Disorders of the neuromuscular junction include Myasthenia gravis, Lambert-Eaton myasthenic syndrome, Botulism, Tetanus, Strychnine intoxication, Organophosphates poisoning and neuromyotonia. Pharmacology of the NMJ is also reviewed in brief.

1. Disorders of the
Neuromuscular Junction
Daniel Vela-Duarte, MD
Department of Neurology
Loyola University Medical Center
October 2013

2. Differential diagnosis of flaccid
paralysis
Anterior horn disease
Disorders of the NMJ
 Polyemyelitis
 Amyotrophic lateral sclerosis
 Myasthenia gravis
 Lambert-Eaton disease (Myasthenic
syndrome)
 Botulism
 Snake, scorpion, spider bites
Peripheral neuropathy
Disorders of muscle
 Guillain-Barre syndrome
 Diphteric neuropathy
 Heavy metals, biologic toxins, drug
intoxication
 Acute intermittent porphyria
 Vasculitic neuropathy
 Critical illness neuropathy
 Lymphomatous neuropathy







Hypokalemia
Hypophosphatemia
Inflammatory myopathy
Critical illness myopathy
Acute Rhabdomyolisis
Acid maltase deficency
Periodic paralysis
Acute myelopathy (Spinal shock phase)
 Space-occupying lesions or Acute transverse myelitis

6. Mechanisms of disease.

Binding and Activation of Complement
•
•
•
Antibody 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

7. Mechanisms of disease.
cont’d

Antigenic Modulation
(accelerated degradation of AChR)

Antibody can crosslink two
antigenic molecules

Leads to accelerated
endocytosis and degradation

Leads to reduction of AChR at
the NMJ

8. Mechanisms of disease.
cont’d

Functional AChR Block

Ab binding to ACh binding sites

Block AChR binding site

Cause failure of neuromuscular
transmission

9. Myasthenia Gravis. Epidemiology

Myasthenia gravis is one of the most frequent, autoimmune
diseases of the neuromuscular junction (NMJ)

Frequent in young woman
 (<40 years old) and old men (> 65 years old).

15% of patients experience a myasthenic crisis during the course of
disease.
The vast majority of patients with generalized MG (~85%) and pure
ocular MG (~50%) will have antibodies to the skeletal nicotinic
acetylcholine receptor (AChR)


8-10% of patients with generalized form will have Ab’s to musclespecific tyrosine kinase receptor (MuSK)

10. 
Take-home points on: “natural course of the disease”


Generalized myasthenia gravis will develop in more than 50% of patients
who present with ocular MG, typically within 2 years.
Prednisone

40-60 mg/daily, followed with the dosage tapered for 5-6 weeks
 Daily or alternate-day doses of 2.5 to 10mg to prevent diplopia

Tensilon Test

Mean dose of edrophonium (Tensilon) was 3.3mg for ptosis and 2.6mg for
ocular motor dysfunction. Therefore, the test should be administered using
increments of 1 -2mg.
 Generalized MG developed within 2 years in 4/58 treated (7%) and 13/36
untreated (36%) pts

11. Symptoms. Generalized presentation

12. Myasthenia Gravis. Five new things…
Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.

Plasmapheresis vs IVIg
 No
difference in between both, fewer adverse events
with IVIg (Neurology 2011;76:2017-2023)
 Both
treatments are equally effective for myasthenic
crisis, but PLEX seems superior for crisis requiring
ventilatory support.
 Higher
frequency of extubation with PLEX ?
 0.4g/kg for 3-5 days or 1g/kg for 2 days

13. Myasthenia Gravis. Five new things (2)
Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.

MuSK phenotype
 Role in AChR clustering at the postsynaptic
neuromuscular junction
 It makes up ~40% of AChR-negative MG pts
 Female predominance: 78% - 100 women
 The majority of case series report poor response to
cholinesterase inhibitors
 Poor response to thymectomy

14. Myasthenia Gravis. Five new things (3)
Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.

New (and old treatment strategies)
 Thymectomy
Not indicated for ocular myasthenia
 Role of thymectomy for non-thymomatous
myasthenia gravis. (Ongoing trial - Aug 2015)

 Rituximab
Indicated for refractory myasthenic pt
 Dramatic response in MuSK patients
 B-cell depletion. Population levels monitoring


15. Myasthenia Gravis. Five new things (4)
Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.

Myasthenia gravis and pregnancy
 1/3
of women will experience exacerbations of
symptoms during 1st trimester and puerperium
 Treatment
should be individualized
Mild disease: Pyridostigmine <600mg/day are
safe for the fetus
 Corticosteroid poses little, if any teratogenic risk.
They CAN be continued.
 Azathioprine, IVIg, PLEX are safe
 Avoid Mycophenolate.


16. Myasthenia Gravis. Five new things (5)
Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.

New antibody testing
 10%
of patients remain Ab negative
 Lrp4: low density lipoprotein receptor-related
protein 4. (Described in 2011) Arch Neurol. 2012 Apr;69(4):445-51
 The protein is required for agrin-induced
activation of MuSK.

thought to induce clustering of synaptic-vesicle
related proteins in the NJM.
 3-50%
of seronegative patients were found to
be Ab positive to Lrp4

17. Thymomatous myasthenia
gravis

18. Treatment modalities.
Modulation of Neuromuscular Transmission
Cholinesterase Inhibitors (e.g.,
Pyridostigmine, Neostigmine, Ambenonium)
Binding to Acetylcholinesterase (AChE) to inhibit 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.

19. Lambert-Eaton myasthenic
syndrome
Epidemiology
 10 fold less common than myasthenia gravis


60% of cases associated with small cell lung CA
Syndrome may precede radiologic diagnosis of
tumor by several years

20. Lambert-Eaton Sx. Diagnosis

Clinical Features:

Proximal > Distal limb weakness
 Initial presentation with difficulties to walk.
(proximal limb weakness)
 Occular, Bulbar, and Respiratory weakness is
uncommon
 Autonomic symptoms such as dry mouth,
constipation, impotence, and bladder urgency
(Lack of Ach)

21. Lambert-Eaton Sx. Treatment


3,4 diaminopyridine (3,4-DAP)
Blocks presynaptic potassium channels, thereby
increasing the opening time of the available Voltagegated Calcium channesls

The blocking of K+ channels prolongs the depolarisation during nerve
action potentials, thereby increasing the open-time of voltage-gated
Ca2+ channels and consequently the influx of Ca2+ into the nerve
terminal. This increased Ca2+ influx enhances the quantal
neurotransmitter release which is Ca2+ dependant.

Mestinon (Pyridostigmine)

Effective treatment of cancer

22. Lambert-Eaton myasthenic
syndrome

23. Neuromyotonia

Acquired or paraneoplastic syndrome

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 myokymia

24. 
Where is the site of action of the
following toxins in the neuromuscular
junction?

Botulism,
 Tetanus,
 Organophosphorates,
 Strychnine

26. Botulism. Mechanism of disease
JAMA. 2001 Feb 28;285(8):1059-70.

27. Botulism. Mechanism of disease
JAMA. 2001 Feb 28;285(8):1059-70.

28. Tetanus. Mechanism of disease
1.
2.
3.
4.
Peripheral nerve terminal binding
Endocytosis of toxin
Retograde axonal transport
Release of the toxin into the
presynaptic space
5.
Binding to the membrane of the
inhibitory interneuron.
6.
Endocytosis
Translocation of toxin into cytosol
Inhibtion of the VAMP complex
(Essential for synaptic vessicle
fusion)
7.
8.

29. Tetanus. Mechanism of disease

Clostridium tetani
 Tetanospasmin

Sustained muscular rigidity
and, in severe cases, reflex
spasms.


Early manifestations of
generalized tetanus are
rigidity of the masseter
muscles (lockjaw) and facial
muscles, with straightening
of the upper lip or risus
sardonicus.
Autonomic instability, mostly
hypersympathetic state, may
occur in severe cases.
"The contracted"
Opisthotonus, By Sir Charles Bell (1809)
Contracted body of a soldier suffering from tetanus.

30. Strychnine (Nonanticoagulant
Rodenticide)
Mechanism
•
Antagonizes glycine, an inhibitory
neurotransmitter released by postsynaptic
inhibitory neurons in the spinal cord.
•
Binds to the chloride ion channel (Inhibitory
synapse) causing increased neuronal
excitability and exaggerated reflex arcs.
Clinical features
•
•
Muscular stiffness and painful cramps
precede generalized muscle contractions
Extensor muscle spasms, and opisthotonus.
•
Muscle contractions are intermittent and
easily triggered by emotional, auditory, or
minimal physical stimuli.
Repeated and prolonged muscle contractions
often result in hypoxia, hypoventilation,
hyperthermia, rhabdomyolysis,
myoglobinuria, and renal failure.
•
.
•

31. 
What are the diagnostic criteria of
critical illness myopathy?
Major diagnostic features
1. Sensory nerve amplitudes >80 % of the lower limit of normal in 2 or more nerves
2. Needle EMG with short-duration, low-amplitude MUPs with early or normal full
recruitment, with or without fibrillation potentials
3. Absence of a decremental response on repetitive nerve stimulation
4. Muscle histopathologic findings of myopathy with myosin loss
Supportive features
1. Motor amplitudes <80 % lower limit of normal in 2 or more nerves without
conduction block
2. Elevated serum CK (best assessed in the first week of illness)
3. Demonstration of muscle inexcitability

32. 
What are the characteristics of the
episodes seen in familial hypokalemic
periodic paralysis?