of pts with AChR Ab +ve MG.
 70% have lymphoid follicular hyperplasia and more than 10%
have a thymoma.
• Accepted theory
 Presence of muscle-like cells within the thymus bear AChRs
on their surface & serve as a source of auto antigen.
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28. Diagrams of (A) normal and (B) myasthenic neuromuscular junctions.
The MG junction demonstrates a normal nerve terminal; a reduced number
of AChRs (stippling); flattened, simplified postsynaptic folds; and a widened
synaptic space
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29. CLINICAL FEATURES
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34. DIAGNOSIS
 Clinical
 Ice pack test
- sensitivity 89%
- resolution or improvement in the ptosis is considered
positive and highly specific for MG.
 Edrophonium (Tensilon) test
sensitivity
_ 60% to 95% of patients with OMG
_72% to 95% with GMG
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35. Diagnostic Testing for Myasthenia Gravis
Auto-Antibodies
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37. RNS study
 considered positive if the decrement is greater than 10%.
 Important to sample distal and proximal muscle to maximize
the yield.
 Distal muscles are technically easier, but they have a lower
diagnostic sensitivity.
 To maximize the sensitivity
_ the muscles tested should be warm
_ Acetyl cholinesterase inhibitors should be held for 12
hours before the study.
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39. TREATMENT
Goal
 To achieve remission
– no symptoms or signs of MG.
– Mild Weakness on examination that didn’t interfere
normal function.
– Patient shouldn’t be on ChEIs for support symptomatic Rx.
 Treatment must be individualized
_ ocular vs. generalized
_ severity of disease
_ the presence or absence of concomitant disease
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41. Symptomatic Management: Cholinesterase Inhibitors
 Pyridostigmine bromide and neostigmine bromide are the
most commonly used ChEIs.
 The initial oral dose in adults is 30–60 mg every 4–8 hour for
pyridostigmine.
 No fixed dosage schedule suits all patients
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42. Short-Term Immune Therapies
Plasma Exchange
 temporarily reduces the
levels of circulating
antibodies
 Indicated for
 severe MG
 myasthenia crisis
 in preparation for surgery
 to prevent corticosteroid-
induced exacerbations.
 A typical course of PLEX
consists of 5–6 exchanges.
Intravenous Immunoglobulin .
 infusion of 1-2 g/kg given
over 2 to 5 days.
 Sever disease or crisis
 reduces perioperative
morbidity
 may be used chronically in
selected refractory patients.
• Common side effects
- headaches, chills, and fever.
Serious side effects
_ renal toxicity, stroke
_ leucopenia, aseptic meningitis
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43. choice between PLEX and IVIg
 clinical trials suggest they are equally effective in the
treatment of impending or manifesting myasthenia crisis.
 expert consensus suggests that PLEX is more effective and
works more quickly.
 depends on individual patient factors and on the availability.
 The efficacy of IVIg is less certain in milder MG or in ocular
MG.
 PLEX may be more effective than IVIg in MuSKMG.
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44. Long-Term Immune Therapies
Corticosteroids
 the first immunosuppressant's to be widely used in MG.
 remain the most commonly used immune therapy today.
 Prednisone produces marked improvement or complete relief
of symptoms in more than 75% of MG patients.
 Patients with thymoma usually respond well to prednisone.
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45. Corticosteroids
 Transitory worsening of weakness occurs in one-third to one
half of patients treated with high-dose daily prednisone .
 usually begins within the first 7 to 10 days with high dose
prednisone.
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47. Thymectomy
 With rare exceptions, all patients with MG with thymoma
should undergo surgery to remove the tumor.
 In non- thymomatous MG
– to avoid or minimize the dose or duration of
immunotherapy
– Failure to respond to an initial trial of immunotherapy or
intolerable side-effects from that therapy.
– About 80% of patients without thymoma become
asymptomatic or go into complete remission after
thymectomy.
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48. Myasthenia Crisis
 Myasthenic crisis is respiratory failure from myasthenic
weakness.
 arises in about 10% of myasthenic patients.
 It is more likely to occur in patients with dysarthria,
dysphasia, and documented respiratory muscle weakness.
 Myasthenic crisis and exacerbations can be triggered by
infections, surgery, and medications.
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51. Treatment
Myasthenic Crisis
 Address precipitants
 Respiratory support
 Plasma exchange or IVIG
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52. prognosis
 With the current therapy mortality due to MG is less than 5%.
 higher morbidity and mortality
 Patients with thymoma
 more refractory type of generalized MG
 co morbidities
 Factors associated with refractory disease
 thymoma
 anti-MuSK antibody
 younger age at onset and female sex.
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53. Refractory MG
 defined by unchanged or worsened symptoms after
corticosteroid treatment and
 at least two other immunosuppressant's used at adequate
doses for an adequate duration or until intolerable side
effects occurred.
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54. MYASTHENIA IN PREGNANCY
 The pregnancy outcome for mothers with MG is generally
very good.
 20% to 30% of women can experience an exacerbation
_ in the first trimester or in the postpartum period.
 Improvement can occur in the second and third trimesters
 Pyridostigmine, IVIg, plasma exchange, and prednisone are
generally safe during pregnancy
 MMF should be avoided during pregnancy
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55. During delivery
 Fatigue
 protracted labor 2nd stage labor
 fetal distress
 For women with MG, epidural analgesia is the anesthetic
intervention of choice for delivery.
 Magnesium sulfate is not recommended for management of
eclampsia in MG.
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57. REFFERENCES
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.
2016 American Academy
of Neurology

58. THANK YOU
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