Disorders Of The Neuromuscular Junction

Question 1

Myasthenia Gravis

is caused by a defect of neuromuscular transmission due to an antibody-mediated attack upon nicotinic acetylcholine receptors (AChR) on muscle membrane.

Most cases are sporadic, but high frequency of HLA haplotypes B8 and DR3.

more common in younger women and older men

Three general characteristics:

• 1. Fluctuating weakness – “excessive fatigability”
• 2. Distribution of weakness – Ocular muscles are affected first in 40% of patients and ultimately involved in 85%. Often see ptosis and diplopia – Other common symptoms: dysarthria, dysphagia, limb, and neck weakness
• 3. Clinical response to cholinergic drugs

Answer 1

Diagnosis

Laboratory data

• Acetylcholine receptor antibodies (anti AChR Ab’s) - Present in 55% of ocular MG and 80% of generalized MG - Up to 10% may be antibody negative
• MUSK antibodies
• EMG findings - Decremental response on repetitive stimulation - Increased “jitter” on single fiber EMG
• Tensilon (edrophonium) test - Positive in >90% of patients - Be aware of side effects (bradycardia, ventricular arrythmias)

Question 2

Myasthenia Gravis

Treatment

Acetylcholinesterase inhibitors (e.g. Mestinon)

– Prednisone

– Other immunosuppressive agents (e.g. azathioprine, cyclosporine, rituximab)

– Plasma exchange / IVIg (generally used for patients in crisis or prior to undergoing surgery to avoid crisis)

– Thymectomy probably helpful, but optional in patients without thymoma and probably not indicated in purely ocular disease

Question 3

Lambert – Eaton Myasthenic Syndrome (LEMS)

Due to an autoimmune attack against voltage-gated calcium channels (VGCC’s) on the presynaptic nerve terminal.

Presynaptic abnormality of Ach release at the neuromuscular junction leads to weakness.

Often associated with cancer (esp. SCCL)

Answer 3

Clinical presentation

• Proximal weakness, loss of deep tendon reflexes, myalgias, dry mouth, impotence.
• Oropharyngeal and ocular muscles may be mildly affected but not to the degree seen in MG.
• Strength may improve after exercise.
• May see slight (but usually not dramatic) response to Tensilon

Laboratory Data

• Voltage Gated Calcium Channel Antibodies (anti VGCC) - Present in the majority of patients with LEMS
• EMG findings - Low amplitude motor responses that facilitate (increase) after a brief period of exercise - Incremental response on fast repetitive stimulation (often greater than 100%)

Question 4

Treatment

First look for and treat malignancy

• Acetylcholinesterase inhibitors – Mestinon may improve weakness in some patients

• 3-4 Diaminopyridine – Helps most LEMs patients, but some moderate side effects

• Guanidine hydrochloride - Helps most LEMS patients, but beware of side effects of severe toxicity (esp. bone marrow suppression)

• Immunosuppression

• IVIg

Question 5

Botulism

Toxin blocks presynaptic mechanisms for release of ACh

Clinical Presentation:

Dry, sore mouth and throat, blurred vision, diplopia, nausea, vomiting. Can see hypohydrosis, total external ophthalmoplegia, facial, oropharyngeal, limb and respiratory paralysis.

Treatment:

ICU monitoring with respiratory support and general medical car e Specific treatments include

Antitoxin (horse serum product which may cause serum sickness or anaphylaxis)

Guanidine Hydrochloride (side effects including bone marrow suppression)