1. Neuromuscular Junction
Chris Robinson, DO
Department of Neurology
Loyola University Medical Center
2012.

2. Brief Review

3. THE MOTOR UNIT
• A single motor unit contains 1 motor neuron
and all the muscle fibers it innervates
• Cell bodies of motor neurons located in
brainstem and spinal cord
• Axons of neurons are myelinated to propagate
action potential at high velocity
• When an action potential is produced, all
muscle fibers contract simultaneously

4. THE MOTOR UNIT

5. Review
• Cortical input descends through white matter
tracts to synapse in the ventral gray matter.
• Efferent’s from the ventral horn exit via
ventral rami and exit through peripheral
nerves.
• Peripheral nerve travels to muscle terminus,
where myelin sheath ends and axons divide
into terminal boutons localized to specific
muscle sites

6. Review
• Distribution of lower motor
neurons in the ventral horn
– Motor neurons controlling
flexors lie dorsal to extensors
– Motor neurons controlling
axial muscles lie medial to
those controlling distal
muscles

7. Review
• Two Types of Muscle
Fiber
– Extrafusal fibers:
Innervated by alpha
motor neurons
– Intrafusal fibers:
Innervated by gamma
motor neurons

8. Review
• Gamma Loop
• Golgi Tendon Organ
– Regulate muscle tension and
proprioception

9. Neuromuscular Junction

11. Terminal Axon (Presynaptic Cleft)
• Consists of numerous vesicles contain AcH, as
well as voltage gated Ca2+ channels
– When an action potential spreads over the terminal,
these channels open and calcium ions diffuse to the
interior of the nerve terminal.
– The calcium ions, exert an attractive influence on the
acetylcholine vesicles, drawing them to the neural
membrane adjacent to the dense bars.
– The vesicles then fuse with the neural membrane and
empty their acetylcholine into the synaptic space

13. Synaptic Cleft
• Within the synaptic cleft lies AcH, AcHe,
Nicotinic Ach Receptor, and Voltage Gated Na+
Channel
• AcH binds to ligand gated (nicotinic) receptor,
stimulating Na+ influx
• Na+ influx from ligand gated ion channel
generates end plate potential (EPP)
• Following equilibrium potential of AcH
receptors, AcHe binds and hyrolyzes AcH

15. Post-Synaptic Receptors
1. AcH Receptor
a. Contains 5 subunits (most importantly 2 alpha subunits)
b. 1 AcH molecule must bind to both alpha subunits to activate
c. Allows for influx of Na+ to depolarize
2. MUSK Receptor
a. Receptor tyrosine kinase, needed specifically for NMJ formation
b. Allows for recruitment of AcH receptors to post-synaptic
membrane
3. Voltage Gated Na+ Channel
a. Propogates endplate potential throughout sarcolemma

16. Neuromuscular Junction
Disroders

17. Disorders of the Motor Unit
• Motor neuron disease
• Peripheral nerve disorders
• Neuromuscular junction disease
• Muscle disease

18. NMJ Disorders
• Myasthenia Gravis
• Lambert-Eaton Syndrome
• Neuromyotonia
• Botulinum Toxin

19. Myasthenia Gravis
• A autoimmune neuromuscular disorder that
leads to a breakdown in communication
between neural input and muscle contraction
• Can be paraneoplastic from malignant
thymoma (sero-positive AcH Ab)
• Involves antibodies (Ab) against nicotinic
acetylcholine receptors (nAChR) and Muscle-
specific Tyrosine Kinase (MuSK)
• Leads to muscle weakness and fatigability,
generally non-fatal

20. Myasthenia Gravis
• Epidemiology:
– Disease of young woman ( <40 y/o) and old men
(> 65 y/o).
– Often associated w/ other autoimmune disorders
– More likely to occur with:
a. Family history
b. Coexisting thyroid disease

21. Myasthenia Gravis
• Signs and Symptoms:
• Muscle fatigue that worsens with activity and
improves with rest
• Ptosis
• Difficulty speaking (dysarthia)
• Trouble with making facial expression and swallowing
(dysphagia)
• Other muscles can be affected:
– Myasthenic crisis occurs if there is paralysis of
respiratory muscles
• Ventilation

22. Myasthenia Gravis
• Mechanisms
1) Binding and Activation of Complement
• Ab binds to AChR activating complement cascade
• Leads to the formation of a Membrane Attack Complex (MAC)
• Triggers localized destruction of post-synaptic NMJ – destroying
muscle morphology

23. Myasthenia Gravis
• Mechanisms
• 2) Antigenic Modulation (accelerated
degradation of AChR)
– Ab can crosslink two antigenic
molecules
– Leads to accelerated endocytosis
and degradation
– Leads to reduction of AChR at the
NMJ

24. Myasthenia Gravis
• Mechanisms
• 3) Functional AChR Block
– Ab binding to ACh binding sites
– Block AChR binding site
– Cause failure of neuromuscular
transmission

25. Myasthenia Gravis
• Diagnostic Tests:
• 1) Clinical Tests
– Edrophonium (diagnostic drug)
– Ice-pack test (cooling decreases activity of acetylcholinesterase)
– Have patient do sustained task (e.g. look up)
• 2) Assays of Serum Ab (blood tests)
– Anti-AChR – 85% MG patients
– Anti-MuSK – detectable in 30-40% patients with Anti-AChR-negative
MG
• 3) Electrodiagnostic Tests
– Electromyography (EMG) – Repetitive stimulation of peripheral nerves
– Single fiber EMG – very sensitive

26. Myasthenia Gravis
Tx Modalities:
Modulation of Neuromuscular Transmission
Cholinesterase Inhibitors (e.g., Pyridostigmine, Binding to Acetylcholinesterase (AChE) to inhibit
Neostigmine, Ambenonium) the degradation of acetylcholine
General Immunosuppression
Azathioprine Acts through purine synthesis inhibition thus
inhibiting T and B lymphocyte division.
Cyclosporine Inhibits protein phosphatase (calcineurin) role in
activating T cells of the immune system.
Mycophenolate Mofetil (CellCept) Inhibits de novo purine synthesis in lymphocytes
Tacrolimus Lowers AChR antibody for patients who have
undergone thymectomy and were using steroid
and receiving cyclosporine
Cyclophosphamide High doses help repopulate the immune system
with new lymphocytes by removing old ones from
the bone marrow.
Methotrexate Inhibits the metabolism of folic acid which leads to
T cell destruction and production.

27. Myasthenia Gravis
• Tx Modalities Cont.
RAPIDLY-ACTING
IMMUNOTHERAPIES
Thymectomy Surgery to remove thymus gland (site of T cells
maturation)
Plasmapheresis Removal of antibody and replacement of antibody-free
plasma
Intravenous Immunoglobulin (IVIg) A concentrated solution of immunoglobulins composed
primarily of IgG of different donors. The mechanism is
numerous and includes cytokine inhibition and competition
with autoantibodies.

28. Lambert-Eaton Myasthenic Sx (LEMS)
• Paraneoplastic Sx associated w/ Ab to Voltage
Gated Ca2+ presynaptic motor terminals,
autonomic terminals, and cerebellar purkinje
cells
• Leads to reduction of Ca2+ influx, thus
insufficient AcH is released to initiate an end
plate potential
• Repeated impulses increase Ca2+ influx, and
eventually enough AcH is released to generate an
action potential

29. Lambert-Eaton Myasthenic Sx (LEMS)
• Epidemiology
- 10 fold less common than MG
- 60% of cases associated w/ SCLC (3% of all
SCLC cases)
- NMJ sx may precede radiologic dx of tumor by
several years
- Non-cancer associate LEMS may occur in
children or adults w/out any specific
autoimmune predilection

30. Lambert-Eaton Myasthenic Sx (LEMS)
• Clinical Features:
- Proximal > Distal Limb Weakness
- Initially presents w/ difficulty walking
(proximal limb weakness)
- Occular, Bulbar, and Respiratory weakness
uncommon
- Autonomic sx such as dry mouth,
constipation, impotence, and bladder urgency

31. Lambert-Eaton Myasthenic Sx (LEMS)
• Diagnosis:
- Anti-VGCC (voltage gated Ca2+ channel) Ab
detected in ~90% cases (specific)
- EMG – w/ repetitive stimulation or voluntary
contraction, evidence of increased action
potentials

32. Lambert-Eaton Myasthenic Sx (LEMS)
• Tx:
- 3,4 diaminopyridine (3,4-DAP), which blocks
presynaptic potassium channels, thereby
increasing the opening time of theavailable
VGCC
- Mestinon (pyridostigmine)
- Effective tx of cancer insult

33. Neuromyotonia
• Acquired or paraneoplastic sx (SCLC or
Thymoma) involving antibodies to VGKC
(voltage gated K+ Channel) at presynaptic
membrane
• Inhibition of VGKC prolongs depolarization,
thereby increasing AcH release
• Increased AcH hyperexcites postsynaptic
membrane, resulting in twitching or
myokemia

34. Neuromyotonia
• Clinical Features:
- Mean age of onset 30-40 years
- Skeletal Muscle over activity resulting in
twitching or myokemia
- Pt’s may complain of fasciculation's, muscle
cramps, or stiffness

35. Neuromyotonia
• Diagnosis:
- Anti VGKC Antibodies – immunoassay detects
Ab in ~ 50% of cases
- EMG – classic findings are spontaneous
doublet, triplet, or multiple discharges from
motor nerves

36. Neuromyotonia
• Treatment:
- Many pt’s gain sx relief from downregulation
of VGKC through use of AED’s. (Tegretol,
Dilantin, and Lomtrigine)
- PLEX has much greater short term benefit
over IVIG
- Resistant cases have shown to benefit from
prednisolone + imuran combination

37. Botulism
• Disperses widely via vascular sx
• Neurotoxin secreted from clostridium
botulinum
• Binds in NMJ at presynaptic bulb
• Enters terminus through endocytosis and
destroys formation of Ach, affecting its
release

38. Botulism
• Clinical Features:
1. Bilateral Cranial Nerve Abnormalities
2. Symmetric Descending Weakness
3. No sensory deficits w/ exception of blurry
vision
4. Absence of Fever
5. The pt remains responsive

39. Botulism
• Dx:
- ELISA or mouse toxicity
- EMG – decreased CMAP amplitude in 2
separate muscles, and 20% facilitation of
CMAP amplitude during tetanic stimulation

40. Botulism
• Tx:
1. Age > 1 year – equine serum botulism
antitoxin
2. Age < 1 year – Human derived botulinum
imunnoglobulin

41. Thank You