Topic 13: Neuromuscular Junction Disorders

What is the neuromuscular junction (NMJ)?

A specialized synapse where the terminal end of a lower motor neuron (LMN) meets the muscle fiber membrane.

What is found in the presynaptic terminal of the NMJ?

Synaptic vesicles filled with acetylcholine (ACh).

What is the synaptic cleft?

The gap between the nerve terminal and the muscle membrane.

What is found in the postsynaptic membrane of the NMJ?

Acetylcholine receptors (AChRs) concentrated in junctional folds.

What happens when an action potential reaches the NMJ?

It opens voltage-gated calcium channels in the nerve terminal.

What does calcium influx cause at the NMJ?

Fusion of synaptic vesicles with the membrane and release of ACh.

What happens after ACh is released?

It diffuses across the synaptic cleft and binds to AChRs on the muscle membrane.

How does binding of ACh to its receptor cause contraction?

It changes muscle membrane permeability, triggering an action potential in the muscle fiber.

What stops the NMJ signal?

Acetylcholinesterase breaks down acetylcholine, ending stimulation and allowing relaxation.

What are the two main categories of NMJ pathophysiology?

1) Defective release of ACh (pre-junctional pathology)

2) Destruction/blockade of ACh receptors (post-junctional pathology).

What is the hallmark symptom of NMJ disorders?

Muscle weakness.

Do NMJ disorders cause sensory loss?

No, sensation is spared.

What causes botulism?

The neurotoxin from Clostridium botulinum.

What is the mechanism of botulism at the NMJ?

The toxin blocks calcium-mediated exocytosis of synaptic vesicles, preventing ACh release.

What are the clinical features of botulism?

Flaccid paralysis, descending symmetrical weakness, cranial nerve involvement, and possible respiratory muscle paralysis.

What is Lambert-Eaton Myasthenic Syndrome (LEMS)?

A paraneoplastic syndrome, often associated with small cell lung carcinoma.

What is the mechanism of LEMS at the NMJ?

Autoantibodies attack presynaptic voltage-gated calcium channels, reducing ACh release.

What are the clinical features of LEMS?

Proximal muscle weakness, autonomic symptoms (e.g., dry mouth, impotence), and strength that often improves with activity.

What is Myasthenia Gravis (MG)?

An autoimmune disease in which antibodies attack acetylcholine receptors (AChRs) on the muscle membrane.

What is the mechanism of MG at the NMJ?

Destruction of AChRs reduces the number of functional receptors, impairing neuromuscular transmission.

What are the hallmark clinical features of MG?

Fluctuating weakness, especially ptosis (drooping eyelid) and diplopia (double vision), bulbar symptoms (speech, swallowing), fatigability that worsens with use and improves with rest.

How is Myasthenia Gravis diagnosed?

Elevated AChR antibodies, fatigability on repetitive stimulation, and improvement with anticholinesterase drug (Tensilon test).

What is the mechanism of Lambert-Eaton Myasthenic Syndrome (LEMS)?

Autoantibodies block presynaptic voltage-gated calcium channels → decreased ACh release.

What are the clinical features of LEMS?

Proximal muscle weakness (often legs more than arms), autonomic symptoms (dry mouth, impotence), often paraneoplastic.

How does LEMS differ clinically from MG?

LEMS strength may improve transiently with exertion ("facilitation"), while MG worsens with use.

What is the mechanism of botulism?

Toxin from Clostridium botulinum prevents presynaptic release of acetylcholine.

What are the clinical features of botulism?

Acute, descending, symmetric paralysis starting with cranial nerve palsies; may cause respiratory failure.

What is the hallmark of all neuromuscular junction (NMJ) disorders?

Muscle weakness without sensory loss.

In Myasthenia Gravis, which muscles are often affected early?

Extraocular (causing diplopia) and eyelid elevators (causing ptosis); also bulbar muscles.

How does fatigability present in Myasthenia Gravis?

Weakness worsens with exertion and improves with rest.

How does facilitation present in Lambert-Eaton syndrome?

Muscle strength may improve temporarily after exertion.

Which NMJ disorders affect ACh release?

Botulism and LEMS.

Which NMJ disorder affects ACh receptors?

Myasthenia Gravis.

What serologic tests help confirm NMJ disorders?

ACh receptor antibody titers (MG) and anti-VGCC antibodies (LEMS).

What electrophysiologic test helps diagnose NMJ disorders?

Repetitive nerve stimulation: decremental response in MG; incremental response in LEMS.

What pharmacologic test can help diagnose Myasthenia Gravis?

Edrophonium (Tensilon) test → temporary improvement in strength.

What is another bedside test that can help in MG with ptosis/diplopia?

Ice pack test → reduces ptosis, especially if diplopia also present.

What is the pathophysiology of Myasthenia Gravis (MG)?

Autoimmune attack against acetylcholine receptors (AChRs) at the neuromuscular junction, impairing synaptic transmission.

What is the hallmark symptom of MG?

Fluctuating muscle weakness that worsens with exertion and improves with rest.

Which muscles are most commonly affected first in MG?

Ocular muscles → ptosis and diplopia.

What percentage of MG patients present initially with ocular symptoms?

40-70% present with ocular symptoms initially; 85-90% develop them as disease progresses.

Which bulbar symptoms may occur in MG?

Dysarthria, dysphagia, chewing fatigue.

What is spared in MG, distinguishing it from neuropathies?

Sensation → MG is purely a motor disorder.

What test confirms MG by detecting autoantibodies?

Acetylcholine receptor antibody testing (positive in ~85% of generalized MG cases).

What electrophysiological test is used in MG, and what is an abnormal finding?

Repetitive nerve stimulation → >10% decrement in CMAP amplitude.

What is the Tensilon (Edrophonium) test, and what constitutes a positive result?

IV injection of short-acting acetylcholinesterase inhibitor; positive if there is temporary rapid improvement in muscle strength (e.g., ptosis).

What bedside test can help confirm MG in cases of ptosis/diplopia?

Ice pack test → improvement in ptosis after cooling the eyelid.

Why does the ice pack test work for MG?

Cold inhibits acetylcholinesterase, prolonging ACh action at the NMJ.

Why should all patients with MG be screened for thymoma?

~10-15% of MG patients have a thymoma; thymus plays a central role in MG pathogenesis.

What imaging is recommended in MG to rule out thymoma?

Chest imaging.

What is the first-line pharmacologic treatment for Myasthenia Gravis (MG)?

Acetylcholinesterase inhibitors (e.g., pyridostigmine), which enhance neuromuscular transmission by preventing ACh breakdown.

When is thymectomy indicated in MG?

In patients with thymoma, and often in younger patients with generalized MG, as it can improve symptoms or induce remission.

What role do corticosteroids and immunosuppressants play in MG treatment?

They are used when acetylcholinesterase inhibitors alone are insufficient; examples include prednisone, azathioprine, and mycophenolate.

What advanced therapies are used in severe or crisis cases of MG?

Plasmapheresis (removes circulating antibodies) and IVIG (provides passive immunity).

What is a myasthenic crisis, and how is it managed?

Life-threatening respiratory weakness due to severe MG exacerbation; managed with plasmapheresis, IVIG, and supportive ventilation if needed.

What percentage of MG patients have an associated thymoma?

Approximately 10-15%.

How is chiropractic care positioned in the management of MG?

Subluxation-based supportive care as an adjunct to medical management; described in case reports, not a replacement for medical therapy.