DISEASES OF NEUROMUSCULAR JUNCTION

Specialized area where a motor nerve terminates on a skeletal muscle fiber

NEUROMUSCULAR JUNCTION (NMJ)

As axon supplying skeletal muscle fiber approaches termination, it loses its myelin sheath and divides into a number of?

terminal boutons

Folds found in the motor endplate which increase surface area for receptors

Junctional folds

Neurotransmitter found at the NMJ

Acetylcholine

Description of ACH vesicles

small, clear

two components of ACH

Choline and Acetyl-CoA

True or False:
Choline enters the terminal bouton from ECS via Ca++-dependent choline transport

False:
Choline enters the terminal bouton from ECS via Na+-dependent choline transport

True or False:
ACh transported from cytoplasm into vesicles by vesicle-associated transporter 

True

What triggers the release of ACH into the synaptic cleft?

Ca+

This enzyme is the main player in the reuptake mechanism of ACH, abundant in the postsynaptic cleft

Acetylcholinesterase

Enzyme which helps with the formation of ACH

Choline-actyletransferase

• Fluctuating, fatigable weakness of commonly used muscles 

  • Strong —> Weak

Myasthenia Gravis

Most common NMJ disorder

Myasthenia Gravis

mm groups affected by Myasthenia Gravis

ocular, bulbar, respiratory

Myasthenia Gravis can be associated with these conditions

Thymoma, thymic hyperplasia

Antibodies that are elevated in myasthenia gravis

• IgG Ab to AChR

• MuSK antibodies

What structure gets destroyed in the NMJ when a patient has Myasthenia gravis?

Junctional Folds

True or False:
MG affects the limb muscles the most

False:
MG affects the bulbar muscles the most

multiple lymphoid follicles show germinal centers in the thymus

Thymus hyperplasia

Thymus hyperplasia

• AChR Ab are synthesized by _____ cells in hyperplastic thymus 

• About 70% of thymus in adult MG patients are not involuted, weigh more than normal, and demonstrate _________ hyperplasia 

Thymus hyperplasia

• AChR Ab are synthesized by B cells in hyperplastic thymus 

• About 70% of thymus in adult MG patients are not involuted, weigh more than normal, and demonstrate lymphoid hyperplasia 

True or False:
Thymus hyperplasia is considered as a metastatic tumor

False

encapsulated benign tumor in the thymus

• present in 10% of MG patients

• T cells with epithelial cells 

• May invade pleura, pericardium or blood vessels 

Thymoma

Cinical presentations of MG:

• _____ , _____ weakness 

• Response to _____ medications 

• Electrophysiologic evidence of _____ _____

• Demonstration of circulating antibodies to _____ or _____

• Exacerbation → _____ _____ weakness and even _____ compromise (d/t stress, malmedications, etc.) 

• Crisis → most likely to occur in patients with _____ or _____ muscle weakness 

  • Dysphagia, dysarthria, respiratory compromise

Cinical presentations of MG:

• Fluctuating, fatigable weakness 

• Response to cholinergic medications 

• Electrophysiologic evidence of abnormal neuromuscular transmission 

• Demonstration of circulating antibodies to AChR or MuSK 

• Exacerbation → proximal fatigable weakness and even respiratory compromise (d/t stress, malmedications, etc.) 

• Crisis → most likely to occur in patients with oropharyngeal or respiratory muscle weakness 

  • Dysphagia, dysarthria, respiratory compromise

These muscles are initially affected in 40% but ultimately involved in 85%

Ocular muscles

True or False:
Patients with MG affecting their facial muscles can have dysarthria, dysphagia and limited facial movement

True

True or False:

MG presents with sensory deficits and impaired reflexes

False:

MG with this antibody have a higher risk of respiratory insufficiency, faster progression and involves ocular, facial and bulbar muscles

MuSK MG

Triggers of MG

• Respiratory infection 

• Surgery 

• Emotional stress

• Systemic illness 

• No apparent provocation

Diagnostic tests for MG:
Testing fluctuating muscle weakness by eliciting muscle fatigue.

Fatigue Test

Diagnostic tests for MG:

• Pack of ice over ptotic eye for 2 min

• Cold decrease cholinesterase activity and promotes efficiency of ACh at eliciting depolarizations

Ice pack test

Medication for MG:

• Neostigmine

• Edrophonium (Tensilon)

short acting AChE inhibitor 

Edrophonium (Tensilon)

Side effects of Edrophonium (Tensilon)

• Increased oropharyngeal secretions

• respiratory compromised

• bradyarrhythmia

• ventricular fibrillation

Medication to reverse the effects of Edrophonium (Tensilon)

Atropine

Results of RNSS of a patient with MG

Progressively fewer fibers respond to the arrival of the impulse

Increased variability of latencies among muscle fibers innervated by a single motor neuron

jitters

Jitters can be seen in this EMG

Single fiber EMG

acetylcholinesterase inhibitor = increases ACh 

Piridostigmine

Immunosuppressants most commonly used for treatment of MG

Azathioprine

Medication given immediately for sever MG patients

Immunoglobin or Plasma exchange

Enumerate all cholinesterase inhibitors

• Pyridostigimine bromide

• Neostigmine

• Cyclophosphamide

• Rituximab

Which cholinesterase inhibitors exhibit side effects of:

• abdominal cramps

• diarrhea

• GI hypermobility

• nausea

• vomiting

• diaphoresis

• fasciculations

• muscle cramps

• increased bronchial secretions

• increased salivations

• miosis

  
  

• Pyridostigmine bromide

• Neostigmine

Serious symptoms of both pyridostigmine bromide and neostigmine

• Anaphylaxis

• AV nodal block

• Bradycardia

• Respiratory compromise

• Seizures

Serious side effect specific to pyridostigmine bromide

Cholinergic crisis

Serious side effect specific to Neostigmine

Bronchospasm

True or false:
Seizures are both side effects of Pyridostigmine bromide and Neostigmine, but is rarer in Neostigmine

True

Monitoring CBC, BUN, UA, serum electrolytes, serum creatinine, liver function tests is done when administering this cholinesterase inhibitor

Cyclophosphamide

which is administered 5 times a week every other day, IVIg or Plasma exchange?

Plasma Exchange

Which is administered in 5 daily doses of 2g/kg BW, IVIg or Plasma exchange?

IVIg

Risk of Plasma Exchange

Infections

Risk of IVIg

Thromboembolic events

Treatment of thymus hyperplasia and thymoma

thymectomy

• Proximal limb weakness, which improves after exercise 

• Autonomic dysfunction

Weak to Strong

Lambert Eaton Myasthenic Syndrome (LEMS)

LEMS has a strong association with this condition

Small cell lung cancer

Antibody present in Lambert Eaton syndrome

VGCC-ab

True or False:
LEMS is an autoimmune disease of the CNS

False:
LEMS affects the peripheral nerves

Is LEMS a presynaptic abnormality or postsynaptic abnormality of ACh release?

Presynaptic

Clinical features of LEMS:

• Proximal limb weakness with ________ or _________ that improves with exercise

• ____ mouth, myalgia

• _____ symptoms

• Less ______ symptoms and ______ impairment

Clinical features of LEMS:

• Proximal limb weakness with hyporeflexia or areflexia that improves with exercise

• Dry mouth, myalgia

• Autonomic symptoms

• Less bulbar symptoms and respiratory impairment

MG prevalence in gender:

_____ in >40yrs; _____ in <40yrs

M=F in >40yrs; F>M in <40yrs

Treatment of LEMS

• Search and treat for cancer

• PE, IVIg, steroids, immunosuppressants

• Amifampridine or guanidine

Which illness is more susceptible to males, LEMS OR MG

LEMS

Which NMJ disease exhibits exertional weakness

MG

Which NMJ disease exhibits transient improvement after brief exercise followed by weakness

LEMS

This NMJ disease has a (+) endrophonium test in 90-95%

MG

This NMJ disease has a (+) Endrophonium test in 37%

LEMS

This NMJ disease is treated by anticholinesterase drugs

MG

This NMJ disease is treated by Amifampridine or guanidine

LEMS

True or False:
LEMS and MG have the same immunotherapeutic treatment

True

Which NMJ dysfunction is treated by a thymectomy

MG

This NMJ dysfunction has a normal CMAP at rest and no change after brief exercise

MG

This NMJ dysfunction has a low CMAP at rest and an incremental response after brief exercise

LEMS

This NMJ disease has a decremental response during low-rate stimulation

LEMS and MG

This NMJ disease has a decremental response or is normal during high-rate stimulation

MG

This NMJ disease has a incremental response during high-rate stimulation

LEMS